Heart Plasticity in Response to Pressure- and Volume-Overload: A Review of Findings in Compensated and Decompensated Phenotypes

Abstract

The adult human heart has an exceptional ability to alter its phenotype to adapt to changes in environmental demand. This response involves metabolic, mechanical, electrical, and structural alterations, and is known as cardiac plasticity. Understanding the drivers of cardiac plasticity is essential for development of therapeutic agents. This is particularly important in contemporary cardiology, which uses treatments with peripheral effects (e.g., on kidneys, adrenal glands). This review focuses on the effects of different hemodynamic loads on myocardial phenotype. We examine mechanical scenarios of pressure- and volume overload, from the initial insult, to compensated, and ultimately decompensated stage. We discuss how different hemodynamic conditions occur and are underlined by distinct phenotypic and molecular changes. We complete the review by exploring how current basic cardiac research should leverage available cardiac models to study mechanical load in its different presentations.

Keywords: concentric hypertrophy; eccentric hypertrophy; heart failure; mechanical load; myocardial remodeling; myocardial slices; pressure overload; volume overload.

FIGURE 1

Ventricular pressure-volume dynamics under normal and at onset of pressure-, and volume-overload. Notice that increases in pressure increase left-ventricular pressure and abbreviate stroke volume. Volume-overload shifts the EDV to the right, and SV increases due to higher preload. The sum of the area encompassed by the PV-loop of normal (Cohn et al., 2000) and the ESPVR and EDPVR (Yang et al., 2016) is known as pressure-volume area (PVA) and it correlates with myocardial oxygen consumption. ESPVR, end-systolic pressure-volume relationship; EDPVR, end-diastolic pressure-volume relationship; SV, stroke volume; EDV, end-diastolic volume.

FIGURE 2

Signaling cascade and phenotypic outcomes during pressure-overload induced cardiac remodeling; GPCRs, G-Protein Couple Receptors; β1-AR, β1-Adrenoceptor; ET-1, Endothelin-1; PI3Ks, Phosphoinositide-3-Kinases; Akt (PKB), Akt/Protein Kinase B; G6P, Glucose-6-Phosphate; GSK-3β, Glycogen Synthase Kinase-3β; mTOR, Mammalian Target of Rapamycin; NFAT-P, Phosphorylated Nuclear Factor Activated T-cells; CaMK, Calmodulin Kinase; HATs, Histone Acetylases; HDACs, Histone Deacetylases; MEF2, Myocyte Enhancer Factor-2; MAPK, Mitogen Activated Protein Kinase; SR, Sarcoplasmic Reticulum.

FIGURE 3

Left ventricular pressure (LVP) and stress (σ) transients during the compensatory phase of pressure-, and volume-overload and compared to normal load. Notice that hemodynamic profiles differ in terms of cardiac LVP generation. The ventricular chamber must generate pressure greater than that in the aorta to eject blood. An increase in afterload in pressure-overload results in increased LVP. In the compensated state, stress is normalized by thickening of the ventricular wall according to LaPlace’s law. Modified from Figure 5 of Grossman et al. (1975).

FIGURE 4

Signaling cascade and phenotypic output in volume-overload. CT-1, Cardiotrophin-1; GP130/LIFR, Glycoprotein-130/Leukemia Inhibitory Factor Receptor; JAK, Janus Kinases; STAT, Signal Transducer and Activator of Transcription Proteins.

FIGURE 5

Convergence and divergence in cardiac remodeling.