The Cardiac Arrhythmia Suppression Trial

Myerburg, Robert J.; Kessler, Kenneth M.; Prineas, Ronald J.; Snitzer, Jack L.; Fornace, John; Schmidt, Georg; Ulm, Kurt; Barthel, Petra; Flax, John; Uprichard, Andrew; Canter, Arthur; Ruskin, Jeremy N.

doi:10.1056/nejm198912213212510

Cited by 21 publications

(6 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite decades of research, anti-arrhythmic therapy has failed to reduce this risk. 1 Beta-adrenergic receptor (β-AR) antagonists are a cornerstone of HF therapy 2 and one of the few treatments to reduce SCD. 3 However, the role of β-AR stimulation in arrhythmogenesis is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Local β-Adrenergic Stimulation Overcomes Source-Sink Mismatch to Generate Focal Arrhythmia

Myles

Wang

Kang

et al. 2012

Circulation Research

136

141

View full text Add to dashboard Cite

Rationale Beta-adrenergic receptor (β-AR) stimulation produces sarcoplasmic reticulum (SR) Ca2+ overload and delayed after-depolarizations (DADs) in isolated ventricular myocytes. How DADs are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown. Objective To determine if local β-AR stimulation produces spatio-temporal synchronization of DADs and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia. Methods and Results Simultaneous optical mapping of transmembrane potential (Vm) and Ca2+ transients (CaT) was performed in normal rabbit hearts during subepicardial injections (50µL) of norepinephrine (NE) or control (normal Tyrodes). Local NE produced premature ventricular complexes (PVCs) from the injection site, which were dose-dependent (low-dose [30–60µM]: 0.45±0.62 vs. high-dose [125–250µM]: 1.33±1.46 PVCs/injection, p<0.0001) and were inhibited by propranolol. NE-induced PVCs exhibited abnormal Vm-Ca2+ delay at the initiation site, and were inhibited by either SERCA inhibition or reduced perfusate [Ca2+], indicating a Ca2+-mediated mechanism. NE-induced PVCs were more common at RV vs. LV sites (1.48±1.50 vs. 0.55±0.89, p<0.01) which was unchanged following chemical ablation of endocardial Purkinje fibers, suggesting source-sink interactions may contribute to the greater propensity to RV PVCs. Partial gap junction uncoupling with carbenoxolone (25µM) increased focal activity (2.18±1.43 vs. 1.33±1.46 PVCs/injection, p<0.05), further supporting source-sink balance as a critical mediator of Ca2+-induced PVCs. Conclusions These data provide the first experimental demonstration that localized β-AR stimulation produces spatio-temporal synchronization of SR Ca2+ overload and release in the intact heart and highlight the critical nature of source-sink balance in initiating focal arrhythmias.

show abstract

Section: Introductionmentioning

confidence: 99%

Local β-Adrenergic Stimulation Overcomes Source-Sink Mismatch to Generate Focal Arrhythmia

Myles

Wang

Kang

et al. 2012

Circulation Research

136

141

View full text Add to dashboard Cite

show abstract

“…89 The Beta-Blocker Heart Attack Trial (BHAT) study showed that β-blockade with propranolol reduced all-cause mortality by 25%, especially in patients with diminished LV function and/or ventricular arrhythmias. 90 A randomized trial of nearly 46,000 patients showed that, in the acute MI setting, early oral administration of high-dose β-blocker drugs has been shown to prevent VF.…”

Section: Introductionmentioning

confidence: 99%

“…89,93 Class I drugs (mexiletine, encainide, flecainide), calcium antagonists, and class III drugs ( d -sotalol, dofetilide) all failed to reduce or even increase the incidence of SCD after a MI. 94 Amiodarone also has been shown to have no definitive effect on mortality in patients after MI in preventing SCD, as manifested in the SCD in Heart Failure Trial (SCD-HeFT).…”

Section: Introductionmentioning

confidence: 99%

Strategies for the prevention and treatment of sudden cardiac death

Herzog¹,

Javed²,

Aziz³

2010

OAEM

View full text Add to dashboard Cite

Cardiovascular diseases account for 40% of all deaths in the West. Sudden cardiac death (SCD) is a major health problem affecting over 300,000 patients annually in the United States alone. Presence of coronary artery disease (CAD), usually in the setting of diminished left ventricular ejection fraction, is still the single major risk factor for SCD. Additionally, acute myocardial ischemia, structural cardiac defects, anomalous coronary arteries, cardiomyopathies, genetic mutations, and ventricular arrhythmias are all attributed to SCD, demonstrating the perplexity of this condition. With the recent advancements in cardiovascular medicine, the incidence of SCD is expected to increase steeply as the prevalence of CAD and heart failure is uprising in general population. Considering SCD, the major challenge confronting contemporary cardiology, multiple strategies for prevention against SCD have been developed. β-blockers have been shown to reduce the risk of SCD, whereas implantable cardioverter–defibrillator devices are found to be effective at terminating the malignant arrhythmias. In recent years, multiple clinical trials were carried out to identify patients who may benefit from preventive intervention, including medical therapy and automatic cardioverter–defibrillator implantations. This review article provides insight into the advanced strategies for the prevention and treatment of SCD based on the data available in medical literature to date.

show abstract

“…Many of today’s cardiovascular drugs are designed to modulate well-known “legacy” targets, in essence pathways far downstream, such as blood pressure, membrane stability, and lipid levels, which may have limited specificity for the underlying disease mechanism. Many such drugs are only modestly effective or are limited in their utility by “on-target” and “off-target” toxicity 1 , 2 , 3 , 4 , 5 . For example, the focus of the current antiarrhythmic armamentarium is the modulation of myocardial automaticity, refractoriness, or conduction.…”

mentioning

confidence: 99%

“…The resultant targeting of “final common pathways” or even normal physiology with blunt pharmacological tools rather than the precise manipulation of disease-specific mechanisms leads to predictable problems 6 , 7 , 8 . Not surprisingly, many effective antiarrhythmic agents are also highly proarrhythmic in particular contexts, and these “on-target” adverse effects have become all too apparent, with several costly failures in large randomized clinical trials 3 , 9 , 10 . In this paper, we outline evidence that most existing cardiovascular drug targets are poorly validated, review emerging data on the role of mechanistic insight in drug discovery for specific cardiovascular diseases in humans, and discuss recent advances using direct in vivo chemical screens in zebrafish for the discovery of novel cardiovascular tool compounds and drug leads.…”

mentioning

confidence: 99%

Using Zebrafish for High-Throughput Screening of Novel Cardiovascular Drugs

Kithcart

MacRae

2017

JACC: Basic to Translational Science

View full text Add to dashboard Cite

SummaryCardiovascular diseases remain a major challenge for modern drug discovery. The diseases are chronic, complex, and the result of sophisticated interactions between genetics and environment involving multiple cell types and a host of systemic factors. The clinical events are often abrupt, and the diseases may be asymptomatic until a highly morbid event. Target selection is often based on limited information, and though highly specific agents are often identified in screening, their final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index, or substantial toxicities. Our understanding of complexity of cardiovascular disease has grown dramatically over the past 2 decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in cardiac or vascular disease. Despite these insights, the majority of active cardiovascular agents derive from a remarkably small number of classes of agents and target a very limited number of pathways. These agents have often been used initially for particular indications and then discovered serendipitously to have efficacy in other cardiac disorders or in a manner unrelated to their original mechanism of action. In this review, the rationale for in vivo screening is described, and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. An overview is provided of the complex mechanisms underlying most clinical cardiovascular diseases, and insight is offered into the limits of single downstream pathways as drug targets. The zebrafish is introduced as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology are discussed, including in vivo screening of zebrafish genetic disease models.

show abstract

The Cardiac Arrhythmia Suppression Trial

Cited by 21 publications

References 9 publications

Local β-Adrenergic Stimulation Overcomes Source-Sink Mismatch to Generate Focal Arrhythmia

Local β-Adrenergic Stimulation Overcomes Source-Sink Mismatch to Generate Focal Arrhythmia

Strategies for the prevention and treatment of sudden cardiac death

Using Zebrafish for High-Throughput Screening of Novel Cardiovascular Drugs

Contact Info

Product

Resources

About