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Countywide burden, pathology, and genetics of lethal hypertrophic cardiomyopathy: from the POST SCD study
Leila Haghighat1, Andrew Connolly2, Francesca N Delling1
1Division of Cardiology, Department of Medicine, University of California-San Francisco, San Francisco, California, USA.
Insights
Hypertrophic cardiomyopathy (HCM) causes 2% of sudden arrhythmic deaths up to age 90, particularly in those under 35. Most HCM cases remain undiagnosed before sudden cardiac death, suggesting a higher burden than previously understood.
Area of Science:
- Cardiology
- Pathology
- Genetics
Background:
- Sudden cardiac death (SCD) incidence in hypertrophic cardiomyopathy (HCM) cohorts is estimated at 1% annually.
- This estimate may be inaccurate, potentially missing cases that occur before diagnosis and assuming all SCDs are arrhythmic.
Purpose of the Study:
- To determine the incidence and causes of sudden cardiac death (SCD) in individuals with hypertrophic cardiomyopathy (HCM) using a comprehensive post-mortem investigation.
- To assess the proportion of HCM-related SCDs that are arrhythmic and undiagnosed prior to death.
Main Methods:
- Prospective cohort study (POST SCD) involving autopsy, clinical records, and toxicology for presumed SCDs (pSCDs) in San Francisco County (2011-2022).
- HCM identification through pathology, echocardiography (TTE), and genetic testing.
- Incidence calculated using county data and estimated HCM prevalence (1:500).
Main Results:
- Of 1022 pSCDs, 13 had HCM (1.3% of pSCDs, 2% of arrhythmic deaths).
- 11 of 13 HCM cases (85%) were arrhythmic deaths, significantly higher than non-HCM pSCDs (54%).
- Only 2 (15%) HCM cases had a pre-mortem diagnosis; incidence was highest in individuals under 35.
Conclusions:
- Hypertrophic cardiomyopathy is associated with autopsy-confirmed arrhythmic sudden death, accounting for a significant proportion of SCDs, especially in younger individuals.
- The majority of HCM-related SCDs occur in undiagnosed individuals, indicating that the true burden of HCM-related sudden death is likely underestimated.
Aims:
Incidence of sudden cardiac death (SCD) is 1%/year in cohorts with hypertrophic cardiomyopathy (HCM), but this estimate presumes arrhythmic cause and misses occult cases dying before diagnosis.
Methods And Results:
POST SCD (POstmortem Systematic InvesTigation of Sudden Cardiac Death) is a prospective cohort study using autopsy, clinical records, and toxicology to adjudicate arrhythmic or non-arrhythmic causes among presumed SCDs (pSCDs) meeting WHO criteria aged 0-90 years in San Francisco County. We included all incident cases 2/1/2011-3/1/2014 (n = 525) and approximately every third day 3/1/2014-9/1/2022 (n = 497) based on medical examiner call schedule. We identified HCM victims via three approaches: (i) pathology; (ii) echocardiogram [transthoracic echocardiogram (TTE)]; (iii) genetic criteria. Incidence calculations used county data and estimated HCM prevalence of 1:500 from studies of persons aged 23-35 years old. Of 1022 pSCDs [558 (54.6%) arrhythmic deaths] during the study period, 13 had HCM: 10 met pathology criteria; 2 via review of 203 TTEs (missed on initial report); 1 via genetic testing. Of these, 11 were arrhythmic deaths, yielding 1.3% burden of sudden death (pSCD) and 2% of arrhythmic death. Only 2 of 13 (15%) pSCDs with HCM had pre-mortem diagnosis. Incidence for persons with HCM 18-35 years old was 0.2% pSCDs/year and 0.1% SADs/year. pSCDs with HCM had a higher proportion of arrhythmic cause [11/13 (85%) vs. 547/1009 (54%), P = 0.03] than those without. pSCD burden due to HCM decreased with age (P = 0.003), highest among victims <35 years old, for whom HCM accounted for 7.1% of pSCD and 9.4% of arrhythmic death. Genetic testing of 317 consented pSCDs yielded pathogenic or likely pathogenic variants in 40% (2/5) and identified one additional case without clinical phenotype.
Conclusion:
In this 11-year countywide post-mortem study, HCM meeting pathologic, clinical, or genetic criteria was associated with autopsy-confirmed arrhythmic cause of sudden death, accounting for 2% of SADs up to age 90, highest in cases <35 years old. Since 85% of cases were undiagnosed before pSCD, the true burden of HCM-related sudden death may be substantially underestimated.
