Introduction

Although therapeutic advances have improved survival in patients with pulmonary arterial hypertension (PAH), 5-year survival rates remain poor. Moreover, severely reduced cardiorespiratory fitness and consequent fatigue and exertional dyspnea limit the quality of life for individuals living with PAH. Treatment for PAH has focused on the use of pulmonary arterial vasodilators, which showed some benefit, but also a large residual burden on symptoms and impaired survival in patients with PAH. In this issue of JACC: Basic to Translational Science, Kazmirczak et al¹ take a novel approach to addressing right ventricular (RV) dysfunction in PAH by using a dietary intervention known as intermittent fasting. Nonpharmacological therapies, such as dietary interventions, are being studied across a variety of chronic noncommunicable diseases, yet have received limited exploration in PAH.²

Kazmirczak et al¹ used 2 established models of PAH in rats due to monocrotaline (MCT) and Sugen-hypoxia (SuHx) that are characterized by pulmonary arterial remodeling and RV dysfunction. In these models, the investigators tested whether intermittent fasting influences RV dysfunction, a prognostically important feature of PAH that currently lacks therapeutic strategies. An umbrella term rather than a specific intervention, intermittent fasting encompasses various approaches to fasting, or abstaining from kilocalorie-containing food and beverages for a window of time (Figure 1).³ The study showed that in experimental PAH, intermittent fasting induced adenosine monophosphate–activated protein kinase signaling and prevented dysfunction of mitochondrial and peroxisomal fatty acid metabolism in comparison to a regular feeding schedule.¹ Intermittent fasting also partially restored abnormal mitochondrial cristae morphology and protected against increases in peroxisomal density in comparison to MCT and SuHx rats fed on an ad libitum typical schedule. In both MCT and SuHx models of PAH, intermittent fasting prevented downregulation of several electron transport chain subunit proteins and improved oxygen consumption in several electron transport chain complexes. Intermittent fasting also lessened microtubule proliferation, prevented increases in junctophilin-2 levels, and assisted in restoring T-tubule architecture in comparison to regular feeding. These findings represent positive metabolic and structural effects of intermittent fasting on the RV.

Overall, the molecular changes observed with intermittent fasting in the 2 models of PAH were associated with changes in measures of RV function and of coupling of RV and pulmonary vasculature. Intermittent fasting significantly improved the ratio between the ventricular elastance (Ees) and the pulmonary arterial elastance (Ea) in the MCT model, with a nonsignificant improvement in the tricuspid annulus plane systolic excursion (TAPSE). On the other hand, intermittent fasting significantly improved the TAPSE with a nonsignificant improvement in the Ees/Ea in the SuHx model. While promising, these data require confirmation in additional studies and better understanding on the underlying mechanisms.

However, the majority of clinical studies of intermittent fasting in patients to date have focused on healthy individuals or those with obesity without significant comorbidities and have often centered on weight loss. There is very limited work exploring intermittent fasting in PAH and this has thus far been limited to preclinical models of PAH. Kazmirczak et al¹ uses a form of intermittent fasting referred to as complete alternate-day fasting, which is a complete abstinence from intake of kilocalorie-containing food and beverages on alternating days. In clinical studies of complete alternate-day fasting, participants have achieved weight loss comparable to traditional energy restriction strategies, although many studies have carried serious limitations. Moreover, when complete alternate-day fasting studies have included an isocaloric control group, meaning participants are matched for daily kilocalories, complete alternate-day fasting has not produced more favorable effects on cardiometabolic risk factors such as body composition, insulin sensitivity, or lipid profiles. In one trial, subjects assigned to the energy-restricted complete alternate-day fasting intervention lost less fat mass than the isocaloric nonfasting comparison group despite a lack of difference in weight loss, raising concerns for greater muscle protein breakdown and net catabolism.⁴ Moreover, a concerning reduction in estimated physical activity energy expenditure was also observed from baseline only in the energy-restricted complete alternate-day fasting group.⁴ In PAH, disorders of lean mass loss such as cachexia and sarcopenia are already common. Lean mass, a surrogate measure for skeletal muscle mass, is also a major determinant of cardiorespiratory fitness which is already reduced in PAH. It is, therefore, vital to carefully monitor and assess the impact of any intervention which is likely to impact weight and particularly lean mass. However, recent observational work in patients with heart failure did show that the length of eating window and, therefore, time spent fasting may not impact body composition or cardiorespiratory fitness.⁵

Although clinical studies of intermittent fasting have failed to prove that observed benefits of intermittent fasting are independent from energetic restriction and resulting weight changes, Kazmirczak et al¹ has shown in this experimental setting that there were no significant differences in food intake. However, a trend was noted in the total food intake and weight gain in SuHx intermittent fasting rats vs both SuHx ad libitum and the control group; and, for the MCT intermittent fasting and ad libitum rats, data on both weight and intake are not shown^.1 These experiments were only conducted in male SuHx and MCT rats; and the investigators note that males present with more severe RV dysfunction. However, women represent a greater proportion of patients with PAH (upwards of 85% in some registries), but they present with less severe RV dysfunction and better clinical outcomes than men. It has been suggested that sex hormones, particularly estrogen, may play a role in the differential prevalence and prognosis observed in patients with PAH. Some preclinical work also indicates that intermittent fasting may have sex-specific effects, and a small body of clinical research has further proposed that intermittent fasting may have differential effects on sex hormones (ie, preserving estrogen levels while lowering testosterone). Large randomized clinical trials of intermittent fasting where women have composed from 40% to 80% of enrolled participants, however, have not demonstrated differential effects on primary or secondary outcomes.

Based on the data seen in the experimental models of PAH, a randomized control trial of intermittent fasting in patients with PAH seems reasonable, measuring not only the effects on pulmonary artery pressures and RV function but also monitoring the effects of intermittent fasting on body weight, lean mass, and, most importantly, on cardiorespiratory fitness as a final common measure of impact. Sex-specific effects of intermittent fasting should also be examined, including impacts on sex hormones. Additionally, it would be important to measure the effects of intermittent fasting on dietary intake. Although intermittent fasting has been associated with favorable clinical outcomes in observational studies of patients with coronary artery disease, which are primarily related to religious fasting, intermittent fasting has never before shown benefits on survival or major cardiovascular outcomes in a randomized control trial.

In summary, Kazmirczak et al¹ are to be congratulated for exploring intermittent fasting to determine the impact on complex clinical condition such as PAH. Intermittent fasting has promising therapeutic impacts that deserve careful assessment in the setting of well-controlled preclinical and clinical studies.

Footnotes