Implementing genome-driven personalized cardiology in clinical practice.

Genomics designates the coordinated investigation of a large number of genes in the context of a biological process or disease. It may be long before we attain comprehensive understanding of the genomics of common complex cardiovascular diseases (CVDs) such as inherited cardiomyopathies, valvular diseases, primary arrhythmogenic conditions, congenital heart syndromes, hypercholesterolemia and atherosclerotic heart disease, hypertensive syndromes, and heart failure with preserved/reduced ejection fraction. Nonetheless, as genomics is evolving rapidly, it is constructive to survey now pertinent concepts and breakthroughs. Today, clinical multimodal electronic medical/health records (EMRs/EHRs) incorporating genomic information establish a continuously-learning, vast knowledge-network with seamless cycling between clinical application and research. It can inform insights into specific pathogenetic pathways, guide biomarker-assisted precise diagnoses and individualized treatments, and stratify prognoses. Complex CVDs blend multiple interacting genomic variants, epigenetics, and environmental risk-factors, engendering progressions of multifaceted disease-manifestations, including clinical symptoms and signs. There is no straight-line linkage between genetic cause(s) or causal gene-variant(s) and disease phenotype(s). Because of interactions involving modifier-gene influences, (micro)-environmental, and epigenetic effects, the same variant may actually produce dissimilar abnormalities in different individuals. Implementing genome-driven personalized cardiology in clinical practice reveals that the study of CVDs at the level of molecules and cells can yield crucial clinical benefits. Complementing evidence-based medicine guidelines from large ("one-size fits all") randomized controlled trials, genomics-based personalized or precision cardiology is a most-creditable paradigm: It provides customizable approaches to prevent, diagnose, and manage CVDs with treatments directly/precisely aimed at causal defects identified by high-throughput genomic technologies. They encompass stem cell and gene therapies exploiting CRISPR-Cas9-gene-editing, and metabolomic-pharmacogenomic therapeutic modalities, precisely fine-tuned for the individual patient. Following the Human Genome Project, many expected genomics technology to provide imminent solutions to intractable medical problems, including CVDs. This eagerness has reaped some disappointment that advances have not yet materialized to the degree anticipated. Undoubtedly, personalized genetic/genomics testing is an emergent technology that should not be applied without supplementary phenotypic/clinical information: Genotype≠Phenotype. However, forthcoming advances in genomics will naturally build on prior attainments and, combined with insights into relevant epigenetics and environmental factors, can plausibly eradicate intractable CVDs, improving human health and well-being.

Duke Scholars

Author Ares D. Pasipoularides Surgery, Cardiovascular and Thoracic Surgery