Spironolactone Improves Arrhythmogenic Substrate in HF
Spironolactone Improves Arrhythmogenic Substrate in HF
This study presents important new information on the protective effect of MR antagonism on attenuating development of an arrhythmogenic substrate in heart failure susceptible to initiation and maintenance of ventricular tachyarrhythmias. Effects of spironolactone on ventricular electrical activation, fibrosis and inflammatory cytokine gene expression were evaluated in a heart failure model induced by RVP. The major new findings include that spironolactone prevents (1) local ventricular electrical activation delays attenuating electrogram widening during premature stimulation and electrogram fractionation; (2) ventricular interstitial fibrosis; and (3) myocardial gene overexpression of profibrotic inflammatory mediators (IL-6, TNF-α). Beneficial effects of spironolactone on electrical, ultrastructural and molecular remodeling in heart failure were independent of improvement in hemodynamics as they occurred without affecting LV size or systolic function. These results indicate that endogenous aldosterone and MR activation have an important role in the process of adverse ventricular electrical and ultrastructural remodeling in heart failure. Attenuation of cardiac inflammation and fibrosis may be an important mechanism contributing to salutary effects of MR antagonism in prevention of arrhythmic death in heart failure.
In an earlier study from our laboratory, delayed myocardial activation in response to closely coupled, premature extrastimuli was shown to be a critical component of the arrhythmogenic substrate in this tachypacing model of systolic heart failure. Using paced electrogram fractionation analysis, it was shown that increased ventricular electrogram duration in response to premature stimuli (ΔPED) is a robust predictor of sustained ventricular arrhythmia inducibility in heart failure. This study confirms that ventricular electrograms are fractionated and their durations prolong with premature excitation in heart failure. This study extends these observations by demonstrating a similar degree of electrogram widening in response to premature stimuli at coupling intervals of 2 and 20 milliseconds greater than refractory period (ΔPED2, ΔPED20). This suggests that functional delays in myocardial activation during premature excitation close to refractoriness reflect slowing of conduction (due to decrease in propagation velocity and/or increase in path length) rather than prolongation in refractoriness demonstrated in this heart failure model. In response to premature excitation, the duration of the vulnerable period (i.e., the time window of premature stimulus coupling intervals that initiate a reentrant wavefront) is directly proportional to the excitable region length or area and inversely proportional to the conditioning wave velocity and the excitability gradient at the premature stimulation site. Therefore any mechanism that slows propagation is proarrhythmic and extends the period of vulnerability (i.e., increases the probability that a premature stimulus will fall within the vulnerable period and initiate a reentrant arrhythmia). Changes in local paced electrogram duration (ΔPED) in response to premature excitation may reflect the arrhythmogenic capacity of local myocardium to generate abnormal patterns of myocardial activation indicative of slowed conduction.Notably slowing of conduction may be promoted via multiple contributing mechanisms (including reduced sodium channel conductance or availability, enhanced dispersion of refractoriness, altered connexins, myocyte disarray and/or increased fibrosis, etc.).
This study further extends our prior observations and suggests their mechanistic basis by linking delayed myocardial activation (ΔPED) to an increase in interstitial myocardial fibrosis and inflammatory gene expression in heart failure. Consistent with earlier studies of this model, the heart failure ventricles were characterized by an increase in interstitial fibrosis that globally affected both ventricles with mean fibrous tissue content comprising about 6% and 4% of LV and RV myocardium, respectively. Increased fibrosis was demonstrated across the transmural walls and affected ventricular base and apex. This degree of ventricular fibrosis is similar to that seen in hearts from patients with dilated, nonischemic cardiomyopathy who underwent cardiac transplantation for severe heart failure. Increased amounts of fibrotic tissue in the heart are strongly correlated with an increased incidence of arrhythmias and sudden cardiac death. Pathological myocardial fibrosis promotes ventricular arrhythmogenesis through multiple mechanisms that enhance a substrate's vulnerability. Fibrosis impairs cell-to-cell coupling causing inhomogeneities and asymmetries in conduction. Fibrosis slows wavefront propagation and increases tissue vulnerability to wave break and spiral wave formation. The morphological changes associated with fibrotic remodeling result in a discontinuous and branching substrate associated with disturbed transverse or zig-zag propagation, multiphasic, fractionated electrograms and regions of delayed activation that create the potential for unidirection block and reentrant proarrhythmia.
As demonstrated in this study, the heart undergoes profound remodeling in response to abnormal, sustained stress. In heart failure, MR activation plays an important role in pathological fibrotic remodeling. Aldosterone production is enhanced and accumulates in the interstitium in failing hearts. Aldosterone stimulates excessive accumulation of collagen and is implicated in myocardial and perivascular fibrosis independent of changes in wall stress or hypertension. Aldosterone-induced fibrosis primarily is a consequence of the reparative response to vascular and myocardial injury, rather than due to a direct effect of aldosterone. The initial pathological event in mineralocorticoid-induced myocardial injury is marked activation of cellular inflammatory response, which precedes cardiac collagen deposition.
Cardiac expression of inflammatory cytokine genes (IL6, TNF-α) was increased substantially in this heart failure model. Inflammation plays a critical role in the response to exogenous aldosterone or MR activation. Following an injurious cardiac insult, increased inflammatory cytokine production triggers a cascade that leads to fibrosis and vascular remodeling. Cytokines stimulate expression of profibrotic factors including TGF-β. However fibrotic and inflammatory remodeling in this model was independent of TGF-β and CTGF activation as mRNA levels of neither of these profibrotic factors were upregulated. Hanna et al. likewise found no increase in TGFβ1 expression in the LV in the ventricular tachypacing model. Similarly vascular inflammatory injury occurred without upregulation of TGFβ1 mRNA levels in an excess aldosterone/salt hypertensive rat model.
MR antagonists reduced mortality in patients with heart failure in 3 clinical trials. However, mechanisms responsible for the beneficial effect of MR blockade on improving mortality are uncertain. The reduction in cardiovascular death with MR antagonists appears to reflect, at least in part, a reduction in sudden death. The Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival studies demonstrated that addition of MR blockade (spironolactone and eplerenone, respectively) reduced the rate of sudden death in patients with heart failure by 20–30%. In moderate-to-advanced heart failure, spironolactone and eplerenone decreased cardiac collagen synthesis biomarker levels and reduced mortality most in those with highest baseline levels.
This experimental study is in accord with these clinical observations and suggests potential cellular and molecular actions of aldosterone antagonism in heart failure that improve the arrhythmogenic substrate. In response to chronic abnormal stress of sustained RVP, spironolactone prevented inflammatory gene expression, interstitial fibrosis and slowing of myocardial activation but did not prevent decline in LV ejection fraction or increase in LV size. Effects of spironolactone on LV function and the electrical substrate were the same as seen with eplerenone in our earlier study. Thus, heart failure animals treated with an MR antagonist display a cardiac phenotype of dilated cardiomyopathy and heart failure without excessive cardiac fibrosis but with reduced ventricular arrhythmia susceptibility. These findings support the notion that beneficial antiarrhythmic effects of aldosterone antagonism are via nonhemodynamic mechanisms related to blockade of MR activation in heart failure. Attenuation of ventricular fibrosis by MR blockade in this nonischemic model is similar to that found in other studies. The key new finding regarding MR blockade is the link established between prevention of fibrosis and local electrical activation delays during premature excitation.
Interest in nonion channel antiarrhythmic drug therapies that target mechanisms involved in formation and evolution of the substrate for ventricular tachyarrhythmias has emerged as a result of recent investigations. Accumulating experimental and clinical evidence demonstrate the protective effect of "upstream" agents against adverse electrical and structural remodeling and occurrence of arrhythmias in specific pathological substrates. This study adds to this evidence by providing mechanistic insights into upstream antiarrhythmic effects of MR antagonism in modifying the electrical and morphological substrate responsible for ventricular arrhythmias in heart failure. Prevention of cardiac inflammation and fibrosis, key mediators of structural remodeling in cardiac disease, were closely linked to improvement in electrical vulnerability and reduced susceptibility to initiation of arrhythmias. By improving impulse propagation and asymmetries in tissue excitability and reducing the potential for electrical fragmentation and wave breaks, anti-fibrotic therapies, such as spironolactone and eplerenone, may thereby reduce cardiac arrhythmic vulnerability. Although our findings are promising, additional confirmatory clinical evidence examining the extent, location and potential for regression of fibrosis in patients with heart failure treated with MR antagonists using novel imaging modalities and their correlation with electrical vulnerability is of interest.
Important questions remain unanswered by our data. This study established that spironolactone prevents development of some elements of pathological remodeling. A study limitation however is that MR antagonist therapy was given concurrent with RVP during evolution of cardiomyopathy, which does not mimic its use in clinical heart failure. It is often not possible to begin treatment in humans before a significant degree of remodeling has occurred. Thus the potential for MR antagonists to reverse the severity of inflammation, fibrosis and electrical remodeling that already has been established is clinically a relevant question.
Discussion
This study presents important new information on the protective effect of MR antagonism on attenuating development of an arrhythmogenic substrate in heart failure susceptible to initiation and maintenance of ventricular tachyarrhythmias. Effects of spironolactone on ventricular electrical activation, fibrosis and inflammatory cytokine gene expression were evaluated in a heart failure model induced by RVP. The major new findings include that spironolactone prevents (1) local ventricular electrical activation delays attenuating electrogram widening during premature stimulation and electrogram fractionation; (2) ventricular interstitial fibrosis; and (3) myocardial gene overexpression of profibrotic inflammatory mediators (IL-6, TNF-α). Beneficial effects of spironolactone on electrical, ultrastructural and molecular remodeling in heart failure were independent of improvement in hemodynamics as they occurred without affecting LV size or systolic function. These results indicate that endogenous aldosterone and MR activation have an important role in the process of adverse ventricular electrical and ultrastructural remodeling in heart failure. Attenuation of cardiac inflammation and fibrosis may be an important mechanism contributing to salutary effects of MR antagonism in prevention of arrhythmic death in heart failure.
Arrhythmogenic Substrate in Heart Failure
In an earlier study from our laboratory, delayed myocardial activation in response to closely coupled, premature extrastimuli was shown to be a critical component of the arrhythmogenic substrate in this tachypacing model of systolic heart failure. Using paced electrogram fractionation analysis, it was shown that increased ventricular electrogram duration in response to premature stimuli (ΔPED) is a robust predictor of sustained ventricular arrhythmia inducibility in heart failure. This study confirms that ventricular electrograms are fractionated and their durations prolong with premature excitation in heart failure. This study extends these observations by demonstrating a similar degree of electrogram widening in response to premature stimuli at coupling intervals of 2 and 20 milliseconds greater than refractory period (ΔPED2, ΔPED20). This suggests that functional delays in myocardial activation during premature excitation close to refractoriness reflect slowing of conduction (due to decrease in propagation velocity and/or increase in path length) rather than prolongation in refractoriness demonstrated in this heart failure model. In response to premature excitation, the duration of the vulnerable period (i.e., the time window of premature stimulus coupling intervals that initiate a reentrant wavefront) is directly proportional to the excitable region length or area and inversely proportional to the conditioning wave velocity and the excitability gradient at the premature stimulation site. Therefore any mechanism that slows propagation is proarrhythmic and extends the period of vulnerability (i.e., increases the probability that a premature stimulus will fall within the vulnerable period and initiate a reentrant arrhythmia). Changes in local paced electrogram duration (ΔPED) in response to premature excitation may reflect the arrhythmogenic capacity of local myocardium to generate abnormal patterns of myocardial activation indicative of slowed conduction.Notably slowing of conduction may be promoted via multiple contributing mechanisms (including reduced sodium channel conductance or availability, enhanced dispersion of refractoriness, altered connexins, myocyte disarray and/or increased fibrosis, etc.).
This study further extends our prior observations and suggests their mechanistic basis by linking delayed myocardial activation (ΔPED) to an increase in interstitial myocardial fibrosis and inflammatory gene expression in heart failure. Consistent with earlier studies of this model, the heart failure ventricles were characterized by an increase in interstitial fibrosis that globally affected both ventricles with mean fibrous tissue content comprising about 6% and 4% of LV and RV myocardium, respectively. Increased fibrosis was demonstrated across the transmural walls and affected ventricular base and apex. This degree of ventricular fibrosis is similar to that seen in hearts from patients with dilated, nonischemic cardiomyopathy who underwent cardiac transplantation for severe heart failure. Increased amounts of fibrotic tissue in the heart are strongly correlated with an increased incidence of arrhythmias and sudden cardiac death. Pathological myocardial fibrosis promotes ventricular arrhythmogenesis through multiple mechanisms that enhance a substrate's vulnerability. Fibrosis impairs cell-to-cell coupling causing inhomogeneities and asymmetries in conduction. Fibrosis slows wavefront propagation and increases tissue vulnerability to wave break and spiral wave formation. The morphological changes associated with fibrotic remodeling result in a discontinuous and branching substrate associated with disturbed transverse or zig-zag propagation, multiphasic, fractionated electrograms and regions of delayed activation that create the potential for unidirection block and reentrant proarrhythmia.
As demonstrated in this study, the heart undergoes profound remodeling in response to abnormal, sustained stress. In heart failure, MR activation plays an important role in pathological fibrotic remodeling. Aldosterone production is enhanced and accumulates in the interstitium in failing hearts. Aldosterone stimulates excessive accumulation of collagen and is implicated in myocardial and perivascular fibrosis independent of changes in wall stress or hypertension. Aldosterone-induced fibrosis primarily is a consequence of the reparative response to vascular and myocardial injury, rather than due to a direct effect of aldosterone. The initial pathological event in mineralocorticoid-induced myocardial injury is marked activation of cellular inflammatory response, which precedes cardiac collagen deposition.
Cardiac expression of inflammatory cytokine genes (IL6, TNF-α) was increased substantially in this heart failure model. Inflammation plays a critical role in the response to exogenous aldosterone or MR activation. Following an injurious cardiac insult, increased inflammatory cytokine production triggers a cascade that leads to fibrosis and vascular remodeling. Cytokines stimulate expression of profibrotic factors including TGF-β. However fibrotic and inflammatory remodeling in this model was independent of TGF-β and CTGF activation as mRNA levels of neither of these profibrotic factors were upregulated. Hanna et al. likewise found no increase in TGFβ1 expression in the LV in the ventricular tachypacing model. Similarly vascular inflammatory injury occurred without upregulation of TGFβ1 mRNA levels in an excess aldosterone/salt hypertensive rat model.
Antiarrhythmic Effects of MR Antagonism in Heart Failure
MR antagonists reduced mortality in patients with heart failure in 3 clinical trials. However, mechanisms responsible for the beneficial effect of MR blockade on improving mortality are uncertain. The reduction in cardiovascular death with MR antagonists appears to reflect, at least in part, a reduction in sudden death. The Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival studies demonstrated that addition of MR blockade (spironolactone and eplerenone, respectively) reduced the rate of sudden death in patients with heart failure by 20–30%. In moderate-to-advanced heart failure, spironolactone and eplerenone decreased cardiac collagen synthesis biomarker levels and reduced mortality most in those with highest baseline levels.
This experimental study is in accord with these clinical observations and suggests potential cellular and molecular actions of aldosterone antagonism in heart failure that improve the arrhythmogenic substrate. In response to chronic abnormal stress of sustained RVP, spironolactone prevented inflammatory gene expression, interstitial fibrosis and slowing of myocardial activation but did not prevent decline in LV ejection fraction or increase in LV size. Effects of spironolactone on LV function and the electrical substrate were the same as seen with eplerenone in our earlier study. Thus, heart failure animals treated with an MR antagonist display a cardiac phenotype of dilated cardiomyopathy and heart failure without excessive cardiac fibrosis but with reduced ventricular arrhythmia susceptibility. These findings support the notion that beneficial antiarrhythmic effects of aldosterone antagonism are via nonhemodynamic mechanisms related to blockade of MR activation in heart failure. Attenuation of ventricular fibrosis by MR blockade in this nonischemic model is similar to that found in other studies. The key new finding regarding MR blockade is the link established between prevention of fibrosis and local electrical activation delays during premature excitation.
Clinical Implications
Interest in nonion channel antiarrhythmic drug therapies that target mechanisms involved in formation and evolution of the substrate for ventricular tachyarrhythmias has emerged as a result of recent investigations. Accumulating experimental and clinical evidence demonstrate the protective effect of "upstream" agents against adverse electrical and structural remodeling and occurrence of arrhythmias in specific pathological substrates. This study adds to this evidence by providing mechanistic insights into upstream antiarrhythmic effects of MR antagonism in modifying the electrical and morphological substrate responsible for ventricular arrhythmias in heart failure. Prevention of cardiac inflammation and fibrosis, key mediators of structural remodeling in cardiac disease, were closely linked to improvement in electrical vulnerability and reduced susceptibility to initiation of arrhythmias. By improving impulse propagation and asymmetries in tissue excitability and reducing the potential for electrical fragmentation and wave breaks, anti-fibrotic therapies, such as spironolactone and eplerenone, may thereby reduce cardiac arrhythmic vulnerability. Although our findings are promising, additional confirmatory clinical evidence examining the extent, location and potential for regression of fibrosis in patients with heart failure treated with MR antagonists using novel imaging modalities and their correlation with electrical vulnerability is of interest.
Important questions remain unanswered by our data. This study established that spironolactone prevents development of some elements of pathological remodeling. A study limitation however is that MR antagonist therapy was given concurrent with RVP during evolution of cardiomyopathy, which does not mimic its use in clinical heart failure. It is often not possible to begin treatment in humans before a significant degree of remodeling has occurred. Thus the potential for MR antagonists to reverse the severity of inflammation, fibrosis and electrical remodeling that already has been established is clinically a relevant question.
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