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Disfunción miocárdica en los transtornos del ritmo cardíaco Baltasar Sánchez González Médico Adjunto Unidad de Cuidados Intensivos martes 11 de enero de 2011

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Page 1: Disfunción miocárdica en los transtornos del ritmo … · Disfunción miocárdica en los transtornos del ritmo cardíaco Baltasar Sánchez González Médico Adjunto Unidad de Cuidados

Disfunción miocárdica en los transtornos del ritmo

cardíaco

Baltasar Sánchez González Médico Adjunto Unidad de Cuidados Intensivos

martes 11 de enero de 2011

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Introducción

•Es la disfunción ventricular con dilatación secundaria y clínica de insuficiencia cardíaca debida a taquicardias supraventriculares o ventriculares persistentes.

•Puede ser pura o impura.

•La duración y frecuencia de la arritmia marca su severidad.

•Se caracteriza por la recuperación, incluso total, tras su cese.

•No siempre está presente la arritmia en el diagnóstico.

•Gossage AM, Braxton Hicks JA. On auricular fibrillation. QJM. 1913;6:435–440.

•Brill IC. Auricular fibrillation with congestive failure and no other evidence of organic heart disease. Am Heart J. 1937;13:175–182.

•WhippleGH,SheffieldLT,WoodmanEG,etal.Reversiblecongestive heart failure due to chronic rapid stimulation of the normal heart. Proc N Engl Cardiovasc Soc. 1962;20:39–40.

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TACHYCARDIA-INDUCED CARDIOMYOPATHY

Table I.

Conditions Resulting in Tachycardia-InducedCardiomyopathy

Supraventricular causes3–5,13

Atrial fibrillationAtrial flutterAtrial tachycardiaAVRTAVNRT

Permanent form of junctionalReciprocating tachycardia (PJRT)Atrial pacing at high rates

Ventricular causes9–12,14

Premature ventricular complexes (PVCs)Right ventricular outflow tract VTIdiopathic left ventricular tachycardiaBundle-branch reentry VTMyocarditisVentricular pacing at high rates

Extracardiac causes6,7

ThyrotoxicosisGlucagonoma

during systole reduces transmural strain of themuscle fibers, and the recoil in early diastole en-hances filling. Abnormal LV torsion contributesto inefficient LV contraction.23 Disturbed elasticproperties of the LV result in a stiffer ventri-cle, which expends energy inefficiently leadingto worsening LV diastolic function. The underly-ing mechanisms are abnormalities in cardiac struc-tural proteins, extracellular matrix (ECM), and pro-teoglycans.24 Changes in ECM are detailed in aseparate section. Hemodynamically, these changestranslate into depressed ejection fraction, elevatedfilling pressures, elevated pulmonary capillarywedge pressures, and atrial dilatation.

Reversibility of the cardiomyopathy followingtreatment of the SVT or VT is an important char-acteristic of tachycardia-induced cardiomyopathy.However, reversal may not occur or may not becomplete in all cases. Most of the available liter-ature on improvement in LV function relates tothe grossly observed LV contractility. Microscopicabnormalities may reverse more slowly or not atall. Tomita et al.25 reported a case of ectopic atrialtachycardia resulting in dilated cardiomyopathy.The atrial tachycardia was treated by RFA. Oneyear after RFA, although cardiac function returnedto normal, histology revealed areas of myocar-dial fibrosis. In most cases, LV function has beenobserved to recover after the termination of thecausative tachyarrhythmia. Spinale et al.26 mea-sured LV function and mass in dogs at weekly in-

tervals during tachycardia resulting in cardiomy-opathy and during a 1-month recovery period. LVend-diastolic volume and LV wall stress increasedand LV ejection fraction decreased during pacing.After the cessation of pacing, LV ejection fractionimproved within the first week. One week afterrecovery, a 26% increase in LV mass and persis-tent LV chamber dilation were observed with re-duced myocyte percent and myocyte shorteningvelocity. Thus, the termination of the tachycardiaafter onset of the cardiomyopathy resulted in per-sistent LV chamber dilation and abnormal myocytecontractile function. They concluded that the im-proved LV pump function with early recovery fromtachycardia-induced cardiomyopathy was medi-ated by LV hypertrophy and subsequent reduc-tion in LV wall stress rather than normalizationof LV geometry and myocyte contractile function.Yamamoto et al.27 studied LV function and massin a modified cardiomyopathy model in the dogin which right ventricular pacing rates were grad-ually increased over 38 days. They observed re-duced ejection fraction on the last day of pacing,whereas LV end-diastolic diameter index (a ratio ofLV end-diastolic diameter to body weight) and LVmass index (a ratio of LV mass to body weight) wereincreased. Cardiac filling pressures were elevated;LV diastolic dysfunction was set in and coronaryblood flow was impaired. After 4 weeks of recov-ery, LV end-diastolic diameter index and LV massindex remained increased. LV diastolic function,coronary blood flow, and cardiac filling pressuresreturned to normal. LV diastolic dysfunction hasalso been noted to persist 4 weeks after the termi-nation of pacing.28 This may be a result of the para-doxical LV hypertrophy that has been observedafter cessation of pacing.29 These studies suggestthat the above-mentioned mechanisms responsi-ble for the development of tachycardia-inducedcardiomyopathy might continue unabated duringthe recovery phase. Genetic influences may playa role as evidenced by increased mRNA expres-sion. This might also be due to the developmentof a sort of cardiac memory that turns on the com-pensatory switch for LV hypertrophy and cannotbe turned off by mere restoration of normal sinusrhythm.

Indeed, more processes seem to be at workthan have been deciphered so far. Ventricular re-modeling is known to occur during the develop-ment and resolution of tachycardia-induced car-diomyopathy. It is important to understand itsmechanism in order to achieve a better under-standing of the observed changes in ventricularstructure and function. It also provides a win-dow on the temporal profile of this condition.Changes in the ventricular myocardium occur veryearly after the onset of the tachycardia but do not

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Myocardial ischemia may impair systolic function inthe presence of a supraphysiologic heart rate, reducedsystemic arterial pressure, or increased ventricular dia-stolic pressure. Morphologic and functional abnormali-ties of the coronary vasculature have been demonstrated,including abnormal subendocardial and subepicardialblood flow ratios and impaired coronary flow reserve(36,37). However, there is no convincing evidence to sug-gest a primary role for myocardial ischemia in the devel-opment of tachycardia-induced cardiomyopathy.

Abnormal calcium handling may be responsible fortachycardia-induced cardiomyopathy. Extensive abnor-malities in calcium channel activity and calcium trans-port in the sarcoplasmic reticulum appear as early as 24hours after the initiation of rapid pacing, and may persistfor up to 4 weeks after discontinuation of pacing (32,38).The severity of calcium cycling abnormalities correlateswith the degree of ventricular dysfunction (32). In thismanner, calcium availability to myocytes may be de-creased, with subsequent reduction in contractility.

CLINICAL FEATURES AND DIAGNOSTICCONSIDERATIONS

Tachycardia-induced cardiomyopathy occurs in associa-tion with supraventricular tachyarrhythmias, such asatrial fibrillation (10,13,16,39 – 44), atrial flutter (20,21),automatic atrial tachycardia (17–19,45,46), atrioven-tricular nodal re-entry tachycardia (22), automatic atrio-ventricular junctional tachycardia (23), and accessorypathway tachycardia (24), as well as with ventriculartachycardia (25,26,47–50). In animal models, ventriculartachyarrhythmias cause a more profound depressionin left ventricular function than do supraventriculararrhythmias (4). In humans, tachycardia-induced car-diomyopathy due to ventricular arrhythmias has beennoted in association with right ventricular outflow tracttachycardia (26,47,49,50) and idiopathic left ventriculartachycardia (48,51). Right ventricular outflow tracttachycardia, which originates from an automatic focus inan otherwise normal heart, has a characteristic electro-cardiographic appearance (left bundle branch block con-tour in V1 and an inferior axis in the frontal plane). Idio-

pathic left ventricular tachycardia also occurs in appar-ently normal hearts; it originates near the apex of the leftventricle and electrocardiographically has a right bundlebranch block morphology with a superior axis.

Tachycardia-induced cardiomyopathy can occur atany age. It has been documented in fetuses (24 to 33weeks in gestation) with persistent supraventriculartachycardia (52), with resolution occurring following in-trauterine cardioversion. It also occurs in infants andchildren (18,53–55), adolescents (48,50), and adults(21,26,39,46). The incidence of tachycardia-induced car-diomyopathy is unknown; most reports have been smallretrospective series or case studies involving mostly pa-tients with atrial fibrillation. In patients with atrial fibril-lation, approximately 25% to 50% of those with left ven-tricular dysfunction in selected studies have some degreeof tachycardia-induced cardiomyopathy (Table). Pre-sumed risk factors include the type, rate, and duration oftachyarrhythmia, and underlying heart disease.

Clinicians should suspect tachycardia-induced cardio-myopathy when left ventricular systolic dysfunction ac-companies persistent tachycardia. The ventricular ratethat causes tachycardia-induced cardiomyopathy has notbeen determined, although any prolonged heart rategreater than 100 beats per minute may be important. Ev-idence of previously normal systolic function, especiallyin the absence of an intervening events such as an acutemyocardial infarction, is particularly suggestive of thisdisorder. More commonly, the diagnosis is made afterobserving improvement in ventricular function follow-ing rate or rhythm control.

Noninvasive imaging techniques, such as echocardiog-raphy or radionuclide ventriculography, usually show leftand right ventricular dilatation and systolic dysfunction.Tachycardia-induced cardiomyopathy may occur in as-sociation with other forms of heart disease and thus is notexcluded by evidence of other forms of structural heartdisease, particularly because tachycardia may aggravatean already reduced systolic function (56). The degree ofleft ventricular systolic dysfunction may be dispropor-tionate to the severity of coronary atherosclerosis in pa-tients with this syndrome.

Much of the clinical information about the effects of

Table. Frequency of Tachycardia-Induced Cardiomyopathy in Patients with Atrial Fibrillation or Atrial Flutter Referred For Atrio-ventricular Node Ablation or Modification

First Author(Reference)

Type ofArrhythmia Ejection Fraction

Total Numberof Patients

Number of Patients and Percentagewith Tachycardia-Induced

Cardiomyopathy

Luchsinger (21) Atrial flutter !50% 11 6 (55)Redfield (56) Atrial fibrillation !45% 63 16 (25)Edner (39) Atrial fibrillation !50% 14 11 (78)Rodriguez (16) Atrial fibrillation !50% 12 9 (75)

Tachycardia-Induced Cardiomyopathy/Umana et al

52 January 2003 THE AMERICAN JOURNAL OF MEDICINE! Volume 114

Myocardial ischemia may impair systolic function inthe presence of a supraphysiologic heart rate, reducedsystemic arterial pressure, or increased ventricular dia-stolic pressure. Morphologic and functional abnormali-ties of the coronary vasculature have been demonstrated,including abnormal subendocardial and subepicardialblood flow ratios and impaired coronary flow reserve(36,37). However, there is no convincing evidence to sug-gest a primary role for myocardial ischemia in the devel-opment of tachycardia-induced cardiomyopathy.

Abnormal calcium handling may be responsible fortachycardia-induced cardiomyopathy. Extensive abnor-malities in calcium channel activity and calcium trans-port in the sarcoplasmic reticulum appear as early as 24hours after the initiation of rapid pacing, and may persistfor up to 4 weeks after discontinuation of pacing (32,38).The severity of calcium cycling abnormalities correlateswith the degree of ventricular dysfunction (32). In thismanner, calcium availability to myocytes may be de-creased, with subsequent reduction in contractility.

CLINICAL FEATURES AND DIAGNOSTICCONSIDERATIONS

Tachycardia-induced cardiomyopathy occurs in associa-tion with supraventricular tachyarrhythmias, such asatrial fibrillation (10,13,16,39 – 44), atrial flutter (20,21),automatic atrial tachycardia (17–19,45,46), atrioven-tricular nodal re-entry tachycardia (22), automatic atrio-ventricular junctional tachycardia (23), and accessorypathway tachycardia (24), as well as with ventriculartachycardia (25,26,47–50). In animal models, ventriculartachyarrhythmias cause a more profound depressionin left ventricular function than do supraventriculararrhythmias (4). In humans, tachycardia-induced car-diomyopathy due to ventricular arrhythmias has beennoted in association with right ventricular outflow tracttachycardia (26,47,49,50) and idiopathic left ventriculartachycardia (48,51). Right ventricular outflow tracttachycardia, which originates from an automatic focus inan otherwise normal heart, has a characteristic electro-cardiographic appearance (left bundle branch block con-tour in V1 and an inferior axis in the frontal plane). Idio-

pathic left ventricular tachycardia also occurs in appar-ently normal hearts; it originates near the apex of the leftventricle and electrocardiographically has a right bundlebranch block morphology with a superior axis.

Tachycardia-induced cardiomyopathy can occur atany age. It has been documented in fetuses (24 to 33weeks in gestation) with persistent supraventriculartachycardia (52), with resolution occurring following in-trauterine cardioversion. It also occurs in infants andchildren (18,53–55), adolescents (48,50), and adults(21,26,39,46). The incidence of tachycardia-induced car-diomyopathy is unknown; most reports have been smallretrospective series or case studies involving mostly pa-tients with atrial fibrillation. In patients with atrial fibril-lation, approximately 25% to 50% of those with left ven-tricular dysfunction in selected studies have some degreeof tachycardia-induced cardiomyopathy (Table). Pre-sumed risk factors include the type, rate, and duration oftachyarrhythmia, and underlying heart disease.

Clinicians should suspect tachycardia-induced cardio-myopathy when left ventricular systolic dysfunction ac-companies persistent tachycardia. The ventricular ratethat causes tachycardia-induced cardiomyopathy has notbeen determined, although any prolonged heart rategreater than 100 beats per minute may be important. Ev-idence of previously normal systolic function, especiallyin the absence of an intervening events such as an acutemyocardial infarction, is particularly suggestive of thisdisorder. More commonly, the diagnosis is made afterobserving improvement in ventricular function follow-ing rate or rhythm control.

Noninvasive imaging techniques, such as echocardiog-raphy or radionuclide ventriculography, usually show leftand right ventricular dilatation and systolic dysfunction.Tachycardia-induced cardiomyopathy may occur in as-sociation with other forms of heart disease and thus is notexcluded by evidence of other forms of structural heartdisease, particularly because tachycardia may aggravatean already reduced systolic function (56). The degree ofleft ventricular systolic dysfunction may be dispropor-tionate to the severity of coronary atherosclerosis in pa-tients with this syndrome.

Much of the clinical information about the effects of

Table. Frequency of Tachycardia-Induced Cardiomyopathy in Patients with Atrial Fibrillation or Atrial Flutter Referred For Atrio-ventricular Node Ablation or Modification

First Author(Reference)

Type ofArrhythmia Ejection Fraction

Total Numberof Patients

Number of Patients and Percentagewith Tachycardia-Induced

Cardiomyopathy

Luchsinger (21) Atrial flutter !50% 11 6 (55)Redfield (56) Atrial fibrillation !45% 63 16 (25)Edner (39) Atrial fibrillation !50% 14 11 (78)Rodriguez (16) Atrial fibrillation !50% 12 9 (75)

Tachycardia-Induced Cardiomyopathy/Umana et al

52 January 2003 THE AMERICAN JOURNAL OF MEDICINE! Volume 114

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articulosdemedicina.com/activacion-cardiaca

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Alteraciones en la geometría y función ventricular

KHASNIS, ET AL.

resolve rapidly after its termination. The improvedhemodynamics occurs at the expense of increasedwall thickness, increased LV mass, and a probablesecondary chronic background ongoing supply-demand mismatch of myocardial blood flow (MBF)and oxygen demand. This sets the stage for dis-ease progression at the microscopic level whileimprovement seems apparent at the clinical level.Complete resolution over time suggests that rever-sal at the microscopic level may occur after a lagperiod. There is scant literature looking at the mi-croscopic and molecular changes in the recoveryphase of tachycardia-induced cardiomyopathy.

Another interesting question to ask is thatwhat is the long-term effect of tachycardia-inducedcardiomyopathy with regard to future develop-ment of heart failure. It is known that a propor-tion of women with gestational diabetes go onto develop Type 2 diabetes mellitus. Whether asimilar phenomenon (i.e., increased recurrenceof heart failure in later life) develops in patientswith tachycardia-induced cardiomyopathy is notknown. Long-term prospective follow-up of a co-hort of these patients may provide the answer.

Disturbances in Structure and Function of theCardiomyocyte

One of the responses of the ventricular my-ocardium to chronic stimulation is increased ven-tricular mass. Ventricular enlargement and heartfailure have been associated with reversion ofthe adult ventricular cardiomyocytes to the stagewhere they can divide and proliferate. Jovanovicet al.30 using laser confocal microscopy to im-age cross-sections of intact myocardium noted in-creased number of cells in both longitudinal andtransversal sections. Treatment with enalapril re-versed these changes. This study suggests thatthe observed hyperplasia in response to chronicstimulation is a possible mechanism of cham-ber enlargement seen in this condition. The ben-eficial response to enalapril also suggests thepotential for reversibility of such changes andthe need for early intervention. ACE inhibitorscould thus potentially hasten the recovery ofventricular myocardial dysfunction after the elim-ination of the offending arrhythmia. Other mecha-nisms proposed include changes in capillary struc-ture, distribution, and function, and increasedcapillary-myocyte distance in the left ventricu-lar myocardium. These changes may impair MBFand limit oxygen delivery, thus accelerating my-ocardial injury and worsening LV dysfunction.31

Myocardial blood flow is also significantly re-duced and coronary vascular resistance increasedin all stages of tachycardia-induced cardiomyopa-thy.32 This reduced coronary reserve could lead to

chronic ventricular dysfunction and possibly ir-reversible changes resulting in the clinically andgrossly observed deterioration of LV function. Re-duced myocardial blood flow has been observedin the hibernating myocardium following onsetof ischemia. Restoration of blood flow allows sal-vage of this hibernating myocardium. A similarelement of hibernation may exist in tachycardia-induced cardiomyopathy partly explaining the ob-served improvement after cessation of the tachy-cardia. Changes in myocardial structural andcontractile proteins play a role in the LV mod-eling and observed hemodynamic changes. Myo-globin deficiency has also been observed in ex-perimental canine models of pacing-induced heartfailure.33

Table II.

Changes in Myocardial Structure and Function Observedwith Tachycardia-Induced Cardiomyopathy

Ventricular cardiomyopathyGross changes

Dilated ventricleReduced LV contractilityElevated LV end-diastolic pressureMitral regurgitation (2! to annular dilatation)Abnormal LV torsionLV diastolic dysfunction

Microscopic changesMyocyte lengtheningDisruption of basement membrane—sarcolemmal junction

Myocyte hyperplasiaReduced myocardial capillaries andreduced blood flow

Increased capillary-myocyte distanceImpaired coronary reserveExtracellular matrix changesMyocardial fibrosis

Molecular changesDecreased !-receptor expressionAltered !-receptor transductionReduced adenylate cyclase activityReduced myocardial protein contentReduced Gs/increased Gi subunit densityIncreased Gi mRNA contentAbnormal excitation-contraction couplingT-tubule depletionReduced tubulin mRNAAbnormal titin levelsApoptosisMyoglobin deficiency

Continued

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Alteraciones en la estructura y función del cardiomiocito

KHASNIS, ET AL.

resolve rapidly after its termination. The improvedhemodynamics occurs at the expense of increasedwall thickness, increased LV mass, and a probablesecondary chronic background ongoing supply-demand mismatch of myocardial blood flow (MBF)and oxygen demand. This sets the stage for dis-ease progression at the microscopic level whileimprovement seems apparent at the clinical level.Complete resolution over time suggests that rever-sal at the microscopic level may occur after a lagperiod. There is scant literature looking at the mi-croscopic and molecular changes in the recoveryphase of tachycardia-induced cardiomyopathy.

Another interesting question to ask is thatwhat is the long-term effect of tachycardia-inducedcardiomyopathy with regard to future develop-ment of heart failure. It is known that a propor-tion of women with gestational diabetes go onto develop Type 2 diabetes mellitus. Whether asimilar phenomenon (i.e., increased recurrenceof heart failure in later life) develops in patientswith tachycardia-induced cardiomyopathy is notknown. Long-term prospective follow-up of a co-hort of these patients may provide the answer.

Disturbances in Structure and Function of theCardiomyocyte

One of the responses of the ventricular my-ocardium to chronic stimulation is increased ven-tricular mass. Ventricular enlargement and heartfailure have been associated with reversion ofthe adult ventricular cardiomyocytes to the stagewhere they can divide and proliferate. Jovanovicet al.30 using laser confocal microscopy to im-age cross-sections of intact myocardium noted in-creased number of cells in both longitudinal andtransversal sections. Treatment with enalapril re-versed these changes. This study suggests thatthe observed hyperplasia in response to chronicstimulation is a possible mechanism of cham-ber enlargement seen in this condition. The ben-eficial response to enalapril also suggests thepotential for reversibility of such changes andthe need for early intervention. ACE inhibitorscould thus potentially hasten the recovery ofventricular myocardial dysfunction after the elim-ination of the offending arrhythmia. Other mecha-nisms proposed include changes in capillary struc-ture, distribution, and function, and increasedcapillary-myocyte distance in the left ventricu-lar myocardium. These changes may impair MBFand limit oxygen delivery, thus accelerating my-ocardial injury and worsening LV dysfunction.31

Myocardial blood flow is also significantly re-duced and coronary vascular resistance increasedin all stages of tachycardia-induced cardiomyopa-thy.32 This reduced coronary reserve could lead to

chronic ventricular dysfunction and possibly ir-reversible changes resulting in the clinically andgrossly observed deterioration of LV function. Re-duced myocardial blood flow has been observedin the hibernating myocardium following onsetof ischemia. Restoration of blood flow allows sal-vage of this hibernating myocardium. A similarelement of hibernation may exist in tachycardia-induced cardiomyopathy partly explaining the ob-served improvement after cessation of the tachy-cardia. Changes in myocardial structural andcontractile proteins play a role in the LV mod-eling and observed hemodynamic changes. Myo-globin deficiency has also been observed in ex-perimental canine models of pacing-induced heartfailure.33

Table II.

Changes in Myocardial Structure and Function Observedwith Tachycardia-Induced Cardiomyopathy

Ventricular cardiomyopathyGross changes

Dilated ventricleReduced LV contractilityElevated LV end-diastolic pressureMitral regurgitation (2! to annular dilatation)Abnormal LV torsionLV diastolic dysfunction

Microscopic changesMyocyte lengtheningDisruption of basement membrane—sarcolemmal junction

Myocyte hyperplasiaReduced myocardial capillaries andreduced blood flow

Increased capillary-myocyte distanceImpaired coronary reserveExtracellular matrix changesMyocardial fibrosis

Molecular changesDecreased !-receptor expressionAltered !-receptor transductionReduced adenylate cyclase activityReduced myocardial protein contentReduced Gs/increased Gi subunit densityIncreased Gi mRNA contentAbnormal excitation-contraction couplingT-tubule depletionReduced tubulin mRNAAbnormal titin levelsApoptosisMyoglobin deficiency

Continued

712 July 2005 PACE, Vol. 28

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Alteraciones en las reacciones neurohormonales

TACHYCARDIA-INDUCED CARDIOMYOPATHY

Table II.

Changes in Myocardial Structure and Function Observedwith Tachycardia-Induced Cardiomyopathy

Neurohumoral changesElevated endothelin levels(reduced pulmonary metabolism)

Reduced cardiac norepinephrine uptakeANP and BNP levels elevatedReduced cGMP expressionAbnormal sodium handlingIncreased nitric oxide levelsActivation of renin-angiotensin system

Electrical changesAbnormal calcium channel functionAbnormal repolarization

Prolonged QTc intervalReduced spatial dispersion of repolarization

Mechano (stretch)-sensitive channel dysfunctionOther changes

Oxidative stressInflammation

Atrial cardiomyopathyAtrial dilatationContractile dysfunctionAbnormal calcium channel functionNa+/Ca2+-exchanger upregulationIntracellular Ca2+ loading

Abnormalities in Signaling and NeurohumoralPathways

The neurohumoral changes seen withtachycardia-induced cardiomyopathy are similarto those seen in other causes of heart failure. Thereis activation of the renin-angiotensin-aldosteroneaxis with abnormalities in sodium handling andelevated levels of atrial natriuretic peptide (ANP).However, the vasodilator, natriuretic, and renin-lowering effects of ANP are blunted in the caninemodel of tachycardia-induced cardiomyopathy.This is due to reduced cyclic GMP expressionin response to the ANP.34 Abnormal sodiumhandling has a key role in these neurohumoralchanges. Atrial tissue levels of ANP are reduced,whereas serum ANP levels are elevated in exper-imental models. Brain natriuretic peptide (BNP)levels are also elevated, though to a lesser extentthan ANP.35 It has also been shown that the ANPrelease is a consequence of elevated heart rate,elevated right atrial pressure, and increased atrialvolume. ANP release is reduced as heart failureadvances, probably due to depletion of ANPstores.36,37

As seen in other causes of heart failure, itis possible that elevated angiotensin II and al-

dosterone levels could trigger increased myocar-dial fibrosis. Myocardial fibrosis has been noted inthe presence and absence of hypertrophy.38 It isalso known that the activation of the angiotensin-aldosterone axis is both local and systemic. Thiscould also explain how early intervention withACE inhibitors or angiotensin receptor blockershalts and potentially reverses this pathologic pro-cess.

Reduced baroreflex sensitivity has also beenobserved in this condition. It is more likely a re-sult of functional alteration than structural, as itappears to rapidly recover during the recoveryphase.39 In experimental models, elevated nore-pinephrine, renin, and aldosterone levels havebeen observed. Reduced cardiac norepinephrineuptake-1 carrier site density has also been re-ported.40 All these compensatory changes are pos-sible targets for intervention. Enalapril has beenshown to slow the progress of the cardiomyopa-thy and also reverse some of the changes.41 An-giotensin II receptor blockers may also have a rolein this condition.42 Elevated endothelin-1 (ET-1)levels have also been reported and hasten the pro-gression of tachycardia-induced cardiomyopathy.ET-1 produced mitochondrial changes character-ized by reduced respiratory complexes III and Vof the electron transport chain. Using ET-1A, re-ceptor blockade reverses this change.43 The bene-ficial effect of long-term selective ET type A recep-tor blockade has been reported previously.44 Theelevated ET-1 levels in patients with heart failureresult from the reduced pulmonary clearance ofET-1. In a canine model of pacing-induced car-diomyopathy, Dupuis et al.45 have demonstratedreductions in ET-1 extraction in the pulmonaryvascular bed due to a reduced binding affinity tothe ET-A and ET-B receptors. Needless to say thatall these various molecules and receptors couldbecome targets for therapeutic intervention in thefuture.

Abnormalities in Excitation-ContractionCoupling

Electrophysiological abnormalities of the car-diomyocytes accompany the structural changesin the myocardium in patients with tachycardia-induced cardiomyopathy. This can increase thepropensity to dangerous ventricular arrhythmias.L-type Ca2+ channel dysfunction plays an im-portant role in the observed electrical abnormal-ities.46 He et al.47 examined the density of theT-tubule system and L-type Ca2+ channels in acanine model of tachycardia-induced cardiomy-opathy. The failing cardiomyocytes demonstrateda significantly lesser regularity of the T-tubulesystem and a relative loss of T-tubules. Detailedstudies revealed unchanged calcium ion channel

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Alteraciones eléctricas

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Alteraciones en la matriz extracelular

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TACHYCARDIA-INDUCED CARDIOMYOPATHY

Table II.

Changes in Myocardial Structure and Function Observedwith Tachycardia-Induced Cardiomyopathy

Neurohumoral changesElevated endothelin levels(reduced pulmonary metabolism)

Reduced cardiac norepinephrine uptakeANP and BNP levels elevatedReduced cGMP expressionAbnormal sodium handlingIncreased nitric oxide levelsActivation of renin-angiotensin system

Electrical changesAbnormal calcium channel functionAbnormal repolarization

Prolonged QTc intervalReduced spatial dispersion of repolarization

Mechano (stretch)-sensitive channel dysfunctionOther changes

Oxidative stressInflammation

Atrial cardiomyopathyAtrial dilatationContractile dysfunctionAbnormal calcium channel functionNa+/Ca2+-exchanger upregulationIntracellular Ca2+ loading

Abnormalities in Signaling and NeurohumoralPathways

The neurohumoral changes seen withtachycardia-induced cardiomyopathy are similarto those seen in other causes of heart failure. Thereis activation of the renin-angiotensin-aldosteroneaxis with abnormalities in sodium handling andelevated levels of atrial natriuretic peptide (ANP).However, the vasodilator, natriuretic, and renin-lowering effects of ANP are blunted in the caninemodel of tachycardia-induced cardiomyopathy.This is due to reduced cyclic GMP expressionin response to the ANP.34 Abnormal sodiumhandling has a key role in these neurohumoralchanges. Atrial tissue levels of ANP are reduced,whereas serum ANP levels are elevated in exper-imental models. Brain natriuretic peptide (BNP)levels are also elevated, though to a lesser extentthan ANP.35 It has also been shown that the ANPrelease is a consequence of elevated heart rate,elevated right atrial pressure, and increased atrialvolume. ANP release is reduced as heart failureadvances, probably due to depletion of ANPstores.36,37

As seen in other causes of heart failure, itis possible that elevated angiotensin II and al-

dosterone levels could trigger increased myocar-dial fibrosis. Myocardial fibrosis has been noted inthe presence and absence of hypertrophy.38 It isalso known that the activation of the angiotensin-aldosterone axis is both local and systemic. Thiscould also explain how early intervention withACE inhibitors or angiotensin receptor blockershalts and potentially reverses this pathologic pro-cess.

Reduced baroreflex sensitivity has also beenobserved in this condition. It is more likely a re-sult of functional alteration than structural, as itappears to rapidly recover during the recoveryphase.39 In experimental models, elevated nore-pinephrine, renin, and aldosterone levels havebeen observed. Reduced cardiac norepinephrineuptake-1 carrier site density has also been re-ported.40 All these compensatory changes are pos-sible targets for intervention. Enalapril has beenshown to slow the progress of the cardiomyopa-thy and also reverse some of the changes.41 An-giotensin II receptor blockers may also have a rolein this condition.42 Elevated endothelin-1 (ET-1)levels have also been reported and hasten the pro-gression of tachycardia-induced cardiomyopathy.ET-1 produced mitochondrial changes character-ized by reduced respiratory complexes III and Vof the electron transport chain. Using ET-1A, re-ceptor blockade reverses this change.43 The bene-ficial effect of long-term selective ET type A recep-tor blockade has been reported previously.44 Theelevated ET-1 levels in patients with heart failureresult from the reduced pulmonary clearance ofET-1. In a canine model of pacing-induced car-diomyopathy, Dupuis et al.45 have demonstratedreductions in ET-1 extraction in the pulmonaryvascular bed due to a reduced binding affinity tothe ET-A and ET-B receptors. Needless to say thatall these various molecules and receptors couldbecome targets for therapeutic intervention in thefuture.

Abnormalities in Excitation-ContractionCoupling

Electrophysiological abnormalities of the car-diomyocytes accompany the structural changesin the myocardium in patients with tachycardia-induced cardiomyopathy. This can increase thepropensity to dangerous ventricular arrhythmias.L-type Ca2+ channel dysfunction plays an im-portant role in the observed electrical abnormal-ities.46 He et al.47 examined the density of theT-tubule system and L-type Ca2+ channels in acanine model of tachycardia-induced cardiomy-opathy. The failing cardiomyocytes demonstrateda significantly lesser regularity of the T-tubulesystem and a relative loss of T-tubules. Detailedstudies revealed unchanged calcium ion channel

PACE, Vol. 28 July 2005 713

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Alteración en el acoplamiento excitación-contracción

KHASNIS, ET AL.

resolve rapidly after its termination. The improvedhemodynamics occurs at the expense of increasedwall thickness, increased LV mass, and a probablesecondary chronic background ongoing supply-demand mismatch of myocardial blood flow (MBF)and oxygen demand. This sets the stage for dis-ease progression at the microscopic level whileimprovement seems apparent at the clinical level.Complete resolution over time suggests that rever-sal at the microscopic level may occur after a lagperiod. There is scant literature looking at the mi-croscopic and molecular changes in the recoveryphase of tachycardia-induced cardiomyopathy.

Another interesting question to ask is thatwhat is the long-term effect of tachycardia-inducedcardiomyopathy with regard to future develop-ment of heart failure. It is known that a propor-tion of women with gestational diabetes go onto develop Type 2 diabetes mellitus. Whether asimilar phenomenon (i.e., increased recurrenceof heart failure in later life) develops in patientswith tachycardia-induced cardiomyopathy is notknown. Long-term prospective follow-up of a co-hort of these patients may provide the answer.

Disturbances in Structure and Function of theCardiomyocyte

One of the responses of the ventricular my-ocardium to chronic stimulation is increased ven-tricular mass. Ventricular enlargement and heartfailure have been associated with reversion ofthe adult ventricular cardiomyocytes to the stagewhere they can divide and proliferate. Jovanovicet al.30 using laser confocal microscopy to im-age cross-sections of intact myocardium noted in-creased number of cells in both longitudinal andtransversal sections. Treatment with enalapril re-versed these changes. This study suggests thatthe observed hyperplasia in response to chronicstimulation is a possible mechanism of cham-ber enlargement seen in this condition. The ben-eficial response to enalapril also suggests thepotential for reversibility of such changes andthe need for early intervention. ACE inhibitorscould thus potentially hasten the recovery ofventricular myocardial dysfunction after the elim-ination of the offending arrhythmia. Other mecha-nisms proposed include changes in capillary struc-ture, distribution, and function, and increasedcapillary-myocyte distance in the left ventricu-lar myocardium. These changes may impair MBFand limit oxygen delivery, thus accelerating my-ocardial injury and worsening LV dysfunction.31

Myocardial blood flow is also significantly re-duced and coronary vascular resistance increasedin all stages of tachycardia-induced cardiomyopa-thy.32 This reduced coronary reserve could lead to

chronic ventricular dysfunction and possibly ir-reversible changes resulting in the clinically andgrossly observed deterioration of LV function. Re-duced myocardial blood flow has been observedin the hibernating myocardium following onsetof ischemia. Restoration of blood flow allows sal-vage of this hibernating myocardium. A similarelement of hibernation may exist in tachycardia-induced cardiomyopathy partly explaining the ob-served improvement after cessation of the tachy-cardia. Changes in myocardial structural andcontractile proteins play a role in the LV mod-eling and observed hemodynamic changes. Myo-globin deficiency has also been observed in ex-perimental canine models of pacing-induced heartfailure.33

Table II.

Changes in Myocardial Structure and Function Observedwith Tachycardia-Induced Cardiomyopathy

Ventricular cardiomyopathyGross changes

Dilated ventricleReduced LV contractilityElevated LV end-diastolic pressureMitral regurgitation (2! to annular dilatation)Abnormal LV torsionLV diastolic dysfunction

Microscopic changesMyocyte lengtheningDisruption of basement membrane—sarcolemmal junction

Myocyte hyperplasiaReduced myocardial capillaries andreduced blood flow

Increased capillary-myocyte distanceImpaired coronary reserveExtracellular matrix changesMyocardial fibrosis

Molecular changesDecreased !-receptor expressionAltered !-receptor transductionReduced adenylate cyclase activityReduced myocardial protein contentReduced Gs/increased Gi subunit densityIncreased Gi mRNA contentAbnormal excitation-contraction couplingT-tubule depletionReduced tubulin mRNAAbnormal titin levelsApoptosisMyoglobin deficiency

Continued

712 July 2005 PACE, Vol. 28

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Evaluación clínica y tratamiento

•Sospechar en cualquier paciente con disfunción ventricular en el contexto de una arritmia supra o ventricular aunque no siempre está presente la arritmia.

•En ausencia de otras causas de fallo cardíaco, la recuperación miocárdica confirma el diagnóstico.

•Tratamiento:

Precoz

Control de FVM

iECAs, ARA II, Carvedilol

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Conclusión

•Causa reversible de fallo cardíaco

•Diagnóstico precoz necesario aunque requiere una alta sospecha

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Muchas Gracias por su atención

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