**6.2. Mitochondrial therapeutic interventions**

during hypertrophy, but decreased at failure, while mtDNA content progressively decreased with worsening clinical disease [96]. In addition, adult RV samples of various etiologies demonstrate increased mitochondrial membrane potential which positively correlates with the degree of hypertrophy [97]. A complete understanding of mitochondrial function in human right heart failure is limited by methodological constraints of assessing comprehensive ETC function.

Studies of non-energy producing roles of mitochondria are in their infancy in the RV. However, some evidence supports a causative role of ROS, as increased lipid peroxidation is observed in the RV 6 weeks following MCT injection [98]. NADPH oxidase is significant source of ROS in LV hypertrophy, and its expression increases during MCT-induced RV hypertrophy alongside decreased SOD1 and SOD2 expression [99]. Increased expression of pro-apoptotic proteins Bax and capase-3 have also been noted in the RV after PAB, with concomitant increased RV myocyte cell death [100]. Together, the limited investigations of the metabolic and nonmetabolic roles of mitochondria in right heart failure highlight the need for additional work

To date, no RV-directed therapies exist. Right-sided heart failure is typically treated with the goal of improving LV function or lowering pulmonary pressures. Extrapolation of LV pathophysiology and pharmacology to the failing RV has not yet proven fruitful, and in some cases, has accelerated disease progression [101]. Interestingly, lowering of pulmonary pressures (either by pharmaceutical approaches or by lung transplant) does not consistently improve RV function [102], suggesting a cardiac-specific irreversible effect of long-term pressure overload, or contribution of circulating systemic factors. Whatever the reason for insufficient return of RV function despite reduction in afterload, we and others believe that identification

Enhancing glucose oxidation at the expense of FAO as emerged as a therapeutic strategy in RV dysfunction, based on the reciprocal relationship between these two energy sources. In large part, enhancing glucose oxidation has gained attention as a strategy because of the higher ATP production per oxygen molecule provided by carbohydrate compared to lipid sources. Partial inhibitors of FAO are approved for a few human cardiovascular indications including refractory ischemia [103]. These drugs (trimetazidine) have also been experimentally tested in RV dysfunction [86]. Rats with PAB-induced RV dysfunction treated with partial FAO inhibitors had elevated RV glucose oxidation alongside increased exercise capacity and cardiac output. The beneficial effect of this drug has also been demonstrated in MCT-induced RV dysfunction, where trimetazidine enhanced cardiac mitochondrial function and increased

**5.3. Non-energy producing mitochondrial mechanisms of right heart failure**

to elucidate similarly and differentially regulated pathways in left and right HF.

of new, or repurposing of old therapies requires an RV-centric approach.

oxygen consumption while reducing ROS formation [104].

**6. Therapeutic intervention**

16 Mitochondrial Diseases

**6.1. Metabolic therapeutic interventions**

The causal role of ROS in cardiac dysfunction led to the early belief that antioxidants would attenuate cardiovascular disease. In experimental models, treatments with antioxidants have somewhat inconsistently tended to improve cardiac function [107]. However, clinical trials have largely failed to show benefit of antioxidants in treatment of chronic disease [108]. In light of these disappointing results, many groups have taken fundamentally different approaches to improving redox status. Induction of endogenous antioxidants by a phytochemical supplement preserved RV function and prevented RV fibrosis and capillary loss [109], suggesting activation of cytoprotective transcription factors may more robustly attenuate oxidant stress than traditional vitamin supplements. Other groups use mitochondrially-directed peptides to scavenge free radicals. One such peptide, SS31, accumulates more than 1000-fold in mitochondria [110]. This peptide prevented LV hypertrophy, fibrosis, and diastolic dysfunction [111], and reduced mitochondrial oxidant damage [112]. To date, however, targeted mitochondrial peptides have not been tested in models of RV failure.

Interventions which boost mitochondrial function and/or biogenesis have large therapeutic potential in many types of cardiovascular disease, including RV failure. Phytochemical compounds which elicit mitochondrial biogenic properties have received attention lately, such as resveratrol. Resveratrol, the primary polyphenol in red wine, stimulates mitochondrial content, ATP production, and FAO, while inhibiting mitochondrial ROS production in several tissue types and disease contexts [113, 114]. In addition, it is currently in testing as a therapy for chronic obstructive pulmonary disorder (NCT02245932) and non-ischemic heart failure (NCT01914081). Identification of other plant-based or pharmaceutical approaches which stimulate the synthesis of new mitochondria to increase energy production while decreasing oxidant damage may have profound impact on the failing right heart.

#### **6.3. Exercise as right heart therapy**

Exercise-induced cardiac hypertrophy has been known to be cardioprotective for decades [115], though the exact mechanisms underlying physiological hypertrophy have remained somewhat 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 cohort who began exercise training 2 weeks after MCT injection [118].

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.

other cell types within the heart and within the dysfunctional RV may be causally involved in disease progression. Specifically, the cardiac fibroblast is emerging as a vital cell type in regulating cardiac function and pathophysiology [124]. Not only do these cells primarily regulate the extracellular matrix (and thus fibrosis, electrical remodeling, and inflammation), but it is becoming increasingly apparent that they communicate with other cell types such as myocytes to regulate cardiac function. Virtually nothing is known about RV fibroblast mitochondrial metabolism or biology, or how these cell types respond to cardiac stress. In conclusion, the RV is not a thinner, lower pressure LV. Significant physiological and pathophysiological differences separate the two ventricles, and RV-centric approaches are necessary for the iden-

Legend: Mitochondrial alterations in left and right heart failure. Assessment of mitochondrial content, function, dynamics, biogenesis, quality control, and non-energy production roles of mitochondria and changes in HF are

**Mitochondrial phenotype Regulators/assessment LV failure RV failure**

Complex I-V activity respiration (Ouroboros, Seahorse)

Mfn1, Mfn2, OPA1 mitochondrial

PGC-1α, NRF1, TFAM mitochondrial

Apoptosis Pro: Bax, caspase 3 Anti: Bcl-2 ↑ [34, 69, 70, 84] ↑ [34, 108, 114]

•−, H<sup>2</sup> O2 )

(SOD2, catalase) and non-enzymatic

volume

ROS and oxidant damage Protein, lipid, DNA oxidation, ROS

Antioxidant defenses Antioxidant enzyme expression

**Table 2.** Mitochondrial changes in left and right HF.

protein synthesis

production (O<sup>2</sup>

antioxidants

summarized. Arrows indicate directional change with heart failure. NC: no consensus.

mt/nDNA, EM, citrate synthase activity ↓ [68, 71, 77] ↓ [98, 99, 104]

Fis1, Drp1 mitochondrial size ↑ [21, 79] ↑ [99–101]

LC3 II/I, Pink/Parkin, EM NC [28, 80, 81] NC [102, 103]

↓ [68–75] NC [98–100, 112]

19

↓ [21, 68] NC [99, 100]

Mitochondria and Metabolism in Right Heart Failure http://dx.doi.org/10.5772/intechopen.70450

↓ [76, 77] NC [98, 104]

↑ [68–70, 74, 82] ↑ [106, 107]

↓ [68] ↓ [43, 106, 117]

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

tification, repurposing, or development of therapies for RHF.

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

**Author details**

Content: % of cell occupied by

Function: electron transport chain

Biogenesis: turnover and synthesis

Mitophagy: removal of damaged

mitochondria

Fusion: elongation of mitochondrial network

of new mitochondria

mitochondria

Fission: fragmentation of mitochondrial network

activity

CO, USA

Danielle R. Bruns\* and Lori A. Walker
