**Author details**

elusive. RV-specific adaptations to exercise, however, have lagged, in large part due to clinical concerns. Even in healthy individuals with normal pulmonary vascular function, the hemodynamic load on the RV increases with a relatively greater proportion during exercise than LV hemodynamic load. This disproportionate increase in load is accentuated in patients with PH. Exerciseinduced increases in pulmonary artery pressures may exceed RV contractile reserve, resulting in attenuated cardiac output and exercise intolerance. Thus only recently have clinical and preclinical studies begun looking at the cardioprotective role of exercise specifically on the RV.

The primary goal of most of the recent studies of exercise in PH patients was to evaluate safety of low-level exercise training and changes in systolic pulmonary artery pressure. A recent meta-analysis assessing safety outcomes in low intensity aerobic exercise in the form of walking, cycling, and light resistance training found improvement of non-invasive measurements of cardiac performance and exercise capacity, as well as improvement of PH functional class and quality of life [116]. Preclinical studies in rodents with MCT-induced PH also support the benefit of aerobic exercise training. Several animal studies show improvement of mean pulmonary arterial pressure, measured by right heart catheterization following 3–5 weeks of exercise training consisting of 30–60 min of 50–60% maximal aerobic capacity [117]. Subsequent work to investigate the timing of exercise for therapeutic benefit in experimental PH induced by MCT found that exercise initiated early, before MCT injection, was markedly more successful at improving disease outcomes such as survival, diastolic RV function, cardiac output and exercise tolerance, although some benefit was also observed in the

Though exercise stimulates a multitude of cardioprotective mechanisms, endurance exercise is a well-known stimulator of mitochondrial biogenesis, first reported by measuring mitochondrial mass in the myocardium in 1967 [119]. Subsequent mechanistic studies have shown lower mPTP opening rates and apoptosis resistance in endurance trained animals [120], decreased mitochondrial ROS production in exercise trained rats [121], and increased oxidative capacity and mitochondrial volume [122], and increased mitochondrial biogenesis [123]. To our knowledge, no groups have investigated these mechanisms in RV failure and exercise, and virtually nothing is known about the molecular adaptations within the RV that occur in response to exercise therapy.

Understanding of RV metabolism and mitochondrial function has lagged that of the left heart, and arguably even less is known about how RV mitochondria adapt to pathological stress. What little is known about the role of mitochondrial function and metabolism in the dysfunctional or failing RV (summarized in **Table 2**) has largely been extrapolated from studies of LV dysfunction, and there is a large need for more mechanistic studies of the failing RV to more successfully target therapies. In addition to a need for both pre-clinical and clinical investigations of the right heart, a reductionist approach may be needed to make significant strides in RV therapy. The heart (and the RV) is comprised of multiple different cell types. Due to the fact that cardiac myocytes are the work horses of the heart, heart failure studies have historically been myocyte-centric. However, emerging data from our group and others suggests that

cohort who began exercise training 2 weeks after MCT injection [118].

**7. Conclusions and future investigations**

18 Mitochondrial Diseases

Danielle R. Bruns\* and Lori A. Walker

\*Address all correspondence to: danielle.bruns@ucdenver.edu

Division of Cardiology, Department of Medicine, University of Colorado-Denver, Aurora, CO, USA
