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. Based on BAV morphologies, ejection-flows exhibit different wall-impingement and scouring patterns in the proximal aorta, with excessive hydrodynamic wall-shear that correlates closely with mural vascular smooth muscle cell and extracellular matrix disruptions, revealing hemodynamic participation in the pathogenesis of BAV-associated aortopathies. Since the embryologic regions implicated in both BAV and aortopathies derive from neural crest cells and second heart field cells, there may exist a common multifactorial/polygenic embryological basis linking the abnormalities. The use of Electronic Health Records - encompassing integrated NGS variant panels and phenotypic data - in clinical studies could speed-up comprehensive understanding of multifactorial genetic-phenotypic and environmental factor interactions. This Survey represents the first in a 2-article pluridisciplinary work. Taken in toto, the series covers hemodynamic/morphomechanical and environmental (milieu intérieur) aspects in Part 1, and molecular, genetic and associated epigenetic aspects in Part 2. Together, Parts 1-2 should serve as a reference-milestone and driver for further pluridisciplinary research and its urgent translations in the clinical setting.

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). Part 1 explored the heterogeneity among subsets of patients with BAV and BAVA/BAVD, and investigated abnormal fluid dynamic stress and strain patterns sustained by the cusps. Specific BAV morphologies engender systolic outflow asymmetries, associated with abnormal aortic regional wall-shear-stress distributions and the expression/localization of BAVAs. Understanding fluid dynamic factors besides the developmental mechanisms and underlying genetics governing these congenital anomalies is necessary to explain patient predisposition to aortopathy and phenotypic heterogeneity. BAV aortopathy entails complex/multifactorial pathophysiology, involving alterations in genetics, epigenetics, hemodynamics, and in cellular and molecular pathways. There is always an interdependence between organismic developmental signals and genes-no systemic signals, no gene-expression; no active gene, no next step. An apposite signal induces the expression of the next developmental gene, which needs be expressed to trigger the next signal, and so on. Hence, embryonic, then post-partum, AOV and thoracic aortic development comprise cascades of developmental genes and their regulation. Interdependencies between them arise, entailing reciprocal/cyclical mutual interactions and adaptive feedback loops, by which developmental morphogenetic processes self-correct responding to environmental inputs/reactions. This Survey can serve as a reference point and driver for further pluridisciplinary BAV/BAVD studies and their clinical translation.

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. In-place of polygenic models, in accounting for observed defective genotype-phenotype correlations, fuzzy concepts having gradations of significance and unsharp domain-boundaries are invoked, including pleiotropy, genetic-heterogeneity, incomplete penetrance, and variable expressivity. HCM and DCM undoubtedly entail cooperativity of unidentified/elusive causative genomic-variants. Modern genomics can exploit comprehensive electronic/digital health records, facilitating consideration of multifactorial variant-models. Genome-wide association studies entailing high-fidelity solid-state catheterization, multimodal-imaging, molecular cardiology, systems biology and bioinformatics, will decipher accurate genotype-phenotype correlations and identify novel therapeutic-targets, fostering personalized medicine/cardiology. This review surveys successes and challenges of genetic/genomic approaches to CMs, and their impact on current and future clinical care.

Retos y controversias en miocardiopatía hipertrófica: visión integral desde la investigación básica, clínica y genética / Challenges and controversies in hypertrophic cardiomyopathy: clinical, genomic and basic science perspectives

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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.

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. Now on the horizon is an individualized, diverse patient-centered, approach to medical practice that encompasses the development of new, gene-based diagnostics and preventive medicine tactics, and offers the broadest range of personalized therapies based on pharmacogenetics. Over time, translation of genomic and high-tech approaches unquestionably will transform clinical practice in cardiology and medicine as a whole, with the adoption of new personalized medicine approaches and procedures. Clearly, future prospects far outweigh present accomplishments, which are best viewed as a promising start. It is now essential for pluridisciplinary health care providers to examine the drivers and barriers to the clinical adoption of this emerging revolutionary paradigm, in order to expedite the realization of its potential. So, we are not there yet, but we are definitely on our way.

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. Hypertrophy provoking signals, in the form of dynamic stresses and ligand/effector molecules that bind to specific receptors to initiate the hypertrophy, are transcribed across the sarcolemma by several second messengers. They comprise intricate feedback mechanisms involving gene network cascades, specific signaling molecules encompassing G protein-coupled receptors and mechanotransducers, and myocardial stresses. Future multidisciplinary studies will characterize the adaptive/maladaptive nature of the AVS-induced hypertrophy, its gender- and individual patient-dependent peculiarities, and its response to surgical/medical interventions. They will herald more effective, precision medicine treatments.

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. Its management should be comprehensive, embracing not only the valve but also the left ventricle and the arterial system with their interdependent morphomechanics/hemodynamics, which underlie the ensuing diastolic and systolic LV dysfunction. Compared to even a couple of decades ago, we now have an increased appreciation of genomic and cytomolecular pathogenetic mechanisms underlying CAVD. Future pluridisciplinary studies will characterize better and more completely its pathobiology, evolution, and overall dynamics, encompassing intricate feedback processes involving specific signaling molecules and gene network cascades. They will herald more effective, personalized medicine treatments of CAVD/AVS.

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. 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.

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. This survey proposes that "environmental" forces associated with diastolic RV/LV rotatory flows exert important, albeit still unappreciated, epigenetic actions influencing functional and morphological cardiac adaptations. Mechanisms analogous to Murray's law of hydrodynamic shear-induced endothelial cell modulation of vascular geometry are likely to link diastolic vortex-associated shear, torque and "squeeze" forces to RV/LV adaptations. The time has come to explore a new paradigm in which such forces play a fundamental epigenetic role, and to work out how heart cells react to them. Findings from various imaging modalities, computational fluid dynamics, molecular cell biology and cytomechanics are considered. The following are examined, among others: structural dynamics of myocardial cells (endocardium, cardiomyocytes, and fibroblasts), cytoskeleton, nucleoskeleton, and extracellular matrix; mechanotransduction and signaling; and mechanical epigenetic influences on genetic expression. To help integrate and focus relevant pluridisciplinary research, rotatory RV/LV filling flow is placed within a working context that has a cytomechanics perspective. This new frontier in cardiac research should uncover versatile mechanistic insights linking filling vortex patterns and attendant forces to variable expressions of gene regulation in RV/LV myocardium. In due course, it should reveal intrinsic homeostatic arrangements that support ventricular myocardial function and adaptability.

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. The objectives are to provide a perspective on vortical epigenetic effects, to introduce emerging ideas, and to suggest directions of multidisciplinary translational research. The main goal is to make pertinent biophysics and cytomechanical dynamic systems concepts accessible to interested translational and clinical cardiologists. I recognize that the diversity of the epigenetic problems can give rise to a diversity of approaches and multifaceted specialized research undertakings. Specificity may dominate the picture. However, I take a contrasting approach. Are there concepts that are central enough that they should be developed in some detail? Broadness competes with specificity. Would, however, this viewpoint allow for a more encompassing view that may otherwise be lost by generation of fragmented results? Part 1 serves as a general introduction, focusing on background concepts, on intracardiac vortex imaging methods, and on diastolic filling vortex-associated forces acting epigenetically on RV/LV endocardium and myocardium. Part 2 will describe pertinent available pluridisciplinary knowledge/research relating to mechanotransduction mechanisms for intraventricular diastolic vortex forces and myocardial deformations and to their epigenetic actions on myocardial and ventricular function and adaptations.

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. Indeed, clinical/physiological findings seeking validation in vivo failed to support the notion that FT is an index of normal/abnormal diastolic ventricular function. Therefore, FT as originally proposed cannot and should not be utilized as such an index. Evidently, physiologically accurate models accounting for coupled hydrodynamic and (patho)physiological myocardial wall interactions with the intraventricular flow are still needed to enhance our understanding and yield diastolic function indices useful and reliable in the clinical setting.

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. The Galenic corpus is stupendous in magnitude; the index of word-entries in it contains 1300 pages. Galen's errors attracted later attention, but we should balance the merits and faults in his work because both exerted profound influences on the advancement of medicine and cardiology. Galen admonished us to embrace truth as identified by experiment, warning that everyone's writings must be corroborated by directly interrogating Nature. His experimental methods' mastery is demonstrated in his researches, spanning every specialty. In his life-sustaining schema, the venous, arterial, and nervous systems, with the liver, heart, and brain as their respective centers, were separate, each distributing through the body one of three pneumata: respectively, the natural, the vital, and the animal spirits. He saw blood carried both within the venous and arterial systems, which communicated by invisible "anastomoses," but circulation eluded him. The "divine Galen's" writings, however, contributed to Harvey's singular ability to see mechanisms completely differently than other researchers, thinkers and experimentalists. Galen was the first physician to use the pulse as a sign of illness. Some representative study areas included embryology, neurology, myology, respiration, reproductive medicine, and urology. He improved the science and use of drugs in therapeutics. Besides his astounding reputation as scientist-author and philosopher, Galen was deemed a highly ethical clinician and brilliant diagnostician.

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. He declared himself to be a "man without letters" to underscore his disdain for those whose culture was only mnemonics and philosophical inferences from authoritative books. Leonardo read the Book of Nature with the immense curiosity of the pioneering scientist, ushering in the methodology of modern medical science with help from forerunners. He left no publications, but extensive personal Notebooks: on his scientific research, hydrodynamics, physiological anatomy, etc. Apparently, numerous successors availed themselves of his methodologies and insights, albeit without attribution. In his Notebooks, disordered and fragmentary, Leonardo manifests the exactitude of the engineer and scientist, the spontaneous freshness of one speaking of what he has at heart and that he knows well. His style is unrefined, but intensely personal, rich with emotion and, sometimes, poetic. Leonardo, the visionary anatomist, strived consistently not merely to imitate nature by depicting body structures, but to perceive through analysis and simulations the intimate physiologic processes; i.e., the biomechanics underlying the workings of all bodily organs and components, even the mysterious beating heart. It is fitting to regard him as the first modern medical scientist.