# Molecular Phenotyping for Autopsy-Defined Sudden Cardiac Death

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $803,344

## Abstract

PROJECT SUMMARY/ABSTRACT
 Conventional definitions of sudden cardiac death (SCD) presume cardiac cause.4 Our NHLBI-funded ongoing
POST SCD Study, which has autopsied 97% of >1000 consecutive SCDs since 2011, is the first and only
prospective unselected adult SCD cohort, capturing the entirety of SCDs in a community, to use autopsy to refine
SCD to true cardiac causes.5 Recent SCD risk6 and genetic studies7 have reported inconsistent results likely due
to reliance on the presumed SCD phenotype. Guidelines8 and recent studies3 support postmortem targeted
cardiovascular disease (CVD) genetic testing of autopsy-negative sudden deaths < 35 years, but no guidelines
exist for postmortem genetic testing of older SCDs (> 35 years), nor SCDs with structural pathology. In POST
SCD, 98% of cases have common pathology such as coronary artery disease (CAD), left ventricular hypertrophy
(LVH), or dilated cardiomyopathy (DCM). The contribution of clinically actionable monogenic CVD has not been
studied in autopsy-defined adult SCD with a background of such common cardiac pathology. Our pilot data
demonstrate the potential to elucidate associations of established, pathogenic structural gene variants with
arrhythmic risk to inform postmortem testing guidelines and extend and refine phenotypes. We have successfully
engaged the large majority of POST SCD families to deploy a novel, highly efficient web-based tool to address
a major unmet need in SCD prevention – identifying co-segregating first degree relatives of SCD victims who
are at highest risk. Finally, one of the key barriers to new approaches in SCD prevention is a lack of
understanding of the acute cellular milieu that predisposes to fatal arrhythmias in the context of acquired or
inherited structural pathology, e.g., LVH, fibrosis, dilation, or scar. We propose an innovative method to
interrogate postmortem myocardial RNA transcripts – reflecting the sum total effect of all possible factors in the
hours prior to SCD: genetic, epigenetic, ischemia, neurohumoral, and underlying myocardial pathology – as an
insight into the acute cellular alterations that create vulnerable substrate for fatal arrhythmia.
 We will leverage family consent, blood, and left ventricular samples from our autopsy-defined SCDs and
matched controls to address the following Specific Aims: (1A) Determine the yield of pathogenic variants in
clinically actionable CVD genes in adult SCDs with autopsy sub-phenotypes; (1B) Refine genotype-phenotype
correlations with pathogenic variants in HCM genes for SCDs with LVH, DCM genes for SCDs with dilated hearts,
and channelopathy genes in all SCDs; (2) Elucidate genotype-phenotype correlation to identify first degree
relatives with co-segregating monogenic CVD predisposing to SCD; (3) Characterize the myocardial RNA profile
specific to fatal arrhythmias in the setting of sub-phenotypes of SCD. We anticipate that this project will inform
guidelines for postmortem genetic testing in all adult SCDs, ...

## Key facts

- **NIH application ID:** 9884445
- **Project number:** 1R01HL147035-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ZIAN H TSENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $803,344
- **Award type:** 1
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884445

## Citation

> US National Institutes of Health, RePORTER application 9884445, Molecular Phenotyping for Autopsy-Defined Sudden Cardiac Death (1R01HL147035-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9884445. Licensed CC0.

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