Novel insights into the pathobiology of pulmonary hypertension in heart failure with preserved ejection fraction

Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common cause of pulmonary hypertension (PH) worldwide and is strongly associated with adverse clinical outcomes. The American Heart Association recently highlighted a call to action regarding the distinct lack of evidence-based treatments for PH due to poorly understood pathophysiology of PH attributable to HFpEF (PH-HFpEF). Prior studies have described cardiophysiological mechanisms to explain the development of isolated postcapillary PH (ipc-PH); however, the consequent increase in pulmonary vascular (PV) resistance (PVR) may lead to the less understood and more fatal combined pre- and postcapillary PH (cpc-PH). Metabolic disease and inflammatory dysregulation have been suggested to predispose PH, yet the molecular mechanisms are unknown. Although PH-HFpEF has been studied to partly share vasoactive neurohormonal mediators with primary pulmonary arterial hypertension (PAH), clinical trials that have targeted these pathways have been unsuccessful. The increased mortality of patients with PH-HFpEF necessitates further study into viable mechanistic targets involved in disease progression. We aim to summarize the current pathophysiological and clinical understanding of PH-HFpEF, highlight the role of known molecular mechanisms in the progression of PV disease, and introduce a novel concept that lipid metabolism may be attenuating and propagating PH-HFpEF.NEW & NOTEWORTHY Our review addresses pulmonary hypertension (PH) attributable to heart failure (HF) with preserved ejection fraction (HFpEF; PH-HFpEF). Current knowledge gaps in PH-HFpEF pathophysiology have led to a lack of therapeutic targets. Thus, we address identified knowledge gaps in a comprehensive review, focusing on current clinical epidemiology, known pathophysiology, and previously studied molecular mechanisms. We also introduce a comprehensive review of polyunsaturated fatty acid (PUFA) lipid inflammatory mediators in PH-HFpEF.

Keywords: HFpEF; PH; PH-HFpEF; PUFA; diastolic HF.

Figure 1.

Hemodynamic definitions of pulmonary hypertension (PH) due to heart failure (HF) with preserved ejection fraction (HFpEF). PH due to HFpEF (PH-HFpEF) can be classified into compensated HFpEF, HFpEF with isolated postcapillary PH (ipc-PH), or HFpEF with pre- and postcapillary PH (cpc-PH). With the use of right heart catheterization, the gold standard tool for diagnosis, the mean pulmonary arterial pressure (mPAP) can be identified. According to the 2022 European Society of Cardiology/European Respiratory Society Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension, if the mPAP is <20 mmHg, the patient is characterized as having compensated HFpEF, defined as a pulmonary capillary wedge pressure (PCWP) < 15 mmHg at rest or >15 mmHg on provocation with fluid challenge or exercise, pulmonary vascular resistance (PVR) ≤ 2 wood units (WU), and transpulmonary gradient (TPG) ≤ 12 mmHg. Conversely, if the mPAP is >20 mmHg, patients can be defined as either having HFpEF with ipc-PH or with cpc-PH. The defining factor between ipc-PH vs. cpc-PH is PVR. A PVR of ≤2 WU is quantified as ipc-PH, where patients have increased PAWP >15 mmHg, but normal or low TPG of ≤12 mmHg. A PVR >2 is defined as cpc-PH, characterized by PAWP >15 mmHg, but TPG >12, signifying a distinctive hemodynamic process from ipc-PH. Figure was created with a licensed version of BioRender.com.

Figure 2.

Development of pulmonary hypertension (PH) in heart failure (HF) with preserved ejection fraction (HFpEF). Pathophysiology of PH in HFpEF (PH-HFpEF) is complex. Features of metabolic syndrome (metS), such as type 2 diabetes, dyslipidemia, obesity, aging, and hypertension have been well studied to be risk factors and comorbidities of HFpEF via cardiac remodeling and diastolic dysfunction. Subsequent volume overload and increase in left atrial (LA) pressures lead to increased pulmonary venous pressures and isolated postcapillary PH (ipc-PH). Transition from ipc-PH to the more severe, irreversible pulmonary vascular (PV) remodeling and increased PV resistance (PVR) seen in combined pre- and postcapillary PH (cpc-PH) is not well studied. We predict that low-grade inflammation, through lipid metabolism dysregulation, decreased nitric oxide (NO) bioavailability, and increased endothelin-1 (ET-1) contribute to cpc-PH in HFpEF. LV, left ventricular; mPAP, mean pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; WU, wood units. Figure was created with a licensed version of BioRender.com.

Figure 3.

Metabolic syndrome-induced pulmonary hypertension (PH)-heart failure (HF) with preserved ejection fraction (PH-HFpEF) in experimental animal models. PH-HFpEF has been strongly associated with features of metabolic syndrome (metS), including hyperglycemia, adiposity, and insulin resistance. Many studies have explored the association of metS with PH-HFpEF, specifically via the use of animal models. Ranchoux et al. (64) developed a metS rat model through a high-fat diet and olanzapine-induced hyperglycemia and diastolic dysfunction via supracoronary aortic banding. This rat model developed features of PH-HFpEF. Anti-IL-6 antibodies and metformin treatment reversed features of PH, such as pulmonary vascular (PV) remodeling. Meng et al. (65) demonstrated how a metS model via a high-fat diet induced features of PH-HFpEF; no treatment modality was used in this study to reverse the adiposity. Lai et al. (63) studied how pulmonary endothelial injury in leptin receptor-deficient obese mouse model of metS induced PH-HFpEF features. Treatment with nitrite and metformin reversed the features of metS, including hyperglycemia and glucose intolerance, and increased adiponectin levels, a key protector of metabolic and vascular diseases. However, more severely affected PH-HFpEF rats, likely progressed to pre- and postcapillary PH (cpc-PH), did not benefit from nitrite or metformin treatment, suggesting the need for early mets therapeutic intervention as nitric oxide (NO) bioavailability may play a less predominant role in cpc-PH pathogenesis in HFpEF. EF, ejection fraction; LV, left ventricle; LVEF, left ventricle ejection fraction; RVSP, right ventricular systolic pressure; PVR, pulmonary vascular resistance. Figure was created with a licensed version of BioRender.com.

Figure 4.

Role of inflammatory lipid homeostasis in pulmonary hypertension (PH)-heart failure (HF) with preserved ejection fraction (PH-HFpEF). Diagram shows the balance of inflammatory lipid mediator homeostasis that is needed to prevent progression to PH-HFpEF. The comorbidities present with HFpEF establish a baseline state of chronic low-grade inflammation, defined by IL-6 activation, macrophage and neutrophil proliferation, and imbalance of regulatory T cells (Treg)-to-T helper cells (Treg:Th17) ratio. This chronic inflammatory state can be characterized and enhanced by the imbalance of anti-inflammatory lipid metabolites with proresolutory metabolites and proinflammatory metabolites. In a state where the balance is tipped toward proinflammatory lipid metabolism, we predict that this can further increase proliferation of immune cells and cytokines, antibodies, soluble mediators, fibroblasts, and reactive oxygen species (ROS), predisposing to a complex state of the deleterious pre- and postcapillary PH (cpc-PH) in patients with HFpEF. Conversely, we predict that the predominance of proresolutory metabolites can protect against this state, as seen in patients with compensated HFpEF who do not develop cpc-PH or develop isolated postcapillary PH (ipc-PH). PGE₁, prostaglandin E₁; PGI₂, prostacyclin; LXA₄, lipoxin A₄; LXB₄, lipoxin B₄; LTB₄, leukotriene B₄; NO, nitric oxide; ROS, reactive oxygen species; RV, right ventricular. Figure was created with a licensed version of BioRender.com.