Systemic Manifestations of Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a chronic progressive disease characterized by remodeling of the pulmonary vessels, leading to the development of right-sided heart failure. Aside from the symptoms of right ventricular failure and pulmonary circulation impairment, patients with PAH also exhibit changes in other organ systems.
Changes in Pulmonary Circulation Affect Systemic Circulation
Impairment of the pulmonary circulation leads to changes in the partial pressure of oxygen in arterial blood. Endothelial cells of systemic vessels respond to this by altering their metabolism and excessively producing vasoactive substances and other agents. The most affected organs in the systemic circulation include the heart, brain, and kidneys. Patients with PAH have been found to have a 4-times higher risk of developing coronary artery disease. This phenomenon involves the activation of pro-inflammatory cytokines and BRD4 protein (bromodomain protein 4). Given its key role in regulating inflammation and DNA repair, BRD4 protein has been identified as a potential marker of systemic vascular impairment in patients with PAH.
Endothelial dysfunction also leads to reduced blood flow in the cerebral circulation. Patients have shown increased sensitivity of central chemoreceptors, resulting in a decreased ability to respond to elevated CO2 levels in the blood. Ultimately, vascular dysfunction in the brain's circulation may contribute to the development of cognitive disorders, as well as shortness of breath and sleep-related breathing disorders, which are very common in PAH patients.
Kidney impairment is also often associated with heart and lung disease. Microalbuminuria is used as a marker of early-stage renal insufficiency. Some level of albumin excretion was found in up to a quarter of PAH patients. Research has shown that even minimal leakage of albumin through the kidneys (below the threshold for microalbuminuria) is associated with an overall worse prognosis for the patient. However, routine screening for albuminuria is not yet conducted in PAH patients because its benefit for stratifying the risk of complications has not been fully proven.
Metabolic Abnormalities
The prevalence of obesity among PAH patients is gradually increasing. Obesity is associated with dyslipidemia, insulin resistance, and type 2 diabetes mellitus. The highest risk of developing PAH complications was observed in patients with insulin resistance, even regardless of the presence of obesity or diabetes. Hyperlipidemia and related intracellular fat deposits lead to dysregulation of cellular metabolism, formation of reactive oxygen species, and inflammation. Serum fatty acid concentrations were nearly double in PAH patients compared to healthy controls. It was also found that plexiform lesions contain pro-inflammatory lipids (similar to atherosclerotic plaques) that may assist in recruiting pro-inflammatory cells and further disrupt vascular cell function.
Muscle Dysfunction Associated with PAH
Abnormalities in systemic circulation, metabolic dysfunction, and chronic inflammation affect the normal function of muscle tissue. Progressive fatigue, shortness of breath, and exercise intolerance were mainly considered consequences of lung impairment and heart failure. However, recent studies have shown that damaged skeletal and respiratory muscles can directly influence the typical symptomatology of PAH. Changes in mitochondrial function, reduced capillary density, accelerated muscle protein degradation, fiber type switching, and ultimately reduced muscle contraction strength occur in muscle tissue. The presence of systemic myopathy especially increases the risk of patient deterioration. Early recognition and proper and consistent rehabilitation, particularly of respiratory muscles, can help increase exercise tolerance and thereby improve patients' quality of life.
Conclusion
PAH was previously considered a disease of the pulmonary circulation without significant systemic changes. However, research has shown that it is accompanied by a certain degree of abnormalities in the morphology and function of the systemic vascular endothelium. Additionally, the impairment of other organs significantly affects the prognosis of PAH patients. Early recognition and potential treatment and rehabilitation of these changes can influence disease symptomatology, reduce complications, and thereby improve patient quality of life.
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Source: Nickel N. P., Yuan K., Dorfmuller P. et al. Beyond the lungs: systemic manifestations of pulmonary arterial hypertension. Am J Respir Crit Care Med 2020 Jan 15; 201 (2): 148−157, doi: 10.1164/rccm.201903-0656CI.
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