Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction

Waldo, Albert L.; Camm, A. John; deRuyter, Hans; Friedman, Peter L.; MacNeil, Daniel J.; Pauls, John F.; Pitt, Bertram; Pratt, Craig M.; Schwartz, Peter J.; Veltri, Enrico P.

doi:10.1016/s0140-6736(96)02149-6

Cited by 1,244 publications

(565 citation statements)

References 37 publications

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“…Since many conventional therapies for HF‐related arrhythmias that target sarcolemmal ion channels are fraught with pro‐arrhythmic effects, there is a major unmet need for developing novel approaches that are both effective and safe. This is particularly urgent for post‐MI patients in whom conventional anti‐arrhythmic drugs such as flecainide and sotalol have increased rather than decreased mortality 1, 2. Because the extent of mechanical dysfunction is a predictor of adverse arrhythmic events, we hypothesized that improving excitation–contraction coupling, mechanical function, and overall heart failure status by restoring SERCA2a expression by gene transfer may improve electrical remodeling and suppress the incidence of malignant arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

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Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

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Background SERCA2a gene transfer (GT) improves mechano‐electrical function in animal models of nonischemic heart failure Whether SERCA2a GT reverses pre‐established remodeling at an advanced stage of ischemic heart failure is unclear. We sought to uncover the electrophysiological effects of adeno‐associated virus serotype 1.SERCA2a GT following myocardial infarction (MI).Methods and ResultsPigs developed mechanical dysfunction 1 month after anterior MI, at which point they received intracoronary adeno‐associated virus serotype 1.SERCA2a (MI+SERCA2a) or saline (MI) and were maintained for 2 months. Age‐matched naive pigs served as controls (Control). In vivo ECG‐and‐hemodynamic properties were assessed before and after dobutamine stress. The electrophysiological substrate was measured using optical action potential (AP) mapping in controls, MI, and MI+SERCA2a preparations. In vivo ECG measurements revealed comparable QT durations between groups. In contrast, prolonged QRS duration and increased frequency of R′ waves were present in MI but not MI+SERCA2a pigs relative to controls. SERCA2a GT reduced in in vivo arrhythmias in response to dobutamine. Ex vivo preparations from MI but not MI+SERCA2a or control pigs were prone to pacing‐induced ventricular tachycardia and fibrillation. Underlying these arrhythmias was pronounced conduction velocity slowing in MI versus MI+SERCA2a at elevated rates leading to ventricular tachycardia and fibrillation. Reduced susceptibility to ventricular tachycardia and fibrillation in MI+SERCA2a pigs was not related to hemodynamic function, contractile reserve, fibrosis, or the expression of Cx43 and Nav1.5. Rather, SERCA2a GT decreased phosphoactive CAMKII‐delta levels by >50%, leading to improved excitability at fast rates.Conclusions SERCA2a GT increases conduction velocity reserve, likely by preventing CAMKII overactivation. Our findings suggest a primary effect of SERCA2a GT on myocardial excitability, independent of altered mechanical function.

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Section: Discussionmentioning

confidence: 99%

“…Of note, malignant ventricular tachycardia and fibrillation (VT/VF) account for ≈50% of these deaths. Unfortunately, conventional therapies for arrhythmias that target sarcolemmal ion channels have often exacerbated rather than improved outcomes in this high‐risk patient population,1, 2 highlighting the need for novel approaches.…”

Section: Introductionmentioning

confidence: 99%

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

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“…In patients with an ICD implantation, amiodarone, especially in conjunction with beta‐blockers, significantly reduces ICD interventions 37. Sotalol, a rapid delayed rectifier potassium current inhibitor with beta‐blocker properties, is effective in suppressing VAs in patients with coronary artery disease without LV dysfunction, but less effective in NICM patients 38, 39, 40. Ranolazine in combination with other anti‐arrhythmic agents has been explored to suppress VT in otherwise drug‐refractory cases.…”

Section: Management Of Vt In Nicmmentioning

confidence: 99%

Ventricular arrhythmias in nonischemic cardiomyopathy

Chung

Lin

et al. 2018

Journal of Arrhythmia

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Nonischemic cardiomyopathies (NICMs) are composed of variable disease entities, including primary and secondary cardiomyopathies. Determining the etiology of NICM provides pivotal roles of not only the understanding of the individual pathogenesis, but also the clinical management, such as risk stratification, pharmacological treatment, and intervention therapies. Despite the diverse causes of NICM, these cases mostly require clinical attention owing to progressive myocardial injury, resulting in ventricular dysfunction and heart failure. The interaction between the diseased ventricular substrates and systemic/neurophysiological factors contributes to the cornerstones responsible for ventricular arrhythmogenesis and sudden cardiac death (SCD). Prevention of SCD and diminishing ventricular tachyarrhythmias are the important mainstays for the management of NICM patients. Given the understanding of the abnormal ventricular substrates and advancement of navigation systems, radiofrequency catheter ablation (RFCA) has become an adjunctive or alternative strategy for NICM patients who experience drug‐refractory ventricular tachycardias (VTs). Successful ablation can frequently be achieved at the expense of an epicardial intervention. A recent study has proven the survival benefits for NICM patients who are free from recurrent VTs after a successful RFCA, regardless of the New York Heart Association (NYHA) functional class status or left ventricular ejection fraction. Additionally, recent evidence has highlighted the better delineation of a diseased myocardium through the incorporation of cardiovascular magnetic resonance imaging (CMRI) and 3D mapping systems, which can facilitate the identification of critical ventricular arrhythmogenic substrates in NICM patients.

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“…Anti-arrhythmic drug therapy has generally failed to improve prognosis in heart failure even when suppression of arrhythmias has been demonstrated [20][21][22]. This casts doubt on whether arrhythmias play an important role in overall mortality' or sudden death i.n heart failure although it can be argued that it is the drugs that are at fault rather than the concept of sudden death being arrltytnmic.…”

mentioning

confidence: 99%