EXPRESS: Right Heart in Pulmonary Hypertension: From Adaptation to Failure

Abstract

Right ventricular (RV) failure (RVF) has garnered significant attention in recent years because of its negative impact on clinical outcomes in patients with pulmonary hypertension (PH). PH triggers a series of events, including activation of several signaling pathways that regulate cell growth, metabolism, extracellular matrix remodeling, and energy production. These processes render the RV adaptive to PH. However, RVF develops when PH persists, accompanied by RV ischemia, alterations in substrate and mitochondrial energy metabolism, increased free oxygen radicals, increased cell loss, downregulation of adrenergic receptors, increased inflammation and fibrosis, and pathologic microRNAs. Diastolic dysfunction is also an integral part of RVF. Emerging non-invasive technologies such as molecular or metallic imaging, cardiac MRI, and ultrafast Doppler coronary flow mapping will be valuable tools to monitor RVF, especially the transition to RVF. Most PH therapies cannot treat RVF once it has occurred. A variety of therapies are available to treat acute and chronic RVF, but they are mainly supportive, and no effective therapy directly targets the failing RV. Therapies that target cell growth, cellular metabolism, oxidative stress, and myocyte regeneration are being tested preclinically. Future research should include establishing novel RVF models based on existing models, increasing use of human samples, creating human stem cell-based in vitro models, and characterizing alterations in cardiac excitation–contraction coupling during transition from adaptive RV to RVF. More successful strategies to manage RVF will likely be developed as we learn more about the transition from adaptive remodeling to maladaptive RVF in the future.

Fig. 1.

Transthoracic echocardiographic images of right ventricle (RV). (a) Apical four-chamber view showing RV, left ventricle (LV), right atrium (RA), and left atrium (LA). The RV cavity appears triangular (orange dashed line). (b) Subcostal mid-papillary view showing circular LV and crescent-shaped RV. (c) Parasternal long-axis view showing RV, LV, and aortic root (Ao). (d) Three-dimensional drawing of the RV and its relationship to the LV.

Fig. 2.

Molecular mechanism by which RV hypertrophy (RVH) develops in response to pressure overload. G-protein-coupled receptors (GPCRs) are activated during stress, leading to activation of Gα-dependent calmodulin kinase II (CaMKII) and the calcineurin/ nuclear factor of activated T-cells (NFAT) pathway. Mechanical stress also directly stimulates the membrane integrin-associated mitogen-activated protein kinase kinase (MEK) pathway. In addition, inflammatory factors activate respective receptors to induce nuclear factor kappa-light-chain-enhancer of activated B cell (NF-кB) and Janus kinase (JAK)–signal transducer and activator of transcription protein (STAT) signaling. Activation of these three pathways increases transcription factors, thus promoting the cell proliferation, protein synthesis, and growth that lead to hypertrophy. Ang II, angiotensin II; ERK1/2, extracellular-signal regulated kinase; ET-1, endothelin-1; FAK, focal adhesion kinase; HDAC, histone deacetylase; IKK, IкB kinase; IL-6, interleukin 6; IP3, inositol trisphosphate; JNK, c-Jun N-terminal kinase; mTOR, mammalian target of rapamycin; NIK, NF-кB inducing kinase; PLC, phospholipase C; SAIC, stretch-activated ion channels; SR, sarcoplasmic reticulum.

Fig. 3.

(a) Schematic illustration of pressure-volume relationship of the right ventricle (RV) and RV–pulmonary artery (PA) coupling. An adapted RV pressure–volume relationship is also shown (defined by dotted square). E_a, arterial elastance; EDPVR, end-diastolic pressure-volume relationship; EDV, end-diastolic volume; ESD, end-systolic volume; ESPVR, end-systolic pressure-volume relationship, defined as contractility and known as E_es; SV, stroke volume. (b) Mechanism by which contractility is maintained in adapted or compensated RV during PH. An increase in afterload activates three fundamental mechanisms that increase contractility within the RV. These mechanisms remain active throughout the adaptive/compensated phase. See text for details. AC, adenylate cyclase; FS, Frank-Starling; ET-1, endothelin 1; LTCC, L-type calcium channel; PKA, protein kinase A; RyR, ryanodine receptor; SAIC, stretch-activated ion channels; SR, sarcoplasmic reticulum.

Fig. 4.

Features of RV adaptation and RVF. RV adaptation and RVF manifest at different levels of organization. At the organ level, RV adaptation is associated with RVH and maintained function. RVF presents as alterations in anatomy and function. At the cellular level, changes in metabolism and biochemistry occur in both adapted RV and RVF. Some metabolic mediators are found in both adapted and maladapted RV, and their roles in promoting each are controversial. At the molecular level, metabolites, molecules, proteins, and mediators of signaling pathways are altered or modified in adapted RV and RVF. New signaling pathways and mediators have been identified in RVF. BNP, B-type natriuretic peptide; ETC, electron transport chain; HIF-1α, hypoxia-inducible factor 1α; IGF, insulin-like growth factor; miRNA, microRNA; NT-proBNP, N-terminal pro b-type natriuretic peptide; PDE5, phosphodiesterase-5; PDK, pyruvate dehydrogenase kinase; PKG, protein kinase G; ROS, reactive oxygen species; TGF-β1, transforming growth factor beta 1; VEGF, vascular endothelial growth factor.^,,,,,

Fig. 5.

Factors contributing to diastolic dysfunction of the RV in PH.