Altered metabolism in pulmonary hypertension: fuelling the fire or just smoke?

Abstract

]. Pulmonary arterial hypertension (PAH) is characterised by progressive obliteration of the pulmonary vasculature, culminating in right-sided heart failure (HF). In recent years, studies have observed an association between systemic metabolic dysfunction, PAH and right ventricular failure [1]. Patients with PAH have an increased prevalence of obesity [2] and type 2 diabetes [3, 4]. Interestingly, abnormal glucose metabolism is evident even in non-diabetic individuals with PAH [5-7], and serves as an independent predictor of prognosis [8]. Right ventricular function is also associated with metabolic syndrome [9, 10], and myocardial tissue in mouse models of PAH exhibit defects in fatty acid oxidation associated with increased lipid deposition [11]. In addition, peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis and glucose homeostasis, has been implicated in the pathogenesis of vascular remodelling and subsequent development of PAH [12, 13]. PPARγ is also a downstream target of bone morphogenic protein receptor 2 (BMPR2) [14]. BMPR2 mutations are seen in up to 80% of hereditary PAH, and BMPR2 sporadic mutations occur in idiopathic PAH [15]. A rodent model of inducible BMPR2 overexpression develops insulin resistance preceding features of PAH [16]. Collectively, these observations suggest that impaired glucose metabolism may be a causative factor in PAH. However, most of the clinical data above is derived from cross-sectional studies with very limited metabolic outcomes. In this issue of European Respiratory Journal, MEY et al. [17] utilised hyperglycaemic clamp methodology and plasma metabolomics to further characterise metabolism in patients with idiopathic PAH (n=6) compared to age-, sex-and BMI-matched controls (n=6). To perform the hyperglycaemic clamp, glucose was infused at a variable rate to maintain continuous hyperglycaemia (180 mg•dL −1). Levels of insulin and C-peptide were measured to quantify pancreatic β-cell function, while the rate of glucose infused was used as a surrogate for insulin sensitivity. During the clamp, the authors found that peripheral insulin concentrations were lower in subjects with PAH, which translated to a 92% increase in insulin sensitivity in the PAH group. Hepatic insulin extraction (calculated as insulin/C-peptide molar ratio) was greater in PAH than in controls. However, pancreatic β-cell insulin secretion, as assessed by C-peptide concentrations, was similar between the two groups. In addition, PAH was associated with increased fatty acid oxidation and ketogenesis, as evidenced by elevated acetylcarnitine and β-hydroxybutyrate (βOHB) levels. The authors confirmed this metabolic shift using plasma metabolomics in a larger cohort of PAH patients.

Dysbiosis of the Salivary Microbiome is Associated with Hypertension and Correlated with Metabolic Syndrome Biomarkers

“… 36 The mechanisms for the positive association of higher C-peptide levels with the risk of hypertension have not yet been elucidated. However, it is known that elevated levels are associated with insulin resistance and hyperglycemia, 37 as observed in the current study.…”

Targeting Endothelial ENO1 (Alpha-Enolase) -PI3K-Akt-mTOR Axis Alleviates Hypoxic Pulmonary Hypertension

“…11 Such potentials are consistent with our results; however, we cannot completely exclude the cell dysfunction could cause the further adaption of metabolism in reverse. 36 As a result of the vicious cycle, the PH-ECs maintain the phenotypes of proliferation, restoration, inflammation, and then vascular remodeling. 37 In fact, the pivotal role of metabolic alterations is well documented by experimental evidence in rodent models and patients with other forms of PH, 38 but there is lack of studies addressing the role of ECs metabolic dysfunction in HPH.…”