Patients presenting with ventricular fibrillation during the first myocardial infarction.

More than 50% of mortality associated with acute myocardial infarction occurs within the first few hours and is mainly due to ventricular fibrillation (primary VF). This database includes survivors of documented VF in the setting of a first transmural myocardial infarction (cases) and matched infarct patients without VF (controls). This unique resource has been developed by the Academic Medical Center in Amsterdam, which is acting as the coordinating site. Five other hospitals outside the Amsterdam area participate. Analysis of this dataset has confirmed the role of family history as a predictor of sudden cardiac death (SCD) in this population, with a 2.5 fold increase in SCD susceptibility. By contrast, other risk factors, including extent of coronary disease and predictors of coronary disease (e.g. smoking), did not distinguish between the two groups. Between July 2002 and May 2006, 400 cases and 400 controls have been recruited. Ultimately, the dataset is estimated to include 1000 cases and 1000 controls.

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Patients recruited after hospitalization for heart failure, and followed prospectively.

Recent hospitalization for heart failure is an increasingly well-recognized marker for high risk for SCD. The COACH (Coordinating study evaluating Outcomes of Advising and Counselling in Heart failure) cohort has been recruited at the University of Groningen (Dr. T. Jaarsma, Prof. D.J. van Veldhuizen) and is available to the network. COACH is a multi-center trial including 17 centers in the Netherlands, which has the overall goal of assessing the value of nurse-led heart failure management in patients with hospitalization for heart failure. As in other databases, extensive demographic information as well as consented DNA samples are in place. Recruitment started at the end of 2002 and by October 2004 about 1000 patients were included.

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Patients with coronary disease receiving implantable cardioverter defibrillators for primary prevention.

The increasing use of implantable cardioverter defibrillators (ICDs) for primary prevention in patients at very high risk for SCD (e.g. left ventricular ejection fraction (LVEF) <30% and prior myocardial infarction) now presents the opportunity to investigate genetic markers that predict ventricular tachycardia (VT)/ventricular fibrillation (VF) in this high risk population. Inclusion criteria are age =18 years, a history of acute myocardial infarction, LVEF =30% at least 3 weeks after acute myocardial infarction; and implantation of an ICD for primary prevention. The prospective, observational design is appropriate because the study involves clearly defined high-frequency events: 30-35% of ICD patients have ventricular arrhythmias in the first year after implantation and ~10% have firings for rapid VT or VF. This database is managed at Johns Hopkins, where it is the centerpiece of the Reynolds Center (Eduardo Marbán, Director; www.reynolds.jhmi.edu). Subjects are also being accrued at the Munich site.

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Patients with out-of-hospital SCD.

Patients dying of out-of-hospital cardiac arrest are being ascertained through collaborations with Medical Examiner and Coroner offices in Miami, Nantes, Portland Oregon (a Reynolds/Hopkins site), and Amsterdam.
The major question to be addressed is genetic predisposition to cardiac arrest among the victims of acute coronary syndromes, The Miami-Dade County Medical Examiners Office did postmortem examinations for an average of 536 cases per year. Among these, 76% were determined to be due to atherosclerotic cardiovascular disease and 12% of these had anatomic evidence for acute myocardial infarction. The Nantes SAMU (Service d'Aide Médicale Urgente), the French pre-hospital medical emergency service, currently manages 250 out-of-hospital cardiac arrests annually, and DNA is routinely obtained. We anticipate collecting ~600 cases over 3 years.

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Patients with drug induced LQT syndrome.

Exaggerated QT prolongation induced by drugs carries a risk for Torsades de Pointes (TdP) and sudden death. The mechanism is almost always drug block of a key potassium channel, encoded by KCNH2 (HERG); identifying HERG blockers and patients susceptible to TdP has become a major new drug development issue.
While clinical studies have identified risk factors for marked QT prolongation and arrhythmias, this response remains generally unpredictable in an individual subject. To date, genetic analyses of these patients have focused on congenital long QT syndrome genes; the genomic approaches being developed by Network investigators will extend the candidate variants and genes. Since QT prolongation is a well-recognized marker of cardiovascular morbidity and mortality in a wide range of clinical conditions, elucidation of genetic risk for aberrant QT responses in this project holds the promise of identifying new modulators of SCD risk. Leducq sites have accumulated over 300 cases of drug-induced LQTS.

Analysis of this dataset will include controls and a replication set put in place through network collaborations.  The control set is over 700 patients ascertained at the Vanderbilt site exposed to QT prolonging drugs without developing marked QT prolongation.   The replication set will be drawn from over 650 patients, ascertained primarily at Munster, Amsterdam, and Munich, with loss of function mutations in KCNH2 and a spectrum QT intervals. 

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Patients with heritable arrhythmia syndromes.

Study of monogenic arrhythmia syndromes has been a seminal step in identifying key genes controlling normal and abnormal cardiac rhythm. Leducq investigators, notably at the Munster, Nantes, and Amsterdam sites, have been leaders in this work and have accrued large cohorts of well-characterized families.  These cohorts provide a unique resource to enable studies of the role of common genomic variants in modulating SCD risk in these patients groups and thus in the broader populations at risk. 

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Healthy populations

This aspect of the work focuses on KORA, a series of population-based cohorts (that now includes ~18,000 subjects) ascertained in central Germany and followed prospectively for up to 20 years with mortality and morbidity data. KORA subjects are adults who participated in 4 surveys of 4,000-5,000 subjects each. The individuals were from 25 to 74 years of age and randomly selected from a population of 600,000 citizens. Data from two follow-up investigations will be available shortly, covering about 6,000 participants re-investigated after 7-10 years. The oldest age group is now >90. Phenotypic information includes sociodemography, environmental factors, smoking, nutrition, alcohol consumption, general medical history, ECG records and various laboratory parameters. Genomic DNA, serum, plasma, and urine are available from most of the participants and also available are the immortalized cell lines from 1,500 persons (www.gsf.de/kora and www.gsf.de/kora-gen). KORA has been a valuable resource in recent genome-wide studies of cardiovascular risk. Hopkins also has access to healthy populations in Baltimore.

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