Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is typically due to right ventricular (RV) failure. An excellent predictor of mortality in PAH is proximal pulmonary artery stiffening, which is mediated by collagen accumulation in hypoxia-induced pulmonary hypertension (HPH) in mice. We sought to investigate the impact of limiting vascular and ventricular collagen accumulation on RV function and the hemodynamic coupling efficiency between the RV and pulmonary vasculature. Inbred mice were exposed to chronic hypoxia for 10 days with either no treatment (HPH) or with treatment with a proline analog that impairs collagen synthesis (CHOP-PEG; HPH + CP). Both groups were compared to control mice (CTL) exposed only to normoxia (no treatment). An admittance catheter was used to measure pressure-volume loops at baseline and during vena cava occlusion, with mice ventilated with either room air or 8% oxygen, from which pulmonary hemodynamics, RV function, and ventricular-vascular coupling efficiency (ηvvc) were calculated. Proline analog treatment limited increases in RV afterload (neither effective arterial elastance Ea nor total pulmonary vascular resistance significantly increased compared to CTL with CHOP-PEG), limited the development of pulmonary hypertension (CHOP-PEG reduced right ventricular systolic pressure by 10% compared to HPH, p < 0.05), and limited RV hypertrophy (CHOP-PEG reduced RV mass by 18% compared to HPH, p < 0.005). In an acutely hypoxic state, treatment improved RV function (CHOP-PEG increased end-systolic elastance Ees by 43%, p < 0.05) and maintained ηvvc at control, room air levels. CHOP-PEG also decreased lung collagen content by 12% measured biochemically compared to HPH (p < 0.01), with differences evident in large and small pulmonary arteries by histology. Our results demonstrate that preventing new collagen synthesis limits pulmonary hypertension development by reducing collagen accumulation in the pulmonary arteries that affect RV afterload. In particular, the proline analog limited structural and functional changes in distal pulmonary arteries in this model of early and somewhat mild pulmonary hypertension. We conclude that collagen plays an important role in small pulmonary artery remodeling and, thereby, affects RV structure and function changes induced by chronic hypoxia.
These findings are compatible with a major role of one or more of renin, vasopressin, and noradrenaline in the pathophysiology of the fluid retention of heart failure; the manifestations are not counteracted by the rise in atrial natriuretic factor.
Chesler N. Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia. J Appl Physiol 117: 833-839, 2014. First published August 28, 2014 doi:10.1152/japplphysiol.00059.2014.-Chronic hypoxia causes chronic mountain sickness through hypoxiainduced pulmonary hypertension (HPH) and increased hematocrit. Here, we investigated the impact of increased hematocrit and HPH on right ventricular (RV) afterload via pulmonary vascular impedance. Mice were exposed to chronic normobaric hypoxia (10% oxygen) for 10 (10H) or 21 days (21H). After baseline hemodynamic measurements, ϳ500 l of blood were extracted and replaced with an equal volume of hydroxyethylstarch to normalize hematocrit and all hemodynamic measurements were repeated. In addition, ϳ500 l of blood were extracted and replaced in control mice with an equal volume of 90% hematocrit blood. Chronic hypoxia increased input resistance (Z 0 increased 82% in 10H and 138% in 21H vs. CTL; P Ͻ 0.05) and characteristic impedance (Z C increased 76% in 10H and 109% in 21H vs. CTL; P Ͻ 0.05). Hematocrit normalization did not decrease mean pulmonary artery pressure but did increase cardiac output such that both Z 0 and ZC decreased toward control levels. Increased hematocrit in control mice did not increase pressure but did decrease cardiac output such that Z 0 increased. The paradoxical decrease in ZC with an acute drop in hematocrit and no change in pressure are likely due to inertial effects secondary to the increase in cardiac output. A novel finding of this study is that an increase in hematocrit affects the pulsatile RV afterload in addition to the steady RV afterload (Z 0). Furthermore, our results highlight that the conventional interpretation of Z C as a measure of proximal artery stiffness is not valid in all physiological and pathological states. cardiopulmonary hemodynamics; chronic hypoxia; characteristic impedance; blood viscosity; pulmonary vascular impedance CHRONIC MOUNTAIN SICKNESS (CMS), also known as Monge's disease, occurs after chronic exposure to hypoxia at high altitudes and is characterized by increased pulmonary artery pressures and pulmonary vascular resistance (29) as well as increased hematocrit (19). Chronic hypoxia also contributes to worse outcomes in lung diseases such as chronic obstructive pulmonary disease, sleep apnea, and pulmonary fibrosis (1,10,15). In preclinical animal models of pulmonary arterial hypertension (PAH), chronic hypoxia is often used to generate hypoxia-induced pulmonary hypertension (HPH). PAH is a debilitating disease with a low median survival of 2.8 yr (6,17) and is characterized by remodeling throughout the pulmonary vasculature, including distal arterial narrowing and proximal and distal pulmonary artery stiffening, leading to right ventricular (RV) dysfunction that progresses to RV failure as the cause of death (28). HPH in rodents recapitulates the pulmonary vascular remodeling and RV hypertrophy that occur in patients with PAH but also increases hematocrit. Indeed, the increase in ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.