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

Abstract

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.

Keywords: Aortic transvalvular pressure gradient; Aortic valve inflammation, fibrosis and calcific nodule buildup; Aortic valvular stenosis (AVS); Bicuspid aortic valve disease (BAVD); Compensatory myocardial hypertrophy in pressure overload (PO); Feedback control of myocardial hypertrophy; Fetal type genes; Genomics of calcific aortic valve disease (CAVD); Hemodynamics; Immediate early-response genes (IEGs); Intrinsic component of the total systolic ventricular load; Macromolecular crowding and cardiomyocyte diameters in PO hypertrophy; Pressure loss recovery; Replication of cardiomyocyte sarcomeres in-parallel and in-series.

Fig 1

Pathways involved in physiological and in pathological cardiac hypertrophy actuated in 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 an eccentric LV hypertrophy pattern with enhanced 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 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).

Fig 2

Top panels: In a patient with AVS, the congruence in the simultaneously measured flow waveform shapes by transthoracic continuous wave Doppler (CWD) and by an intravascular catheter-mounted electromagnetic flowmeter (EMF) probe is striking. Bottom panels: The marked dependence of the flow-driving pressure gradient values on the matching flow velocities is clear. The high frequency fluctuations on the downstroke of the aortic root EMF velocity waveforms and on the aortic root systolic pressure tracing in AVS are characteristic of the inception of turbulence—decelerating flows are relatively unstable, as a rule, whereas accelerating flows (upstroke) tend to be more stable. These fluctuations tend to be more prominent during even a modest intensity exercise, because of the rise in turbulence intensity ensuing with the higher transvalvular ejection velocities. LV = left ventricular; Ao = aortic; C = chamber; P = pressure. Adapted with permission of PMPH-USA from Pasipoularides A. Heart’s Vortex: Intracardiac Blood Flow Phenomena [13].

Fig 3

Top panels: Multisensor catheter pullback in AVS, performed utilizing a left-heart solid-state multisensor Millar catheter (Millar Instruments, Houston, TX) with 2 laterally mounted micromanometers, one at the catheter tip and the second 5 cm proximal to the first and an electromagnetic flow velocity probe at the level of the proximal micromanometer, demonstrating both the strong increase in the subvalvular flow velocity that is associated with the large measured subvalvular pressure gradient just upstream of the stenosed orifice and the pressure loss recovery in the ascending aorta (see text discussion). From top downward: electrocardiogram; linear velocity in deep chamber (panel A), subvalvular region (panel B), vena contracta (panel C) and dilated ascending aorta (panel D); distal and proximal micromanometric signals. Bottom panel: Micromanometric signals obtained by a left-heart Millar “double-tip” catheter—5 cm distance between the 2 micromanometers—during multisensor catheter pullback revealing that the “transvalvular” pressure gradient in AVS is, nearly in its entirety, intraventricular in origin: “magnifying lens” inset (see text discussion). AO = aortic root pressure; LV = deep left ventricular pressure; LVOT= left ventricular outflow tract pressure; ECG = electrocardiogram; RS = respiration signal. Top panels, slightly modified from Pasipoularides [62] with permission of the American College of Cardiology. Bottom panel, reproduced with permission of PMPH-USA from Pasipoularides A. Heart’s Vortex: Intracardiac Blood Flow Phenomena [13].

Fig 4

A feedback loop generally comprises a chain of actions (a, b, c…) where a modifies or influences b, then b influences c, and so on until ultimately some x circles back around to modify a. In a “negative” feedback loop, the end result of the chain of influences is that the system as a whole tends to stabilize around an equilibrium position; if the system starts to deviate one way or the other, the feedback loop tends to pull it back toward equilibrium through end-product/end-state activation or inhibition. In a “positive” feedback loop, the end result of the chain of influences is that over time the system as a whole moves away from equilibrium, in one direction or another, toward an abnormal condition. Top panels: The output of a negative feedback control system might appear as shown in panel A. In this case, the ratios of successive to preceding values ΔC₂/ΔC₁, ΔC₃/ΔC₂, etc., of the controlled variable C(t) are less than unity. Positive feedback may cause what is known as a vicious cycle, or it may not, depending upon the characteristics of the system, as is exemplified in panel B. In the case of the vicious cycle (unbounded response), the ratios ΔC₂/ΔC₁, ΔC₃/ΔC₂, etc., are greater than unity. When the response does not result in a vicious cycle (bounded response), the ratios ΔC₂/ΔC₁, ΔC₃/ΔC₂, etc., are less than unity. Bottom panel: Diagrammatic representation of the interrelation between contractility, load on the ventricular myocardium and ejection variables. Note the negative feedback between the early ejection afterload and the peak velocity and acceleration of the ventricular myocardial fibers. LVEDV = left ventricular end-diastolic volume; LVVpkv = left ventricular volume at the time of peak velocity: PkA = peak outflow acceleration: PkV = peak ejection velocity. Panels A & B, reproduced with permission of PMPH-USA from Pasipoularides A. Heart’s Vortex: Intracardiac Blood Flow Phenomena [13] ; panel C, adapted from Isaaz and Pasipoularides [77], by permission of the American College of Cardiology.

Fig 5

LV distending wall stress at 10 mm Hg transmural pressure, P_T, (top) and LV muscle stiffness at 20 g/cm² distending wall stress (bottom) plotted as a function of banding period in dog hearts. Observe the early increases in both stress and stiffness before substantial wall mass increase, and the oscillatory behavior of the wall stress—note the long quasi-periodicity, extending over many weeks—with the possibility of normal wall stresses occurring at 3 different times during hypertrophy and incipient heart failure; the system seems to oscillate about its desired normal wall stress goal. Such oscillatory behavior is inherent in any feedback regulatory process. It is referable to the inescapable fact that information delivered by any regulatory feedback loop—subserving homeostatic maintenance of developed cardiomyocyte systolic stress levels within the normal range—can affect only future behavior. It cannot deliver a signal fast enough to correct the behavior/factor that drove the current feedback signal, and using dated information to control the approach to a target systolic stress level is likely to cause the system to miss or overshoot/undershoot its goal. There are necessary delays involved in signal transmission and in implementing corrective measures—i.e., replication of sarcomeres in parallel to adjust the systolic stress level—that may overshoot and undershoot their target (see text discussion). Figure adapted from Mirsky and Pasipoularides [100], by permission of the Federation of American Societies for Experimental Biology.