Elsevier

JACC: Heart Failure

Volume 12, Issue 2, February 2024, Pages 235-247
JACC: Heart Failure

State-of-the-Art Review
Role of Oxygen Starvation in Right Ventricular Decompensation and Failure in Pulmonary Arterial Hypertension

https://doi.org/10.1016/j.jchf.2023.03.010Get rights and content

Highlights

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    Right ventricular function determines the outcome in pulmonary arterial hypertension.

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    The transition from right ventricular hypertrophy to failure is driven by hypoxia.

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    No therapies for right ventricular failure are available at present.

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    We propose antihypoxia strategies as possible treatment strategy for right ventricular failure.

Abstract

Right ventricular (RV) function and eventually failure determine outcome in patients with pulmonary arterial hypertension (PAH). Initially, RV responds to an increased load caused by PAH with adaptive hypertrophy; however, eventually RV failure ensues. Unfortunately, it is unclear what causes the transition from compensated RV hypertrophy to decompensated RV failure. Moreover, at present, there are no therapies for RV failure; those for left ventricular (LV) failure are ineffective, and no therapies specifically targeting RV are available. Thus there is a clear need for understanding the biology of RV failure and differences in physiology and pathophysiology between RV and LV that can ultimately lead to development of such therapies. In this paper, we discuss RV adaptation and maladaptation in PAH, with a particular focus of oxygen delivery and hypoxia as the principal drivers of RV hypertrophy and failure, and attempt to pinpoint potential sites for therapy.

Section snippets

Progression of RV Hypertrophy and Failure in PAH

Progressive increase of pulmonary vascular resistance (PVR) is a hallmark PAH. It is caused by a combination of vasoconstriction and vascular remodeling,4 the latter being characterized by medial hypertrophy and hyperplasia, intimal and adventitial fibrosis, thrombotic and plexiform lesions, as well as perivascular infiltration of inflammatory cells. It affects mainly distal and small precapillary arterioles.5

Increasing PVR leads to increased afterload, forcing the RV to pump blood at increased

Left vs Right Ventricle: Focus on Coronary Blood Flow

The LV originates from the splanchnic mesoderm within the primary heart field, whereas the RV develops from the extracardiac mesoderm within the secondary heart field, which potentially explains differential gene expression in RV vs LV.24 Although prenatal RV is thick walled and generates high pressures, after birth the pulmonary circulation becomes a low-pressure circuit, whereas the systemic circulation turns into a high-pressure system, resulting in LV hypertrophy. Ultimately, the RV becomes

RV Hypoxia in PAH

In RVH related to PAH, RV systolic pressure increases, and so does the RV systolic wall stress. This greatly enhances myocardial oxygen demand and the extravascular compression, whereas the perfusion pressure generated by LV does not change or even falls.34 These factors favor impairment of RV CF and hypoxia. Indeed, human studies indicate that RV CF is reduced in PAH and that magnitude of this reduction correlates with RV systolic pressure and RV wall thickness and that RV CF becomes biphasic

RVH, Failure, and Angiogenesis

Myocardial hypertrophy is associated with increased oxygen demand in proportion to myocardial mass. This increased demand can only be met by augmented coronary flow, which requires increased vessel density. It is of particular importance for RV, as RVH is associated with extravascular compression, absent in normal RV.29

The only method to provide increased RV vessel density is angiogenesis: a process of formation of new blood vessels by sprouting and growth from pre-existing blood vessels,

HIF and Hypoxia

The most important pathway triggered by hypoxia is HIF-1.53 The abundance of its alpha subunits is controlled by the cellular oxygen level (Figure 3). Under normoxia, HIF-1α is rapidly hydroxylated and undergoes proteasomal degradation. During hypoxia, HIF-1α abundance increases, it heterodimerizes with HIF-1β subunit, translocates to the nucleus, and activates transcriptional responses.54 These HIF-1–mediated responses aim to restore normal oxygen tension through increased oxygen delivery,

Angiogenesis, Myocardial Hypertrophy and Failure, Hypoxia, and Oxidative Stress

The hallmark of transition from both LV and RV hypertrophy to failure is inadequate angiogenesis, but why does it become inadequate? Evidence indicates that angiogenesis is hampered by oxidative stress.

Oxidative stress refers to increased abundance of reactive oxygen species (ROS)61 and can be caused by increased production or impaired elimination of ROS. Cardiomyocytes are the major source of ROS, produced mainly by mitochondrial electron transport chain or nicotinamide adenine dinucleotide

Metabolic Reprogramming

RVH and RVF are characterized by metabolic reprogramming, involving reduction of cardiomyocyte adenosine triphosphate (ATP) content and switch from glucose and fatty acid oxidation to anaerobic glycolysis (Figure 4). These changes are primarily driven by up-regulation of the HIF-1 pathway; however, their significance remains unknown. Their potential adverse effects include cell acidification caused by lactate accumulation and lipotoxicity related to accumulation of fat metabolites caused by

Other Mechanisms

Other mechanisms probably are involved in the pathophysiology of RVH and RVF. The activity of the sympathetic nerve system is augmented in patients with PAH and is associated with increased mortality.85 Nevertheless, use of beta-blockers is associated with neither benefits nor harm.86 The renin-angiotensin system is also upregulated in PAH,87 although its blockade at different levels does not provide clear benefits.88 RV myocardial stiffness is increased in proportion to severity of PAH and is

LV vs RV Hypertrophy and Failure

These considerations suggest why RV is more prone to transition from hypertrophy to failure than LV. First, RVH is associated with more pronounced hypoxia than LV hypertrophy, mainly caused by lack of resistance to extravascular compression, which could be at least partially related to poorer development of microvascular bed in the postnatal period in RV vs LV,32 possibly induced by lower oxygen tension in the postnatal LV myocardium. We can speculate that in congenital defects, such as

Reverse Remodeling

In the long term, the only successful therapy for both LVF and RVF is reduction of afterload. Procedural removal of pulmonary thrombi, lung transplantation, successful vasodilation therapy in PAH,91 and debanding in animal pulmonary artery banding models of PH92 result in rapid and spectacular RV reverse remodeling within days of the intervention. Function is first to improve, followed by reduction of cardiomyocyte size, RV volume, RV ischemia, and eventually fibrosis.92,93 Emerging data

RV Oriented Interventional and Device Therapies in PAH

As with pharmacotherapy, RV-oriented interventional therapies are significantly lagging behind those aimed at LV therapy. RV responds poorly to cardiac resynchronization therapy.94 Long-term RV assist devices analogous to LV assist devices are not yet available for patients with PAH; extracorporeal membrane oxygenation can be used in critically ill patients as a bridge to transplant or bridge to recovery95 but is not feasible in the long-term setting. Such procedures as atrial septostomy and

Therapeutic Implications

At present, there is no intervention to prevent or treat RVF in PAH. This is in sharp contrast to LV failure, for which there are established therapies: mainly antagonists of neurohormonal systems, providing long-term benefits.97

Moreover, attempts to interfere with specific pathways resulting in RV decompensation and failure, such as metabolic interventions,98 anti-ROS strategies,99 HIF-1– promoting interventions, and proangiogenic agents100 proved only partially successful in animal

Conclusions

Recently, we have demonstrated in monocrotaline-induced PH that RV is indeed hypoxic.38 We then used a new allosteric effector of hemoglobin, Myo-inositol trispyrophosphate (ITPP), that binds to the same allosteric pocket as its physiological regulator—2,3-diphospho-D-glycerate—resulting in rightward shift of hemoglobin-O2 dissociation curve, especially under low O2 conditions, which could explain its effects in hypoxic tumors.106 ITPP improved oxygen tension in RV without affecting normal

Funding Support and Author Disclosures

This study was supported by the National Science Centre, Poland Grant Number 2019/35/B/NZ5/04432. Dr Kieda is a shareholder of Normoxys Inc, manufacturer of ITPP. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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    © 2024 by the American College of Cardiology Foundation. Published by Elsevier.