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

Abstract

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.

Keywords: Aortic valvular stenosis; Blood flow; Calcineurin; Cardiomyocyte apoptosis; Concentric LV hypertrophy; Extracellular signal-regulated kinases 1 and 2; Fetal gene reexpression; G protein-coupled receptors; Mitochondrial biogenesis; Mitogen-activated protein kinases; Myocardial fibrosis; Myocardial hypertrophic and hyperplastic growth; PI3K(p110α) lipid kinase–Akt serine/threonine kinase pathway; Pathological cardiac hypertrophy and failure; Physiological cardiac hypertrophy; Pressure overload; Receptor tyrosine kinases; Replication of cardiomyocyte sarcomeres in-parallel and in-series; Resident endogenous stem/progenitor cells and myocardial regeneration; Subendocardial ischemia; Transvalvular gradient.

Fig. 1

Pathways involved in physiological and in the pathological cardiac hypertrophy of calcific aortic valve disease (CAVD). Signal transduction pathways pave the way for cellular mechanisms controlling gene expression; a cascade of molecules leading to the activation of one or more specific transcription factors is actuated. The extracellular signals in the form of ligands/effector molecules, which bind to specific receptors to initiate the hypertrophy-producing pathways, are transcribed across the sarcolemma via an assortment of second messengers. In physiological forms of cardiomyocyte/myocardial growth, only direct mechanotransduction routes and the PI3K(p110α) lipid kinase-Akt serine/threonine kinase pathway are activated, downstream from receptor tyrosine kinases (RTK), leading to left ventricular (LV) remodeling involving replication of cardiomyocyte sarcomeres both in-parallel and in-series and to an eccentric LV hypertrophy pattern with amplified systolic myocardial performance. On the other hand, in the pathological form of hypertrophy that is induced in conjunction with the LV pressure overload of CAVD (or hypertension), there ensues activation of a diverse, wider variety of signaling pathways, involving G protein-coupled receptors (GPCR). GPCR mediate pathological cardiac hypertrophy through downstream mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases 1 and 2 (ERK1/2) and calcineurin, a Ca²⁺-dependent phosphatase that controls hypertrophic gene transcription by dephosphorylating transcription factors such as nuclear factor of activated T cells (NFAT). This ultimately leads to the identifiable expression of a maladaptive genetic program, with activation of protein translation concluding with replication of cardiomyocyte sarcomeres in-parallel and a typically concentric LV hypertrophy; these effects are complicated by cellular apoptosis and ECM fibrosis, by (subendocardial) ischemia with diastolic and systolic dysfunction, and by transition to heart failure with subsequent LV chamber dilatation (see particulars in text). Modified from Pasipoularides [1] with permission from the Journal of Cardiovascular Translational Research

Fig. 2

Multichannel oscillograph recordings of coronary hemodynamics obtained in the chronically instrumented, conscious dog. Phasic waveforms for aortic root pressure, left circumflex coronary artery diameter, blood flow, and left ventricular pressure are shown at rapid paper speed. Before construction of this figure, the pens on the oscillograph were aligned to illustrate accurately the ≈10-ms delay between the rise in aortic pressure and the rise in coronary artery diameter; this delay most likely reflects the fact that the coronary dimension measurements are derived just distal to the measurement of aortic pressure. Note the similar features of the aortic root pressure and coronary diameter waveforms. Coronary blood flow was measured just distal to the coronary artery diameter. The waveform for coronary diameter was similar to that of coronary flow in that both showed downward deflections with atrial systole and isovolumic ventricular contraction. The marked sinus arrhythmia is characteristic of the conscious dog. Adapted, slightly modified, from Vatner et al. [68] with permission from the Journal of Clinical Investigation

Fig. 3

Myocardial microstructure. Clockwise, Top panel: Cardiomyocytes represent the major myocardial constituent by volume, although myocardial fibroblasts are the most numerous cell type. Fibroblasts deposit and remodel the extracellular matrix (ECM) in which all myocardial cells reside and function. Fibrillar ECM proteins like collagen form the scaffold within which these cells organize, while proteins such as laminin and fibronectin are present in smaller amounts with multiple cell binding sites. Bottom panel: Cardiomyocytes in the myocardium are arrayed into a complex crisscrossing pattern of layered sheets; within each sheet, they are mechanically connected to one another by extracellular adherens junctions and desmosomes, which connect intracellularly to actin and desmin filaments of the cytoskeleton, respectively; cadherin/catenin complexes at adherens junctions link the ends of myofibrils from neighboring cells to transmit intercellular active/passive stresses. Left panel: The sarcomeric Z-disks define the lateral borders of individual sarcomeres and are important for intracellular signaling, stretch mechanosensation, and mechanotransduction mechanisms of cardiomyocytes; at costameres, integrins (green) link the ECM to the Z-disc and transmit stresses bidirectionally. Within the sarcomere, titin (the largest known protein in the human body; Gk mythology: the Titans were giants, immortal and powerful) extends between the Z-disc and the M-line (not shown) in the middle of the A-band and acts as an intracellular strain sensor; it encompasses a huge spring-like structure that can stretch or compress as needed building up force as the shape changes; when the cardiomyocytes relax/recoil, it is titin that allows restitution of the original size/configuration

Fig. 4

Immediately after balloon aortic valvuloplasty (BAV) on a patient with AVS, there is a spectacular reduction of the ventricular ejection pressure gradient, which is offset by a complementary increase of the aortic root systolic pressure. LV systolic pressure (total systolic load) remains unchanged; it does not decrease acutely. This is a manifestation of complementarity and competitiveness—see discussion in part 1 [1]—between the competing intrinsic component (ventricular ejection pressure gradient, hatched area) and extrinsic component (aortic root systolic pressure) of the total ventricular systolic load (LV systolic pressure). AoP: aortic root pressure; LVP: left ventricular pressure; these pressure waveforms are ensemble averages of many steady-state beats obtained by a double-tip multisensor Millar left-heart catheter. Redrawn from Shim et al. [93] by permission of Circulation Research