Pathophysiology of the right ventricle and its pulmonary vascular interaction

Abstract

The right ventricle and its stress response is perhaps the most important arbiter of survival in patients with pulmonary hypertension of many causes. The physiology of the cardiopulmonary unit and definition of right heart failure proposed in the 2018 World Symposium on Pulmonary Hypertension have proven useful constructs in subsequent years. Here, we review updated knowledge of basic mechanisms that drive right ventricular function in health and disease, and which may be useful for therapeutic intervention in the future. We further contextualise new knowledge on assessment of right ventricular function with a focus on metrics readily available to clinicians and updated understanding of the roles of the right atrium and tricuspid regurgitation. Typical right ventricular phenotypes in relevant forms of pulmonary vascular disease are reviewed and recent studies of pharmacological interventions on chronic right ventricular failure are discussed. Finally, unanswered questions and future directions are proposed.

FIGURE 1

The systemic, organ, cellular and molecular causes and subsequent physiological consequences of right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH). Increased afterload paired with derangements in autonomic tone and myocardial perfusion/demand mismatch lead to pathogenic changes in cardiomyocyte structure and function driven in part by mitochondrial metabolic dysfunction, heightened fibrosis due to fibroblast proliferation and activation and pathological inflammation. These cellular and organ level alterations increase RV stiffness and impair contractility that leads to right atrial dilation/dysfunction, RV dilation and tricuspid regurgitation. This ultimately results in end-organ hypoperfusion and venous congestion causing hepatic and renal dysfunction. HIF: hypoxia-inducible factor; PDK: pyruvate dehydrogenase kinase; WNT: wingless/int; lncRNA: long noncoding RNA; n-acetylcholine: nicotinic acetylcholine; AMPK: AMP kinase; NLRP: NACHT-, LRR-, and pyrine domain-containing protein.

FIGURE 2

Novel right ventricular (RV) imaging in pulmonary hypertension. a) RV longitudinal strain patters demonstrate regional heterogeneity. A 65-year-old female with scleroderma presenting with undifferentiated dyspnoea underwent supine bicycle echocardiography. Rest images demonstrate a heterogeneous pattern of strain-derived regional contractility [70], tricuspid annular plane systolic excursion (TAPSE) 2.12 cm, normal RV systolic pressure (RVSP). With 75 W of exercise, the basal segment does not augment while there is increase in regional contractility of the midventricular and apical segments, TAPSE 1.53 cm, associated with chamber dilatation (increase in RV end-diastolic area and end-systolic area, increase midventricular dimension) and RVSP 58 mmHg [71]. Echocardiography-based strain imaging on exercise is technically difficult and not at this stage recommended for standard clinical use. Magnetic resonance imaging four-dimensional flow measurements in b) a healthy control and c) a patient with pulmonary arterial hypertension (PAH). In the healthy person only forward flow and the RV serves as a bellow in which all parts of the RV contribute to the flow movement. In PAH the contribution of the apical region to forward flow is minimal, indicating the heterogeneous contribution of the RV to power output. In addition, the flow is not linear in the atrium and vortex flow can be observed in the pulmonary artery.

FIGURE 3

a–h) While distinguishing types of pulmonary hypertension (PH) based on echocardiography is challenging and depends on the stage of disease, presented here are example images of echocardiographic features of PH subtypes. a) and b) Severe idiopathic pulmonary arterial hypertension (PAH) with a) marked dilation of the right chambers and b) flattening of the interventricular septum, with a squeezed left ventricle (LV) (eccentricity index >1.5). Due to the prominence of the right chambers, this may be described as “right phenotype”. c) and d) PH associated with connective tissue disease (CTD). Patients show prominence of the right chambers, but may have thickening of the mitral (dashed arrow) or the aortic valve and a certain degree of LV diastolic dysfunction. e) and f) PAH associated with an atrial septal defect (#) demonstrating enlarged right atrium (RA) and right ventricle (RV). g) and h) PAH associated with a ventricular septal defect (*) in natural history (Eisenmenger syndrome). Typically, these patients show severe right ventricular hypertrophy (arrow) with a normal or only mildly dilated right ventricle. i–p) Typical echocardiographic features of group 2, 3 and 4 PH. i) and j) Typical remodelling of a patient with heart failure and reduced ejection fraction with isolated post-capillary PH (IpcPH) (“left phenotype”). There is a marked prevalence of the left chambers (g) and a round-shaped left ventricle (eccentricity index 1). k) and l) Patients with combined post- and pre-capillary PH (CpcPH) show an intermediate phenotype (“neither right nor left”) with i) bi-atrial dilation and left ventricle prevalence, but j) initial flattening of the interventricular septum. m) and n) Patients with PH associated with lung disease have usually a prevalence of the right chambers (“right phenotype”), but they are often older than PAH patients and may have a component of left-heart involvement. o) and p) Patients with chronic thromboembolic PH (CTEPH) have a “right phenotype” indistinguishable from PAH patients. Nevertheless, some may have by chance a left-heart disease and features of left heart involvement. CHD: congenital heart disease; LA: left atrium.