Pulmonary arterial hypertension: pathogenesis and clinical management

Abstract

Pulmonary hypertension is defined as a resting mean pulmonary artery pressure of 25 mm Hg or above. This review deals with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension that primarily affects the pulmonary vasculature. In PAH, the pulmonary vasculature is dynamically obstructed by vasoconstriction, structurally obstructed by adverse vascular remodeling, and pathologically non-compliant as a result of vascular fibrosis and stiffening. Many cell types are abnormal in PAH, including vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells. Progress has been made in identifying the causes of PAH and approving new drug therapies. A cancer-like increase in cell proliferation and resistance to apoptosis reflects acquired abnormalities of mitochondrial metabolism and dynamics. Mutations in the type II bone morphogenetic protein receptor (BMPR2) gene dramatically increase the risk of developing heritable PAH. Epigenetic dysregulation of DNA methylation, histone acetylation, and microRNAs also contributes to disease pathogenesis. Aberrant bone morphogenetic protein signaling and epigenetic dysregulation in PAH promote cell proliferation in part through induction of a Warburg mitochondrial-metabolic state of uncoupled glycolysis. Complex changes in cytokines (interleukins and tumor necrosis factor), cellular immunity (T lymphocytes, natural killer cells, macrophages), and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory disease. Obstructive pulmonary vascular remodeling in PAH increases right ventricular afterload causing right ventricular hypertrophy. In some patients, maladaptive changes in the right ventricle, including ischemia and fibrosis, reduce right ventricular function and cause right ventricular failure. Patients with PAH have dyspnea, reduced exercise capacity, exertional syncope, and premature death from right ventricular failure. PAH targeted therapies (prostaglandins, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase stimulators), used alone or in combination, improve functional capacity and hemodynamics and reduce hospital admissions. However, these vasodilators do not target key features of PAH pathogenesis and have not been shown to reduce mortality, which remains about 50% at five years. This review summarizes the epidemiology, pathogenesis, diagnosis, and treatment of PAH.

Identification of novel dynamin‐related protein 1 (Drp1) GTPase inhibitors: Therapeutic potential of Drpitor1 and Drpitor1a in cancer and cardiac ischemia‐reperfusion injury

“…While abnormalities of mitochondrial metabolism, notably a shift to aerobic glycolysis called the Warburg phenomenon, contribute to the proliferation/apoptosis imbalance in cancer, this study focuses on developing therapeutic agents that target another, more recently recognized abnormality, namely dysregulation of mitochondrial dynamics. 7 This suggests the RV dysfunction, which is commonly the cause of mortality in PAH, 22 may in part be due to mitochondrial fission. 10,11 Inhibition of Drp1 triggers a cell cycle checkpoint and results in cell cycle arrest and induction of apoptosis.…”

“…21 We have shown previously that there is a basal fragmentation of mitochondria in RV myocytes of monocrotaline rats with pulmonary arterial hypertension (PAH), even in the absence of induced IR. 7 This suggests the RV dysfunction, which is commonly the cause of mortality in PAH, 22 may in part be due to mitochondrial fission. Our current results confirm prior studies and demonstrates that inhibiting mitochondrial fission in RV cardiomyocytes by targeting Drp1 decreases mitochondrial ROS production and is cardioprotective ex vivo, evident as a preservation of RV diastolic function 7,8,23 (Figure 8).…”

The Effect of Epicardial Fat on the Right and Left Ventricular Function in Subjects with Various Etiological Types of Pulmonary Arterial Hypertension

“…Pulmonary arterial hypertension (PAH) represents an increase in the pulmonary arterial pressure above 25 mmHg, triggered by a progressive rise in pulmonary vascular resistance due to vasoconstriction, vascular remodeling, fibrosis, and inflammation. 1 Several studies have identified the presence of proinflammatory cytokines as promoters of PAH, including interleukins, tumor necrosis factor, and autoantibodies, which advocate for the autoimmune inflammatory pathogenesis of the disease. 2,3 Vessel remodeling and increased vascular resistance in the pulmonary arterial circulation leads to overload of the right cardiac chambers, with right ventricular hypertrophy, tricuspid regurgitation, and subsequent right atrial remodeling, and in case of associated right ventricle ischemia or fibrosis, the evolution is towards right cardiac failure.…”

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

“…PDE5i might offer a compelling way forward for this purpose. Importantly, PDE5i are a safe and well tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction, benign lower urinary tract symptoms and pulmonary arterial hypertension 21, 47 . High dose PDE5i show safety and efficacy for treating heart failure with reduced ejection fraction 48 .…”