DIABETIC HEART DISEASE

WHO Definition of Diabetes Mellitus Diabetes mellitus is a state of chronic hyperglycaemia which may result from many environmental and genetic factors, often acting jointly WHO Expert Committee on Diabetes Mellitus 1980

Re-definition of Diabetes Diabetes is a state of premature cardiovascular death which is associated with chronic hyperglycaemia and may also be associated with blindness and renal failure Miles Fisher, Dublin 1996

Diagnostic CriteriaA diagnosis of diabetes must be confirmed on a subsequent day by any of the above tests in the absence of unequivocal hyperglycemia. FPG is preferred because of ease of administration, convenience, acceptability to patients, and lower cost. Fasting is defined as at least 8 hours of no caloric intake. 2-hour testing involves an equivalent of 75 g anhydrous glucose dissolved in water.

Diabetes ClassificationType 1 DMPatient profileMost diagnosed < 30 y/o; 20% diagnosed after age 30.Caucasian race or population with substantial white genetic admixture (including African Americans)Significant weight loss despite polyphagia (severe catabolic state)Thin body habitusPresence of other autoimmune diseasesKetoacidosis prone

Type 2 Diabetes90-95% of casesCombination of insulin resistance and inadequate compensatory insulin secretion.Insulin resistanceObesity (particularly abdominal/visceral)Habitual inactivityKetoacidosis less common but can occur with severe stressors or new onset DM.Insulin secretory defectBeta-cells incapable of compensating for insulin resistance.Progressive loss of beta-cell function with time.Strong genetic predisposition Nearly 100% concordance among monozygotic twins (compared to 50% in autoimmune type 1 DM)Genetics are more complex (polygenic)

PREVALENCE OF TYPE 1 DIABETES IN THE US 1 million people

Caucasians constitute the majority of type 1 diabetics

Most prominent during childhood

PREVALENCE OF TYPE 2 DIABETES IN THE US Most common type of diabetes among all ethnic groups

17 million patients with known diabetes

45% of children and teens with new diagnoses

Diabetes in the WorldmillionsYear2010Reference: Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Diabetes Care. 2004; 27(5): 1047-1053.

Cardiovascular Disease and Diabetes

Pathophysiologyof Type 2 Diabetes andInsulin Resistance

Natural History of Type 2 Diabetes

Development of Type 2 Diabetes

Hyperglycemia in Type 2 Diabetes Results From Three Major Metabolic Defects

Insulin Resistance: Associated Conditions

Complications of Diabetes

DiabetesAmputationBlindnessRenal failureNerve damageCardiovascularcomplications

Cardiovascular Complications

Heart AttackStrokeCoronary artery diseasePeripheral vascular disease

Diabetes and Cardiovascular DiseaseMacrovascular disease including CAD and other vascular events (CVA, PVD) is responsible for nearly 80% of all diabetes mortality

75% of all hospitalizations in diabetes patients is due to cardiovascular events

A third of individuals have CVD by the time they are diagnosed with diabetes

Beaser R, et al.

Diabetes and heart abnormalitiesCoronary heart diseaseSpecific heart disease of diabetesDiabetic autonomic neuropathy

Heart Disease RiskAge: men over 45 and women over 55Family history of heart diseaseLittle or no daily exerciseDyslipidemiaelevated LDL (smaller, denser)reduced HDLelevated triglyceridesHypertensionSmokingPre-diabetesHyperglycemia /DiabetesMetabolic syndrome

Hypertension and diabetesHypertension worsens diabetes by promoting insulin resistance

Diabetes and hypertension doubles CVD risk

Aggressive hypertension management reducer CVD RISK

Risk of CVD and HyperglycemiaHyperglycemia promotes vascular dysfuction, dyslipidemia and hypercoagulability

Meta- anaysis faund relation between increased CVD risk and plasma glucose level

Increase risk began to appear ay HbA1c of 0,2 % but ability to decrease risk with tight control has been harder to prove

Metabolic Syndrome(insulin resistance syndrome)Any two of the following

Blood pressure: >130/85 mm HgFBG >100 mg/dL; two-hour >140 mg/dL HDL

Myocardial infarctionMortality twice the non-diabeticIncreased silent or painless infarction Delay in receiving treatment Increased congestive cardiac failure, cardiogenic shock, rupture, re-infarction

Coronary artery diseaseMost commom vascular complication of diabetesAge adjusted prevalence of CAD in white Americans with type 2 DM is 2 4 times that of non diabeticAngina, MI and sudden death are at 2 6 times as common in patients with type 2 diabetes

Mortality DataRelative risk of age specific death from MI among diabetic patients during the first year of dyalysis ia 89 times higher than that of the general population

CAD accounts for 40% of all death in renal transplant patients

Post myocardial infarctionFirst month after MI, mortality 14-26 % higher in diabetic men and 21-39% higher in diabetic womenIn first 28 days, diabetes in diseases mortality by 58 % in men and by 160 % in women5 year mortality may be as high as 50 % more than twice that non diabetic

10 year mortality may be 60 % in males with diabetes and as high as 80% in women with diabetesIncrease in mortality and major morbidity, including congestive heart failure and reinfarction

Diabetic cardiomyopathy

CHF development is 2.4-5.1 times higher in diabetics than controls Even in pt with DM2 without significant coronary arterial disease myocardial histopathological changes are noted (Regan et al.)there are abn in LV myocardial contractilityThus the diabetic milieu appears to result in abn in myocardial structure and function Result is diabetic cardiomyopathy

Rubler 1972Described postmortem findings in 4 diabetic adults with CHF no coronary artery disease no valvular cardiac disease no hypertensive cardiac disease no alcoholic cardiac disease - Postulated to represent either a result of diabetic microangiopathy or a direct consequence of the abnormal myocardial metabolism in DM

Interstitial FibrosisRegan et al.autopsy of 11 diabetic patients, with no discernable CAD. Suggested that filamentous PAS positive glycoprotiens accumulated early in DM (? coinciding with abnormalities in LVDD even at this stage.)Later accumulation of collagen as a consistent backgroundSimilar to changes in diabetic glomeruli

Small Vessel diseaseBlumenthal et al.Series of 116 diabetic compared to 105 controlsEndothelial proliferation and PAS (periodic acid schiff) material in 50% of diabetics compared to 21% of non diabeticsRegan et al12 diabetics underwent angiograms and studies of myocardial fn. During atrial pacing induced tachycardia no lactate production in coronary sinus vv bld samplingSmall vessel disease prominence in cardiomyopathy questioned.

Metabolic Syndrome(insulin resistance syndrome)Any two of the following

Blood pressure: >130/85 mm HgFBG >100 mg/dL; two-hour >140 mg/dL HDL

Treatment RecommendationsA1c

Lifestyle ConsiderationsPhysical activityWeight reduction and maintain healthy weightMeal plan designed to lower blood glucose and alter lipidsRisk reduction (smoking cessation)Stress managementAlcohol in moderationTake medication (if prescribed)

Treatment RecommendationsA1c

How should we protect the diabetic heart?Treat the diabetes (primary prevention)Treat the cardiovascular risk factorsOther preventative measuresTreat the heart disease

Miles Fisher Dublin 1996

Problems:Biochemical and aetiological, no mention of symptoms or physical effectsEffect of diabetes rather than cause.CVD is the primary cause of death among 55% of patients with diabetes compared with 31% of deaths in the general population.Ischemic heart disease (IHD) accounts for about 40% of deaths in patients with diabetes. The risk of mortality due to diseases of the heart is 2 to 4 times higher among patients with diabetes than in persons without diabetes.Data from a 10-year period show a 37% increase in the number of hospitalizations that listed major CVD as the primary diagnosis and diabetes as a secondary diagnosis.

Geiss LS, et al. In Diabetes in America, 2nd ed. NIH Publication No. 95-1468.1995:243,558.Centers for Disease Control and Prevention. National Vital Statistics Reports. 2000;48:5.

Insulin resistance is a primary defect in type 2 diabetes. As reported in a recent study by Haffner and colleagues, 92% of patients with type 2 diabetes have insulin resistance. It can be defined as an impaired response to the physiological effects of insulin, including those on glucose, lipid, and protein metabolism, and the effects on vascular endothelial function. Haffner SM, et al. Diabetes Care. 1999;22:562-568.Consensus Development Conference of the American Diabetes Association. Diabetes Care. 1998;21:310-314.

Before the manifestation of the metabolic defects that lead to type 2 diabetes, fasting and postprandial insulin levels are similar and constant. In the majority of patients in whom type 2 diabetes develops, increasing insulin resistance leads to compensatory increases in circulating insulin, which prevents an increase in glucose levels.As time progresses, the insulin resistance reaches a peak and stabilizes, while the compensatory increase in insulin continues to prevent fasting glucose levels from becoming abnormal. However, at some point, either because of early beta-cell dysfunction or because of a natural limit of beta-cell capacity, challenge of this delicate balance with a glucose load may demonstrate that, although fasting glucose levels remain normal, postprandial glucose levels become abnormal as a limitation in insulin response is reached. Following the onset of beta-cell dysfunction, insulin levels can no longer keep up in overcoming the insulin resistance, and fasting and postprandial glucose levels increase progressively over time.

Insulin resistance and impaired beta-cell function are primary defects that occur early in the course of development of type 2 diabetes. Insulin resistance leads to an obligatory hyperinsulinemia in order to maintain normal glucose tolerance. In most cases of type 2 diabetes, beta-cell dysfunction develops subsequent to the development of insulin resistance, and it is not until such beta-cell dysfunction develops that any abnormality in glucose tolerance is seen.The condition that results is termed impaired glucose tolerance (IGT). In some cases beta-cell dysfunction may develop in the absence of early insulin resistance. However, exposure of tissues to hyperglycemia in the face of beta-cell dysfunction increases resistance to the effects of insulin whether or not insulin resistance was present to begin with. Ultimately, type 2 diabetes is the result of worsening beta-cell function, either in the most common situation of chronic pre-existing insulin resistance or, in the less common scenario of decreased beta-cell function without pre-existing insulin resistance.

Saltiel A, Olefsky JM. Diabetes. 1996;45:1661-1669.Three major metabolic defects contribute to hyperglycemia in patients with type 2 diabetes: increased hepatic glucose production, impaired pancreatic insulin secretion, and peripheral tissue insulin resistance.After eating a meal or ingesting glucose, insulin is secreted, hepatic glucose output is suppressed, and insulin-dependent glucose uptake by peripheral tissues is stimulated. In type 2 diabetes, insulin resistance and impaired insulin secretion inhibit normal suppression of hepatic glucose output. As a consequence, the liver continues to release glucose into the circulation. Moreover, peripheral insulin resistance coupled with insufficient insulin results in decreased uptake of glucose by insulin-dependent target tissues, notably skeletal muscle and adipose tissue. These mechanisms contribute to postprandial hyperglycemia in type 2 diabetes.In type 2 diabetes, increased hepatic glucose production is the primary factor responsible for the fasting hyperglycemia. Moreover, in patients with type 2 diabetes, fasting blood glucose levels correlate strongly with rates of hepatic glucose output. In the setting of peripheral insulin resistance, insulin-mediated glucose uptake cannot accommodate the increased hepatic glucose output and rise in fasting glucose levels.

Kruszynska YT, et al. J Invest Med. 1996;44:413-428.Henry RR. Ann Intern Med. 1996;124:97-103.

Central obesity is associated with insulin resistance and elevated levels of FFAs. As illustrated in slide 23, FFAs can reduce insulin-mediated glucose disposal under experimental conditions. However, it remains to be determined whether increased FFAs cause insulin resistance or vice versa in obese subjects. In either case, insulin resistance and elevated FFAs stimulate hepatic apolipoprotein B secretion and increase hepatic lipase activity. This enzyme catalyzes the removal of lipids from LDL and HDL, which makes them smaller and more dense. In turn, these effects lead to hypertriglyceridemia, production of small, dense LDL particles, and reduced HDL2-cholesterol levels. This dyslipidemic pattern, which has been termed the atherogenic lipoprotein phenotype, is also characteristic of that found in type 2 diabetes.

Brunzell JD, et al. Diabetes Care. 1999;22(suppl 3):C10-C13.

In addition to type 2 diabetes, insulin resistance is associated with the development of a broad spectrum of clinical conditions. These include hypertension, atherosclerosis, dyslipidemia, decreased fibrinolytic activity, impaired glucose tolerance, acanthosis nigricans, hyperuricemia, polycystic ovary disease, and obesity.

Adapted from Consensus Development Conference of theAmerican Diabetes Association. Diabetes Care. 1998;21:310-314.Complications of DiabetesMicrovascular and macrovascular complications constitute the major burden of diabetes on both the patient and the health care systemDiabetes is the leading cause of renal failure, blindness in adults, and amputationsSubstantial improvements in glycemic control can greatly reduce the risk of microvascular complicationsMacrovascular disease (myocardial infarction, stroke, and peripheral vascular disease) is the major cause of death in patients with diabetes

http://www.cdc.gov/diabetes/pubs/factsheet.htm#contents. Accessed 2/10/04.Complications of DiabetesMicrovascular and macrovascular complications constitute the major burden of diabetes on both the patient and the health care systemDiabetes is the leading cause of renal failure, blindness in adults, and amputationsSubstantial improvements in glycemic control can greatly reduce the risk of microvascular complicationsMacrovascular disease (myocardial infarction, stroke, and peripheral vascular disease) is the major cause of death in patients with diabetes

http://www.cdc.gov/diabetes/pubs/factsheet.htm#contents. Accessed 2/10/04.