Obesity-Related PAH: A Paradoxical Phenomenon

A phenomenon in the worlds of obesity and pulmonary arterial hypertension care is known as the “obesity paradox.” This paradox describes the apparent survival advantage high body mass index (BMI) seems to impart on patients with PAH. As reported by an article in the journal Chest, the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) contained patient information suggesting that there is an approximately 25% reduced risk for death by PAH in patients who are obese, but that there is an increased risk for poor six-minute walk distance (6MWD). The same applies for patients with idiopathic PAH, because another article from Acta Cardiologica reports that lower BMI is predictive of greater mortality.

The “trade-off” of higher BMI being protective of survival but destructive of exercise capacity raises the question of how prevalent PAH is in obese patients. A recent study conducted with over 1,000 individuals referred to Mayo Clinic in Florida reviewed patient charts for concurrent diagnoses of PAH and metabolic syndrome. Just over 600 patients had right heart catheterization-confirmed PAH, and 39% of these individuals had some form of metabolic syndrome (defined as having at least three of systemic hypertension, diabetes mellitus, hyperlipidemia, or BMI greater than 30). Patients with metabolic syndrome were spread out over the different groups of PAH, with the majoring in group 3 PAH associated with lung disease and/or hypoxemia (low oxygen in organs).

Possible Causes of Obesity and Pulmonary Hypertension

Along the lines of hypoxemia, it was commonly believed among obesity-related PAH researchers that the disease resulted from hypoventilation and hypoxia (low oxygen in blood) due to the increased effort required to move and oxygenate excess body fat. Recent evidence has suggested otherwise, and a group of researchers from University of Colorado investigated how inflammation without hypoxia can lead to PAH in obese rats. The study, “Obesity-Related Pulmonary Arterial Hypertension in Rats Correlates with Increased Circulating Inflammatory Cytokines and Lipids and with Oxidant Damage in the Arterial Wall but not with Hypoxia,” was published in the journal Pulmonary Circulation. The researchers created a model of obesity-related PAH using a high-fat diet and an overfeeding diet in rats. The rats developed remodeling of the pulmonary artery and saw an increase in right ventricle wall thickness. There was no evidence of hypoxia or other hypoventilation, but there was a high level of circulating inflammatory molecules and oxidative damage.

Another theory for why obesity and PAH are linked involves the hormone leptin, which is secreted by adipose tissue and is commonly associated with obesity alone. Leptin enhances metabolism and suppresses appetite, but it also seems to regulate cardiovascular function. A group of researchers from Cleveland Clinic conducted a study with leptin-deficient and control mice to examine how a lack of leptin could be involved in obesity-related PAH. As reported in “Leptin Deficiency Recapitulates the Histological Features of Pulmonary Arterial Hypertension in Mice,” the pulmonary arterial walls of leptin-deficient mice were nearly five times as thick as those of the control mice and had 25% thicker right ventricle walls. Although the researchers did not conduct any functional tests, the mice had visual signs of PAH due to a lack of leptin and the development of obesity.

Also secreted by adipose tissue is the molecule adiponectin. Found in high abundance in lean individuals, adiponectin has anti-inflammatory properties. Similar to leptin, if adiponectin is deficient, PAH may develop. A review of the literature by researchers from Boston University and Massachusetts General Hospital suggests that adiponectin suppresses overgrowth of smooth muscle cells along the walls of the pulmonary arteries and inhibits inflammatory actions of macrophage cells in the circulation. While a lack of adiponectin and the presence of obesity may not directly cause PAH, the inflammatory state and consequential remodeling that are present may contribute and could potentially be addressed by increasing levels of adiponectin.

Experimental Treatments May Treat Obesity-Related PAH

The theory of increasing adiponectin to combat PAH was tested using the peroxisome proliferator-activated receptor-gamma (PPARγ) agonist rosiglitazone. Rosiglitazone is in the class of thiazolidinedione drugs, which also include the antidiabetic drug pioglitazone. By stimulating the protein PPARγ in adipose tissue, there is an increase in adiponectin, which a group of researchers from Stanford University School of Medicine hypothesized could prevent PAH in high-fat diet mice. As reported in “Pulmonary Arterial Hypertension is Linked to Insulin Resistance and Reversed by Peroxisome Proliferator-Activated Receptor-Gamma Activation,” mice fed a high-fat diet showed increased right ventricular hypertrophy that was not as pronounced in the same mice treated with rosiglitazone. The treated mice also had normal muscle thickness in the walls of their pulmonary arteries.

Another experimental treatment is based on PAH treatments that are already in use for PAH management. Specifically, prostaglandin analogs have been used to treat PAH because they are able to act to relax the walls of blood vessels to decrease the amount of work the heart must use to pump blood, as explained by the PH Association in the United Kingdom. Logically, if there are more prostaglandin molecules available, there is a greater vessel dilation effect. This logic was tested in a study from Actelion Pharmaceuticals Ltd. in Switzerland using molecules that prevent the reuptake of prostaglandin to increase the pool of available blood vessel dilating molecules. One molecule, named nr 146, improved high-fat glucose tolerance in obese mice and reduced characteristics of PAH. It therefore could be a promising new target for obesity-related PAH.

Scientific Outlook on Obesity and Pulmonary Arterial Hypertension

With various explanations for why obesity and PAH are related, there are various potential treatments for the diseases. It is evident that obesity-related PAH is multi-factorial and results from a combination of genetic, epigenetic, and immune-related factors, as explained by “Severe Pulmonary Hypertension: The Role of Metabolic and Endocrine Disorders.” A number of observations in humans have been investigated directly by creating models of obesity-related PAH in animals. It is encouraging that researchers have found ways to reverse these models, indicating that there may soon be treatments indicated specifically for obesity-related PAH.

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