Linking Genes to Cardiovascular Diseases: Gene Action and Gene–Environment Interactions

Abstract

A unique myocardial characteristic is its ability to grow/remodel in order to adapt; this is determined partly by genes and partly by the environment and the milieu intérieur. In the “post-genomic” era, a need is emerging to elucidate the physiologic functions of myocardial genes, as well as potential adaptive and maladaptive modulations induced by environmental/epigenetic factors. Genome sequencing and analysis advances have become exponential lately, with escalation of our knowledge concerning sometimes controversial genetic underpinnings of cardiovascular diseases. Current technologies can identify candidate genes variously involved in diverse normal/abnormal morphomechanical phenotypes, and offer insights into multiple genetic factors implicated in complex cardiovascular syndromes. The expression profiles of thousands of genes are regularly ascertained under diverse conditions. Global analyses of gene expression levels are useful for cataloging genes and correlated phenotypes, and for elucidating the role of genes in maladies. Comparative expression of gene networks coupled to complex disorders can contribute insights as to how “modifier genes” influence the expressed phenotypes. Increasingly, a more comprehensive and detailed systematic understanding of genetic abnormalities underlying, for example, various genetic cardiomyopathies is emerging. Implementing genomic findings in cardiology practice may well lead directly to better diagnosing and therapeutics. There is currently evolving a strong appreciation for the value of studying gene anomalies, and doing so in a non-disjointed, cohesive manner. However, it is challenging for many—practitioners and investigators—to comprehend, interpret, and utilize the clinically increasingly accessible and affordable cardiovascular genomics studies. This survey addresses the need for fundamental understanding in this vital area.

Calcific Aortic Valve Disease: Part 1—Molecular Pathogenetic Aspects, Hemodynamics, and Adaptive Feedbacks

“…BAV disease (BAVD) has a strong genetic basis and may accompany many other congenital cardiovascular defects including coronary artery anatomic anomalies, aortic coarctation, patent ductus arteriosus, ventricular septal defects, and Marfan syndrome [41]; however, the precise causes and intricate interactions that may implicate signaling pathways of BAV calcification and aortic root dilatation, as well as the multiscale interconnected effects of valvular calcification, hemodynamics, and aortic medial degeneration remain unknown.…”

“…New proteomic approaches that entail genome-wide association studies (GWAS) [41–43] sequencing both haploid genomes of individuals should identify genomic variations, such as loci of common single-nucleotide polymorphisms (SNPs) [41, 43] across the genome, and correlate them with susceptibility to CAVD and severity of AVS, with the ultimate goal of defining causal genetic pathways and molecular mechanisms [44]. I have examined difficulties and caveats of such studies of multifactorial diseases recently [41]; they pertain primarily to the fact that expressed traits/phenotype are the outcome of primary causal mutations/variants, of modifier genes ushering into the picture gene–gene interactions (GxG), and also of environmental factors contributing gene–environment (GxE) interactions. Once we identify diverse pathobiologic mechanisms controlling why certain individuals develop CAVD, while others live well into old age without expressing it, we may be in position to identify rational targets for the development of small molecule, gene transfer, or cell-based therapies to prevent or retard the progress of CAVD and to customize such treatments as needed in variously susceptible individuals—personalized medicine!…”

“…In the diagnostic evaluation of the patient with CAVD/AVS, examination of all four cardiac valves and checking for other lesions that might be mistaken for aortic valvular disease are important; e.g., other diagnostic possibilities might include a subaortic membrane, mitral regurgitation, ventricular septal defect, and hypertrophic cardiomyopathy [13, 41, 54, 62, 74, 79, 83, 87]. A thorough examination encompasses exclusion/confirmation of each differential diagnosis, as well as the appraisal of the aortic valve itself.…”

“…Interestingly, in the third beat of the panel, where the velocity is highest, the downstream pressure exhibits a prominent mid-systolic dip coincident with peak velocity . Such a “dip” requires meticulous effort to be demonstrated in aortic stenosis, although a large-scale counterpart is typically present in micromanometric recordings from the outflow tract or the aortic root in cases of hypertrophic cardiomyopathy with large dynamic systolic gradients [13, 41, 62, 79]. This is a good example of the important, albeit subtle, hemodynamic measurement findings and insights that are within the province of the translational cardiologist with requisite preparation in and understanding of cardiac fluid dynamics, while appearing to be “accidents” without apparent cause and void of any significance for the more casual observers.…”

“…Accordingly, feedback activation and inhibition encompass time delays of gene expression and adjustment implementation; these embody finite times for transduction, nuclear transmission, transcription, transcript splicing and processing, cytoplasmic translocation and protein synthesis, etc. [4, 5, 13, 41]. They can, therefore, result in oscillatory behavior of the “level” of the controlled system variable, viz.…”