Sudden Unexplained Death

Heritability and Diagnostic Yield of Cardiological and Genetic Examination in Surviving Relatives

Hanno L. Tan, MD, PhD; Nynke Hofman, BSc; Irene M. van Langen, MD; Allard C. van der Wal, MD, PhD; Arthur A.M. Wilde, MD, PhD

From the Departments of Cardiology (H.L.T., A.A.M.W.), Clinical Genetics (N.H., I.M.v.L.), and Pathology (A.C.v.d.W.), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Correspondence to Arthur A.M. Wilde, MD, PhD, Academic Medical Center, University of Amsterdam, Department of Cardiology, M0–105, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail a.a.wilde@amc.uva.nl

Received November 18, 2004; revision received March 24, 2005; accepted April 4, 2005.

Background— Sudden death mostly follows from cardiac disorders that elicit lethal ventricular arrhythmias. In young individuals, it often remains unexplained because history and/or postmortem analysis are absent or provide no clue. Because such sudden unexplained deaths (SUDs) may have heritable causes, cardiological and genetic assessment of surviving relatives of SUD victims may reveal the underlying disease and unmask presymptomatic carriers. We aimed to establish the diagnostic yield of such assessments.

Methods and Results— We investigated 43 consecutive families with 1 SUD victim who died at 40 years of age. All studied relatives underwent resting/exercise ECG and Doppler echocardiography. Molecular genetic analysis was conducted to confirm the diagnosis. We identified an inherited disease and likely cause of death in 17 of 43 families (40%). Twelve families had primary electrical disease: catecholaminergic polymorphic ventricular tachycardia (5 families), long-QT syndrome (4 families), Brugada syndrome (2 families), and long-QT/Brugada syndrome (1 family). Furthermore, we found arrhythmogenic right ventricular cardiomyopathy (3 families), hypertrophic cardiomyopathy (1 family), and familial hypercholesterolemia (1 family). Molecular genetic analysis provided confirmation in 10 families. Finding the diagnosis was more likely when more relatives were examined and in families with 2 SUD victims 40 years of age. The resting/exercise ECG had a high diagnostic yield. These efforts unmasked 151 presymptomatic disease carriers (8.9 per family).

Conclusions— Examination of relatives of young SUD victims has a high diagnostic yield, with identification of the disease in 40% of families and 8.9 presymptomatic carriers per family. Simple procedures (examining many relatives) and routine tests (resting/exercise ECG) constitute excellent diagnostic strategies. Molecular genetics provide strong supportive information.

Key Words: arrhythmia • death, sudden • genetics • long-QT syndrome • tachyarrhythmias

Comments by Dr. Wilde in an interview:  Of the 333 first- and second-degree relatives tested, 151 had the same previously unrecognized and potentially fatal heart abnormality as their dead family member. That works out to an average of 8.9 people in each family. Of those 151 people, 138 had mutated genes known to predispose people to early death, the study found.

"Based on our findings, we strongly advise that first-degree relatives (immediate family members) and second-degree relatives (grandparents, aunts and uncles) be referred to a cardiologist for testing," Wilde said.

"Most of the diseases we identified in our study are not only amenable to treatment, but if treated correctly, are also associated with a virtually normal life expectancy," he added.

Sudden Cardiac Death Spells Heart Trouble in Family
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Other interesting facts:  Men with a high resting heart rate, more than 75 beats per minute, were nearly 3 1/2 times as likely to die suddenly from a heart attack as those with fewer than 60 beats per minute, according to a study in last week's New England Journal of Medicine. The study, which followed French men for more than 20 years, also showed that those whose heart rates shot up higher during exercise and decreased quickly upon stopping were less likely to die from a sudden heart attack. That profile, says Tim Church, who has done similar research at the Cooper Institute in Texas, is typical of someone in good shape. Heart rate can often be improved with exercise. Researchers say they do not know if a similar result would be found in women.

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