Clinical-pathological correlations of BAV and the attendant thoracic aortopathies. Part 2: Pluridisciplinary perspective on their genetic and molecular origins.

Bicuspid aortic valve (BAV) arises during valvulogenesis when 2 leaflets/cusps of the aortic valve (AOV) are fused together. Its clinical manifestations pertain to faulty AOV function, the associated aortopathy, and other complications surveyed in Part 1 of the present bipartite-series. Part 2 examines mainly genetic and epigenetic causes of BAV and BAV-associated aortopathies (BAVAs) and disease syndromes (BAVD).

Clinical-pathological correlations of BAV and the attendant thoracic aortopathies. Part 1: Pluridisciplinary perspective on their hemodynamics and morphomechanics.

Clinical BAV manifestations pertain to faulty aortic valve (AOV) function, the associated aortopathy, and other complications such as endocarditis, thrombosis and thromboembolism. BAV arises during valvulogenesis when 2 of the 3 leaflets/cusps of the AOV are fused together. Ensuing asymmetric BAV morphologies alter downstream ejection jet flow-trajectories.

Morphomechanic phenotypic variability of sarcomeric cardiomyopathies: A multifactorial polygenic perspective.

Morphology underlies subdivision of the primary/heritable sarcomeric cardiomyopathies (CMs) into hypertrophic (HCM) and dilated (DCM). Next-generation DNA-sequencing (NGS) has identified important disease-variants, improving CM diagnosis, management, genetic screening, and prognosis. Although monogenic (Mendelian) analyses directly point at downstream studies, they disregard coexisting genomic variations and gene-by-gene interactions molding detailed CM-phenotypes.

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.

Genomic translational research: Paving the way to individualized cardiac functional analyses and personalized cardiology.

For most of Medicine's past, the best that physicians could do to cope with disease prevention and treatment was based on the expected response of an average patient. Currently, however, a more personalized/precise approach to cardiology and medicine in general is becoming possible, as the cost of sequencing a human genome has declined substantially. As a result, we are witnessing an era of precipitous advances in biomedicine and bourgeoning understanding of the genetic basis of cardiovascular and other diseases, reminiscent of the resurgence of innovations in physico-mathematical sciences and biology-anatomy-cardiology in the Renaissance, a parallel time of radical change and reformation of medical knowledge, education and practice.

Calcific Aortic Valve Disease: Part 2-Morphomechanical Abnormalities, Gene Reexpression, and Gender Effects on Ventricular Hypertrophy and Its Reversibility.

In part 1, we considered cytomolecular mechanisms underlying calcific aortic valve disease (CAVD), hemodynamics, and adaptive feedbacks controlling pathological left ventricular hypertrophy provoked by ensuing aortic valvular stenosis (AVS). In part 2, we survey diverse signal transduction pathways that precede cellular/molecular mechanisms controlling hypertrophic gene expression by activation of specific transcription factors that induce sarcomere replication in-parallel. Such signaling pathways represent potential targets for therapeutic intervention and prevention of decompensation/failure.

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

Aortic valvular stenosis (AVS), produced by calcific aortic valve disease (CAVD) causing reduced cusp opening, afflicts mostly older persons eventually requiring valve replacement. CAVD had been considered "degenerative," but newer investigations implicate active mechanisms similar to atherogenesis--genetic predisposition and signaling pathways, lipoprotein deposits, chronic inflammation, and calcification/osteogenesis. Consequently, CAVD may eventually be controlled/reversed by lifestyle and pharmacogenomics remedies.

Linking Genes to Cardiovascular Diseases: Gene Action and Gene-Environment Interactions.

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.

Mechanotransduction Mechanisms for Intraventricular Diastolic Vortex Forces and Myocardial Deformations: Part 2.

Epigenetic mechanisms are fundamental in cardiac adaptations, remodeling, reverse remodeling, and disease. A primary goal of translational cardiovascular research is recognizing whether disease-related changes in phenotype can be averted by eliminating or reducing the effects of environmental epigenetic risks. There may be significant medical benefits in using gene-by-environment interaction knowledge to prevent or reverse organ abnormalities and disease.

Mechanotransduction mechanisms for intraventricular diastolic vortex forces and myocardial deformations: part 1.

Epigenetic mechanisms are fundamental in cardiac adaptations, remodeling, reverse remodeling, and disease. This two-article series proposes that variable forces associated with diastolic RV/LV rotatory intraventricular flows can exert physiologically and clinically important, albeit still unappreciated, epigenetic actions influencing functional and morphological cardiac adaptations and/or maladaptations. Taken in toto, the two-part survey formulates a new paradigm in which intraventricular diastolic filling vortex-associated forces play a fundamental epigenetic role, and examines how heart cells react to these forces.

Vortex formation time is not an index of ventricular function.

The diastolic intraventricular ring vortex formation and pinch-off process may provide clinically useful insights into diastolic function in health and disease. The vortex ring formation time (FT) concept, based on hydrodynamic experiments dealing with unconfined (large tank) flow, has attracted considerable attention and popularity. Dynamic conditions evolving within the very confined space of a filling, expansible ventricular chamber with relaxing and rebounding, and viscoelastic muscular boundaries diverge from unconfined (large tank) flow and encompass rebounding walls' suction and myocardial relaxation.

Galen, father of systematic medicine. An essay on the evolution of modern medicine and cardiology.

Galen (129-217) was the ultimate authority on all medical subjects for 15 centuries. His anatomical/physiological concepts remained unchallenged until well into the 17th century. He wrote over 600 treatises, of which less than one-third exist today.

Historical continuity in the methodology of modern medical science: Leonardo leads the way.

Early modern medical science did not arise ex nihilo, but was the culmination of a long history stretching back through the Renaissance, the Middle Ages, Byzantium and Roman times, into Greek Antiquity. The long interval between Aristotle and Galen and Harvey and Descartes was punctuated by outstanding visionaries, including Leonardo, the ultimate Renaissance man. His attitude and mindset were based on Aristotelian pursuit of empirical fact and rational thought.

Greek underpinnings to his methodology in unraveling De Motu Cordis and what Harvey has to teach us still today.

William Harvey's writings betray amazing insights born out of countless hours of thoughtful experimentation. Throughout his life, Harvey worked as a tireless and thoughtful researcher and a transmitter and intermediary between the ancient Greek natural philosophers and physicians and the "moderns," for whom he founded two forward-looking, interlinked sciences: modern physiology and nascent cardiology. Harvey's methodology and demonstrations were of such fundamental and standardizing nature as to secure the sure progress of these two sciences.

Evaluation of right and left ventricular diastolic filling.

A conceptual fluid-dynamics framework for diastolic filling is developed. The convective deceleration load (CDL) is identified as an important determinant of ventricular inflow during the E wave (A wave) upstroke. Convective deceleration occurs as blood moves from the inflow anulus through larger-area cross-sections toward the expanding walls.

Historical Perspective: Harvey's epoch-making discovery of the Circulation, its historical antecedents, and some initial consequences on medical practice.

In Harvey's Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus of 1628, we see the mechanisms of the Circulation worked out more or less in full from the results of experimental demonstration, virtually complete but for the direct visual evidence of a link between the minute final terminations and initial branches of the arterial and venous systems, respectively. This would become available only when the capillaries could be seen under the microscope, by Malpighi. Harvey's amazingly modern order of magnitude analysis of volumetric circulatory flow and appreciation of the principle of continuity (mass conservation), his adroit investigational uses of ligatures of varying tightness in elegant flow experiments, and his insightful deductions truly explain the movement of the blood in animals.

Right and left ventricular diastolic pressure-volume relations: a comprehensive review.

Ventricular compliance alterations can affect cardiac performance and adaptations. Moreover, diastolic mechanics are important in assessing both diastolic and systolic function, since any filling impairment can compromise systolic function. A sigmoidal passive filling pressure-volume relationship, developed using chronically instrumented, awake-animal disease models, is clinically adaptable to evaluating diastolic dynamics using subject-specific micromanometric and volumetric data from the entire filling period of any heartbeat(s).