Right ventricular adaptation and failure in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patient's functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.

Figure 1. Right ventricular failure in Pulmonary Arterial Hypertension

The Pulmonary Arterial Hypertension Phenotype: An obstructed vascular bed resulting in a hypertrophied dilated, right ventricle. Left hand images: Pulmonary arteries (PAs) become “pruned” in PAH. PAs develop medial hypertrophy, intimal fibrosis, vasoconstriction and inflammation in the adventitia, which causes severe luminal obstruction in PAH, compared to control. Right hand images: Right ventricle in normal individual is thin and small, compared with hypertrophied, fibrotic, ischemic, remodeled right ventricle in PAH.

Figure 2. Electrocardiogram of patients with PAH

ECG in patients with PAH frequently shows (A) right bundle branch block; (B) prominent R wave and ST depression across the precordium; (C) right axis deviation; and (D) S₁Q₃T₃ pattern.

Figure 3. Nuclear Assessment of the Right Ventricle

(A)(1) Diagram of MIBG images, MIBG Uptake in the LV in (2) a healthy volunteer and (3) PH patients, a patient with mild Group1 PH (mPAP 22mmHg) and a patient with severe Group 1 PH (mPAP 77mmHg). In this image decreased myocardial MIBG uptake in is shown as green or blue color in region of interventricular septum in both patients and in inferior LV wall in the severe PH patient. (B) Increased ¹⁸FDG in the RV of PAH patients on epoprostenol. FDG-PET images of patients with mild (A, mean pulmonary artery pressure, 33 mm Hg) and severe pulmonary hypertension (B, mean pulmonary artery pressure, 81 mm Hg). (C) PET showing Increased ¹⁸F-fluorodeoxyglucose(FDG) uptake in RV and lung in monocrotaline (MCT) animal. (D) Fused PET/CT of RV and pulmonary trunk in an iPAH patient.

Figure 4. Metabolic Treatment of Animal Models of PAH with Dichloroacetate

Dichloroacetate (DCA) has demonstrated hemodynamic effects in animal models of pulmonary arterial hypertension (PAH): (A & B). Fawn-hood rat (FHR) model of PAH: DCA increases cardiac output and RV function (TAPSE). (C) Chronic hypoxic model of PAH: DCA decreases mean pulmonary artery pressure and pulmonary vascular resistance. (D) Monocrotaline model of PAH: DCA prolongs in pulmonary artery acceleration time, reflective of a decrease in pulmonary vascular resistance. Reproduced with permission from ^,,.

Figure 5. Mechanisms of Right ventricular ischemia in PAH

(A) Coronary artery perfusion pressure is reduced in both pulmonary artery banding (PAB) and monocrotaline (MCT) models. (B) Right ventricular capillary density is reduced in both MCT and Chronic Hypoxia-Sugen (SuHx) models, but not in PAB model. Dystrophin is labeled green, marking myocyte membranes. Both dystrophin and CD31 (in red) are shown in the left column of panel B. CD31 only is shown in the right panel. The red circles are CD31 positive endothelial cells showing the loss of microvascular bed in monocrotaline RVs. Reproduced with permission from ^,.