Diabetes Enters Stage Right: Genetic Association Studies Suggest Diabetes Promotes Pulmonary Hypertension and Right Ventricular Dysfunction

Abstract

Diabetes is a health care epidemic as there were a staggering 21.9 million adults diagnosed with diabetes in the United States in 2014. 1 Projections suggest this could be just the tip of the iceberg as the number of adults with diabetes in the United States may be as high as 39.7 million in 2030 and 60.6 million in 2060. 1 It is well established that diabetes is a major risk factor for multiple cardiovascular diseases including coronary artery disease, stroke, peripheral vascular disease, and both systolic and diastolic heart failure. 2 In cardiac biology, the bulk of investigations evaluating the effects of diabetes are focused on left ventricular structure/function. However, the relationships between diabetes and pulmonary hypertension and right ventricular (RV) function are not as well defined. As the hemodynamic definition of pulmonary hypertension has changed, 3 the expected number of patients with pulmonary hypertension has risen to as many as 1% of the worldwide population and up to 10% of those aged 65 or greater. 4 Pulmonary hypertension is a heterogeneous group of diseases, and multiple etiologies can underlie the rise in pulmonary pressures. 5 Despite this heterogeneity, pulmonary hypertension is lethal as it frequently culminates with RV failure, 5 a condition that currently lacks effective treatments. 6 Even in expert centers, survival in pulmonary hypertension is quite poor as median survival ranges from 2 to 7 years, depending on the cause. 7 Thus, defining what pathways may be targetable to combat adverse pulmonary vascular remodeling and RV failure may improve outcomes for a large number of patients worldwide. In the innovative study in this issue of the Journal of the American Heart Association (JAHA), Bagheri et al 8 integrated unbiased genetics approaches with clinical variables associated with pulmonary hypertension and RV function to define genetic associations between clinical conditions and pulmonary hypertension and RV compensation. The authors analyzed over 14 000 subjects and found diabetes was the most statistically significant clinical code associated with pulmonary pressure as defined by echocardiography. Importantly, both 2‐sample univariable Mendelian randomization and multivariable Mendelian randomization analyses documented that diabetes, but not obesity, was independently associated with pulmonary pressures and RV dysfunction. The association between diabetes and pulmonary pressures and RV function were independent of multiple clinical measures of left heart disease including left ventricular ejection fraction, left ventricular mass, and left atrial maximal diameter. These results suggest there is a direct relationship between diabetes and the right heart‐pulmonary circulation unit. Diabetes shares many common pathogenic mechanisms with adverse pulmonary vascular remodeling and RV dysfunction (Figure). In particular, diabetes results in chronic inflammation, endothelial cell dysfunction, impaired lipid handling, and mitochondrial metabolic derangements, 2 pathways that are implicated in both preclinical and clinical pulmonary vascular disease 9 and RV failure. 10 , 11 , 12 , 13 As the authors point out, multiple groups have documented insulin resistance in pulmonary arterial hypertension, 14 , 15 , 16 , 17 providing more evidence that these 2 diseases share common pathophysiological mechanisms. Figure 1 Shared pathogenic mechanisms in diabetes and pulmonary hypertension and right ventricular (RV) failure. Figure created using biorender.com In summary, Bagheri et al should be congratulated on this study. The authors have shed new light on an association between diabetes and pulmonary hypertension and RV dysfunction. However, there are important questions to be considered moving forward. First, does this association apply to more diverse populations, as this study was conducted in a population with predominantly European ancestry? In addition, does diabetes duration and severity modulate its relationships with pulmonary pressures and right heart function? One may imagine that patients with long‐standing and poorly controlled diabetes may be at even greater risk for pulmonary hypertension and RV decompensation, but this hypothesis is untested. Finally, would currently available therapeutics implemented in diabetes improve RV‐pulmonary circulation relationships if used in pulmonary hypertension? These questions loom large as the number of patients with diabetes continues to rise at alarming rates. Certainly, clinicians will need to understand the best approaches to treat these complex patients as this study suggests we may be seeing a large influx of patients with diabetes in our pulmonary hypertension clinics in the near future. Disclosures K.W.P. served as a consultant to Edwards and receives grant funding from Bayer. F.K. is funded by National Institutes of Health (NIH) R01 HL162927, and K.W.P. is funded by NIH K08 HL140100, NIH R01s HL158795, and HL162927.