Pulmonary arterial hypertension
Some research has looked at adipose tissue–produced substances in PAH, but the most well-established association in obesity and PAH involves insulin resistance.
“I don’t think we’re certain as a community that obesity [in general] is the problem – it’s not itself considered a risk factor for PAH,” Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn., said in an interview. She noted that it’s “hard to dissect obesity” apart.
Researchers are “more confident,” she said, “that insulin resistance – one feature of obesity [in some people] – is associated with worse outcomes in PAH.” Metabolic disease resembling insulin resistance is common in PAH and is believed to contribute to pulmonary vascular disease and right ventricular (RV) failure – the main cause of mortality in PAH – at least in part because of increased oxidative stress.
Dr. Hemnes led a mechanistic phase II clinical trial of metformin in PAH in which the drug was associated with improved RV fractional area change and reduced RV lipid deposition (J Am Heart Assoc. 2020;9[22]:e018349), and she’s now leading a National Institutes of Health–funded multicenter trial looking at the impact of metformin and an exercise intervention on 6-minute walk distance and World Health Organization functional class in PAH.
At the Rush Lung Center, in the meantime, Dr. Mokhlesi is utilizing animal models of OSA and OHS to explore the effect of hypoxia and nighttime hypercapnia on the development of PAH. “I think the jury is still out as to whether obesity itself is a major risk factor, but if so, by what mechanism?” he said. “Is it worsening [sleep-disordered breathing], which then worsens PAH?”
COPD
The focus in COPD has traditionally been on underweight, but the relationship between obesity and COPD has increasingly been recognized in the last 10-15 years, said Frits M. E. Franssen, MD, PhD, of CIRO, a research institute in Horn, the Netherlands, that treats COPD and other chronic lung diseases, and of the department of respiratory medicine at Maastricht University.
Researchers like Dr. Franssen are trying, for one, to understand obesity’s impact on COPD pathophysiology and to tease apart the impact of both conditions on disease severity and patient-related outcomes such as exercise capacity and exercise-related symptoms.
When Dr. Franssen’s group compared responses to weight-bearing exercise (6-min. walk test) and weight-supported exercise (cycling) in obese and normal weight COPD patients matched for age, gender, and degree of airflow limitation, the researchers found that walking capacity was significantly reduced while cycling capacity was preserved in the obese group (Respirology. 2016;21[3]:483-8).
Exercise-related symptoms (dyspnea and leg fatigue) were largely comparable between the obese and normal-weight COPD patients in both exercise modalities. However, in other studies, dyspnea ratings during cycling – at any given level of ventilation – have been lower in obese patients, indicating that “additional fat mass may have a beneficial effect on lung functioning [in non–weight-bearing exercise],” he said in an interview.
Dr. Franssen’s group also has assessed body composition in overweight and obese patients with COPD and found that a significant number have low muscle mass. These patients had worse lung function, exercise tolerance, and muscle strength compared to patients with comparable BMI and normal muscle mass (Respir Res. 2021 Mar 25. doi: 10.1186/s12931-021-01689-w).
“We’d always thought that obese patients have normal muscle mass ... but now we know it can be dramatically low,” he said. In assessing obesity and formulating any weight loss plans, “we’re now interested not only in weight but in the distribution of fat mass and fat-free mass ... and in maintaining muscle mass in patients who are [prescribed dietary interventions].”
Paradoxically, in patients with severe COPD, obesity is associated with prolonged survival, while in patients with mild to moderate COPD, obesity is associated with increased mortality risk, he noted.
The impact of adipose tissue and the chronic inflammation and metabolic disturbances that characterize obesity are currently largely unexplored, he said. Researchers have not yet studied what optimal weights may be for patients with COPD. “And we’re interested in the questions, are body weight and body composition the result of the disease, or [are they] determining the type of COPD one will get?” Dr. Franssen said.
Patients with COPD who are obese have “more of the phenotype of chronic bronchitis,” he noted, “while typical emphysema patients are normally underweight.”