Cardiac genetic investigation of sudden cardiac death: advances and remaining limitations

Abstract

Directing a thorough postmortem investigation of a young sudden unexpected death is one opportunity that a forensic pathologist has to save lives. Achieving a diagnosis of an inherited heart condition in the decedent means that family members can be screened for the condition and effective protective therapies can be put into place. Since these conditions are almost always autosomal dominant, 50% of family members are at risk. Diagnosis is achieved through a thorough high-quality autopsy examination, storage and analysis of DNA, and involvement of the family in the investigation, including cardiac tests upon them. Forensic pathologists should form a partnership with a cardiac genetic service and liaise with them in cases of sudden unexplained death, particularly in 1-to 40-year olds, and when cardiomyopathy is diagnosed at autopsy. The molecular autopsy in sudden unexplained death should include the most common long QT genes and RyR2, the cardiac ryanodine gene linked to catecholaminergic polymorphic ventricular tachycardia. Alternatively or in addition, genetic testing can be guided by cardiac findings in first-degree relatives. With such an approach, a diagnosis can be achieved in up to 50%. Most sudden death in young people occurs at sleep, rest or light activity, and not during sport. Pathologists should be aware that long QT and catecholaminergic polymorphic ventricular tachycardia can be misdiagnosed as epilepsy in life. These ion channelopathies and the cardiomyopathies such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy can present with drowning in a competent swimmer, straight road car accidents, and death that can be triggered by certain medications or toxins.

Spatiotemporal Patterns of Early Afterdepolarizations Underlying Abnormal T-wave Morphologies in a Tissue Model of the Purkinje-Ventricular System

“…With partial concurrent blockade (20%) of I Kr and I CaL , few changes in the excitation patterns can be observed, while major concurrent blockade (60%) of [24] and T-wave alternans with reduced beat-to-beat variations in QT intervals (QT=443.2 ms, 596.9 ms; ↓47%) and increased beat-to-beat differences in T pe (T pe =82. and Epi tissues and led to inverted, asymmetric broad-based T-wave morphology [25] in the rst beat (QT=504.8 ms; T pe =172.8 ms) and T-wave alternans with substantial beat-to-beat variations in T pe intervals (T pe =172.8 ms, 43.2 ms).…”

Spatiotemporal patterns of early afterdepolarizations underlying abnormal T-wave morphologies in a tissue model of the Purkinje-ventricular system

“…Interestingly, as pacing CLs increase (from 750 ms to 850 ms; Fig 5A ), localized EAD events may exclusively arise from midmyocardial tissues to significantly prolong QT (443.2 ms; ↑37%) and T pe (82.4 ms; ↑129%) intervals, with late-appearing (QT prolongation) and pointed (exclusive EADs in the midmyocardium) T-wave morphology [ 23 ] and T-wave alternans with reduced beat-to-beat variations in QT intervals (QT = 443.2 ms, 596.9 ms; ↓47%) and increased beat-to-beat differences in T pe (T pe = 82.4 ms, 33.6 ms; ↑1425%). In Fig 5B , under certain conditions (complete inhibition of I Kr and 20% reduction of I CaL at CL = 550 ms), localized EAD events can synchronously arise from two neighboring tissue types, i.e., M and Epi tissues and led to inverted, asymmetric broad-based T-wave morphology [ 24 ] in the first beat (QT = 504.8 ms; T pe = 172.8 ms) and T-wave alternans with substantial beat-to-beat variations in T pe intervals (T pe = 172.8 ms, 43.2 ms).…”

Spatiotemporal Patterns of Early Afterdepolarizations Underlying Abnormal T-Wave Morphologies in a Tissue Model of the Purkinje-Ventricular System

“…In Fig. 4B, under certain conditions (complete inhibition of I Kr and 20% reduction of I CaL at CL = 550 ms), localized EAD events can synchronously arise from two neighboring tissue types, i.e., M and Epi tissues and led to inverted, asymmetric broad-based T-wave morphology [25] in the rst beat (QT = 504.8 ms; T pe =172.8 ms) and T-wave alternans with substantial beat-to-beat variations in T pe intervals (T pe =172.8 ms, 43.2 ms).…”