Prevention of sudden cardiac death in the young: Developing a rational, reliable, and sustainable national health care resource. A report from the Cardiac Safety Research Consortium.

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses important issues regarding sudden cardiac death in the young (SCDY), a problem that does not discriminate by gender, race, ethnicity, education, socioeconomic level, or athletic status. The occurrence of SCDY has devastating impact on families and communities. Sudden cardiac death in the young is a matter of national and international public health, and its prevention has generated deep interest from multiple stakeholders, including families who have lost children, advocacy groups, academicians, regulators, and the medical industry. To promote scientific and clinical discussion of SCDY prevention and to germinate future initiatives to move this field forward, a Cardiac Safety Research Consortium-sponsored Think Tank was held on February 21, 2015 at the US Food and Drug Administration's White Oak facilities, Silver Spring, MD. The ultimate goal of the Think Tank was to spark initiatives that lead to the development of a rational, reliable, and sustainable national health care resource focused on SCDY prevention. This article provides a detailed summary of discussions at the Think Tank and descriptions of related multistakeholder initiatives now underway: it does not represent regulatory guidance.

Improving public health by improving clinical trial guidelines and their application.

Evidence generated from randomized controlled trials forms the foundation of cardiovascular therapeutics and has led to the adoption of numerous drugs and devices that prolong survival and reduce morbidity, as well as the avoidance of interventions that have been shown to be ineffective or even unsafe. Many aspects of cardiovascular research have evolved considerably since the first randomized trials in cardiology were conducted. In order to be large enough to provide reliable evidence about effects on major outcomes, cardiovascular trials may now involve thousands of patients recruited from hundreds of clinical sites in many different countries. Costly infrastructure has developed to meet the increasingly complex organizational and operational requirements of these clinical trials. Concerns have been raised that this approach is unsustainable, inhibiting the reliable evaluation of new and existing treatments, to the detriment of patient care. These issues were considered by patients, regulators, funders, and trialists at a meeting of the European Society of Cardiology Cardiovascular Roundtable in October 2015. This paper summarizes the key insights and discussions from the workshop, highlights subsequent progress, and identifies next steps to produce meaningful change in the conduct of cardiovascular clinical research.

Heart Failure Clinical Trials in East and Southeast Asia: Understanding the Importance and Defining the Next Steps.

Heart failure (HF) is a major and increasing global public health problem. In Asia, aging populations and recent increases in cardiovascular risk factors have contributed to a particularly high burden of HF, with outcomes that are poorer than those in the rest of the world. Representation of Asians in landmark HF trials has been variable. In addition, HF patients from Asia demonstrate clinical differences from patients in other geographic regions. Thus, the generalizability of some clinical trial results to the Asian population remains uncertain. In this article, we review differences in HF phenotype, HF management, and outcomes in patients from East and Southeast Asia. We describe lessons learned in Asia from recent HF registries and clinical trial databases and outline strategies to improve the potential for success in future trials. This review is based on discussions among scientists, clinical trialists, industry representatives, and regulatory representatives at the CardioVascular Clinical Trialist Asia Forum in Singapore on July 4, 2014.

Cardiac Safety Research Consortium (CSRC): Cardiovascular Safety and Adverse Event Case Report Forms.

Detection of off-target cardiovascular (CV) effects remains a significant challenge to drug development. Documentation of CV events in non-CV trials is often inadequate to interpret imbalances between treatment arms, which may lead to concerns about potential CV safety "signals." The Cardiac Safety Research Consortium (CSRC) public-private partnership has developed CV case report forms (CRFs) for adverse CV events, including death. These CRFs are intended to encourage collection, as near to the occurrence of an event as possible, of the minimum information necessary to assess, or possibly adjudicate, the event. A broad range of stakeholders (representing industry, academia, and regulatory authorities) developed these forms with the goal of balancing the collection of key information with the resources likely to be available. Use of these forms is optional, and sponsors may modify them. These forms have not undergone any type of "validation" process. The CSRC will continue to sponsor a working group to invite public comment and feedback on these forms.

Pharmacological prevention of atrial tachycardia induced atrial remodeling as a potential therapeutic strategy.

Atrial fibrillation (AF) is the most common cardiac arrhythmia requiring medical therapy, and present treatment modalities are inadequate. Over the past few years, we have learned a great deal about the phenomenon of electrical remodeling, by which rapid atrial activation leads to changes in atrial electrical properties that promote AF initiation and maintenance. This knowledge opens up the possibility that electrical remodeling may itself be a novel therapeutic target in AF. The present paper reviews what is known about the basic mechanisms of atrial electrical remodeling and then discusses the experimental and clinical evidence that remodeling can be prevented by drug therapy. Despite great potential value, the development of pharmacological interventions to prevent atrial electrical remodeling is still in its infancy.

Preserved effects of potassium channel blockers in the pacing-induced remodeled canine atrium: a comparison between E4031 and azimilide.

This study was designed to evaluate the electrophysiologic effects of E4031 (a pure IKr blocker) and azimilide (AZ: a combined Ikr + IKs blocker) at various stages of atrial electrical remodeling. Twelve dogs underwent continuous rapid atrial pacing (400/min) for 14 days. The electrophysiologic study was performed on the day before as well as after 2, 7, and 14 days of rapid atrial pacing both before and after the administration of either E4031 (n = 6) or AZ (n = 6). In response to rapid atrial pacing, the atrial effective refractory period (ERP), conduction velocity, and wavelength decreased significantly at pacing cycle lengths (PCLs) of 200 and 400 ms (P < 0.05). E4031 prolonged ERP in a reverse use-dependent manner throughout the study period. AZ also prolonged ERP during the 14 days of rapid pacing. ERP prolongation at a PCL of 200 ms was significantly greater with AZ than with E4031 (P < 0.05). The effects of blocking IKr by E4031 and IKr + IKs by AZ were well preserved at various stages of atrial electrical remodeling. However, the effect of prolonging ERP at a shorter PCL was more prominent by AZ than by E4031. Thus, IKs blockade may add a favorable anti-fibrillatory effect to IKr blockade even in the remodeled atrium.

Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone.

BACKGROUND: The basis of the unique effectiveness of amiodarone for atrial fibrillation (AF) is poorly understood. The present study tested the hypothesis that amiodarone blocks electrical remodeling induced by atrial tachycardia. METHODS AND RESULTS: Mongrel dogs were subjected to atrial tachycardia (400 bpm for 7 days) in the absence and presence of therapy with amiodarone, the class III cardiac antiarrhythmic drug dofetilide, or the class I agent flecainide begun 3 days before the onset of tachypacing and maintained until a final electrophysiological study. AF vulnerability (percentage of sites with AF induction by single premature extrastimuli), mean AF duration, atrial effective refractory period (ERP), and conduction velocity were compared among these dogs and in unpaced dogs in the absence or presence of treatment with the same agents. Only amiodarone prevented promotion of AF duration and vulnerability by atrial tachycardia. Furthermore, only amiodarone eliminated tachycardia-induced ERP abbreviation and loss of ERP rate adaptation while obviating L-type Ca2+-current alpha1c-subunit downregulation as determined by Western blot. In an additional series of dogs monitored with repeated electrophysiological studies, amiodarone administered after the induction of atrial tachycardia remodeling reversed remodeling within several days, despite continued atrial tachypacing during amiodarone therapy. CONCLUSIONS: Amiodarone is uniquely effective against AF promotion by atrial tachycardia remodeling in this experimental model and prevents electrophysiological and biochemical consequences of remodeling. Amiodarone also reversed remodeling established by 4 days of atrial tachycardia. The inhibition of atrial tachycardia remodeling may therefore contribute to the superior efficacy of amiodarone in AF.

Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs.

BACKGROUND: Clinical atrial fibrillation (AF) often results from pathologies that cause atrial structural remodeling. The reversibility of arrhythmogenic structural remodeling on removal of the underlying stimulus has not been studied systematically. METHODS AND RESULTS: Chronically instrumented dogs were subjected to 4 to 6 weeks of ventricular tachypacing (VTP; 220 to 240 bpm) to induce congestive heart failure (CHF), followed by a 5-week recovery period leading to hemodynamic normalization at 5-week recovery (Wk5(rec)). The duration of burst pacing-induced AF under ketamine/diazepam/isoflurane anesthesia increased progressively during VTP and recovered toward baseline during the recovery period, paralleling changes in atrial dimensions. However, even at full recovery, sustained AF could still be induced under relatively vagotonic morphine/chloralose anesthesia. Wk5(rec) dogs showed no recovery of CHF-induced atrial fibrosis (3.1+/-0.3% for controls versus 10.7+/-1.0% for CHF and 12.0+/-0.8% for Wk5(rec) dogs) or local conduction abnormalities (conduction heterogeneity index 1.8+/-0.1 in controls versus 2.3+/-0.1 in CHF and 2.2+/-0.2 in Wk5(rec) dogs). One week of atrial tachypacing failed to affect the right atrial effective refractory period significantly in CHF dogs but caused highly significant effective refractory period reductions and atrial vulnerability increases in Wk5(rec) dogs. CONCLUSIONS: Reversal of CHF is followed by normalized atrial function and decreased duration of AF; however, fibrosis and conduction abnormalities are not reversible, and a substrate that can support prolonged AF remains. Early intervention to prevent fixed structural abnormalities may be important in patients with conditions that predispose to the arrhythmia.

Effects of inhibiting Na(+)/H(+)-exchange or angiotensin converting enzyme on atrial tachycardia-induced remodeling.

BACKGROUND: Inhibitors of the Na(+)/H(+)-exchanger (NHE1) and of angiotensin-converting enzyme (ACE) have been shown to reduce short-term (<6 h) tachycardia-induced atrial electrical remodeling. The role of NHE1 and ACE in longer-term electrical remodeling, as might occur with persistent AF, has not been studied. METHODS: Dogs were subjected to atrial-tachypacing (400 bpm) for 7 days during treatment with 240 mg/day (standard clinical dose) of the NHE1 inhibitor cariporide (CariL, n=6), 1000 mg/day cariporide (CariH, n=6), 2 mg/kg/day of the ACE inhibitor enalapril (E, n=6), or no-drug controls (n=7). To ensure steady state concentrations at the onset of pacing, treatment began 3 days before the initiation of atrial tachypacing. Results were compared to those of unpaced dogs (n=9). RESULTS: Atrial tachypacing reduced atrial effective refractory period (ERP), e.g. at a basic cycle length of 300 ms from 126+/-4 ms (unpaced, mean+/-S.E.) to 79+/-8 ms (no-drug controls, P<0.001). ERP abbreviation was unchanged by CariL (83+/-8 ms), CariH (80+/-7 ms), or E (76+/-5 ms). Atrial tachypacing increased mean duration of the longest AF episode in each dog (DAF) from 130+/-80 s (unpaced) similarly in all groups: 864+/-364 s, no-drug controls; 609+/-376 s, CariL; 709+/-353 s, CariH; 645+/-365 s, E (P=NS for differences among groups). Sustained AF requiring cardioversion for termination was induced in 0% of unpaced dogs vs. 33% of CariL, 33% of CariH, 33% of E, and 43% of control dogs. AF inducibility by single extrastimuli increased from 4+/-2% in unpaced dogs to 48+/-13% (P<0.01) in no-drug control dogs, an effect not changed by CariL (33+/-14%), CariH (35+/-17%) or E (48+/-16%). CONCLUSIONS: In contrast to short-term (several-hour) atrial tachycardia-induced remodeling, remodeling by 7-day tachycardia is not affected by NHE1 or ACE inhibition. These results support the notion that short-term atrial tachycardia remodeling involves different mechanisms from longer-term remodeling, and urges caution in extrapolating results from studies of short-term remodeling to effects in longer-term remodeling as often occurs clinically.

Discordant temporal changes in electrophysiological properties during electrical remodeling and its recovery in the canine atrium.

Prolonged rapid atrial excitation gives rise to atrial electrical remodeling, which perpetuates atrial fibrillation (AF). However, there has been controversy regarding the nature of temporal changes in conduction characteristics during the development and recovery of electrical remodeling. This study was designed to clarify the nature of the development and recovery of electrical remodeling in relation to AF inducibility in dogs subjected to rapid atrial pacing. Eleven dogs underwent rapid atrial pacing (400/min) for 28 days. The electrophysiological study was performed on the day just prior to the commencement of pacing, on days 2, 7, 14, and 28 of rapid pacing, as well as 1 and 7 days after the cessation of pacing. In response to rapid atrial pacing, atrial effective refractory period (ERP), conduction velocity and wavelength decreased significantly (p < 0.05). ERP had shortened significantly and rapidly within 2 days of pacing, while conduction velocity decreased more gradually. During the recovery, ERP returned to almost baseline levels within a day, whereas conduction velocity returned to baseline by day 7. Sustained AF became inducible in 37% of the dogs from 7 days of pacing until 1 day after the cessation, when wavelength fell below 8.7 cm. In conclusion, rapid atrial excitation causes a progressive but discordant temporal pattern of a decrease in ERP and conduction velocity. The resultant shortening of the wavelength determines the inducibility and maintenance of AF. The electrophysiological changes produced by one month of rapid atrial pacing can be fully reversed within a week, although in a discordant temporal pattern.

Consequences of atrial tachycardia-induced remodeling depend on the preexisting atrial substrate.

BACKGROUND: All animal studies of atrial tachycardia (AT) remodeling to date have been performed in normal hearts, but clinical atrial fibrillation (AF) often occurs in the setting of heart disease. This study evaluated the effects of a pathological AF substrate on AT-induced remodeling. METHODS AND RESULTS: Fourteen control dogs, 12 AT-only dogs (400 bpm for 1 week), 14 congestive heart failure (CHF) dogs (CHF only, ventricular tachypacing, 220 to 240 bpm for 5 weeks), and 13 CHF+AT dogs (ventricular tachypacing-induced CHF, 1 week of AT superimposed on the last week of ventricular tachypacing) were studied for evaluation of AT effects in normal hearts (AT-only versus control dogs) and CHF hearts (CHF+AT versus CHF-only dogs). In normal hearts, AT strongly decreased the effective refractory period (ERP) and abolished ERP rate adaptation, whereas conduction velocity was unaltered. In CHF dogs, AT reduced ERP to a significantly lesser extent, did not alter ERP rate adaptation, and reduced conduction velocity. AT alone increased atrial vulnerability to extrastimuli and prolonged AF. In the presence of CHF, AT had no clear effect on atrial vulnerability but increased the prevalence of prolonged AF. CONCLUSIONS: The electrophysiological effects of AT are different in hearts with a CHF-induced pathological substrate for AF than in normal hearts. These findings have potentially important implications for understanding how AF occurring in diseased hearts begets AF.