review article review article ecg of the month...review article ecg of the month review article use...

Review Article ECG of the Month

Review ArticleUse of NOACs in Heart Failure

Dr. Ajay Kumar Sinha, Dr. BP Singh

Review ArticleSalt-Sensitivity and Hypertension

Dr. ME Yeolekar, Dr. Mayur M Mewada

Heart Failure with Preserved Ejection Fraction-A Disease Beyond Heart!

Dr. Nishant Kumar Abhishek, Dr. M.M. Razi, Dr. S.K. Sinha, Dr. Ramesh Thakur

Electrocardiogram in Neonate Presenting with Heart Failure

Dr. SR Mittal

September-October 2019 Vol. XXIII No. 5

Cardiology TODAY

VOLUME XXIII No. 5September-October 2019

PAGES 169-212

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EDITORIALShooting off the Hips – A Norm in Medicine? 171OP YADAVA

REVIEW ARTICLESalt-Sensitivity and Hypertension 173ME YEOLEKAR, MAYUR M MEWADA

REVIEW ARTICLEExploring the Role of Insulin Resistance in Cardiovascular Ageing and Disease 178VINOD NIKHRA

REVIEW ARTICLEHeart Failure with Preserved Ejection Fraction-A Disease Beyond Heart! 189NISHANT KUMAR ABHISHEK, M.M. RAZI, S.K. SINHA, RAMESH THAKUR

Cardiology Today VOL.XXIII NO.5 SEPTEMBER-OCTOBER 2019 169

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REVIEW ARTICLEUse of NOACs in Heart Failure 195AJAY KUMAR SINHA, BP SINGH

REVIEW ARTICLENew Antidiabetic Medications for Improving CV Outcomes in Diabetes: Dawn of a New Era 198PC MANORIA, PANKAJ MANORIA

ECG OF THE MONTHElectrocardiogram in Neonate Presenting with Heart Failure 205SR MITTAL

PICTORIAL CMEIntra-Atrial Conduction Delay Simulating Double 'P’ Waves in Electrocardiogram 210MONIKA MAHESHWARI

170 Cardiology Today VOL.XXIII NO.5 SEPTEMBER-OCTOBER 2019

Cardiology Today VOL.XXIII NO. 5 SEPTEMBER-OCTOBER 2019 171

Shooting off the Hips – A Norm in Medicine ?

EDITORIAL

The age old wisdom of over-consumption of red meat as being deleterious to health has been challenged recently by a systematic review of 5 randomised trials, which showed that consumption of red meat in amounts that we currently do, does not aff ect cardiovascular mortality or cardiometabolic and cancer outcomes. It found virtually no eff ect of red meat consumption on either all cause mortality (Hazard ratio – HR 0.99; 95%, Confi dence Interval – CI 0.95-0.13) or cardiovascular mortality (HR 0.98; CI 0.91-1.06). Infact, they did not even fi nd any eff ect of red meat consumption on the causation of cardiovascular disease (HR 0.99; CI 0.94-1.05), cancer mortality (HR 0.95; CI 0.89-1.01) or their incidence, including colo-rectal and breast cancers.1

The American College of Cardiology was ‘Alarmed’ by these ‘Reckless’ fi ndings. Cristopher Gardner from Stanford University echoed the sentiments and challenged the trials included in the review in the Annals as ‘Horrible’ and ‘Not Relevant’. Lot of other movers and shakers in the fi eld have vehemently criticised the studies included in the review with Walter Willett, a Harvard Professor, slamming the authors for their ‘Ignorance’. The angst was so strong that 13 high-end professionals in the fi eld of nutrition, including the likes of Willett and Dean Ornish, wrote to the Editor-in-Chief of Annals of Internal Medicine, which had published the paper to request a retraction of the paper ‘pending further review’. They wrote, ‘This is, simply, an overt misrepresentation. Such distortion is a direct threat to public understanding and public health’. However, such was the industry pressure that their request was denied and the paper published. It was all right till such point that these fi ndings were confi ned to the trials, with a reader having the option of exercising his erudition and wisdom in the interpretation and likely adoption of the fi ndings in his day-to-day practice, but what is worrying is that these fi ndings have been cajoled into the guidelines,2 which though may not be mandatory, but are certainly directive and most not so academically minded clinicians take them as gospel truth and follow them in letter and spirit. The guidelines recommend that adults continue consuming current levels of both unprocessed and processed red meat (Weak recommendation, low certainty evidence).2 The very fact that the evidence is of low certainty and

DR. OP YADAVACEO and Chief Cardiac Surgeon

National Heart Institute,New Delhi

172 Cardiology Today VOL.XXIII NO.5 SEPTEMBER-OCTOBER 2019

the recommendation weak, raises a doubt on the authenticity of these recommendations and whether they are well meant or driven with certain ulterior motives. They start becoming all the more suspect when one realises that the researcher leading the study, Dr. Johnston, has confl icts of interest as he has ties with the meat industry. The New York Times, reported that this particular author had earlier been involved in conducting studies for the Cola companies to justify consumption of high sugar drinks. Infact even the panel writing the guidelines has been challenged by the Harvard’s TH Chan School of Public Health, which labelled it as a ‘self-appointed panel’. They continued further, ‘It is one thing to

publish a study that challenges the existing paradigm, but another to publish controversial guidelines that contradict the evidence.’ Even cancer groups have refused to accept the guidelines. All this brouhaha emerges due to the fact that there has never been, and never likely to be in future, a randomized controlled trial looking at long-term outcomes of red meat consumption. This is again a moment where the ethical pedestal of medical profession is being challenged and we seem to be playing in to the hands of the industry. Dollar has become the adored deity and though it may seem acceptable in the world of commodities for a corporate group to make a fast buck, it certainly does

not behove the medical profession to treat a precious human life as a commodity. It is sooner the better that we mend our ways, otherwise we will come to rue our downfall due to our own follies. As it stands today, let us go by the dictum that we know very little of what is right and wrong and what is good for us. Its best therefore to take the middle path of moderation with no absolute abhorrence of any food, yet with no excess either.

REFERENCES1. Zeraatkar D, Johnston BC, Bartoszko J, et al. Effect of

lower versus higher red meat intake on cardiometabolic and cancer outcomes: A systematic review of randomised trials. Ann Intern Med; 01 Oct 2019. doi:10.7326/m19-0622 (Epub ahead of print)

2. Johnston BC, Zeraatkar D, Han MA, et al. Unprocessed red meat and processed meat consumption: Dietary guideline recommendations from the nutritional recommendations (Nutri RECS) Consortium. Ann Intern Med. 01 Oct 2019. doi:10.7326/m19-1621 (Epub ahead of print).

EDITORIAL

Cardiology Today VOL. XXIII NO. 5 SEPTEMBER-OCTOBER 2019 173

INTRODUCTIONHypertension (HTN) continues to be a global pandemic in current times1 and constitutes a major non-communicable disease (NCD) public health problem in India.

Dietary salt has been the subject of intense scientifi c research linked to HTN and CV (Cardiovascular) mortality. The relationship between dietary salt intake and the development of HTN has been the subject of passionate and ongoing

Salt-Sensitivity and Hypertension

REVIEW ARTICLE

ME YEOLEKAR, MAYUR M MEWADA

Keywords salt sensitivity hypertension kidney malfunction endothelial dysfunction

Dr. ME Yeolekar is Professor and Head Department of Internal Medicine and Dr. Mayur M Mewada is Assistant Professor Department of Internal Medicine, KJ Somaiya Medical College and Hospital, Ayurvihar, Sion, Mumbai.

AbstractHypertension is a complex trait determined by both genetic and environmental factors and is a major public health problem due to its high prevalence and concomitant increase in the risk for cardiovascular disease. There is substantial evidence that suggests some people can effectively excrete high dietary salt intake without an increase in arterial blood pressure (BP), and other people cannot excrete effectively without an increase in arterial BP. Salt-sensitivity of BP refers to the BP responses for changes in dietary salt intake to produce meaningful BP increases or decreases. The underlying mechanisms that promote salt-sensitivity are complex and range from genetic to environmental infl uences. The phenotype of salt-sensitivity is therefore heterogeneous with multiple mechanisms that potentially link high-salt intake to increases in blood pressure. Moreover, excess salt intake has functional and pathological effects on the vasculature that are independent of blood pressure. According to this hypothesis, hypertension can develop only when something impairs the excretory ability of sodium in the kidney. However, recent studies suggest that nonosmotic salt accumulation in the skin interstitium and the endothelial dysfunction which might be caused by the deterioration of vascular endothelial glycocalyx layer (EGL) and the epithelial sodium channel on the endothelial luminal surface (EnNaC) also play an important role in nonosmotic storage of salt. These new concepts emphasize that sodium homeostasis and salt-sensitivity seem to be related not only to the kidney malfunction but also to the endothelial dysfunction.

REVIEW ARTICLE

174 Cardiology Today VOL. XXIII NO. 5 SEPTEMBER-OCTOBER 2019

debate for the past three decades.2

There is considerable heterogeneity of human blood pressure responses to alterations in sodium and extracellular fl uid balance, and various attempts have been made to study the factors and mechanisms involved that are responsible for this heterogeneity. The human body has immense capacity to adjust to the excess of salt intake. Meticulous physiological regulation of Na (sodium) levels is of critical importance for optimal effi cacy of body functions.

DEFINITIONA common belief prevails that too much salt in diet will lead to increase in blood pressure. Not everyone with high salt diet may develop hypertension. The eff ects of dietary sodium vary from person to person because of their diff erential sensitivity to salt.

Those who are salt sensitive are more likely to develop HTN than those who are resistant to salt.3

Salt-sensitivity of blood pressure is defi ned as physiology in humans by which blood pressure of some people changes in parallel to the changes in salt intake.4 When the mechanism to excrete the excess amount of salt through the

kidney and sweat is defective, increase salt tends to be retained and manifests as high blood pressure.

Salt sensitivity is determined by genetic factors, race and ethnicity,4 age5,6 gender,7 body mass index and diet. Co-morbidities of diabetes mellitus (DM)8 and chronic kidney disease also tend to contribute towards salt sensitivity.

Black race, elderly, females, low potassium intake9 and poor quality diet compared to DASH (Dietary advise to stop hypertension) manifest as higher blood pressure response against salt intake.

DIFFERENTIATION AND MEASUREMENTThe criteria for the defi nition of salt “sensitivity,” “nonsensitivity,” “resistance,” and “counterregulation” of blood pressure have varied markedly.10,11

There is no evidence-based method for measurement of salt sensitive blood pressure in humans. Diff erent individuals have diff erential susceptibilities to blood pressure raising eff ects of salt and this susceptiveness is called as salt-sensitivity.

Consensus exists on sequential low salt diet and high salt diet protocol to identify an individual as salt sensitive or

salt-resistant.12

The recommended method is to give low sodium diet (600 mg of table salt per day) followed by high sodium diet (12 gm of table salt per day) for 4 days. At the end of high sodium period, if the blood pressure increases by atleast 5% from baseline the person can be labelled as salt sensitive.13

Technique of salt loading with acute intravenous saline challenges after achieving sodium and volume depletion through salt reduction, along with diuretic treatment14 subject decrease in mean arterial pressure (MAP) > 10 mmHg after sodium and volume depletion are considered as salt sensitive and those with decrease less than 5 mmHg are salt resistant.14

THE SODIUM (Na) FACTORNormal human being can sustain the ill eff ects of poor sodium intake by conserving sodium through marked reduction in Na losses in the urine and sweat.

Equally, in case of acute or chronic salt challenges, body can quickly excrete very large salt loads without any signifi cant changes in volume, homeostasis or blood pressure.

NOT all hypertensives are salt sensitive and NOT all salt sensitive people are hypertensive.

Normotensive salt sensitive individuals are at high cardiovascular risk and lower survival rate, the BP eventually rise later in life with high salt diet.

Beyond hypertension: Salt-sensiti-vity is an independent risk factor for cardiovascular disease, beyond the detrimental prognosis conferred by hypertension alone.

FACTORS AFFECTING SALT SENSITIVITYHereditary Factors/Genetic FactorsPast studies have shown that salt-sensitivity is more observed in individuals with the homozygous haptoglobin 1-1 genotype than in those with the 2-2 genotype. Individuals with the heterozygotic 2-1 genotype had responses that were intermediate between the other two groups. These fi ndings

Figure 1. Factors affecting Salt sensitivity


were seen in both normotensive and hypertensive populations.15

A genetic basis for other forms of “salt-sensitive” hypertension, resulting from a chimeric mutation of the 11β-hydroxylase/aldosterone synthase gene16 as well as that resulting from mutation in the β-subunit of the epithelial sodium channel - Liddle’s syndrome,17 has been described. It is possible that some individuals with salt-sensitive blood pressure may be found to have milder genetic abnormalities of any of these forms.Demographic ParametersIncreasing salt-sensitivity has been noted with an increasing age in numerous past studies.18,19 The relationship is stronger in hypertensive than in normotensive individuals.20 In a prospective study on subjects who were followed for at least 10 years after the initial classifi cation of salt sensitivity; it was found that salt-sensitive individuals had a rise in blood pressure over time that was signifi cantly (P<.001) greater than in those who were salt resistant.20 Similar suggestion was made by Sullivan indicating that normotensive salt-sensitive subjects are more likely to become hypertensive when followed over a period of time.21

In the context of US, black population has been consistently shown to have a greater frequency of salt-sensitivity than white population. Previous observational studies have shown that 73% of black hypertensive patients were salt sensitive compared with 56% of a white hypertensive group. However, in the normotensive population, the frequency of salt-sensitivity among blacks (36%) was similar to that seen among whites (29%)9,10 thus, pointing towards a strong racial association of salt-sensitivity.

Another interesting aspect of blood pressure response to sodium appears to be the time of day that the sodium is consumed. In a study conducted in Japan, of the seven normotensive women evaluated with 24-hour ambulatory blood pressure monitoring while ingesting 12 g of salt in their diet; it was observed that the average blood pressure was higher and the circadian pattern was altered when 9 g was consumed at lunchtime and

the remainder in the evening compared with 9 g in the evening and the balance at lunchtime.22 Thus, this preliminary fi nding suggests that the timing of sodium ingestion infl uences the blood pressure response. Therefore, the salt ingestion within the limits prescribed can be appropriately divided and distributed over the meals throughout the day.

The RAAS SystemThe juxtaglomerular apparatus is a structure in the kidney that regulates the function of each nephron, the functional units of the kidney. It is the location of renin-secreting cells and the macula densa and lies at the junction between the loop of Henle and the distal nephron at which the tubule comes in close proximity to the aff erent arteriole. Multiple studies have reported lower levels of plasma renin activity and plasma aldosterone concentrations in salt-sensitive subjects.18,19,21

Since suppression of plasma renin activity may refl ect a relative expansion of extracellular fl uid volume and/or sodium balance and since salt sensitivity represents an increase in the

blood pressure response to sodium and volume depletion, one would predict that the greatest fall in blood pressure would be likely in the most volume- expanded subjects, that is, in those with the lowest renin levels. Since the renin- angiotensin-aldosterone system protects against sodium and volume depletion and maintains vascular homeostasis during such situations, individuals in whom the system is relatively unresponsive could be expected to have a greater permissive fall in blood pressure in such circumstances. Comparison of blood pressure responses to a rapid sodium and volume expansion and contraction maneuver with responses in the same individuals after 5 days of a high salt diet and 7 days of a low salt diet was studied by Weinberger MH.23 His observations have confi rmed the above hypothesis.

Alterations in Renal Micro-AnatomyChanges in blood fl ow across aff erent arteriole in the glomerulus is closely linked to RAAS system and blood pressure regulation. There is a selective increase in glomerular capillary pressure

Figure 2 – Renin angiotensin aldosterone effects on sodium and water balance

REVIEW ARTICLE


in response to high salt intake in the salt-sensitive subjects.24,25 Some investigators also proposed that alterations in glomerular surface area or the actual density of glomeruli may be responsible for salt-sensitive hypertension.26,27 To support this hypothesis, observations in experimental animals have provided substantial indirect evidence that salt sensitivity is associated with a reduction in nephron number or glomerular surface area.26

The Role of Sympathetic Nervous SystemThe sympathetic arm of the autonomic nervous sytem is well known to play an important role in blood pressure regulation. The role of Sympathetic system in salt sensitivity was fi rst suggested by Campese et al,28 after they observed higher levels of plasma norepinephrine in salt-sensitive subjects compared with salt-resistant hypertensive subjects.

Reports from a study measured that nine salt-sensitive hypertensive patients had higher urinary excretion of dihydroxyphenylalanine plus a reduced dopamine excretion during a high-salt diet than seven salt-resistant hypertensive patients.29 These fi ndings suggest that both the dopaminergic and the noradrenergic system in the kidney may be diff erent in salt-sensitive and salt-resistant hypertensive patients.

β-adrenergic receptor activity is responsive to changes in sodium balance was demonstrated by Feldman et al.30 Skrabal and colleagues31 who reported alterations in adrenergic receptor activity with changes in sodium intake in normotensive subjects. Upregulation of α2-receptors and downregulation of β2-receptors during high-sodium intake was another important observation made by them. It was then hypothesized by them that an increase in the ratio between α2- and β2-receptors during a high-salt diet could promote vasoconstriction and decreased vasodilation in resistance vessels and increased proximal tubular sodium reabsorption, which would favor a salt-sensitive blood pressure response.31

Black hypertensive patients had the

most sensitive β-receptors as well as the highest receptor density when compared with white hypertensive patients and normotensive subjects of both racial groups.32 This could partially explain why black population have more salt sensitivity than white population.

The Kallikrein-Kinin SystemThe kallikrein-kinin system is a hormonal system consisting of blood proteins that play a role in infl ammation, blood pressure control, coagulation and pain. Bradykinin and kallidin, the main components of this system are vasodilators and act on many cell types. It has been reported that salt-sensitive hypertensive patients have lower levels of urinary kallikrein than those who are salt resistant.33 Moreover, these investigators reported an inverse relationship between atrial natriuretic factor (ANF) and kallikrein in salt-sensitive subjects,33 although they also reported that non-modulators had a decreased response of ANF to saline infusion.34 This apparent discrepancy suggests that salt sensitivity ANF and non-modulation, at least as defi ned by this group, may not be synonymous, although they observed salt sensitivity of blood pressure in the low-renin and non-modulating groups only.34 In yet another study,35 the same group of investigators observed that 10 salt-sensitive hypertensive patients had a decrease in blood pressure after oral administration of kallikrein that was not seen in salt-resistant subjects despite similar natriuretic responses to kallikrein in the two groups. These investigators also found lower levels of urinary kallikrein and higher levels of ANF in their salt-sensitive hypertensive patients.35 Other investigators have provided additional support for diff erences in kallikrein activity in salt-sensitive and salt-resistant subjects.36

Blood Parameters Aff ecting Salt SensitivityNot only have abnormalities of intra-cellular sodium, calcium, and magnesium concentrations been implicated in salt-sensitive hypertension,37,38 but alterations in extracellular pH and

bicarbonate have also been found even before the development of hypertension in salt-sensitive normotensive subjects.39 These studies showed that a decrease in cumulative bicarbonate excretion occurred when the salt-sensitive subjects were given sodium citrate or ammonium chloride compared with their salt-resistant counterparts.39

RECENT STUDIES AND PARADIGM SHIFTSRecent studies have added some insights and questions the classic view of salt senstivity. Two novel pathways have suggested molecular mechanisms of renal handling in salt sensitive hypertension.

Nonosmotic salt accumulation in the skin interstitium and the endothelial dysfunction40 which might be caused by detoriation of vascular endothelial glycocalyx layer (EGL) and the epithelial Na channel on the endothelial luminal surface (EnNaC) may also play an important role in non osmotic storage of salt. This new concepts emphasize that Na homeostatis and salt sensitivity seem to be related not only to the kidney malfunction but also to the endothelial dysfunction.

SALT-SENSITIVITY MATTERSOn a positive note41 it is conceivable to prevent or delay the subsequent age-related increase in blood pressure, and thus, the future development of hypertension and thereby reduce the risk of cardiovascular events and mortality in salt sensitive subjects. “Non-dipper” HTN patients with blunted nocturnal decline in BP are more likely to exhibit salt sensitivity and disturbances in the circadian rhythm of BP. Salt sensitive patients are prone not only for CV events but also renal events, end organ damage, left ventricular hypertrophy (LVH) and proteinuria . More patients with resistant HTN are found to be salt sensitive. Strong relationship between increased salt sensitivity and insulin resistance42 leading to metabolic syndrome and CV disease is more relevant to India, where the salt consumption is very high.

Application of the current status of knowledge pertaining to salt and


hypertension shall invite natural corollaries as regards choice of preparations in current practice. Most guidelines recommend 2.3 grams of sodium intake per day or less. Salt intake amongst Indians tends to be on a higher side between 7-12 grams per day. Alternatives to conventional salt are available and tend to be used and recommended; termed variously as “low sodium salt”, “sodium replacement salt” clubbed as salt alternatives which taste the same as normal table salt, but use potassium instead of sodium as key ingredient. They may help to lower blood pressure because of the helpful eff ects of potassium; substitutes may serve as a good option for patients who are trying to cut back on sodium.

This does not purport to be an exhaustive review of the subject. However, the current thought on causes and mechanisms have been addressed; worldwide eff orts to reduce blood pressure of people and salt intake are certainly called for.

REFERENCES1. Samantha Bromfield and Paul Muntner High Blood

Pressure: The Leading Global Burden of Disease Risk Factor and the Need for Worldwide Prevention Programs Curr Hypertens Rep. 2013 Jun;15(3):134–136.

2. MacGregor GA. Sodium is more important than calcium in essential hypertension. Hypertension.1985; 7:628-637.

3. Koolen MI, Bussemaker-Verduyn E, den Boer E, van Brummelen P. Clinical, biochemical and haemodynamic correlates of sodium sensitivity in essential hypertension. J Hypertens. 1983;1(suppl 2):21-23.

4. Sullivan JM. Salt sensitivity: definition, conception, methodology, and long-term issues. Hypertension. 1991;17(suppl I):I-61-I-68.

5. Rodriquez BL, Labarthe DR, Huang B, Lopez-Gomez J. Rise of blood pressure with age. Hypertension.1994; 24:779-785.

6. Overlack A, Ruppert M, Kolloch R, Kraft K, Stumpe KO. Age is a major determinant of the divergent blood pressure responses to varying salt intake in essential hypertension. Am J Hypertens.1995;8:829-836.

7. Ishibashi K, Oshima R, Matsuura H, Watanabe M, Ishida M, Ishida T, Ozono R, Kajiyama G, Kanbe M. Effects of age and sex on sodium chloride sensitivity: association with plasma renin activity. Clin Nephrol.1994;42:376-380.

8. Tuck ML. Role of salt in the control of blood pressure

in obesity and diabetes mellitus. Hypertension. 1991;17(suppl I):I-135-I-142.

9. Weinberger MH, Luft FC, Bloch R, Henry DP, Pratt JH, Weyman AE, Rankin LI, Murray RH, Willis LR, Grim CE. The blood pressure-raising effects of high dietary sodium intake: racial differences and the role of potassium. J Am Coll Nutr.1982;1:139-148.

10. Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8(suppl II):II-127-II- 134.

11. Sharma AM, Schorr U, Cetto C, Distler A. Dietary v intravenous salt loading for the assessment of salt sensitivity in normotensive men. Am J Hypertens.1994; 7:1070-1075.

12. Elijovich F, Weinberger MH et al salt sensitivity of BP scientific statement of AHA Hypertension 2016:68:e7 –e46.

13. Sullivan JM. Salt sensitivity definition conception, methodology, and long term issues. Hypertension 1991:17.161 – 168.

14. Weimberger MH, miller JZ Luft FC et al. definitions and characteristics of Na sensitivity BP resistance, Hypertension 1986:8 127 – 134.

15. Weinberger MH, Miller JZ, Grim CE, Luft FC, Fineberg NS, Christian JC. Sodium sensitivity and resistance of blood pressure are associated with different haptoglobin phenotypes. Hypertension.1987; 10:443-446.

16. Lifton RP, Dluhy RG, Powers M, Rich G, Cook S, Ulick S, Lalouel JM. A chimaeric 11 - hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature.1992; 355:262-265.

17. Shimkets RA, Warnock DG, Bositis CM, Nelso-Williams C, Hansson JH, Schambelan M, Gill JRJ. Liddle’s syndrome: heritable human hypertension caused by mutations in the subunit of the epithelial sodium channel. Cell.1994; 79:407-414.

18. Osanai T, Kanazawa T, Yokono Y, Uemara T, Okuguchi T, Onodera K. Effect of aging on sensitivity of blood pressure to salt. Nippon Ronen Igakkai Zasshi.1993; 30:30-34.

19. Ishibashi K, Oshima R, Matsuura H, Watanabe M, Ishida M, Ishida T, Ozono R, Kajiyama G, Kanbe M. Effects of age and sex on sodium chloride sensitivity: association with plasma renin activity. Clin Nephrol.1994; 42:376-380.

20. Weinberger MH, Fineberg NS. Sodium and volume sensitivity of blood pressure: age and pressure change over time. Hypertension.1991; 18:67-71.

21. Sullivan JM. Salt sensitivity: definition, conception, methodology, and long-term issues. Hypertension. 1991;17(suppl I):I-61-I-68.

22. Kawasaki T, Itoh K, Cugini P. Influence of reapportionment of daily salt intake on circadian blood pressure pattern in normotensive subjects. J Nutr Sci Vitaminol.1994; 40:459-466.

23. Weinberger MH, Stegner JE, Fineberg NS. A comparison of two tests for the assessment of blood pressure responses to sodium. Am J Hypertens.1993; 6:179-184.

24. Campese VM, Parise M, Karubian F, Bigazzi R. Abnormal renal hemodynamics in black salt-sensitive patients with hypertension. Hypertension.1991; 18:805-812.

25. Bigazzi R, Bianchi S, Baldari D, Sgherri G, Baldari G, Campese VM. Microalbuminuria in salt-sensitive patients. Hypertension.1994; 23:195-199.

26. Brenner BM, Anderson S. The interrelationships among filtration surface area, blood pressure, and chronic renal disease. J Cardiovasc Pharmacol. 1992;19(suppl 6):S1-S7.

27. Kimura G, Frem GJ, Brenner BM. Renal mechanisms of salt sensitivity in hypertension. Curr Opin Nephrol Hypertens.1994; 3:1-12.

28. Campese VM, Romoff MS, Levitan J, Saglikes Y, Fredier R, Massry SG. Abnormal relationship between sodium intake and sympathetic nervous system activity in salt- sensitive patients with essential hypertension. Kidney Int.1982; 21:371-378.

29. Gill JR Jr, Grossman E, Goldstein DS. High urinary dopa and low urinary dopamine-to-dopa ratio in salt-sensitive hypertension. Hypertension.1991; 18:614-621.

30. Feldman RD, Lawton WJ, McArdle WL. Low sodium diet corrects the defect in lymphocyte beta-adrenergic responsiveness in hypertensive subjects. J Clin Invest.1987; 79:647-652.

31. Skrabal F, Kotanko P, Luft FC. Inverse regulation of alpha-2 and beta-2 adrenoceptors in salt-sensitive hypertension: an hypothesis. Life Sci.1989; 45:2061-2076.

32. Mills PJ, Dimsdale JE, Ziegler MG, Nelesen RA. Racial differences in epinephrine and 2- adrenergic receptors. Hypertension.1995; 25:88-91.

33. Ferri C, Bellini C, Carlomagno A, Perrone A, Santucci A. Urinary kallikrein and salt sensitivity in essential hypertensive males. Kidney Int.1994; 46:780-788.

34. Ferri C, Bellini C, Coassin S, Baldoncini R, Luparini RL, Perrone A, Santucci A. Abnormal atrial natriuretic peptide and renal responses to saline infusion in nonmodulating essential hypertensive patients. Circulation.1994; 90:2859-2869.

35. Bellini C, Ferri C, Piccoli A, Carlomagno A, Di Francesco L, Bonavita MS, Santucci A, Balsano F. The influence of salt sensitivity on the blood pressure response to exogenous kallikrein in essential hypertensive patients. Nephron.1993; 65:28-35.

36. Blackwood AM, Inoue J, Sagnella GA, Miller MA, Markandu ND, MacGregor GA. Are the changes in urinary kallikrein excretion on altering sodium intake an index of salt sensitivity? J Hum Hypertens.1994; 8:619-621.

37. Resnick LM, Gupta RK, DiFabio B, Barbagallo M, Mann S, Marion R, Laragh JH. Intracellular ionic consequences of dietary salt loading in essential hypertension. J Clin Invest.1994; 94:1269-1276.

38. Kurtz TW, Morris RC Jr. Sodium-calcium interactions and salt-sensitive hypertension. Am J Hypertens. 1990;3(part 2):152S-155S.

39. Sharma AM, Cetto C, Schorr U, Spies KP, Distler A. Renal acid-base excretion in normotensive salt-sensitive humans. Hypertension.1993; 22:884-890.

40. Choy HY1, Park HC 1,Ha SK 1, Electrolyte Blood Press. 2015 jun:13(1).

41. Mishra S, ingale S jain, Salt sensitivity and its implication in clinical practice, Indian Heart Journal.2018,70:556-564.

42. Ganda OP, Fonseca VA, salt sensitivity insulin resistance and public health india. Endocr pract 2010.16(6), 940 – 944.


Exploring the Role of Insulin Resistance in Cardiovascular Ageing and Disease

REVIEW ARTICLE

VINOD NIKHRA

Keywords cardiovascular disease differential insulin sensitivity insulin resistance metabolic syndrome PI3K/Akt pathway MAPK/Ras pathway visceral adiposity

Dr. Vinod Nikhra is Senior Consultant and Faculty, Department of Medicine, Hindu Rao Hospital and NDMC Medical College, New Delhi

AbstractInsulin is an anabolic hormone and regulates glucose homeostasis and other metabolic processes in various organs including heart and vasculature. Further, with ageing there occurs a reduction in insulin sensitivity leading to insulin resistance (IR) involving liver, striated muscle, heart and other organs. At the cellular level, the insulin triggers signalling cascades that regulate cell metabolism, cell proliferation and cell survival. The insulin stimulated metabolic pathways are important for mitochondrial function and the IR due to chronic relative insulin insuffi ciency affects the mitochondrial function. IR is a major component of metabolic syndrome and has an impact on cardiovascular ageing and cardiovascular disease (CVD). The disruption of insulin signalling impairs the entry of glucose into skeletal muscle cells and adipocytes. To compensate the IR state, -cells initially increase basal and postprandial insulin secretion. The compensatory hyperinsulinemia is an attempt to maintain normoglycaemia. Chronic hyperinsulinemia is benefi cial to some extent as it overcomes the impact of subnormal insulin action in various organs. However, the metabolic derangements in tissues due to differential insulin sensitivity promote the development of atherosclerosis and is accompanied by increased risks of CVD, metabolic diseases such as type 2 diabetes mellitus (T2DM) and degenerative diseases such as Alzheimer’s disease, and reduced longevity. An optimal glucose control is associated with improvement in cognitive functioning in older adults and associated with lower mortality following major adverse cardiac events. Calorie restriction or restricting food intake can reduce ectopic lipid accumulation and improve hepatic and muscle insulin action. Surgical removal of visceral fat improves IR, restores insulin sensitivity and may prolong life span. Administration of resveratrol, a sirtuin activating compound, improves IR and appears to normalise life span.


CORELATING ALTERED INSULIN SENSITIVITY AND METABOLIC SYNDROME (METS)Insulin is an anabolic hormone and regulates glucose homeostasis and other metabolic processes in various organs. It increases rate of glucose uptake into skeletal muscle and adipose tissue, reduces hepatic glucose output (via decreased gluconeogenesis and glycogenolysis) and increases lipid synthesis in liver and fat cells, simultaneously attenuating fatty acids (FAs) release from triglycerides in fat and muscle. At the cellular level, the insulin binding to its receptors at the cell surface triggers the initiation of signalling cascades that regulate cell metabolism (including glucose, amino acid and lipid metabolism), cell proliferation and cell survival.

Insulin resistance (IR) denotes an impaired signal transduction and occurs when the circulating levels of the hormone are insuffi cient, absolutely or relatively, to regulate the metabolic processes appropriately leading to an impairment of insulin signalling in peripheral tissues, particularly liver, skeletal muscle, adipose tissue and heart.1 IR is a component of MetS and has an impact on cardiovascular ageing and incidence of cardiovascular disease (CVD). Apart from IR, ageing process and obesity–the adverse phenotype and metabolic triad - have impact on survival and morbidity (Figure 1).

1.1 Altered Insulin Signalling with AdiposityObesity is a major contributor to the pathogenesis of IR and the increased visceral abdominal or omental (Om) fat is associated with abnormalities in insulin signalling, glucose intolerance, dyslipidaemia and signifi cantly increased CV risk. The intra-abdominal adipose tissue has a relative resistance to anti-lipolytic action of insulin and enhanced sensitivity to catecholamine-induced lipolysis. The enhanced lipolysis increases the portal and systemic concentration of free fatty acids (FFAs), which reduces the insulin sensitivity to glucose metabolism and disposal in skeletal muscle and liver and impair pancreatic insulin secretion.2 The expansion of the Om fat depot leads to raised FFA levels and contributes to IR in skeletal muscle and liver by reduced ability of insulin to stimulate the phosphorylation of several proteins like protein-tyrosine phosphatases (PTPases) which modulate an insulin receptor kinase activation, intracellular signal transduction and signalling cascade in various tissues. In addition, certain PTPases in insulin-sensitive cells, such as PTP1B, appears to be negatively related to regulation of insulin receptor autophosphorylation and post-receptor insulin signalling. The alterations in the intracellular enzymatic activity of PTP1B aff ect insulin action in adipose tissue. The mean endogenous PTPase activity is about 2-fold higher Om adipose tissue as compared with the subcutaneous (Sc) depot, denoting that Om adipose tissue is relatively resistant to the metabolic actions of insulin as compared to the Sc depot.3

1.2 Altered Insulin Signalling with AgeingInsulin secretion is pulsatile with low-amplitude pulses every 8–15 min and ultradian pulses with larger amplitude at a periodicity of 60–140 min. The physiological pulse secretory pattern is disrupted in pathological conditions such as impaired glucose tolerance, obesity and T2DM. With ageing, there occurs an impairment of glucose-stimulated insulin

pulse mass, amplitude and rhythmicity due to a progressive loss of β-cell mass and deterioration of β-cell function.4 Further, there occurs a reduction in insulin sensitivity leading to IR with ageing involving liver, kidney, striated muscle and other organs.

There occur various physiological alterations with ageing including altered body composition, decreased physical fi tness, changes in hormones like growth hormone, insulin-like growth factors, leptin and sex steroids, and lipotoxicity and glucose toxicity due to sustained elevations of circulating FFAs and glucose. The reduced muscle mass, physical fi tness and aerobic capacity (VO2 max) contribute to impaired insulin sensitivity. There are two pathophysiological components, IR-HOMA (Homeostatic model assessment determines β-cell function and IR) and infl ammation, associated with incident frailty with age which is associated with decreased reserve in physiologic systems, functional limitations and adverse outcomes with chronic diseases.5

The regulation of glucose homeostasis by insulin is altered during ageing. There occurs a decline in glucose tolerance and peripheral glucose utilization.6 The decreased insulin action on glucose metabolism is associated with a reduced insulin sensitivity for protein breakdown in older adults. Further, there is impaired skeletal muscle glucose uptake attributable to unopposed norepinephrine induced vasoconstriction due to decreased eNOS activity as result of IR. In addition, there occur autonomic alterations preceding the development of IR.7 The reduced insulin action is associated with a compensatory increase in plasma insulin to improve glucose metabolism in insulin-dependent tissues such as skeletal muscle. Thus, the impaired glucose metabolism in older adults is associated with reduced inhibition of protein breakdown contributing to a progressive loss of body proteins, especially at the skeletal muscle level. This is accompanied by a nearly normal hepatic insulin sensitivity.

Figure 1. The adverse phenotype and metabolic triad; ageing, IR, adiposity, survival and disease progression

Ageing

InsulinResistance

Adiposity

Survival and

Disease

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1.3 Insulin Signalling in Type 2 diabetes mellitus (T2DM) and HypertensionThe muscle glycogen synthesis is the major pathway for glucose metabolism and under hyperglycemic-hyperinsulinemic conditions the defective muscle glycogen synthesis plays a major role in causing IR. Defects in glycogen synthase, hexokinase II and glucose transport have been implicated for the impaired muscle glycogen synthesis in T2DM. Even before the onset of diabetes, off spring of patients with T2DM have lower insulin sensitivity and reduced rate of muscle glycogen synthesis. Apart from this, the characteristics of IR have been shown to diff er in salt-resistant (SR) and salt-sensitive (SS) subjects, independent of blood pressure. The enhanced proximal tubular sodium reabsorption by insulin is preserved in hypertensive subjects and the IR may precede and predict the development of essential hypertension.8

There is an evidence that a genetic predisposition may contribute to IR and the resultant hyperinsulinemia and hypertension. This concept is supported by the fi nding of altered glucose metabolism in normotensive off spring of hypertensive persons. Mechanisms for the development of hypertension in the setting of IR and hyperinsulinemia includes activation of the sympathetic nervous system, renal sodium retention, altered transmembrane cation transport, growth-promoting eff ects of vascular smooth muscle cells and vascular hyperreactivity. Hypertension may be associated with enhanced salt sensitivity and IR. Insulin has a peripheral vasodilatory eff ect, but this response is lost in IR/obese persons suggesting resistance to the action of insulin to induce vascular nitric oxide (NO) production.9

2. PATHOPHYSIOLOGY OF ALTERED INSULIN SENSITIVITYThe insulin stimulated metabolic pathways are important for mitochondrial function and the IR due to chronic relative insulin insuffi ciency and FA-induced diff erential insulin sensitivity aff ects the mitochondrial function.10

FFAs has an impact on mitochondrial

activity and may play a role in the development of mitochondrial dysfunction. In fact, IR individuals have reduced expression of mitochondrial gene mRNAs and lower protein expression of respiratory chain subunits, decreased mitochondrial DNA (mt-DNA), reduced oxidative enzyme activity and decreased mitochondrial size and density.

In fact, the FAs compete with glucose for substrate oxidation at the mitochondrial level. The increase in FAs causes an increase in the intramitochondrial acetyl CoA/CoA and NADH/NAD+ ratios, with subsequent leads to inactivation of pyruvate dehydrogenase, increase in intracellular citrate concentrations, inhibition of phosphor-fructokinase, a key rate-controlling enzyme in glycolysis. Subsequent accumulation of glucose-6-phosphate would inhibit hexokinase II activity, increase in intracellular glucose concentrations and decrease in glucose uptake. There occur FA-induced alterations in upstream insulin signalling events, resulting in decreased glucose transporter gene 4 (GLUT4) translocation to the plasma membrane and reduced glucose transport activity.

2.1 Insulin Receptors and Proximal SignallingThe insulin receptor is a cell-surface receptor and consists of two extracellular α-subunits linked to two intracellular β-subunits through disulfi de bond to form a α2β hetero-tetrameric complex. Insulin binds to the α-subunits, transmits a signal across plasma membrane to activate the tyrosine kinase domain of β-subunit. Through a series of transphosphorylation reactions, the β-subunit phosphorylates its adjacent partner on specifi c tyrosine residues, various tyrosine residues accounting for distinct functions. In addition to tyrosine autophosphorylation, the insulin receptor is subjected to β-subunit serine/threonine phosphorylation, which attenuates receptor function. The counter-regulatory hormones and cytokines can also activate serine kinases, including protein kinase C (PKC), which leads to genesis of IR.

There are two main insulin receptor substrates (IRS), IRS-1 and IRS-2

for propagation of insulin signal. The IRS proteins have an NH2-terminal pleckstrin homology domain (PH domain) domain and phosphotyrosine-binding domain (PTB) domain having a variable-length COOH-terminal tail that contains numerous tyrosine and serine phosphorylation sites, and mediate specifi c interactions with the insulin and IGF-I receptor kinases. The IRS phosphorylation motifs, IRS-1/IRS–1 and IRS-2/IRS-2, which are widely expressed, whereas IRS-4/IRS-4 is limited to the thymus, brain, kidney and possibly β-cells.

On activation, the insulin receptor phosphorylates the insulin receptor substrates-IRS1/2, the Shc adapter protein isoforms, signal-regulatory protein (SIRP) family members, growth associated binder-1 (Gab-1), cannabinoid receptor (CB1) and adaptor proteins (APS), which create recognition sites for additional eff ector molecules containing Src homology 2 (SH2) domains including adaptor proteins growth factor receptor bound-2 (Grb2) and non-catalytic region of tyrosine kinase adaptor protein 1 (NcK), the Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) protein and the regulatory subunit of the type 1A phosphatidylinositol 3–kinase (PI3K). IRS1 and IRS2 appears to have a distinct physiological functions. In studies, the homozygous IRS1-KO mice develop a mild IR but do not become diabetic, because of β-cell compensation, whereas the disruption of the IRS2 gene results in IR, impaired insulin secretion and diabetes.11

2.2 Downstream Insulin SignallingThe IRSs triggers intracellular signalling cascades by activation of two main signalling pathways: the (PI3K)/Akt pathway and the mitogen-activated protein kinases/Ras (MAPK/Ras) pathway, which regulates gene expression and insulin-associated mitogenic eff ects. Other Ser/Thr kinases such as protein kinase A (PKA), c-Jun amino-terminal kinase (JNK) and p38-kDa mitogen-activated protein kinase phosphorylate the insulin receptor and decrease its activity. There is variable overlap and


crosstalk between the gene-regulated protein kinases having impact on the insulin signalling cascades.

The PI3K pathway is the most important pathway for insulin signalling and responsible for many of the metabolic actions of insulin (Figure 2). The PI3K is activated on phosphorylation of motifs in IRS proteins and activates the Akt kinase which translocate to the mitochondria. The activated protein kinase B (PKB or Akt) phosphorylates many substrates to control various signalling reactions and plays a central role in activation and regulation of several metabolic processes including glucose transport, glycogen and protein synthesis and adipogenesis. It infl uences cell proliferation and cell survival through phosphorylation of the Forkhead proteins and the proapoptotic protein BCL2 associated agonist of cell death (BAD) to regulate various metabolic enzymes.12

There occurs a relative decrease in insulin-stimulated association of IRS proteins with reduced activation of PI3K and activation of Akt in IR skeletal muscle in T2DM.13 The intrinsic cell-signalling pathways are also infl uenced by endogenous factors like oxidative stress, endoplasmic reticulum stress and mitochondrial dysfunction; whereas alterations in adipokines, increased FAs levels and the presence of infl ammation in metabolic tissue are the extrinsic factors modulating the peripheral IR.14 The TNF-α expression is high in muscle and fat in obesity and T2DM and has an inhibitory eff ect on insulin signalling in

muscle and adipose tissue leading to IR.15 In obesity, increased plasma FFAs

concentration is associated with increased FAs exposure, leading to intracellular accumulation of FAs and FA metabolites such as diacylglycerol and ceramides, which plays an important role in the pathogenesis of IR. Various studies endorse the relationship between accumulation of intramyocellular triglyceride and IR.16 The accumulation of intracellular fatty acid metabolites, such as diacylglycerol, fatty acyl CoA’s, or ceramides activates a serine/threonine kinase cascade, leading to phosphorylation of serine/threonine sites on IRS. The serine-phosphorylated forms fail to associate with or to activate PI3K, resulting in decreased activation of glucose transport and other downstream events. Evidence supporting this hypothesis comes from studies in transgenic mice that are almost totally devoid of fat because their adipocytes express the A-ZIP/F-1 protein, which blocks the function of several classes of transcription factors.17

2.3 Insulin-Stimulated Glucose Transport and UptakeThe GLUTs are insulin-responsive molecules. The GLUT-4 is main glucose transporter and is located primarily in muscle cells and adipocytes. Following insulin stimulation, there is marked increase in the rate of GLUT4 vesicle exocytosis which recycles between the cell membrane and various intracellular organelle.18 The GLUT4 vesicles

contain the v-SNARE proteins vesicle-associated membrane protein (VAMP2) and VAMP3, which interact with their t-SNARE counterparts, Syntaxin-4 and SNAP23 in the plasma membrane during GLUT4 vesicle translocation. In addition, the SNARE accessory proteins, such as Munc18c, Synip and NSF, are required for the GLUT4 docking and fusion events.19

The IR is a complex phenomenon in which certain genetic defects may combine with external stressors, as in obesity or infections, to generate the IR phenotype. In addition, several key molecules may function at lower than normal potential, resulting in poor signal transduction at multiple levels and glucose transport, or certain proteins are upregulated that inhibit the signalling pathways.20 Skeletal muscle is the major site and to some extent adipose tissue, for insulin-stimulated glucose disposal. The resistance to the stimulatory eff ect of insulin on glucose utilization occurs in obesity, MetS and T2DM.21 In addition, the impairment of insulin-stimulated glucose transport leads to decreased insulin-stimulated glycogen synthesis in skeletal muscle in T2DM.22 Further, the chronic elevation of serum FFAs in obesity or T2DM contributes to the decreased uptake of glucose into muscles and other peripheral tissues in association with a loss of the ability of insulin to stimulate PI3K.23

The hyperglycaemia itself has a detrimental eff ects on insulin secretion and reduced insulin-stimulated glucose uptake.24 There also occurs diversion of glucose from the glycolytic pathway to hexosamine pathway through the enzyme glutamine-fructose-6-phosphate amidotransferase resulting in the production of glucosamine-6-phosphate and other hexosamine products.25 The hexosamine products impair with the insulin stimulated glucose transport process and GLUT-4 translocation in skeletal muscles.26 In addition, in T2DM, the pancreatic β-cells become insensitive to insulin. In this setting, insulin activates a diff erent signalling pathway, through PI3K-C2α leading to proliferation and hyperplasia of pancreatic β-cells to

Figure 2. Major players in insulin (INS) signalling cascades - the 22 hetero-tetrameric insulin receptors and two main insulin signalling PI3K/Akt and MAPK/Ras pathways

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produce extra insulin which exacerbates infl ammation and has been in turn linked to IR.27

2.4 IR and Homeostatic Alterations The insulin or insulin-like growth factor (IGF) signalling system plays a central role through integrating the storage and release of nutrients with the growth, development and maintenance of homeostasis throughout adult life.28 Regulation of growth and longevity by the insulin/IGF-signalling system has been documented in Caenorhabditis elegans, as partial inhibition of insulin/IGF signalling increases nematode life span. The insulin/IGF signalling also coordinates longevity in Drosophila. There are multiple steps which are specifi c to the insulin- or IGF-signaling pathways and some elements are shared with other systems. There occurs dysregulation in insulin signalling cascade at certain steps leading to IR. At the physiological level, overnutrition, obesity, inactivity and ageing are common causes of IR. The chronic hyperinsulinemia exacerbates IR and contributes directly to β-cell failure.

The mutations in the insulin receptor are a rare cause of lifelong IR. The elevated activity of protein or lipid phosphatases, including protein-tyrosine phosphatase 1B (PTP1B), SH2-domain-containing inositol 5-phosphatase (SHIP2) or phosphatase and tensin homolog (PTEN) can be a cause of IR. The high circulating FFAs, fatty acyl-CoAs, diacylglycerol and ceramides, and the stress-induced cytokines and metabolites promote serine phosphorylation of the IRS proteins, which impairs insulin signalling. Another TNF-α-signalling involves activation of the c-Jun NH2-terminal kinase (JNK) pathway, which is stimulated during acute or chronic infl ammation.29 JNK phosphorylates numerous cellular proteins, including IRS-1 and IRS-2, Shc and Gab1 and promotes phosphorylation of a serine residue located on the COOH-terminal side of the PTB domain inhibiting the function of the PTB domain and disrupting the IRS-1 tyrosine phosphorylation, leading to IR.

In addition, the partial failure of the insulin/IGF-signalling system is

associated with various metabolic disorders including dyslipidaemia, hypertension, female infertility and glucose intolerance in the prediabetic phase. The degradation of IRS proteins due to enhanced activity of the ubiquitin/proteasome system in diabetes also exacerbate IR. The chronic hyperinsulinemia to compensate for glucose intolerance appears to diff erentially stimulate IRS-1 and the IRS-2 signals in tissues and cells leading to generation of free radicals and accelerated ageing process.

3. IR: MOLECULAR MECHANISM AND PATHWAYSThere are endocrine, infl ammatory and neuronal pathways link obesity to IR.30 In case of MetS associated with overweight and obesity, the insulin sensitivity of signalling pathways is blunted by factors such as FFAs, the bioactive intracellular lipid intermediates such as diacylglycerols and ceramides, infl ammatory mediators such as TNFα and interleukins-1 and IL−6, adipokines and hepatokines which have been linked to ectopic lipid accumulation and lead to nutrient stress in the endoplasmic reticulum and mitochondria.31 The increased proinfl ammatory cytokines such as TNF-α inhibit lipogenesis, promote lipolysis, disrupt insulin signalling and reduce the expression of GLUT4 in adipose tissue and myocytes, acting through the IKK-beta/NF-kappa-B pathway. IR is often present in setting of visceral adiposity, hypertension, hyperglycaemia and dyslipidaemia involving elevated triglycerides and decreased HDL cholesterol levels. Further, the visceral adiposity is related to nonalcoholic fatty liver disease (NAFLD), leading to an excessive circulating FFAs due to increased lipolysis and increased hepatic glycogenolysis and gluconeogenesis, which exacerbates peripheral IR.32 The dyslipidaemia and IR are also associated with a hypercoagulable state due to impaired fi brinolysis and increased infl ammatory cytokine levels.

There is close interrelationship between obesity, infl ammation, oxidative stress and IR. The obesity-associated

increase in FAs triggers IR through intracellular metabolites that activate PKC, leading to the activation of serine/threonine kinases that impair insulin signalling. In addition, FAs also trigger IR by direct activation of toll-like receptor 4 (TLR4) and the innate immune response. The decreased production of GLUT4 on the cell membrane may also contribute to IR. There are obesity-associated changes in secretion of adipokines that alter insulin signalling. There occurs an obesity-related alteration in the central response to hormonal and nutrient signals. An associated factor is leptin defi ciency and resistance. The endocrine and infl ammatory mediators converge on serine/threonine kinases that inhibit insulin signalling. The studies in mice with obesity and diabetes, leptin replacement has been found to reduce glucose and insulin levels and improve insulin sensitivity.33 Cortisol is another endocrine factor produced by adipose tissue and elevated glucocorticoid levels cause IR.

An important kinase likely to mediate the crosstalk between infl ammatory and metabolic signalling is JUN N-terminal kinase1 (JNK1), a serine/threonine protein kinase that is activated by many infl ammatory stimuli including TNF-α. Activation of JNK1 leads to serine phosphorylation of IRS-1 impairing insulin action. Another class of infl ammatory mediators contributing to obesity-induced IR are suppressor of cytokine signalling (SOCS) proteins, which constitute a negative feedback pathway in cytokine signalling. The SOCS family proteins, induced by adipokines, induce IR either by interfering with IRS-1 and IRS-2 tyrosine phosphorylation or by targeting IRS-1 and IRS-2 for proteosomal degradation. At least three members of the SOCS family (SOCS-1, SOCS-3, and SOCS-6) have been implicated in cytokine-mediated inhibition of insulin signalling. The overexpression of SOCS-1 and SOCS-3 in the liver causes systemic IR.34

There are neuronal mechanisms linking food intake, obesity and IR. The brain regulates feeding behavior and substrate metabolism to promote


homeostasis of energy stores and fuel metabolism. It processes information from adiposity signals such as insulin and leptin, which is related to body fat mass and signals from nutrients such as FAs. In addition, there is an impact on insulin sensitivity through the CNS regulation of the circadian rhythm. Impaired food intake with altered expression of neuroactive peptides, such as leptin, causes metabolic imbalances aff ecting insulin sensitivity. The mice lacking a key component of the molecular circadian clock in the hypothalamus develop a metabolic syndrome of hyperlipidemia, hepatic steatosis, and hyperglycaemia.35 The human study in workers with alternating shift work had a higher risk for developing diabetes compared with their day shift counterparts.36

There is increased nitric oxide (NO) production in setting of obesity because of inducible nitric oxide synthase (iNOS), which is markedly increased in macrophages and other infl ammatory cells. In the presence of O2, NO covalently attaches to cysteine residues of target proteins forming S-nitrosothiol adducts through protein S-nitrosation. The obesogenic diet increases S-nitrosation of the insulin receptor and AKT/PKB in adipocytes and in skeletal muscle and induces IR. The studies in ageing mice have shown increased iNOS expression with S-nitrosation of the insulin receptor IRS-1 and AKT/PKB in skeletal muscle.37

4. CONCEPTS IN IR AND ALTERED HOMEOSTASIS The inter relationship and alterations in the metabolic macro- and microenvironment leading to decreased insulin sensitivity are complex. The disruption of insulin signalling impairs the entry of glucose into skeletal muscle cells and adipocytes. In addition, the cell-intrinsic mechanisms of obesity-associated IR are intensifi ed by cell-extrinsic modulators such as endocrine and infl ammatory signals.38

4.1 The Complex Insulin Signalling SystemThe insulin signalling is an integrated multisystemic network involving the insulin target tissues such as pancreas,

liver, muscle and adipose. The peripheral IR is modulated by increased insulin secretion, as the insulin signalling cascade modulates β‐cell function.39 The increased circulating FAs and other lipids in MetS and obesity lead to ectopic intracellular lipid accumulation in muscle and liver, which impairs insulin signalling through activation of PKC. It also triggers an increase in reactive oxygen species (ROS) leading to mitochondrial dysfunction and cellular endoplasmic reticulum stress which impair insulin signalling (Figure 3).

There are various molecules involved in the intracellular processing of the insulin signalling and include IRS1/2, the protein kinase B (PKB) isoforms and the Forkhead transcription (FoxO) factors. The FoxO family consists of FoxO1, FoxO3, FoxO4 and FoxO6 proteins in mammals and mediate the inhibitory action of insulin or insulin-like growth factor on key functions involved in cell metabolism, growth, diff erentiation, oxidative stress, senescence, autophagy and ageing. The FoxO factors also control upstream signalling elements governing insulin sensitivity and glucose metabolism and the altered FoxO expression, especially FoxO6 in liver, adipose tissue and brain is associated with the pathogenesis of IR, dietary obesity and T2DM and risk of neurodegeneration disease.40

Insulin signalling via PI3K leads to elevated AKT activity. AKT-mediated phosphorylation of FoxO promotes cytoplasmic localization of FoxO, thereby lowering its activity in the nucleus. The endoplasmic reticulum

stress is a potential contributor to IR. During endoplasmic reticulum stress JNK mediated signalling phosphorylates IRS proteins and impairs PI3K/AKT signalling in response to insulin, lowering AKT activity which leads to elevated nuclear FoxO localization. Thus, the ER stress pathway involves the protein kinase RNA-like endoplasmic reticulum kinase (PERK) signalling pathway to modulate cellular insulin responsiveness. The newly synthesized proteins normally are folded, processed and assembled in the endoplasmic reticulum (ER) and the misfolded proteins are eliminated via the endoplasmic reticulum-associated degradation (ERAD) pathway. Under conditions of cellular nutrient overload, the endoplasmic reticulum stress leads to impaired regulatory capacity of the ERAD pathway causing misfolded proteins to accumulate. Elevated endoplasmic reticulum stress is known to cause IR due to reduced activity of FoxO factors through PERK-mediated FoxO phosphorylation.41

4.2 Metabolic and Clinical Fallouts Of IRIR and Diff erential Insulin Sensitivity: IR in both the periphery (primarily muscle and fat) and in the liver aggravates the altered carbohydrate and lipid metabolism. To compensate for the insulin-resistant state, β-cells initially increase basal and postprandial insulin secretion. The compensatory hyperinsulinemia is an attempt to maintain normoglycaemia. Chronic hyperinsulinemia is benefi cial to some extent to the resistant tissues as it overcomes the impact of subnormal

Figure 3. Key factors for IR in adipose tissue, liver and muscle

Hyperglycemia FFFAs Adipokines

Ectopic fat accumlnInflam cytokines ROS OxS

Mitochondrial stressEndopal reticular stress

IR

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insulin action in liver, muscle and adipose tissues; however, it brings about metabolic derangements in tissues bearing normal sensitivity to insulin.42 Again, within the same tissue, some of the insulin-regulated pathways, such as the glucose metabolic pathway, may be more resistant to insulin than others like the mitogenic pathway, which has impact on the cellular functions and survival.43 The compensatory hyperinsulinemia result in activation of the MAPK pathways, which stimulates cellular migration, vascular smooth muscle cell proliferation and a prothrombotic state, and shifts the balance of insulin signalling toward a mitogenic state leading to accelerated atherosclerosis and CV ageing.44 Simultaneously, the IR leads subnormal response to insulin and associated with dyslipidaemia and hypertension. Eventually, β-cells can no longer compensate, and IR and loss of β-cell function eventually lead to the deterioration of glucose homeostasis and to the development of hyperglycaemia.45

Insulin Sensitivity and Longevity: MetS consists of metabolic defects associated with IR, prothrombotic and infl ammatory states. In older adults, there is rise of visceral adiposity and accumulation of senescent cells with infl ammatory phenotype resulting in increased levels of proinfl ammatory cytokines that are likely to interfere with insulin signalling.46 The dysfunctional IRS–PI3–kinase/Akt pathway causes impaired glucose uptake in muscle and fat cells, reduced glycogen synthesis/storage in the liver and failure to suppress hepatic glucose production, along with impaired lipid uptake by adipose tissue. The increased plasma levels of lipids and proatherogenic apoB-containing/triglyceride-rich lipoproteins have a causal role in adverse ageing phenotypes and age-related conditions.47 Thus, IR is accompanied by increased risks of CVD, metabolic diseases such as T2DM and degenerative diseases such as Alzheimer’s disease, and reduced longevity.48

However, there is an evidence that insulin sensitivity and longevity may involve diff erent causal pathways that are not necessarily interconnected. The enhanced insulin sensitivity is

neither a necessary nor a suffi cient step toward increased longevity. In fact, the improvement of insulin sensitivity may not reverse certain features of MetS. Further, it is held that IR is an evolutionary conserved protective mechanism against certain threats to life and the decreased insulin signalling has been linked to regulation of stress response.49 Further, in the face of increased nutrient availability, IR may be necessary to limit glucose uptake in muscle cells where glycogen and lipid stores are already saturated.50 Thus, although insulin sensitivity is essential for normal functioning of organs, IR in ageing humans may play an adaptive role and may contribute to increased longevity with reduced insulin signalling.51

4.3 IR and Benefi cial ‘Spill Over’ Eff ectWith the excess caloric intake, there occurs deposition of lipids in non-adipose tissue, a deregulation of adipokines and other products of adipocytes, which set in an infl ammatory process in adipose tissue and other organs, involving the recruitment of macrophages and other immune cells. This results in mitochondrial dysfunction, endoplasmic reticulum stress and IR at the level of various key organs, such as the liver, muscle and the heart and vasculature. Mitochondrial β-oxidation of fatty acids generates ROS and leads to increased NFκB activity, which triggers systemic IR. In addition, adiposity generated conditions increase the demand on the secretory pathways and lead to ER stress response.

The ‘spill-over’ eff ect from adipose tissue appears to prevent the tissue damage due to the ectopic lipid accumulation if adipose tissue is able to expand beyond the limits present under normal physiological conditions. Allowing adipose tissue to expand further results in improvements in metabolic parameters related to glucose and lipid metabolism. There occur reduced triglyceride levels in the liver and muscle with improved hepatic and systemic insulin sensitivity, preservation of β cell mass and a positive impact on the infl ammatory profi le.

The underlying mechanism appears to be related to increased peroxisome proliferator-activated receptors (PPARγ) activity in adipocytes and adiponectin which results in a redistribution of lipids from ectopic deposits in liver and muscle to the subcutaneous adipose depots. Experimentally, in diabetic ob/ob mice, modestly increasing the levels of circulating adiponectin increased expression of PPAR-γ target genes and led to reduction in macrophage infi ltration in adipose tissue and systemic infl ammation. These mice thus, represent a novel model of morbid obesity associated with an improved metabolic profi le.52

5. IR AND CVDThe role of insulin is more than simply regulating carbohydrate metabolism and insulin in physiological concentration is necessary to maintain normal vascular functions and IR contributes to vascular impairment.53 Within cardiovascular physiology, insulin plays a key role in cardiac contractility and vascular tone. One of its main functions is endothelial nitric oxide synthase enzyme (eNOS) activation, which leads to nitric oxide (NO) production in the vascular endothelium. The NO diff uses into both the lumen and vascular smooth muscle cells, activates the guanylate cyclase enzyme to increase cyclic guanosine monophosphate (cGMP) levels and induces vasorelaxation. The increased blood fl ow leads to increased delivery of glucose to target tissues. Insulin also regulates glucose transport in cardiomyocytes, mainly through glucose transporter C, apart from glucose, lipid and protein metabolism regulation. The signalling pathway for insulin and IGF-I, PI3K system also mediates the increases in NO, Na+ pump, K+ channel and calcium (Ca2+) myofi lament sensitivity by increasing the traffi cking and translocation of NO synthase and cation pump units apart from glucose transporters. The resistance to the actions of insulin and IGF-I occurs whenever there is reduced PI3 -kinase activation.

IR and Coronary artery disease:A number of large prospective studies have shown that hyperinsulinemia is


a predictor of coronary artery disease (CAD).54 The Kuopio Ischaemic Heart Disease Risk Factor Study outlined the robust association of hyperinsulinemia with CAD in Finland population. This study correlated the high fasting insulin concentrations as an independent predictor of CAD.55 In addition, several recent studies highlighted a relationship between carotid wall atherosclerotic lesions, CVD and insulin levels/resistance. The visceral obesity which is often accompanied by IR and hyperinsulinemia is associated with increased risk for CVD and stroke. The hyperinsulinemia in visceral obesity is associated with increased levels of plasminogen activator inhibitor-1 (PAI-1). Other risk factors associated with visceral obesity and IR include hypertension, increased fi brinogen, blood viscosity, and C-reactive protein. In addition, hyperuricemia, a risk factor for CHD, may be a component of the IR syndrome.56

There are disturbances of the fi brinolytic system observed in hyperinsulinemia and IR. There are elevated levels of fi brinogen and thrombin-antithrombin complexes and the circulating levels of Lp (a) are often elevated in the metabolic syndrome. By inhibiting fi brinolysis, increased levels of Lp (a) delay thrombolysis and thus contribute to plaque progression. The elevated levels of fi brinogen in the insulin-resistant state acts as an independent risk factor for CVD acting synergistically with the dyslipidaemia and hypertension.

IR is a predisposing factor for hypertension, dyslipidaemia, hyper-coagulability, endothelial dysfunction, albuminuria and premature CVD by virtue of reduced insulin signalling leading to decreased NO synthase/Na+, K+ gene activation/expression and the increased peripheral vascular resistance characteristic of insulin-resistant states.57 Both insulin and IGF-I reduce vascular tone, in part through eff ects on cation metabolism and by attenuating calcium (Ca2+) infl ux into vascular smooth muscle cells (VSMC) by decreasing receptor-mediated and voltage-operated Ca2+ channel currents associated with VSMC contractile responses. As NO

activates Ca2+-dependent K channels, eff ects of insulin/IGF-I on these channels is mediated in part via increased NO production by endothelial cells and VSMC. Another mechanism by which insulin/IGF-I decreases VSMC intracellular Ca2+/vasoconstriction, is through the Na+, K+-ATPase pump, which stimulates the transport of Na+ and K+ ions against concentration gradients, using energy supplied through ATP hydrolysis. The insulin/IGF-I activation of the PI3K pathway is critical for the peptides to stimulate the pump. The altered PI3K responses to insulin/IGF-I may, thus, explain the decreased ability of those peptides to mediate vasodilation in insulin-resistant patients. The overexpression of the renin–angiotensin system (RAS) may be another major factor in insulin/IGF-I resistance. The angiotensin converting enzyme (ACE) inhibitors inhibit the overexpression of the RAS and lead to increased microvascular blood fl ow in insulin-sensitive tissues such as skeletal muscle tissue and adipocytes. Another mechanism by which ACE inhibitors may improve insulin sensitivity is by decreasing the inhibitory eff ects of Ang II on insulin signalling.

IR and CV Ageing: In the CVS, insulin induces arterial vasodilatation through the release of nitric oxide (NO) by the vascular endothelium and exerts a positive inotropic eff ect on myocardium in part through stimulation of glucose uptake by cardiomyocytes and mediated by PI3K activation, enhanced Ca2+ infl ux through L-type Ca2+ channels and facilitation of sarcoplasmic reticular calcium transport. The insulin binding to insulin receptors activates two intracellular pathways; the PI3K/Akt pathway which in the endothelium leads to eNOS phosphorylation and NO production and the MAPK pathway which induces the release of the vasoconstrictor peptide endothelin 1. Both the PI3K/Akt and MAPK pathways are diff erentially aff ected by IR, with the activation of PI3K/Akt being signifi cantly reduced and the activation of the MAPK pathway remaining unaltered. This imbalance results in a predominance

of the vasoconstrictor and proliferative actions of insulin contributing to the impairment of cardiovascular function. In this respect, the benefi cial eff ect of CR preventing the ageing-induced decrease in myocardial function appears to be mediated by decreased activation of MAPK and increased activation of the PI3K/Akt pathways.58

Age is one of the major risk factors associated with CVD. About one-fi fth of the world population will be aged 65 or older by 2030, with an exponential increase in CVD prevalence.59 CV ageing is an intrinsic process that results in cardiac dysfunction, accompanied by molecular and cellular changes. Insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) signalling and IR have been implicated in CV ageing. There lies an interplay and crosstalk between senescence, atherosclerotic disease and metabolic disorders.

Pathophysiology of CV ageing: There occurs vascular wall thickening, collagen deposition, perivascular fi brosis and vessel dilatation. The progressive myo-intimal thickening is the hallmark of the vascular ageing and is due to enhanced elastin degradation and collagen deposition in the vascular media as well as intimal hyperplasia.60 There is an altered vascular tone resulting from the imbalance between vasoconstriction and vasorelaxation. Apart from its eff ect on the vasculature, ageing aff ects the heart as well. There occurs cardiomegaly with loss of functional cardiac cells along with myocardial fi brosis leading to an impaired diastolic and systolic function.61

The ageing adversely aff ects the metabolic pathways leading to vascular and cardiac senescence. The mitochondrial adaptor p66Shc is an important molecular eff ector correlating the eff ects of ageing on metabolic and cardiovascular disease.62 Several stimuli activate protein kinase C βII (PKCβII) isoform to induce Ser-36 phosphorylation of p66Shc, allowing transfer of the protein from the cytosol to the mitochondrion where it fosters ROS accumulation by oxidizing cytochrome c leading to mitochondrial disruption and activates

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apoptotic pathways.63 Further, the p66Shc activation is critically involved in endothelial IR, adipogenesis, IR and other vascular complications.64

AMP-activated protein kinase (AMPK), the master regulator, activates endothelial nitric oxide synthase (eNOS), and promotes autophagy and mitophagy, thus preventing mitochondrial insuffi ciency, infl ammation and cellular death. It modulates mTOR signalling by phosphorylating the TSC1/2 complex and regulates the IGF-1 pathway and sirtuin activity.65 The perturbation of the SIRT1–LKB1–AMPK pathway leads to energy imbalance, cellular stress and activation of the apoptotic pathways leading to vascular ageing.66 The insulin signalling via phosphorylation of FOXO-1 is selectively impaired in visceral adipose tissue and endothelial cells of obese subjects.67 Nuclear factor kappa-B (NF-kB) is another important transcription factor responsible for regulating gene expression of factors that control cell adhesion, proliferation, infl ammation and redox state. Activation of NF-kB mediates vascular and myocardial infl ammation and fi brosis in metabolic and age-related diseases.68 The activator protein-1 (AP-1) transcription factor, JunD, is a key molecule implicated in age-related diseases, mostly by modulating oxidative stress levels. The vascular JunD expression progressively declines with ageing, thus altering the balance between pro-oxidant (NADPH oxidase) and antioxidant enzymes (manganese superoxide dismutase (MnSOD) and aldehyde dehydrogenase-2 (ALDH-2)), with subsequent accumulation of free radicals. The JunD protein levels are decreased in patients with end-stage heart

failure.69

There are other variables involved apart from hormones and metabolites, such as leukocyte telomere length (LTL), which is the marker of replicative cellular senescence and refl ects the vascular biological age. Individuals with short telomeres are more likely to show accelerated vascular ageing, atherosclerosis, coronary heart disease and T2DM. Increased arterial stiff ness is associated with shorter telomere length and impaired glucose metabolism.70

6. CONCLUSION: DEALING WITH IR AND CV RISKThe strongest relationship between IR and CV risk factors is observed in middle-aged persons rather than in older individuals, although cardiovascular morbidity and mortality increase with age.71 IR promotes the development of atherosclerosis through hyperinsulinemia and hyperglycaemia.72 IR also reduces the ability of adipose tissue to store proatherogenic lipids and produces a variety of proinfl ammatory mediators from the adipose tissue, which contribute to atherosclerosis.73

Diabetic cardiomyopathy (DCM) is characterized by dysfunctional eff ects on the heart by a combination of several metabolic disorders including hyperglycaemia, IR and dyslipidaemia. In DCM, the molecular myocardial abnormalities that lead to the development of myocardial dysfunction with co-existence of additional stressors such as obesity, hypertension and coronary artery disease.74 Biochemical stressors for the development of DCM include infl ammation, 12/15-LOX signalling, FA oxidation and lipotoxicity and upregulation of signalling pathways,

such as NF-κB, c-Jun NH2-terminal kinase, or p38-MAPK associated with IR. Multiple factors impede the ability of insulin to suppress adipose lipolysis, including infl ammation. Activated adipose tissue macrophages (ATMs) are recruited via chemokine signalling and release cytokines that promote lipolysis. TNF-α lowers perilipin expression, presumably enhancing lipolysis. Insulin defi ciency may also suppress adipose LpL expression, which could further compound the hypertriglyceridaemia seen in diabetic states.

The cardiometabolic risk is high in South Asians, with clustering of risk factors starting at an early age.75 MetS is one of the emerging health problems of the world with prevalence higher among Asians, including Indians, and is rising especially in the rural area.76

Better glucose control in the elderly has been associated with improvement in cognitive functioning and lower mortality following myocardial infarction.77 Calorie restriction (CR) or restricting food intake can reduce ectopic lipid accumulation and improve hepatic and muscle insulin action. Indeed, euglycaemic clamp studies in caloric-restricted animals revealed enhanced insulin sensitivity compared with normally fed controls.78 Surgical removal of visceral fat in ageing rodents restored insulin sensitivity and prolonged life span.79 Administration of resveratrol, a compound that activates sirtuin in ageing mice on a high-calorie diet increases insulin sensitivity and normalizes their life span.80

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Heart Failure with Preserved Ejection Fraction-A Disease Beyond Heart!

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NISHANT KUMAR ABHISHEK, M.M. RAZI, S.K. SINHA, RAMESH THAKUR

Keywords HFpEF HFrEF LVEF quality of life life expectancy

Dr. Nishant Kumar Abhishek, Dr. M.M. Razi, Dr. S.K. Sinha, Dr. Ramesh Thakur. LPS institute of Cardiology, GSVM Medical College, Kanpur, UP, India

Abstract“The results of PARAGON HF trial studying the effects of ARNI (Angiotensin Receptor-Neprilysin Inhibitor) are out and the study narrowly misses its statistical signifi cance of the primary endpoint.” In the background of high hopes surrounding ARNI, the limited results of this trial have again put forth a question mark regarding our approach towards heart failure with preserved ejection fraction (HFpEF). This study confi rms the safety profi le of this drug and the totality of evidence has been presented at the annual meeting at the European Society of Cardiology (ESC) Congress September 2019. The researchers plan to engage in formulating the next steps on this drug.2

The earliest description of HFpEF was given by Dr. Robert Luchi in 1982, when he admitted elderly patients with symptoms of acute congestive heart failure and demonstrated normal left ventricular ejection fraction (LVEF) by nuclear imaging, when reduced EF was an essential pre-requisite for the diagnosis of heart failure.3 Since then, the entity of HFpEF has remained an enigma and represents the huge unmet need for the cardiologists. The counterpart, heart failure with reduced ejection fraction (HFrEF) has found its way with decreased mortality and improved patient morbidity with various modalities of treatment. With the on-going decline in mortality with HFrEF, HFpEF patients are fast catching up and are soon expected to outnumber them.4,5 HFpEF encompasses a heterogeneous group of conditions that are described by the presence of left ventricular ejection fraction (LVEF) >50% with an evidence of impaired diastolic properties and elevated natriuretic peptide levels in the background of typical heart failure signs and symptoms. As the long list of trials exploring treatment in HFpEF fails to achieve its target endpoint, we are at crossroads of realizing it as a multisystem disease with various treatment defi ning phenotypes. This review article aims to redefi ne the problem and highlight the value of HFpEF as a disease beyond heart and its comorbid associations.

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INTRODUCTIONHeart failure is a complex clinical syndrome aff ecting 26 million people worldwide and the numbers continue to rise with the ageing population. Patients with this diagnosis have a reduced quality of life (QoL) and life expectancy (50% fi ve-year mortality of HF patients).7 The current proportion of HFpEF is around 50% of HF patients and its prevalence is destined to increase and it will soon occupy the dominant spectrum. This is attributed to the better treatment response of HFrEF and the general ageing of the population with associated co-morbidities like obesity, hypertension, diabetes mellitus, metabolic syndrome, coronary artery disease (CAD), atrial fi brillation, chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD).8,9 The mortality rates are similar between HFpEF and HFrEF, but death due to non-cardiac causes are found to be more in HFpEF. Female gender susceptibility is higher according to the population registries.

The heterogeneous syndrome of heart failure is divided into three groups on the basis of EF10

HFrEF: LVEF <40% HFmrEF: mid-range EF i.e. 40–50% HFpEF: EF >50%

The treatment options in the fi rst two groups have done wonders but there are limited treatment options in HFpEF group, which will form the focus of this review article.

DEFINING THE PROBLEMThe syndrome of HFpEF has failed

to respond to the time tested and trial proven formula of RAAS antagonism and neurohormonal blockade that, over the years has provided landmark success in stabilization, or complete reversal of HFrEF. This brings us into questioning mode that “is HFpEF only a cardiac entity per se or an amalgamation of

cardiac diastolic dysfunction, vascular stiff ness, endothelial dysfunction, systemic infl ammation, skeletal muscle dysfunction, autonomic disease or an end product of comorbidities?”

Recent work has underpinned multiple and complex pathophysiologic basis in HFpEF but the magnitude in which they exist in a susceptible individual is not yet realized. This has directed physicians to approach the disease via a phenotypic approach8,9 of classifying HFpEF into multiple sectors and defi ning treatments for the same.

MAKING THE DIAGNOSISDiagnosing a patient with HFpEF is a challenging prospect whereas HFrEF presents in an overt manner. Sometimes, patients of HFpEF remain asymptomatic between exacerbations forming an iceberg. Keeping high-index of suspicion in a possible background of co-morbidities, it can be diagnosed clinically with support of other investigations.

ESC guidelines outline a quick guide to diagnosis of HFpEF11,12

Signs and symptoms of heart failure (HF clinical criteria Framingham or Boston.)

Elevated B-type natriuretic peptide (BNP)>35 pg/ml or N-terminal-pro-BNP (NT-pro-BNP)>125 pg/ml.

A preserved EF>50% and left ventricular end-diastolic volume (LVEDV)<97 ml/m2.

Expected antecedent or co-morbid conditions present and non-cardiac causes of symptoms need to be excluded.

Additional non-invasive supportive evidence in form of –

1) Left atrial volume index >34 ml/m2 2) LV mass index >149/122 M/F gm/m2

3) Mean E’ septal and lateral < 9cm/s4) E/e’ ratio >15

Additional invasive evidence

pulmonary capillary wedge pressure (PCWP) >15 mmHg, LVEDP >16 mmHg.Any singular fi nding cannot be

completely diagnostic, and the value of biomarkers has been found to be less signifi cant in HFpEF, so a normal level does not rule out HFpEF. The equivocal cases should be subjected to detailed non-invasive and invasive clues to label the fi nal diagnosis. Exercise stress testing can be used to provide functional status, presence of chronotropic incompetence (frequent association with HFpEF, more so, in diabetes mellitus) and presence of associated CAD. Cardiopulmonary testing can delineate any concomitant pulmonary diagnosis or the presence of deconditioning. The magnetic resonance imaging (MRI) may be required to rule out infi ltrative cardiomyopathies.

PATHOPHYSIOLOGY UNDERLYING HFpEF- HEART AND BEYOND13

It is now of paramount importance that we look again into the mechanism that governs the development of this constellation of HFpEF. HFpEF is not a single disease confi ned to the heart but a holistic entity involving the heart, the vasculature, metabolic pathways, infl ammatory milieu and spectrum of co-morbid conditions.

The pathophysiology and the treatment implications can be divided in the following categories as suggested by the work of Lam et al (2018):

Cardiac Aetiology-Diastolic Dysfunction-Left Heart Disease12

As a time tested concept, diastolic dysfunction remains the cornerstone of pathophysiology of HFpEF, the contents being LV hypertrophy, impaired relaxation and LV stiff ness. Hypertension is frequently encountered with HFpEF resulting in pressure overload leading to LV hypertrophy and diastolic dysfunction

Furthermore, it emphasises on the abnormalities of the vasculature that could potentially contribute to the pathophysiology of HFpEF and which represent the other half of this disease. This review also summarizes what we have, till date, on HFpEF and gives a short insight on what the future holds in the context of the development of novel and effective treatment paradigms.


which in series results in increased left atrial pressure, pulmonary venous hypertension, secondary pulmonary arterial hypertension and resultant right heart dysfunction. LV stiff ness and delayed active relaxation is the genesis of elevated LV fi lling pressures. This stiff ness has been implicated in the interplay between the cardiomyocytes and the extracellular matrix. The landmark hemodynamic study by Zile et al., (2017)14 showed that patients with diastolic heart failure have impaired relaxation and increased stiff ness. The development of this diastolic dysfunction predisposes to the development of HFpEF. The resultant left atrial morphological changes and the remodelling blunts the left atrial boost with exercise which distinguishes HFpEF from pure hypertension. Left atrial dysfunction was directly related to the symptom onset in patients.15 This observation was further elucidated in COMPASS HF trial subset which showed that measured increase in the estimated pulmonary artery diastolic pressure was associated with deterioration from chronic to acute decompensated heart failure.

Therapeutically, left atrial hyper-tension was targeted using a transcatheter inter-atrial shunt device (IASD, Corvia Medical, USA) which improved the 6-minute walk distance and exercise capacity in REDUCED LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) study.16 A larger trial, REDUCED LAP-HF II is examining the eff ects of this device and is expected to come up with the results in 2024. Pulmonary artery pressure as a conjugate has been targeted by the CardioMEMS17 heart sensor device in CHAMPION trial using a wireless pulmonary artery pressure transducer that helps to take hemodynamically guided heart failure treatment decisions. It was associated with 46% reductions in heart failure readmissions over 6 months, as of now, CardioMEMS device has achieved class II b recommendations in recent ESC guidelines.

Pulmonary Vascular DiseaseAround 80% of the patients develop some

amount of pulmonary hypertension which is associated with poorer outcome of HFpEF in increasing severity. In HFpEF, patients have post capillary pulmonary hypertension but overlaps of pre and post capillary do coexist. This identifi cation of the mixed variety is important as they respond well to pulmonary vasodilatation. Pulmonary arterial hypertension causing RV dysfunction contributes to the worst outcomes in HFpEF, thus calling for a potential therapeutic target. Treatment directed at pulmonary hypertension to reduce RV workload appears promising but the results, surprisingly have been disappointing. In the largest of the RELAX18 trials, sildenafi l did not improve the exercise capacity or the clinical status. In a newer development according to COMPERA registry, patient of HFpEF with combined pre and post capillary pulmonary hypertension showed improvement in NYHA class, six-minute walk distance (6MWD) and 3 monthly and 12 monthly biomarker levels. Similar work on tadalafi l is under study. Other drugs used in pulmonary hypertension like endothelin antagonists, prostacyclin analogues, soluble guanylate cyclase stimulators like riociguat and vericiguat have shown potential benefi ts in HFpEF but are still not in recommendations.

Plasma Volume ExpansionPlasma volume expansion has been suggested as the primary pathology in patients of T2DM and obesity which are frequently associated with HFpEF. In the CHAMPION trial it was seen that use of a diuretic by the pressure guided approach led to lesser incidences of hospital admission. The same concept extended to the usage of sodium-glucose co-transporter-2 (SGLT2) inhibitors like empaglifl ozin which can be used as an osmotic diuretic with pleotropic eff ects regardless of glycaemic status. This is being investigated in EMPEROR HF trial and the results are awaited. The future of SGLT2 inhibitors in HFpEF is particularly attractive for patients of metabolic syndrome with HF.

Vascular Model of HFpEF19

The focus in HFpEF is shifting

gradually from predominant diastology to impairment of vascular functions thus, providing a domain of new target therapies for this disease as well as explaining the limited success achieved with conventional treatment which has been stupendous in HFrEF. The work by Lyle MA, et al., (2018) reviewing the vascular background in HFpEF reveals the other side of this disease. Vascular pathophysiology mentions the development of increased aortic stiff ness and faulty vascular tone. The relation between the heart and the vascular system is generally underestimated in heart failure and in HFpEF, this is of major importance. Increase in aortic impedance and thickness was initially attributed to the proliferation of extracellular matrix and fi brosis, but newer evidence suggests vascular smooth muscle activation as the culprit factor. This smooth muscle activation is due to focal adhesions which are prevented by Src kinase inhibitor PP2, thus revealing a potential therapeutic target. Animal models have depicted that smooth muscles contain both non-muscle (NM) myosin and smooth muscle (SM) myosin. Noticeably, in hypertension and HFpEF, NM myosin is preferentially increased leading to vascular stiff ness. PKG (Protein Kinase G) is found to be instrumental in maintaining the vascular tone in humans via NO-cGMP pathway by second messenger system. PKG mediated MYPT1 (Myosin Targeting Subunit Phosphorylation) produces vascular relaxation, the depletion of which has been found to be present in HFpEF, thus enlightening a potential fi eld for targeting the expression and activation of this protein in future.

The Cardiometabolic Abnormalities:13, 20The failing heart is characterized by impaired myocardial energetics, mitochondrial dysfunction, ATP handling, change in substrate utilization and intracellular calcium overload leading to diastolic dysfunction. Many drugs that are targeting these contexts have come into consideration. Partial adenosine A1 agonist, Capadenoson and Neladenoson were initially thought

REVIEW ARTICLE


to be promising. Neladenoson was evaluated in the PANACHE study and it failed to achieve statistical benefi ts. Fatty acid beta oxidation inhibitor, Trimetazidine has been tested in HFrEF and has shown preliminary benefi ts, but more studies are still needed in HFpEF. Mitochondrial enhancer, Elamipretide binds to cardiolipin which increases the effi ciency of mitochondrial respiration under conditions of oxidative stress, reduces free radical generation showing promising results in animal studies. The presence of iron defi ciency was found to be around 60% in HF. Treatment with i.v. iron in the form of ferric carboxymaltose might possibly hold a promising future in HFpEF.

Cellular Model (Titin)21The giant sarcomeric protein titin is the chief determinant of myocardial tension and left ventricular stiff ness. Titin regulates cardiomyocytes stiff ness at the transcriptional and post transcriptional levels. It shifts from its compliant isoform N2BA towards its stiff isoform N2B. Subtle diff erences in titin phosphorylation were found between HFpEF and controls. Therapeutically, increased PKG activity can be achieved by inhibiting the breakdown of cGMP by phosphodiesterase type 5 inhibitor (PDE-5A) inhibitors like sildenafi l, but, it failed in human studies. Recent focus is shifting on PDE 9 to be implicated in increasing cGMP activity. Molecular strategy targeting post translation manipulation of an RNA motif to up regulate compliant titin is in early days.

Microvascular Infl ammation Hypothesis13

HFpEF is associated with immune infl ammation leading to vascular stiff ness and left ventricular remodelling. Infl ammation model of HFpEF implicates co-morbidities leading to systemic insult causing adverse eff ects on cardiomyocytes and vascular functions through decreased nitric oxide bioavailability, reduced cGMP production and impaired phosphorylation of Titin.

Trials with anti-infl ammatory molecules like Anakinra failed to show any benefi ts. The nitrate's eff ect on activity, tolerance in heart failure with preserved ejection fraction (NEAT-HFpEF) trial assessed the eff ect of nitrates and the results were found to be inadequate paving the path for further studies with inorganic nitrites which showed increased exercise tolerance and decreased arterial stiff ening. iNDIE HFpEF trial22 done with inorganic nitrites failed to achieve the targets. Still, nitrate/nitrite-NOcGMP pathway holds ground for prospects. As mentioned earlier, targeting soluble guanylate cyclase stimulator, Vericiguat in SOCRATES PRESERVED23 Trial did not demonstrate change in primary endpoint, but showed improvement in quality-of-life (QoL), The New York Heart Association (NYHA) class and symptoms of heart failure in exploratory analysis. This calls for more studies with this compound.

How to Approach the Problem?There is no doubt that inspite of on-going research and a list of trials, the treatment of HFpEF represents the unmet need of the cardiologists. The drugs that have achieved class 1 recommendation in HFrEF time and again fail to impress in HFpEF. This has evoked interest

in contemplating an entirely diff erent approach for the categorization of patients of HFpEF. A single solution to a multi-dimensional disease has not been found to be eff ective, leading to the emergence of the ‘phenotypic model’ as proposed by many studies. In this model, the comorbidities are categorically placed under diff erent classes to defi ne classes for diff erent treatment modalities.

Mesquita et al (2018)24 described three subgroups in his phenotypic model.

GROUP 1: Consisted of younger patients with moderate diastolic dysfunction and relatively normal BNP levels. They have mild pulmonary hypertension.

GROUP 2: Involved obese and diabetic patients with high prevalence of sleep apnoea. This group showed the highest incidence of pulmonary hypertension.

GROUP 3: Composed of older patients with CKD and pulmonary hypertension. They had severe myocardial remodelling and worse right ventricular function.

A stepladder approach in HFpEF has been developed in many studies.25

Step 1: Suspect and diagnose HFpEFStep 2: Evaluate for rare causes of

HFpEFStep 3: Type of HFpEF to guide

work-upStep 4: General treatment

recommendations- treat hypertension and volume overload

Step 5: Target the comorbiditiesStep 6: Plan a phenotypic variant on

the basis of clinical or etiological class

HFpEF AND DIABETES27

The growing epidemic of type 2 diabetes mellitus (T2DM) especially in the Indian sub-continent has assumed a lot of importance. Recent data reveals that about 45% of the patients with HFpEF have T2DM. A study by Cheng et al (2014)28 using data from guidelines-heart failure (GWTG-HF) registry found equivalent mortality between HFrEF and HFpEF. T2DM per se created a nidus for HFpEF due to its association with systemic infl ammation, endothelial dysfunction, hypertension, renal disease and metabolic

Circulatory biomarkers Circulatory biomarkers

in HFpEF in HFpEF

1) C-reactive proteins (CRP)1) C-reactive proteins (CRP)

2) Interleukins-1 (IL-1)2) Interleukins-1 (IL-1)

3) Growth/differentiation 3) Growth/differentiation

factor 15 (GDF15)factor 15 (GDF15)

4) Tumor necrosis factor (TNF-4) Tumor necrosis factor (TNF-))

6) ST2 and pentraxin 36) ST2 and pentraxin 3

1) Multisystemic inflammation 1) Multisystemic inflammation effects like pulmonary arterial effects like pulmonary arterial hypertension (PAH) and renal hypertension (PAH) and renal impairment.impairment.

2) Trial of calorie restriction in 2) Trial of calorie restriction in obese patients increased the obese patients increased the work capacity.work capacity.

3) Statins treatment showed 3) Statins treatment showed benefit in observational benefit in observational studies but no trial studies but no trial recommendation in HFpEF.recommendation in HFpEF.

Inflammatory Evidence

Biopsy Biopsy

evidence of evidence of

inflammationinflammation


syndrome. In the largest of heart failure registries (GWTG-HF) in which patients were retrospectively studied (n=232656) between 2006 and 2017, it was concluded that there is signifi cant increase in in-hospital and post-discharge morbidity in the patients of T2DM when compared to the non-diabetic subset.

FACTORS IN T2DM AGGRAVATING HFpEF:

Alteration in sodium handling and increased volume overload.

Release of pro-infl ammatory cytokines and production of free radicals.

Poor skeletal muscle function and impaired peripheral oxygen delivery.

Chronotropic incompetence due to autonomic neuropathy.

Increased adiposity and decreased capillary density.EMPEROR PRESERVE trial awaits

the validity of empaglifl ozin in HFpEF.

SUMMARY OF TRIALS IN HFPEF29

• CHARM preserved–Candesartan– No reduction in CV death; decreased hospitalization.

• PEP CHF–Perindopril–No reduction in all-cause mortality.

• DIG CHF- Digoxin–no overall eff ect on mortality.

• I PRESERVE–Irbesartan–no improvements in primary endpoints.

• SENIORS – Nebivolol in HF showed early benefi t but later on extended to

ELANDD trial which showed inadequate increase in exercise capacity with this drug.

• J DHF trial–Carvedilol.• ALDO HF–spironolactone-

changes in diastolic dysfunction but no change in exercise capacity, symptoms or QOL.

• TOPCAT–No improvement in the composite endpoints but signifi cant decrease in hospitalization.

• PARAMOUNT-ARNI compared to valsartan.

• RELAX–Phosphodiesterase inhibitor sildenafi l- no overall benefi t.

• RAAM HF – Eplerenone – no change in six-minute walk distance (6

Exercise-induced increased Exercise-induced increased

lV filling pressureslV filling pressures

1) ACE-I/ARB 1) ACE-I/ARB

2) Exercise conditioning2) Exercise conditioning

3) Inter atrial shunt 3) Inter atrial shunt

device (IASD) device (IASD)

Right heart failure secondary to Right heart failure secondary to

pulmonary hypertensionpulmonary hypertension

1) Diuresis, cardioMEMS1) Diuresis, cardioMEMS

2) Treat underlying pulmonary 2) Treat underlying pulmonary

hypertensionhypertension

Stratification based on clinical phenotype25

Volume overloadVolume overload

1) Spironolactone 1) Spironolactone

2) SGLT2 inhibitor2) SGLT2 inhibitor

3) CardioMEMS in 3) CardioMEMS in

refractory casesrefractory cases

1) Garden variety associated with hypertension, obesity, T2DM and/or CKD1) Garden variety associated with hypertension, obesity, T2DM and/or CKD

2) Coronary artery disease2) Coronary artery disease

3) Pulmonary hypertension with right heart failure3) Pulmonary hypertension with right heart failure

4) Atrial fibrillation4) Atrial fibrillation

5) Hypertrophic cardiomyopathy phenotype5) Hypertrophic cardiomyopathy phenotype

6) Valvular HFpEF6) Valvular HFpEF

7) High output HFpEF7) High output HFpEF

Stratification based on aetiology25

Systemic hypertensionSystemic hypertension

• ACE-I/ARB, thiazide diuretics and vasodilating beta-blockers like carvedilol.• ACE-I/ARB, thiazide diuretics and vasodilating beta-blockers like carvedilol.

• Thiazide like diuretics (chlorthalidone, indapamide• Thiazide like diuretics (chlorthalidone, indapamide2626).).

• Treat secondary hypertension.• Treat secondary hypertension.

CADCAD

• ACE-I/ARB, beta-blockers are still recommended in the subset of HFpEF-CAD.• ACE-I/ARB, beta-blockers are still recommended in the subset of HFpEF-CAD.

• Coronary revascularization by percutaneous coronary intervention (PCI) or coronary • Coronary revascularization by percutaneous coronary intervention (PCI) or coronary

artery bypass grafting (CABG).artery bypass grafting (CABG).

• Aspirin and statins.• Aspirin and statins.

Atrial fibrillationAtrial fibrillation

• Restoration of normal sinus rhythm.• Restoration of normal sinus rhythm.

• Rate control strategies with beta-blocker or calcium channel blockers (CCBs).• Rate control strategies with beta-blocker or calcium channel blockers (CCBs).

• Anti-coagulation with warfarin or new oral anticoagulants (NOACs).• Anti-coagulation with warfarin or new oral anticoagulants (NOACs).

ObesityObesity

• Diet counselling and fluid restriction.• Diet counselling and fluid restriction.

• Referral for obesity management programme in the form of bariatric surgery. • Referral for obesity management programme in the form of bariatric surgery.

CKDCKD

• Collaboration with the nephrology team in patients with GFR <30.• Collaboration with the nephrology team in patients with GFR <30.

• Hemofiltration in patients of volume overload with falsely low serum creatinine.• Hemofiltration in patients of volume overload with falsely low serum creatinine.

Obstructive sleep apnea (OSA)Obstructive sleep apnea (OSA)

• Risk factors of HFpEF overlap with OSA. OSA can cause LVH, hypertension, pulmonary • Risk factors of HFpEF overlap with OSA. OSA can cause LVH, hypertension, pulmonary

hypertension and right heart failure.hypertension and right heart failure.

• All patients diagnosed with OSA have high propensity of developing HFpEF, so early • All patients diagnosed with OSA have high propensity of developing HFpEF, so early

consultation with sleep specialist to initiate CPAP.consultation with sleep specialist to initiate CPAP.

CHRONIC LUNG DISEASECHRONIC LUNG DISEASE

• Even mild lung disease aggravates HFpEF adding to the vicious cycle of hypoxemia, • Even mild lung disease aggravates HFpEF adding to the vicious cycle of hypoxemia,

decreased exercise tolerance and secondary pulmonary hypertension.decreased exercise tolerance and secondary pulmonary hypertension.

• Volume overload in the form of pulmonary oedema often requires monitoring and • Volume overload in the form of pulmonary oedema often requires monitoring and

judicious use of diuretics.judicious use of diuretics.

• Treatment of chronic obstructive pulmonary disease (COPD) increases the QoL.• Treatment of chronic obstructive pulmonary disease (COPD) increases the QoL.

Management of comorbidities in HfpEF- A multiorgan road map25

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MWD) but improvement in diastolic dysfunction.

• SOCRATES preserved- Vericiguat – improvement in QoL.

• EDIFY trial – Ivabradine – did not improve outcomes.

CONCLUSIONHFpEF is a heterogeneous clinical syndrome with its boundaries extended beyond the heart demanding a holistic approach by the cardiologist. The trials in the last twenty odd years have failed to achieve the expected outcome, thus, indirectly testifying to the notorious and maybe a totally unexplored nature of the disease. This review article tries to bring forth the recent outlook towards this problem and underpinning the pathophysiology. Overall, approaching HFpEF in a ‘single hit hypothesis’ remains a far-fetched utopian dream. The multi-systemic approach according to the phenotypic model seems to be pragmatic. Trials awaiting the results of devices, anti-infl ammatory drugs and SGLT-2 inhibitors are something to look forward to. Clinicians should thoroughly look for an underlying aetiology and target any potential reversible causes. Emphasis on the vascular abnormalities, reducing vascular stiff ness and augmenting NO mediated vasodilatation is at an early stage of development. T2DM, hypertension and other co-morbidities must be aggressively tackled. Molecular genetics and targeting translational

proteins implicated in ventricular stiff ness remains an elusive model. Shifting focus away from the diastolic dysfunction and managing infl ammation, vascular dysfunction and comorbidities under the umbrella of phenotypic classifi cation of HFpEF presents the most practical overall approach of the management of HFpEF at this point of time.

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www.novartis.com/news/media-releases/novartis-provides-update-phase-iii-paragon-hf-trial-heart-failure-patients-preserved-ejection-fraction-hfpef. Accessed on September, 2019.

3. Luchi RJ. Left ventricular function in hospitalised geriatric patients. J Am Geriatric Soc. 1982; 30:700–5.

4. Owan TE. Trends in prevalence and outcomes of heart failure with preserve ejection fraction. NEJM.2006;355:251.

5. Campbell. what we have learnt about patients with heart failure and preserved ejection fraction from DIG-PEF,CHARM- preserved and I- Preserved? J Am Coll Cardiol.2012; 60:2349.

6. Lyle MA. HFpEF a disease of the vasculature: A closer look at the other half, Mayo clinic Proc. 2018; 93(9):1305–1314.

7. Juenger J. Health related quality of life in patients with congestive heart failure: comparison with other chronic diseases and relation to functional variables. Heart 2002; 87:235–41.

8. Kao DP. Characterization of subgroups of heart failure patients with preserved EF with possible implications for prognosis and treatment response. Eur J Heart Fail.2015;17(9):925–35.

9. Shah SJ, Katz DH, Selvaraj S, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation.2015; 131(3):269–79.

10. Harper RA, Patel HC, Lyon AR. Heart failure with preserved ejection fraction. Clinical medicine. 2018; 18(2);s24–s9.

11. Borlaug BA. The pathophysiology of heart failure with preserved EF. Nat Rev Cardiol 2014;11:507–15

12. Ponikowski P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J.2016; 37(27):2129–2200.

13. C.S.P. Lam, Voors AA, de Boer RA, et al. Heart failure with preserved ejection fraction: from mechanism to therapies. European Heart J. 2018; 1–13 doi:10.1093/eurheart/ehy301.

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16. Feldman T, Mauri L, Kahwash R, et al. A trans-catheter inter-atrial shunt device for treatment of HFpEF: a phase 2 trial. Circulation. 2017; 137:364–375.

17. Heywood JT. Impact of practice based management of pulmonary artery pressures in 2000 patients implanted with the CardioMEMS sensor. Circulation. 2017; 135:1509–1517.

18. Redfield MM, Chen HH, Borlaug BA, et al. Effect of PDE5 inhibition on exercise capacity and clinical status in HFpEF. JAMA 2013; 309:1268.

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INTRODUCTIONHeart failure (HF) is a hypercoagu-

lable state that is associated with adverse events including stroke, systemic embolism, and mortality. Elevated levels of pro-thrombotic and pro-infl ammatory cytokines are seen in patients with HF. Left ventricular wall motion abnormalities in patients with systolic dysfunction predispose to local thrombosis due to blood stasis as does atrial fi brillation (AF), which leads to blood stasis in regions of the atria. The high-risk of thromboembolism in HF patients with AF has resulted in the use anticoagulation therapy to prevent the occurrence of catastrophic events. There is evidence that the pro-infl ammatory,

pro-thrombotic state do exist in HF patients who are in sinus rhythm. The novel oral anticoagulants (NOACs) have been shown in randomized controlled trials (RCT) to have at least equivalent effi cacy in reducing stroke as warfarin while exposing patients to a lower risk of bleeding. The fact that the NOACs don't require routine monitoring to assure that patients remain within the therapeutic range and have relatively simple dosing requirements and a safer risk profi le makes them attractive substitutes to warfarin in HF patients with atrial fi brillation.

The story of non-vitamin K antagonist in cardiovascular disease has evolved over last one decade, although history of oral anticoagulants is of more than 50 years.

Use of NOACs in Heart Failure

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AJAY KUMAR SINHA, BP SINGH

Keywords heart Failure NOACS rivaroxaban atrial fi brillation vitamin K antagonists

Dr Ajay Kumar Sinha, Ex-Director-Cardiology, Paras HMRI Hospital, Patna and DR B P Singh, Prof & Head, Deptt of Cardiology, IGIMS, Patna

AbstractRecent years have shown the benefi ts of antithrombotic therapy in the management of heart failure (HF). Long-term anti-coagulation has defi nite benefi t in stroke prevention with atrial fi brillation (AF). AF and HF often coexist, and patients with AF and HF have a higher risk of thromboembolic events and overall mortality compared with those with AF without HF. However, the role of non-vitamin K antagonists, or commonly known as NOACS, is evolving in HF with reduced ejection fraction (EF). More recently, non-vitamin K antagonists oral anticoagulants NOACs, have emerged as therapeutic alternative for stroke prevention in patients with non-valvular AF, as they have been shown to be at least as effi cacious and safe, with less intracranial bleeding events, compared with vitamin K antagonists.

"The blood formed extensive clots …possible consequences of the obstruction could be grouped into three categories; Phenomena due to the irritation of the vessel and its surroundings; Phenomena due to blood coagulation; Phenomena due to the interruption of the bloodstream."

Rudolf Virchow (1856)

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They are a mainstay of cardiovascular therapy, and for over 60 years vitamin K antagonists (VKAs) were the only available agents for long-term use.

BACKGROUND AND EVIDENCESHF is a hypercoagulable state with increased incidence of left ventricular (LV) thrombi, ischaemic strokes, and other thromboembolic events, even in the setting of sinus rhythm.1

The Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm (WARCEF) trial was designed to be a larger, randomized, double-blinded trial specifi cally looking at warfarin versus aspirin use in the heart failure with reduced ejection fraction (HFrEF) patient population in sinus rhythm. The effi cacy of anticoagulation in patients with systolic HF in sinus rhythm was fi nally disproven in the WARCEF study.2

While there is an increased risk of thromboembolic events in patients with HFrEF, there are no convincing data to support use of systemic anticoagulation with vitamin K antagonists (VKAs) in these patients who remain in sinus rhythm.3,4,5,6 While warfarin use has been shown to signifi cantly reduce the rate of ischaemic strokes in this population when compared to aspirin, the increased rate of major bleeding while on a VKA outweighs the benefi t. The novel oral anticoagulants with improved safety profi les are an attractive option in this population with the potential to see overall

thromboembolic risk reduction without increased risk of major haemorrhage, though this will need to be shown in clinical trials.

EVIDENCES FAVOURING NOACS IN HFThe story of anticoagulants started some 60 years back, but evidences in the favour of NOACS in HF came with ATLAS-ACS-2 TIMI-51 trial.

Patients with both acute coronary syndromes (ACS) and congestive HF are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fi brinolysis. ATLAS-ACS-2 thrombolysis in myocardial infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526).7 In this post-hoc subgroup analysis, subjects with a history of CHF at randomisation (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite endpoint of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confi dence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs

placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no signifi cant increase in noncoronary artery bypass graft-related bleeding thrombolysis in myocardial infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial haemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding.

2018-19 EraWhether anticoagulation benefi ts patients with HF in sinus rhythm is uncertain. The COMMANDER HF8 randomized clinical trial evaluated the eff ects of adding low-dose rivaroxaban to anti-platelet therapy in patients with recent worsening of chronic HF with reduced ejection fraction, coronary artery disease (CAD), and sinus rhythm. Although the primary endpoint of all-cause mortality, myocardial infarction, or stroke did not diff er between rivaroxaban and placebo, there were numerical advantages favoring rivaroxaban for myocardial infarction and stroke.

The trial randomized 5022 patients postdischarge from a hospital or outpatient clinic after treatment for worsening HF between September 2013 and October 2017. Patients were required to be receiving standard care for HF and CAD and were excluded for a medical condition requiring anticoagulation or a bleeding history. Patients were randomized in a 1:1 ratio. Analysis was conducted from June 2018 and January 2019.

For this post-hoc analysis, a thromboembolic composite was defi ned as either (1) myocardial infarction, ischaemic stroke, sudden/ unwitnessed death, symptomatic pulmonary

Heart FailureHeart Failure

Blood flow Blood flow abnormalitiesabnormalities

• Impaired contractility• Impaired contractility• LV aneurysm• LV aneurysm• Low cardiac output• Low cardiac output

Vessel wall Vessel wall abnormalitiesabnormalities

• Endothelial dysfunction• Endothelial dysfunction• Vascular remodelling• Vascular remodelling

Abnormal blood Abnormal blood constituentsconstituents

• Coagulation abnormalities• Coagulation abnormalities• Platelets abnormalities• Platelets abnormalities• Rheological abnormalities• Rheological abnormalities• Activation of neuroendocrine • Activation of neuroendocrine system system

THROMBOSISTHROMBOSIS

Figure 1. Reproduced with permission from Lip GYH, Ponikowski P, Andreotti F, et al. Thrombo-embolism and antithrombotic therapy for heart failure in sinus rhythm: a joint consensus document from the ESC heart failure association and the ESC working group on thrombosis. Eur J Heart Fail 2012; 14:681–695.


embolism, or symptomatic deep venous thrombosis or (2) all of the previous components except sudden/unwitnessed deaths because not all of these are caused by thromboembolic events.

Of 5022 patients, 3872 (77.1%) were men, and the overall mean (SD) age was 66.4 (10.2) years. Over a median (interquartile range) follow-up of 19.6 (11.7–30.8) months, fewer patients assigned to rivaroxaban compared with placebo had a thromboembolic event including sudden/unwitnessed deaths: 328 (13.1%) vs 390 (15.5%) (HR, 0.83; 95% CI, 0.72-0.96; p = .01). When sudden/unwitnessed deaths were excluded, the results analyzing thromboembolic events were similar: 153 (6.1%) vs 190 patients (7.6%) with an event (HR, 0.80; 95% CI, 0.64-0.98; p = .04). In this study, thromboembolic events occurred frequently in patients with HF, CAD, and sinus rhythm. Rivaroxaban may reduce the risk of thromboembolic events in this population, but these events are not the major cause of morbidity and mortality in patients with recent worsening of HF for

which rivaroxaban had no eff ect. While consistent with other studies, these results require confi rmation in prospective randomized clinical trials.

Rivaroxaban cuts major stroke risk by 31% in COMMANDER HF post-hoc analysisThe main trial, looking at HFrEF patients with CAD but no AF, was neutral, but investigators say the stroke data are compelling.

Virchow passed away in 1902 from HF complications following immobilisation after a femur fracture. In the century following his careful description of the vascular and haematological derangements that lead to unwanted thrombus formation, the pathophysiological mechanisms have been unravelled and targeted therapies aimed at restoring normal balance between thrombosis and bleeding have been developed. However, HF patients continue to suff er from unacceptably high rates of adverse outcome.

Inclusion of patients across a large

spectrum of risk into COMMANDER HF might attenuate any potential signal for benefi t. Lastly, if the ideal scenario occurs, and the study is ‘positive’, rivaroxaban is likely to emerge as an exciting new therapeutic option for HF.9

CONCLUSIONThe era of anticoagulant, which started some 50 years back with atrial fi brillation, has given birth to the concept of using NOACS in heart failure. The proof of concept is currently being validated in so many trials which are throwing light on the use of NOACS in heart failure without AF. Hopefully day is not far away when NOACS will have a place in heart failure management without AF.

REFERENCES1. Lip GY, Gibbs CR. Does heart failure confer a

hypercoagulable state? Virchow's triad revisited. J Am Coll Cardiol. 1999;33:1424–6.

2. Homma S, Thompson JL, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med. 2012; 366:1859–69.

3. Lip GY, Ponikowski P, Andreotti F, et al. Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm. Thromb Haemost. 2012;108:1009–1022.

4. Lip GY, Ponikowski P, Andreotti F, et al. Thrombo-embolism and antithrombotic therapy for heart failure in sinus rhythm. A joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. Eur Heart J Heart Fail 2012:14:681–695.

5. Lip GY, Gibbs, CR. Anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review. QJM. 2002; 95:451–459.

6. Rengo G, Pagano G, Squizzato A, et al. Oral anticoagulation therapy in heart failure patients in sinus rhythm: a systematic review and meta-analysis. Plos One 2014;8:e52952.

7. Korjian S, Braunwald E, Daaboul Y, et al. Usefulness of Rivaroxaban for Secondary Prevention of Acute Coronary Syndrome in Patients With History of Congestive Heart Failure (from the ATLAS-ACS-2 TIMI-51 Trial). Am J Cardiol. 2018; 1;122(11):1896–1901.

8. Greenberg B, Neaton JD, Anker SD, et al. Association of rivaroxaban with thromboembolic events in patients with heart failure, coronary disease, and sinus rhythm: a post hoc analysis of the COMMANDER HF Trial. JAMA Cardiol. 2019;4(6):515–523.

9. Tariq Ahmad and Javed Butler. Disrupting Virchow’s triad: can factor X inhibition reduce risk of adverse outcomes in patients with ischaemic cardiomyopathy? European Journal of Heart Failure. 2015; 17, 647–651.

COMMANDER HF is not another trial of OAC in HF but rather examination of

an intervention to modulate thrombin-mediated 'crosstalk', a potential driver of multiple negative feedback cycles, including inflammation, endothelial

dysfunction, and thrombosis in patients with HFrEF and CAD.

Hazard ratio (HR) for neurologic endpoints, rivaroxaban vs placebo in COMMANDER-HF trial

Endpoint HR (95% CI) Endpoint HR (95% CI)

Any stroke or transient ischaemic attack (TIA) 0.69 (0.50–0.95) Any stroke or transient ischaemic attack (TIA) 0.69 (0.50–0.95)

Ischaemic stroke 0.64 (0.43–0.95) Ischaemic stroke 0.64 (0.43–0.95)

Haemorrhagic stroke 0.74 (.025–2.13) Haemorrhagic stroke 0.74 (.025–2.13)

TIA 0.77 (0.34–1.75) TIA 0.77 (0.34–1.75)

Stroke or TIA incidence per 100 patient-years by CHA2DS2-VASc stratumStroke or TIA incidence per 100 patient-years by CHA2DS2-VASc stratum

Endpoint Placebo, Rate Rivaroxaban, Rate NNTEndpoint Placebo, Rate Rivaroxaban, Rate NNT

Overall 1.9 1.29 164Overall 1.9 1.29 164

CHACHA22DSDS22VASc <4 1.44 1.13 316VASc <4 1.44 1.13 316

CHACHA22DSDS22VASc>4 2.56 1.52 96VASc>4 2.56 1.52 96

NNT = Number needed to treat to prevent one endpoint.NNT = Number needed to treat to prevent one endpoint.


INTRODUCTIONWith better control of infective and metabolic complications, diabetes has emerged as a cardiovascular disease (CVD). As per the study analysis, around 70% diabetics die because of CVD particularly acute myocardial infarction. For close to 100 years, to be precise up to 93 years since the introduction of insulin for clinical use in 1922, no antidiabetic medication had demonstrated benefi t for cardiovascular risk in randomized cardiovascular outcomes trials (CVOTs).

The Rosiglitazone controversy created a fl utter and the US Food Drug Administration (USFDA) in the year 2008 mandated that all new antidiabetic agents must undergo an adequately powered,

glycaemic equipoise cardiovascular outcome trials (CVOTs) in high-risk type 2 diabetic patients, during post-marketing phase to demonstrate their safety by showing non-inferiority against placebo. The non-inferiority was defi ned as hazard ratio (HR) of <1.3 for the upper bound of 95% confi dence interval (CI), superiority can also be claimed if upper boundary of 95% CI is found to be <1.0 in a subsequent statistical analysis.1 In 2012, The European Medicines Agency also issued similar guidelines.2 As a consequence of this, since post–2008, all newer antidiabetic agents approved by USFDA and European Medical Association (EMA) have undergone or currently undergoing CVOTs.

New Antidiabetic Medications for Improving CV Outcomes in Diabetes: Dawn of a New Era

REVIEW ARTICLE

PC MANORIA, PANKAJ MANORIA

Keywords cardiovascular outcomes antidiabetic glycaemic control type 2 diabetes

Dr. PC Manoria is Director & Chief Cardiologist and Dr. Pankaj Manoria is Chief Interventional Cardiologist, Manoria Heart & Critical Care Hospital, Bhopal.

AbstractA new era of improving cardiovascular (CV) outcomes in diabetes with new antidiabetic medications has begun. The new agents like sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon like peptide-1 receptor agonists (GLP-1RAs) in CV outcome trials (CVOTs) have shown improved CV outcomes in patients with diabetes and cardiovascular complications. In addition, the above new agents also have the potential to decrease weight and blood pressure thereby improving comorbidities and on top of this they produce minimal or no hypoglycaemia. Thus, we can kill three birds with the same stone, i.e., optimising glycaemic control, minimising comorbidities and above all improving CV outcomes.


The era of improved cardiovascular (CV) outcomes with new antidiabetic medications was kicked off in 2015 by Empaglifl ozin CV outcome event trial in type 2 diabetes mellitus (T2DM) patients (EMPA-REG OUTCOME) trial. Currently, we have three positive CV outcome trials with sodium-glucose transport protein 2 (SGLT2) inhibitors i.e. EMPA-REG OUTCOME (empaglifl ozin), CANVAS (canaglifl ozin) and DECLARE TIMI 58 (Dapaglifl ozin) and fi ve trials

with glucagon like peptide-1 receptor agonists (GLP-1Ras) i.e. LEADER (Liraglutide), SUSTAIN-6 (Semiglutide), HARMONY OUTCOME (Albaglutide), and REWIND (Dulaglutide). All trials with gliptins have shown CV neutrality from the point of view of atherosclerotic major adverse cardiac events (MACE) i.e. cardiovascular death, MI and stroke but saxagliptin in SAVOR-TIMI trial showed statistically signifi cant increase in hospitalization for heart failure (hHF)

and the EXAMINE trial with alogliptin showed a numerical increase in hHF. THE FREEDOM trial with ITCA 650 have been completed and the results are keenly awaited.

Both SGLT2 inhibitors and GLP1RA trials have shown improved renal outcomes also. The CREDENCE trial with canaglifl ozin is the fi rst dedicated renal outcome trial released in 2019.

It is very exciting that both SGLT2 inhibitors and GLP-1Ras in addition to

Trials Drug Comparator Status Participants Established CVD (%)

Primary outcome

DPP-IV Inhibitors

SAVOR TIMI-533 Saxagliptin Placebo Completed 2013 16492 78% 3P-MACECV neutral, ↑ hospitalisation for HF

EXAMINE4 Alogliptin Placebo Completed 2013 5380 100% 3P-MACECV neutral, numerical ↑ hospitalisation for HF

TECOS5 Sitagliptin Placebo Completed 2015 14735 100% 4P-MACECV neutral, no increase in hospitalisation for HF

CARMELINA6 Linagliptin Placebo Completed 2018 6979 57% 3P-MACE neutral

CAROLINA Linagliptin Glimiperide Completed 2019 6033 42% 3P-MACE neutral

SGLT2 inhibitors

EMPA-REG7 Empagliflozin Placebo Completed 2015 7020 99% 3P-MACEPositive CV outcome

CANVAS8 Canagliflozin Placebo Completed 2017 4330 67% 3P-MACEPositive CV outcome

DECLARE TIMI 589 Dapagliflozin Placebo Completed 2018 17160 40.6% (a) 3P-MACE neutral(b) Composite of CV death or HHF Positive

GLP1-RA

ELIXA10 Lixisenatide Placebo Completed 2015 6068 100% CV neutral

LEADER11 Liraglutide Placebo Completed 2015 9340 81% Positive CV outcome

SUSTAIN 612 Semaglutide Placebo Completed 2016 3297 58.8% Positive CV outcome

EXSCEL13 Exenatide-LAR Placebo Completed 2017 14752 73.1% CV neutral

HARMONY OUTCOME14

Albiglutide Placebo Completed 2018 9463 100% Positive CV outcome

REWIND15 Dulaglutide Placebo Completed 2019 9901 31% Positive CV outcome

PIONEER-616 Oral Semaglutide

Placebo Completed 2019 3138 85% CV neutral

Table-1. Completed CV outcome trials with new antidiabetic medications in T2DM

MACE: Major adverse cardiovascular events

REVIEW ARTICLE


their glycaemic control and improving cardiorenal outcomes, they also improved cardiometabolic profi le by decreasing weight and blood pressure and all this is achieved with minimal or no hypoglycaemia.

Several CVOTs are still ongoing like; the VERTIS-CV trial with Ertuglifl ozin, SCORED trial with SGLT1 and SGLT2 inhibitor sotaglifl ozin etc. The completed CV outcome trials with new antidiabetic medications are shown in table-1.

The ongoing CVOT trials are outlined in table 2.

Results of CVOTs with Antidiabetic Medicationsa. Major Adverse Cardiac Events

(MACE) in CVOTs The eff ect on MACE of new

antidiabetic medications in CVOTs in T2DM is mentioned below:

(i) DPP-4 inhibitors trials: All the fi ve DPP-4 inhibitors trials,

SAVOUR TIMI-53, EXAMINE, TECOS, CARMELINA and CAROLINA achieved the non-inferiority margin on MACE endpoints as laid down by the FDA in 2008, thereby, suggesting that saxagliptin, alogliptin, sitagliptin and linagliptin all are CV neutral drugs. However, no superiority on MACE was observed with any of the four DPP-4 inhibitors.3-6

(ii) SGLT2 inhibitors: The empaglifl ozin in EMPA-REG

OUTCOME7 trial not only achieved the non-inferiority but also demonstrated a substantial superiority against placebo. EMPA-REG found a

signifi cant relative risk reduction in the primary outcome of 3P-MACE (composite of CV death, nonfatal myocardial infarction, and nonfatal stroke) by 14% (HR=0.86, 95% CI=0.74–0.99, P=0.04 for superiority) compared to the placebo.7

The CANVAS8 trial with canaglifozin also showed improved CV outcomes with exactly the same relative risk reduction of 14% in the primary outcome of similar 3P-MACE (HR=,0.86; 95% confi dence interval [CI], 0.75 to 0.97; P<0.001 for non-inferiority; P=0.02 for superiority) like the EMPA REG OUTCOME trial. However, in CANVAS, while all three components of MACE moved in the right direction (i.e., HR<1.0), none achieved statistical signifi cance, perhaps refl ecting the fact that the study involved about one third of patients who had no prior history of CVD unlike EMPA which did not include any such patients. Interestingly, in the CANVAS primary prevention subgroup, the hazard ratio for the primary outcome was 0.98, suggesting that those without CVD do not experience the CV benefi t as those with CVD.

The DECLARE TIMI 58 trial9 with dapaglifl ozin had two primary end points. The primary end point of hHF-CVD showed a statistically signifi cant reduction of 17% (HR=0.83; 95% CI, 0.73 to 0.95; P=0.005). The other primary point of 3 POINT MACE showed a non-signifi cant numerical decrease of 7% (HR=0.93; 95% CI,

0.84 to 1.03; P=0.172). It should be noted that all three trials of

SGLT2i are not comparable because the subset of patient are not similar in all the trials. In the EMPAREG OUTCOME trial all patients had established cardiovascular disease (CVD), in the CANVAS trial 67% has CVD while in the DECLARE TIMI 58 trial 40.6% had CVD. If the results of CANVAS trial are dissected into primary and secondary prevention group, the results in the secondary prevention group are comparable to EMPAREG OUTCOME. It should also be noted that while 3P-MACE reduction in EMPAREG was mainly driven by reduction in the CV death which was due to the reduction in death from hHF and not atherosclerotic events.

The mechanism of action of the CV eff ects of SGLT2 inhibitors remain to be fully elucidated. They potentially pertain to the drug's glucoretic-natriuretic properties. Another school of thought points to the tendency for these agents to shift fuel metabolism in favour of the consumption of ketones (instead of glucose and free fatty acids). Such a change, it has been proposed, may provide an energy advantage for cardiomyocytes. Clearly, more mechanistic studies are needed to better understand these concepts, which might have implications for the management of CVD.

(iii) GLP-1 RAs trials: Of the seven completed CVOTs with

GLP1RAs, four have shown positive results i.e. LEADER, SUSTAIN-6, HARMONY and REWIND. The ELIXA, EXSCEL and PIONEER-6 trials have shown CV neutrality.

The LEADER found 13% relative risk reduction (HR=0.87; 95% CI= 0.78–0.97; P=0.01), SUSTAIN-6 demonstrated even a larger 26% relative risk reduction (HR=0.74; 95% CI=0.58-0.95; P=0.02), the HARMONY trial showed 22% reduction (HR=0.78, 95% CI=0.68-0.90, P<0·0001 for non-inferiority;

Table 2. Large non-insulin ongoing CV outcomes trials in T2DM

TrialsTrials DrugDrug ComparatorComparator StatusStatus

Dipeptidyl peptidase-4 (DPP4) InhibitorsDipeptidyl peptidase-4 (DPP4) Inhibitors

OMNEONOMNEON Omarigliptin Omarigliptin Placebo Placebo OngoingOngoing

SGLT2 InhibitorsSGLT2 Inhibitors

VERTIS CVVERTIS CV1414 ErtugliflozinErtugliflozin PlaceboPlacebo Ongoing Ongoing

SGLT2 T1 InhibitorsSGLT2 T1 Inhibitors

SCORED SCORED Sotagliflozin Sotagliflozin Placebo Placebo Ongoing Ongoing

GLP1-RAGLP1-RA

FREEDOM FREEDOM ITCA 650ITCA 650 Placebo Placebo CompletedCompleted


P=0·0006 for superiority) and the REWIND trial showed a 12% relative risk reduction (HR=0.88, 95% CI, 0.79-0.99; P=0.026) in 3P-MACE. The PIONEER 6 trial16 investigated the CV safety of oral semaglutide 14 mg dose vs. placebo. The trial confi rmed that CV safety of the drug with a composite primary end point of CV death nonfatal MI and nonfatal stroke and was found non inferior with P<0.001 but in the test for superiority, the observed 21% reduction with semaglutide did not reach statistically signifi cance (P=0.17). However, the CV death was decreased by 51% (HR, 0.49; 95% CI, 0.27–0.92) and all-cause mortality by 49% (HR=0.1, 95% CI, 0.31–0.84). The result was inferior to SUSTAIN 6 trial, perhaps because

the duration of the trial was only 16 months and the number of patients enrolled were also smaller. Oral semaglutide failed to show reduction in stroke like the SUSTAIN 6 trials. It only showed a non-signifi cant decrease in stroke by 26% (HR=0.74, 95% CI, 0.35–1.57). In terms of Glycosylated haemoglobin (HbA1C) reduction oral semaglutide is better than other oral agents and has greater weight loss than any other oral agent. The drugs are under evaluation by FDA.

The MACE fi ndings in CV outcomes

trials with new antidiabetic medications are shown in Figure-1

(b) CV Death in CVOTsCV death was reduced only in two CV

outcome trials, EMPAREG OUTCOME and LEADER trial. The EMPAREG showed a statistically signifi cant reduction in CV death by 38% (HR=0.62; 95% CI=0.49–0.77; P<0.0001) and LEADER trial by 22% (HR=0.78; 95% CI=0.66–0.93; P=0.007). No other trials besides this have shown reduction in CV death. The eff ect on CV death in CV outcomes trials with new antidiabetic medications is shown in Figure 2.

(c) Nonfatal MI in CVOTsOnly one trial i.e. HARMONY outcome has shown a statistically signifi cant reduction in nonfatal MI by 25%, CI (0.61–0.90), P=0.003, all other trials have been negative in this respect. The eff ect on nonfatal MI in CV outcomes trials is shown in Figure 3.

Figure 1. MACE findings in CV outcomes trials with new antidiabetic medications

Figure 2. CV death in CV outcomes trials with new antidiabetic medications

Figure 3. Nonfatal MI in CV outcomes trials with new antidiabetic medications

Figure 4. Nonfatal stroke in CV outcomes trials with new antidiabetic medications

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(d) Nonfatal Strokes in CVOTsOnly one trial i.e. SUSTAIN-6 has shown a statistically signifi cant reduction in nonfatal stroke by 39% HR=0.61; 95% CI=0.38–0.99; P=0.04. The eff ect on nonfatal stroke in CV outcomes trials is shown in Figure 4.

HEART FAILURE HOSPITALIZATION IN CVOTsHospitalization due to heart failure (hHF) was an exploratory end point in all the trials. Saxagliptin in SAVOR-TIMI showed a statistically signifi cant 27% increase in the relative risk of HHF (HR=1.27; 95% CI = 1.07–1.51, P = 0.007). This hHF in SAVOR-TIMI was more pronounced within its fi rst-year of randomization. Similar trend of increase in hHF was also observed with alogliptin in EXAMINE trial (HR = 1.19; 95% CI = 0.89–1.58; P=0.24), although it was statistically insignifi cant. Intriguingly, the post-hoc analyses from both SAVOR-TIMI and EXAMINE found that certain subgroups had a signifi cant increase in hHF that included, patients with a history of heart failure and renal disease.17-19 Curiously, a post-hoc analysis of EXAMINE also suggested a signifi cant increase in hHF in patients without any history of heart failure (HR = 1.76, 95% CI = 1.07–2.90; P = 0.026).20 On the contrary, sitagliptin in TECOS found no signal of hHF. Further extensive analysis of TECOS also could not fi nd any signal of the heart failure, regardless of

time, subgroups and method of statistical analysis applied.21,22 Meanwhile, FDA put a warning on April 5, 2016 which states that “safety review has found that T2DM medicine containing saxagliptin and alogliptin may increase the risk of heart failure particularly in the patients who already have heart or kidney disease. It should be noted that hHF was neither a primary or secondary objective of these studies and thus, any sub-analysis could be subject to statistical error or may be a play of chance.

However, empaglifl ozin showed a robust reduction in hHF by 35% (HR=0.65, 95% CI=0.50–0.85; P=0.002) in EMPA-REG OUTCOME trial Interestingly, the CANVAS showed identical trend in reduction in HF hospitalization (HR=.67; 95% CI 0.52– 0.67). The DECLARE TIMI 58 trial showed a reduction of 27% (HR=0.73, 95% CI= 0.61–0.88; P=0.005)

LEADER had a non-signifi cant reduction in hHF, which sounds encouraging for liraglutide as earlier two trials conducted in patients with exclusive heart failure subjects, had disappointing results. While functional impact of GLP-1 for heart failure treatment (n=300) conducted in patient with advanced heart failure (median left ventricular ejection fraction of 25%) with liraglutide (FIGHT) had a non-signifi cant trend of increase in hHF (HR=1.30; 95% CI=0.89–1.88; P=0.17) and death

(HR=1.10; 95% CI=0.57–2.14; P=0.78). The eff ect of liraglutide on left ventricular function in chronic heart failure patients with and without T2D (LIVE) also had a signifi cant increase in serious adverse cardiac events when compared to placebo (12 vs. 3, respectively, P=0.04).23,24 Intriguingly, SUSTAIN-6 had a non-signifi cant increase in trend of hHF. Figure 5 depicts the hHF in all CVOTs.

ALL-CAUSE MORTALITY IN CVOTsEmpaglifl ozin reduced all-cause mortality by 32% (HR=0.68; 95% CI=0.57–0.82; P<0.0001), while LEADER reduced it by 15% (HR=0.85; 95% CI=0.74–0.97; P=0.02). This suggests that EMPA-REG had larger and robust reduction in all-cause mortality compared to LEADER (32% vs.15%, respectively) with persuasive P value (<0.0001 vs. 0.02, respectively).

The TECOS was neutral in all-cause mortality while SAVOR TIMI and SUSTAIN-6 showed a non-signifi cant increase in it. The EXAMINE, ELIXA AND CANVAS showed a non-signifi cant decrease in all-cause mortality. Figure 6 depicts the all-cause mortality across all CVOTs.

Hospitalization Due to Unstable Angina in CVOTsNo statistically signifi cant diff erence in hospitalization due to unstable angina was observed in all eight CVOTs as shown in Figure 7.

Figure 5. Heart failure hospitalization in CV outcomes trials with new antidiabetic medications

Figure 6. All-cause mortality in CV outcomes trials with new antidiabetic medications


Improved Renal OutcomesAll SGLT2i has shown improved renal outcomes in the 3 CV outcome trials i.e. EMPAREG OUTCOME, CANVAS and DECLARE TIMI 58 trials. The EMPAREG OUTCOME trial with empaglifl ozin showed a 39% reduction in new or worsening nephropathy (HR=0.61;CI 0.53–0.70), and decreased progression to macroalbuminuria by 38% (HR=0.62; CI 0.54 to 0.70), the CANVAS trial with canaglifl ozin showed decreased progression of albuminuria by 27% (HR= 0.73;CI=0.67–0.79 ), regression of albuminuria by 30% (HR=1.70; CI=0.51–1.91) and reduction in renal composite of 40% decrease eGFR, dialysis/transplant and renal death by 40%. The DECLARE TIMI 58 trial, the dapaglifl ozin showed 24% reduction in the renal composite endpoint (HR=0.76; CI=0.67–0.87). The GLP1 trials have also shown improved renal outcomes but to a lesser degree than SGLT2 inhibitors. The fi rst dedicated renal outcome trial with canaglifl ozin– CREDENCE was released in 2019 and showed very exciting results.

Credence Trial25:The trial was carried out with canaglifl ozin compared to placebo in patients of T2D and established chronic kidney disease (CKD). A total number 4401 patients were randomized in a 1:1

fashion to either canaglifl ozin 100 mg daily (n=2202) or matching placebo (n=2,199). The duration of follow-up was 2.62 years.

The inclusion criteria were T2D, age ≥30 years, HbA1c of ≥6.5% and ≤12%, CKD with estimated glomerular fi ltration rate (eGFR) 30 to <90, albuminuria (urinary albumin-to-creatinine ratio >300 to 5000 mg/g), stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) was given for ≥4 weeks before randomization.

The trial was stopped early due to overwhelming benefi t. The primary outcome, end-stage renal disease (ESRD), doubling of serum creatinine, renal or CV death, for canaglifl ozin vs. placebo, was 43.2 vs. 61.2 per 1,000 patient-years (P-Y) (P=0.00001). Doubling of serum creatinine: 20.7 vs. 33.8/1,000 P-Y (P<0.001) for canaglifl ozin vs. placebo, ESRD: 20.4 vs. 29.4/1,000 P-Y (P=0.002) for canaglifl ozin vs. placebo.

The results of this trial indicate that canaglifl ozin is superior to placebo in improving glycemic control and reducing adverse renal events among patients with T2DM and established CKD. The incidence of amputation was similar between two groups unlike the CANVAS trial.

Safety Analysis of CVOTsa. DPP–4 inhibitorsFrom the existing 5 trials, all DPP-4

inhibitors saxagliptin, alogliptin, sitagliptin, and linagliptin are CV neutral drugs form the point of view of atherosclerotic MACE but not from the point of hHF. Saxagliptin had undoubtedly shown increase in hHF in certain subgroups of patients. Alogliptin showed numerical increase in hHF. Sitagliptin in TECOS trial showed no signal of HF.

b. SGLT2 inhibitorsThe adverse events with SGLT2

inhibitors include mycotic genital infections, amputation with canaglifl ozin and rarely euglycemic diabetic ketoacidosis. Other less common side eff ects are volume depletion, urinary tract infections and rarely fournier’s gangrene.

GLP-1 RAThe most common side eff ects are

gastrointestinal symptoms mainly nausea. Other eff ects injection site reactions, headache and nasopharyngitis but they do not result in discontinuation of drug. The drug is usually well-tolerated and do not require strict monitoring.

CONCLUSIONThus, the new agents SGLT2i and GLA-1 RA have paved the way for a new therapeutic path for diabetes of optimizing glycaemic control, minimizing co-morbidities and improving cardiorenal outcomes coupled with minimal or no hypoglycaemia. Indeed, this is the beginning of a new revolution which we have desired for many years.

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Industry Diabetes Mellitus: Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes; 2008. Available from: http://www.fda.gov/downloads/Drugs/ Guidance Compliance Regulatory Information /Guidances /ucm071627.

2. European Medicines Agency. Guideline on Clinical Investigation of Medicinal Products in the Treatment or Prevention of Diabetes Mellitus. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.

3. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.

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Figure 7. Unstable angina hospitalization in cardiovascular outcome trials

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5. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.

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19. EMDAC Briefing Document Cardiovascular Outcomes Trial EXAMINE/NDAs 022271, 022426, & 203414 Nesina (Alogliptin), Oseni (Alogliptin/Pioglitazone), & Kazano (Alogliptin/ MetforminHCl); 2015. Available from: http://www.fda.gov/ downloads/Advisory Committees/Committees Meeting Materials/Drugs/Endocrinologic

and Metabolic Drugs Advisory Committee/UCM442062. Accessed on September, 2019.

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Electrocardiogram in Neonate Presenting with Heart Failure

ECG OF THE MONTH

SR MITTALKeywords congenital heart disease cyanosis echocardiography electrocardiography heart failure

Dr. SR Mittal is Head, Department of Cardiology at Mittal Hospital and Research Centre, Ajmer, Rajasthan

Stridor, cough and wheezing suggest possibility of respiratory cause. Skiagram of chest is helpful. Respiratory disease shows ground glass opacity, reticulogranular pattern, coarse nodular opacities or atelectasis in contrast to pulmonary oedema seen in cases of heart failure. Meconium stained liquor supports possibility of meconium aspiration syndrome. Prematurity and maternal diabetes predispose to idiopathic respiratory distress syndrome. Electrocardiogram is not very useful. Respiratory problems specially idiopathic respiratory distress syndrome and meconium aspiration syndrome are usually associated with pulmonary artery hypertension, right ventricular hypertrophy and failure. Murmur of additional patent ductus arteriosus may not be audible in preterm infants with respiratory distress.

(ii) Vascular Rings Th ese can present with respiratory distress, dyspnoea, stridor, cough and occasional wheezing and may simulate respiratory disease. Th ere are no diagnostic fi ndings on clinical examination, electrocardiogram and skiagram of chest. Echocardiography may raise suspicion. However, computerised tomography or magnetic resonance imaging are needed for confi rmation.

ABSTRACTClinical examination, correlated with surface electrocardiogram, helps in narrowing the diff erential diagnosis. Final diagnosis comes from echocardiography.

ELECTROCARDIOGRAM IN NEONATE PRESENTING WITH HEART FAILUREHeart failure in neonatal period is suspected by feeding diffi culty, perspiration during feeding, tachycardia (heart rate more than 140/min) and tachypnoea (respiratory rate more than 45/min). Clinical examination correlated with surface electrocardiogram can help in narrowing the diff erential diagnosis. Th is correlation helps in more focused echocardiographic evaluation for fi nal diagnosis. It is discussed under following heads.

(A) NORMAL EXAMINATION OF CARDIOVASCULAR SYSTEM 1. Electrocardiogram normal for ageExclude

(i) Non cardiac causes for respiratory distress(a) Acute idiopathic respiratory

distress syndrome.(b) Hyaline membrane disease. (c) Meconium aspiration syndrome.(d) Broncho-pulmonary dysplasia

and obstruction.(e) Hypoglycaemia.


2. Disproportionate tachycardia(1) Regular rhythm

(a) P wave seen before QRS Atrial tachycardia(b) No P wave Junctional tachycardia(c) Atrial fl utter waves Atrial fl utter

(2) Irregular rhythmAtrial fi brillation

Vulnerable neonatal myocardium may not respond adequately to tachycardia. Prolonged duration of tachycardia may per-se cause tachycardia-cardiomyopathy.

3. Bradycardia-complete atrio-ventricular blockUsually congenital complete atrio-

ventricular block is asymptomatic. However, heart with bradycardia may not respond adequately to increased circulatory demand, specially in the vulnerable neonatal period, to stress of metabolic acidosis, slow heart rate and stress of febrile illness.

Electrocardiogram-Ventricular rate less than 90/min, faster atrial rate, no relation between P and QRS, normal QRS axis and narrow QRS. T waves are usually normal but deep T wave inversion or coving may sometimes occur it right and mid precordial leads.

4. Right axis deviation peaked P waves, qR in lead V1, T wave upright in leads V1, V2 beyond 3 days of life. Right ventricular hypertrophy and right atrial enlargement (Figure 1). (a) Severe coarctation of aorta.(b) Complete interruption of aortic

arch.(c) Hypoplastic left heart syndrome. (d) Severe pulmonary vein stenosis.

Echocardiography is needed for diff erential diagnosis.

5. Right ventricular hypertrophy, right atrial enlargement + left atrial enlargement (broad and notched P wave in lead II) or prominent negative defl ection

of P wave in lead V1 (Figure 2).(a) Critical aortic stenosis.(b) Left ventricular infl ow

obstruction.i. Congenital mitral stenosis.ii. Supravalvular stenosing ring. iii. Cor triatriatum.

Echocardiography is needed for diff erential diagnosis.

6. Q with tall R, ST segment depression and T wave inversion in leads V5 and V6, broad and notched P wave in lead II and or prominent negative defl ection of P wave in lead V1-severe left ventricular hypertrophy with left atrial enlargement (Figure 3).

- Primary enodcardial fi broelastosis. Echocardiography is needed for

ECG OF THE MONTH

Figure 2. Electrocardiogram from a neonate showing right axis deviation and clockwise rotation suggestive of right ventricular enlargement, peaked P waves in lead II suggesting right atrial enlargement and negative P wave in lead V1 suggestive of left atrial enlargement.

Figure 1. Electrocardiogram from a neonate showing sinus tachycardia, right axis deviation, peaked P waves, prominent R in lead V1 and upright T waves in leads V1 and V2. Findings are suggestive of right ventricular hypertrophy and right atrial enlargement.


confi rmation.

(B) Short low pitched early diastolic murmur along left upper sternal border

Electrocardiogram- Right axis deviation, rsR’ in lead V1 without peaked P waves, T upright in right precordial leads-right ventricular volume overload.

Severe pulmonary regurgitation due to congenital absence of pulmonary

Figure 3. Electrocardiogram from a neonate showing prominent q wave, tall R wave, ST segment depression and T wave inversion in leads V5 and V6 suggestive of severe left ventricular hypertrophy. P wave is broad and notched in lead II and lead V5 and is negative in lead V1 suggesting left atrial enlargement.

valve.

Echocardiography is needed for confi rmation.

(C) Central cyanosis without any murmur

Electrocardiogram.

(1) Right axis deviation and right ventricular hypertrophy

(a) Tetralogy of fallot with pulmonary

atresia (Figure 4).(b) Transposition of great arteries with

no intercirculatory communication. Echocardiography is needed for

diff erentiation.

(2) Right axis deviation, right ventricular hypertrophy with tall peaked P waves suggestive of right atrial enlargement

- Total anomalous pulmonary venous connection with obstruction (mostly infradiaphragmatic).


(3) Prominent R wave with prominent positive T waves in leads V5 and V6 suggestive of left ventricular dominance.

(a) Normal QRS axis (+30 to +90°)

Pulmonary artesia with intact interventricular septum and signifi cant tricuspid regurgitation.


(b) Left axis deviation (Figure 5) Tricuspid atresia with pulmonary

atresia. Echocardiography is needed for

confi rmation.

(c) Right upper quadrant axis

Figure 4. Electrocardiogram from a cyanotic neonate showing right axis deviation, prominent R in lead V1 and sudden transition to RS configuration in lead V2.

Figure 5. Electrocardiogram from a cyanotic neonate showing mean frontal plane QRS axis of -30°. Leads V5 and V6 show prominent R wave with positive T waves suggestive of left ventricular dominance.


ECG OF THE MONTH

Critical pulmonary stenosis. Echocardiography is needed for

diff erentiation from pulmonary atresia.

(D) Central cyanosis with systolic murmur over left lower sternal border

Electrocardiogram –

Right axis deviation, tall P waves suggestive of right atrial enlargement, low voltage splintered QRS in lead V1, no right ventricular hypertrophy (Figure 6). - Ebstein anomaly. Echocardiography is needed for

confi rmation.

(E) Central cyanosis with ejection systolic murmur over left second

intercostal space Electrocardiogram – - Tall P waves, right ventricular

hypertrophy with (a) Right axis deviation (Figure 7) - Severe pulmonary stenosis with intact

interventricular septum. (b) Left axis deviation Severe pulmonary stenosis with

dysplastic pulmonary valve (Noonan syndrome).

Figure 6. Electrocardiogram from a cyanotic neonate showing right axis deviation, peaked P waves (suggestive of right atrial enlarge-ment), low voltage splintered QRS in lead V1 suggestive of Ebstein anomaly.

Figure 7. Electrocardiogram from a neonate showing right axis

deviation, peaked P wave in lead II (suggestive of right atrial

enlargement) and prominent R wave in lead V1 (suggestive of

severe right ventricular hypertrophy).


Answers: (1) A,C, (2) C, (3) D, (4) A, (5) A, (6) A, (7) A,B, (8)D, (9)C, (10) A, (11) C, (12)A, (13)A, (14)D, (15)C.

MCQsElectrocardiogram in neonate presenting with heart failure

Q1. What could be the causes of respiratory distress in a neonate?

(A) Hyaline membrane disease(B) Methymoglobinemia (C) Hypoglycaemia (D) Right aortic arch

Q2. What could be the cause of heart failure with irregular rhythm in a neonate ?

(A) Idiopathic respiratory distress syndrome

(B) Atrial fl utter(C) Atrial fi brillation (D) All

Q3. In a new born upright T waves in leads V1 and V2 suggests

(A) Severe right ventricular hypertrophy

(B) Severe left ventricular hypertrophy (C) Biventricular enlargement (D) None

Q4. In a new born T waves in leads V1 and V2 become inverted in

(A) First week of life (B) Aft er one month(C) Aft er three months (D) Aft er one year

Q5. In a new born, upright T waves in leads V1 and V2 aft er seven days suggests

(A) Right ventricular hypertrophy (B) Left ventricular hypertrophy (C) Biventricular hypertrophy (D) None

Q6. In a neonate with heart failure, qR in V1, peaked P waves and upright T waves in leads V1 and V2 beyond 3 days of life suggest possibility of

(A) Hypoplastic left heart syndrome(B) Congenital mitral stenosis (C) Severe aortic stenosis (D) Severe pulmonary valve stenosis

Q7. In a neonate with heart failure, qR in lead V1, upright T wave in leads V1, V2 beyond three days of

life with bilateral enlargement suggests possibility of

(A) Congenital mitral stenosis (B) Stenosing ring above mitral valve (C) Hypoplastic left heart syndrome (D) Severe pulmonary vein stenosis

Q8. In a neonate with heart failure, no murmur, without cyanosis or murmur, normal QRS axis, left ventricular hypertrophy with ST segment depression and T wave inversion in leads V5 and V6, suggests possibility of

(A) Critical aortic stenosis (B) Complete interruption of aortic

arch (C) Pulmonary atresia (D) Primary endocardial fi broelastasin

Q9. A neonate with heart failure, no cyanosis, short low pitched early diastolic murmur along left upper sternal, right axis deviation, rsR’ in lead V1 without peaked P wave suggests possibility of

(A) Large secundum ASD(B) Large primum ASD(C) Congenital absence of pulmonary

valve(D) LV-RA shunt

Q10. In a neonate with central cyanosis and heart failure, presence of right axis deviation and right ventricular hypertrophy without tall P waves suggests possibility of

(A) Tetralogy of Fallot(B) Pulmonary atresia (C) Ebstein anomaly (D) None

Q11. In a neonate with central cyanosis and heart failure, right axis deviation, rsR’ in V1 and tall peaked P waves suggests possibility of

(A) Tetralogy of Fallot(B) Tricuspid regurgitation (C) Total anomalous pulmonary

venous connection with obstruction

(D) Tricuspid atresia

Q12. In a neonate with central cyanosis and heart failure, normal QRS axis with prominent R wave with prominent positive T waves in leads V5 and V6 suggests possibility of

(A) Pulmonary atresia (B) Tricuspid atresia (C) Critical pulmonary stenosis (D) Critical aortic stenosis

Q13. In a neonate with central cyanosis and heart failure, left axis deviation with prominent R and prominent positive T waves in leads V5 and V6 suggests possibility of

(A) Tricuspid atresia (B) Pulmonary atresia (C) Aortic atresia (D) None

Q14. In a neonate with central cyanosis and heart failure, left axis deviation, right ventricular hypertrophy and tall P waves suggests possibility of

(A) Tricuspid atresia(B) Pulmonary atresia (C) Severe pulmonary stenosis (D) Noonan syndrome with severe

pulmonary stenosis

Q15. In a neonate with central cyanosis, systolic murmur over left lower sternal border, right axis deviation, tall P waves, low voltage splintered QRS in lead V1 but no right ventricular hypertrophy suggests possibility of

(A) Severe valvular pulmonary stenosis

(B) Tricuspid atresia (C) Ebstein anomaly (D) Tetralogy of Fallot


PICTORIAL CME

MONIKA MAHESHWARI

Dr. Monika Maheshwari is Professor, Jawahar Lal Nehru Medical College, Ajmer, Rajasthan

Intra-Atrial Conduction Delay Simulating Double ‘P’ Waves in Electrocardiogram

Atrial conduction disorders are frequent in patients with mitral valve disease, hypertrophic cardiomyopathies, and hypertension. Th e resultant electrophysiological perturbations leads to higher risk of paroxysmal or persistent atrial tachyarrhythmias, either atrial fi brillation, atrial fl utter or other forms

of atrial tachycardias. Such intra- and interatrial conduction abnormalities delays and disrupt (spatial and temporal dispersion) electrical activation, and promote initiation and perpetuation of reentrant circuits. Preventive therapeutic interventions induce variable, sometimes paradoxical eff ects as with the proarrhythmic eff ect of class I antiarrhythmic drugs. Similarly, atrial pacing may promote proarrhythmias or an antiarrhythmic eff ect according to the pacing site(s) and mode. Multisite atrial pacing has been tried to correct, as much as possible, abnormal activation induced by spontaneous intra- or interatrial conduction disorders or by single site atrial pacing. Atrial electrical resynchronization can also be used to correct mechanical abnormalities like left heart AV dyssynchrony resulting from intraatrial conduction delays. Early and aggressive treatment of hypertension, diastolic dysfunction, and obesity can also prevent intraatrial conduction delay.1

We recently encountered one such case wherein ECG showed double P waves (P1 & P2) due to marked intra-atrial conduction delay. Patient was referred to higher centre for electrophysiological study and management.

REFERENCE1. Weijs B, De Vos CB, . Tieleman RG, Pisters R , Cheriex

EC , Prins MH et al Clinical and echocardiographic correlates of intra-atrial conduction delay .EP Europace 2011:13 ;1681–1687.

Figure 1. Electrocardiogram lead II showing double P waves (P1,P2) .

Figure 2. Electrocardiogram lead III showing double P waves (P1,P2)

Figure 3. Electrocardiogram lead aVF showing double P waves (P1,P2)

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