Ventricular arrhythmias in heart failure: Mechanisms and prevention

idity worldwide. 
• Although the incidence of cardiovascular disease has decreased in the 
last decade, the incidence and prevalence of HF continues to rise. 
• It is estimated that 8 to 10 million people worldwide are living with chronic 
HF, with about 400,000 to 500,000 new cases documented yearly. 
• Am J Public Health 1994, 84:20–28. Circulation 1985, 72: 681–685. Am Heart J 1997, 133:703–712. Heart 
Fail Rev 2002, 7:255–260. 1/9/2018 Pham huu Van, HRS of HCM city 2 
Mechanisms contributing to the development of ventricular arrhythmias 
in chronic heart failure 
• Structural and hemodynamic abnormalities 
• Myocardial scar and reentry 
• Hypertrophy 
• Chamber stretch 
• Bundle branch reentry 
• Ischemia and subendocardial ischemia 
• Metabolic abnormalities 
• Neurohormonal activation and enhanced catecholamines 
• Enhanced sympathetic activation and nerve sprouting 
• Electrolyte abnormalities 
• Pharmacologic agents 
• Electrophysiologic changes 
• Action potential prolongation 
• Altered calcium handling and the role of the sodium-calcium exchanger 
• Altered potassium currents 
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Underlying arrhythmias 
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Structural and Hemodynamic Abnormalities 
• Myocardial scar 
• Possibly the best understood relationship between mechanisms of arrhythmias 
and structural changes is represented by post– MI myopathy and reentry. 
• In these Pts, focal areas of scar develop, resulting in a heterogeneous 
environment of infarcted and noninfarcted myocardium in close proximity. 
• In addition, areas of scar are often interlaced with surviving myocardium, leading 
to intact muscular channels of slowed conduction that further contribute to 
complex anisotropy. 
• Circulation 1993. Circulation 1985. 
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Chamber hypertrophy and stretch 
• In the failing ventricle, a variety of compensatory mechanisms are constantly 
competing to improve CO, but these mechanisms also may contribute to the 
arrhythmogenic milieu seen in HF. 
• Hypertrophy has been described as a contributor to a variety of proarrhythmic EP 
changes. 
• Some of these include reduced cell-to-cell coupling, depressed membrane 
potentials, subendocardial ischemia, and a variety of ion current alterations. 
• Other mechanical contributors to arrhythmias include increased preload and 
afterload, which are commonly seen in the failing heart and have been reported to 
alter the action potential by shortening repolarization. 
• Circulation 1993.. Cardiovasc Res 1996. Circulation 1992. Cardiovasc Res 1996. 
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Bundle branch reentry 
• This macro-reentrant circuit involves the His-Purkinje system and 
ventricular septum and most commonly demonstrates a typical LBBB 
morphology, most common in HF, specifically in those with nonischemic 
dilated cardiomyopathy. 
• Although this form of VT does not make up a large proportion of the 
tachycardias seen in HF, it is particularly important because RFA has a 
high success rate in curing this arrhythmia. 
• Braunwald E: Heart Disease: A Textbook of Cardiovascular Medicine; 2001. Zipes DP: Cardiac Electrophysiology: From Cell to Bedside. 2004. 
Josephson ME: Clinical Cardiac Electrophysiology. 2002. 
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Ischemia 
• Ischemia is also responsible for arrhythmias in its acute stages. 
• In animal models of HF, the incidence of ischemia appears to be significantly 
greater than in those without HF. 
• The mechanisms surrounding 1A arrhythmias are related to tissue hypoxia, 
acidosis, and extracellular potassium accumulation resulting in the slowing of 
conduction and the heterogeneous recovery of excitability. 
• The mechanisms surrounding 1B arrhythmias are less well understood. 
• They appear to be related to cell-to-cell uncoupling. 
• Am J Physiol 1991. J Cardiovasc Electrophysiol 2001. Circulation 1995. J Cardiovasc Electrophysiol 2001. Circ Res 
1991. J Cardiovasc Electrophysiol 2001. Circ Res 1991. 
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Metabolic Abnormalities 
• Neurohormonal activation 
• The activation of the sympathetic nervous system and the renin-angiotensin 
system are the predominant compensatory mechanisms responsible for a 
variety of proarrhythmic changes. 
• Their activation is reflected by an increase in circulating levels of norepinephrine 
and tissue angiotensin II. 
• This increase has been thought to play a very important role in the prognosis of 
HF and has been postulated to be partially responsible for the beneficial effects 
of beta-blockers and ACE inhibitors on SD. 
• Circulation 1992. Circulation 1993. Circulation 1993.. N Engl J Med 1991. Circ Res 2000. Circulation 2000 
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Electrolyte abnormalities 
• Hyperkalemia is a common abnormality. 
• ACE inhibitors, angiotensin-receptor blockers, and aldosterone 
antagonists all may contribute to it. 
• One proarrhythmic feature of hyperkalemia is slowing of AP upstroke; 
in severe cases it may cause atrioventricular block or 
 lifethreatening VT or VF. 
• Circulation 1992, 85:70–76. 
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Electrolyte abnormalities 
• Hypokalemia is also common and may be secondary to increases in 
activity of the renin-angiotensin system or diuretic therapy. 
• The result is increased automaticity within Purkinje fibers, shortening of 
the action potential plateau phase, and increased rapid repolarization. 
• These changes may contribute to early afterdepolarizations and put Pts at 
risk of polymorphic VT and VF. 
• Hypomagnesemia is another common abnormality seen in Pts with CHF. 
• The exact mechanisms are much less clear. 
• Circulation 1992. 
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The Contribution of Pharmacologic Agents 
• In addition to the direct effect of neurohormonal activation on 
arrhythmogenesis, the pharmacotherapy directed at modifying this system may 
often contribute to the proarrhythmic milieu. 
• For example, diuretic therapy, ACE inhibitors, and aldosterone antagonists often 
create electrolyte disturbances that significantly contribute to 
arrhythmogenesis and may enhance the proarrhythmic effect of other 
medications. 
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Demonstration of the AP prolongation of ventricular myocytes in the setting of congestive HF. The effect of tetrodotoxin (TTX 1.5 mol/L) is shown both in normal 
donor hearts (A) and failing human hearts (B). 
Note the amount of AP prolongation and the dramatic shortening following exposure to TTX in patients with congestive HF. 
This suggests that action potential prolongation was due in part to enhanced late sodium currents. Early afterdepolarizations (EADs) are also demonstrated in the 
HF group. 
• Circulation 1998, 98:2545–2552. 
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Electrophysiologic Changes in Heart Failure 
• Action potential prolongation 
• Alteration in the AP in HF has been known for some time. In a human 
study of isolated myocytes from the failing ventricle, they demonstrated 
marked prolongation of the AP. 
• The AP prolongation and its relationship to early afterdepolarizations led 
investigators to reexamine individual ion currents and their changes in HF. 
• Circ Res 1993. Circulation 1998. 
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Electrophysiologic Changes in Heart Failure 
• Calcium handling 
• Many electrophysiologic changes are present in HF. 
• None appears to be as intricately involved in arrhythmogenesis as calcium 
homeostasis. 
• Normally, excitationcontraction coupling is the result of calcium release from the 
sarcoplasmic reticulum (SR), triggered by calcium entry into the cytoplasm 
during AP. 
• Because of its role as a modifier of both excitation and myocyte contraction, 
alterations of calcium handling are proarrhythmic from a variety of different 
sources. 
• Cardiovascular Research 2000. Circulation 2001.. Circ Res 2000.. 
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The roles of the sodium calcium exchanger (NaCaX), inward rectifier current (IK1), beta-adrenergic receptor (-AR), and sarcoplasmic reticulum calcium 
(SR Ca) load in contractile dysfunction and arrhythmogenesis in heart failure. AP—action potential; ATP—adenosine triphosphate; DADs—delayed 
afterdepolarizations; Em—membrane potential; ICa—calcium current; Iti—transient inward current; PKA—protein kinase A; PLB—phospholaban; RyR—
ryanodine receptor. 
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Conclusions 
• VA and SCD continue to be an important source of morbidity and mortality for Pts with 
HF. 
• Only through an understanding of the mechanisms responsible for these arrhythmias 
will we learn how to successfully prevent such events. 
• The relationship between neurohormonal activation and catecholamine excess makes 
beta-adrenergic blockade and ACE inhibition the cornerstone of present therapy for 
HF. 
• With better models of HF and advancing technology, we will undoubtedly see the ion 
channel heterogeneities become a more focused part of HF therapy and arrhythmia 
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Conclusion (conti.) 
• Although ICDs have effectively demonstrated their ability to reduce the 
incidence of sudden death, they do little to prevent the triggers for these 
malignant arrhythmias. 
• We cannot rely on ICDs to prevent all sudden death; we must work 
towards more progressive preventive therapy. 
• Through continued research into the mechanisms of these arrhythmias, 
we may significantly advance our knowledge and improve the quality of 
life for our Pts. 
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THANK YOU FOR YOUR ATTENTION ! 
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