Prospective Risk Stratification in Renal Transplant Candidates for Cardiac Death

AbstractThe cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90–129 and 130–179 when compared to amino acids 1–89 and 200–288. Our data support variations among 90–130 as being a hotspot for sudden cardiac death and the region 131–179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90–129 and 130–180) and low risk (regions 1–89 and 200–288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification.

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Sudden Cardiac Death in Hereditary Dilated Cardiomyopathy

Sudden Cardiac Death ◽

10.5772/intechopen.91702 ◽

2020 ◽

Author(s):

Marianna Leopoulou ◽

Jo Ann LeQuang ◽

Joseph V. Pergolizzi ◽

Peter Magnusson

Keyword(s):

Sudden Cardiac Death ◽

Left Ventricle ◽

Sudden Death ◽

Risk Stratification ◽

Dilated Cardiomyopathy ◽

Cardiac Death ◽

Disease Risk ◽

Systolic Dysfunction ◽

Preventive Strategies ◽

Genetic Origin

Dilated cardiomyopathy (DCM) is characterized by the phenotype of a dilated left ventricle with systolic dysfunction. It is classified as hereditary when it is deemed of genetic origin; more than 50 genes are reported to be related to the condition. Symptoms include, among others, dyspnea, fatigue, arrhythmias, and syncope. Unfortunately, sudden cardiac death may be the first manifestation of the disease. Risk stratification regarding sudden death in hereditary DCM as well as preventive management poses a challenge due to the heterogeneity of the disease. The purpose of this chapter is to present the epidemiology, risk stratification, and preventive strategies of sudden cardiac death in hereditary DCM.

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