**4.1. Metabolic remodeling and mitochondrial dysfunction in left heart failure**

hypertrophy, dysfunction, and eventual failure. PH can be modeled in animals by different approaches including chronic exposure to hypoxia, pharmaceuticals which accelerate pulmonary dysfunction, or their combination. Here, we will briefly discuss the most common laboratory approaches to PH, but refer readers to an extensive review of animal models of PH [50]. Exposure to chronic hypoxia while causing systemic reduction in oxygen supply, selectively induces pressure overload on the RV. Animal models of chronic hypoxia are often driven by normobaric hypoxia, accomplished by nitrogen replacement to reduce partial pressure of oxygen, or by hypobaric hypoxia (simulated ~14,000–17,000 feet), reducing overall atmospheric pressure and thus reducing oxygen partial pressure in the inhaled air. Animal models of hypoxia-driven PH have been used at least since the early 1960s [51] and can be used to elicit predictable and reproducible PH within many animal strains. However, there are some unique differences between species worth noting. Bovine models produce robust responses to simulated altitude and hypoxia, and were among the most common model used in early research [52]. Neonatal calves exposed to chronic hypobaric hypoxia develop severe PH with striking remodeling of the pulmonary vasculature [52]. Rodent models of hypoxia are also common in the literature, with certain strains of rats developing more severe PH, and mice

In addition to hypoxia exposure, other models of PH include monocrotaline (MCT) injection, a pyrrolizidine alkaloid oxidized in the liver to a bioactive molecule which selectively injures the lung vascular endothelium, causing PH [53]. MCT as a model of PH has been in use for almost 50 years, and can be produced by a single subcutaneous or intraperitoneal injection of the drug. Within hours of injection, pulmonary damage occurs, by 2 weeks PVR has increased, and by 3 weeks, increased RV mass is often reported [54]. Some reports also describe liver and kidney damage [55], as well as myocarditis of both the RV and LV [56], limiting the use of MCT to study isolated RV hypertrophy and failure. A relatively recent model to the PH literature is a model of severe PH that combines chronic hypoxia plus a pharmaceutical vascular endothelial growth factor (VEGF) receptor inhibitor. This model, coined the Sugen hypoxia (SuHx) model after the VEGF receptor inhibitor Sugen 5416, has been modified for both mice and rats, and is characterized by persistent pulmonary vasculature disease and right heart failure [57]. Alternative animal models of PH worth mentioning include bleomycin injury and single gene mutations. Bleomycin, an antibiotic, is a common model for pulmonary fibrosis in mice. A single intratracheal dose results in PH after 2–5 weeks, a doubling of right ventricular systolic pressure, and a drop in cardiac output [58]. Lastly, several human mutations have been linked to elevated pulmonary pressures and PH, with the bulk of experimental PH stud-

ies using models with mutations of bone morphogenetic protein receptor type II [59].

All cell types within the heart respond to stress, including in response to chronic pressure overload [60]. However, the majority of research has focused on changes within the myocytes as they are the primary cell type responsible for contraction and heart failure is a disease of impaired cardiac function. The hallmark molecular change of myocyte remodeling is hypertrophy. In

developing the least severe perivascular remodeling [50].

12 Mitochondrial Diseases

**4. Molecular mechanisms of left heart failure**

Mitochondrial and metabolic abnormalities are well-established in left-sided HF. Since this topic will be more extensively covered elsewhere, we will just briefly discuss mitochondrial dysfunction and the metabolic switch in the failing left heart. Considerable evidence exists for an energetic deficit in HF, both in pre-clinical animal models of disease, and in studies from explanted human hearts (reviewed in [4]). One of the hallmarks of the hypertrophied or failing heart is a metabolic switch [63]. As the heart remodels, it undergoes a switch from fatty acid oxidation (FAO) to glycolytic carbohydrate metabolism. Although it is still a matter of debate whether this switch is causal, associative or compensatory, it is clear that the energy starved heart no longer produces the majority of its ATP from lipid sources. It has been suggested that this switch is designed to allow more efficient energy production with respect to oxygen since under states of low oxygen availability carbohydrate metabolism produces more ATP per mole of oxygen [64].

Due to their primary role as ATP generators, mitochondrial dysfunction has been mechanistically linked to the energy starved failing heart. Mitochondrial dysfunction is well described in the failing LV across many different pre-clinical models including guinea pigs [65], rats [66], rabbits [67], and dogs [68] with dilated, ischemic, and diabetic heart failure. Similarly, decreased respiration and respiratory control ratios, associated with an overall loss of oxidative capacity [69], have been observed in human explanted hearts from patients with ischemic and dilated cardiomyopathy. In addition to depressed oxidative phosphorylation, mitochondrial biogenic signaling is depressed in HF, with PGC-1α downregulated in different models of HF [70, 71]. Together, substantial data links mitochondrial respiratory deficits with the failing LV and suggests interventions aimed at preservation of mitochondrial function may have therapeutic potential. Observations of changes in the shape of mitochondria in HF spurred the idea that the major proteins regulating mitochondrial dynamic could be causally involved in development of the disease [72–74].

As discussed above, ROS production in the healthy heart is countered by enzymatic and nonenzymatic scavenging of ROS to prevent cellular damage. However, increased ROS and oxidant stress have been reported in many types have cardiovascular disease, including early in the development of pressure overload-induced left HF [75]. In addition to damaging cellular macromolecules, increased ROS can activate several cell-signaling processes including apoptosis and opening of the mitochondrial transition pore (mPTP) which are known to correlate with adverse health outcomes. Opening of this pore is associated with oxidant stress and mitochondrial dysfunction, and increased opening is observed in HF [75]. Although apoptosis of cardiomyocytes is rare in the healthy heart, it is well-established that apoptosis increases in human HF [76]. As adult cardiac myocytes have limited regenerative capacity, the loss of these cells is often counteracted by replacement with non-myocytes, promoting fibrosis and cardiac dysfunction.

predisposes the hypertrophied myocardium to contractile dysfunction, and maintaining the inherent metabolic profile of fatty acid fuel preference may be a more beneficial approach [89].

Mitochondria and Metabolism in Right Heart Failure http://dx.doi.org/10.5772/intechopen.70450 15

Similar to the LV, mitochondrial dysfunction is also implicated in RHF, albeit with less literature supporting the mechanistic link, and more conflicting reports depending on the model. MCT and SuHx models of RHF tend to demonstrate more severe mitochondrial dysfunction and depression of mitochondrial biogenesis. Decreased PGC-1α expression and a net loss of mitochondrial protein and oxidative capacity have been reported in SuHx rats, alongside abnormal mitochondrial shape and size by electron microscopy [90]. On the other hand, changes in mitochondrial function in chronic hypoxia models have been particularly discordant and warrant further discussion. Chronic hypoxia decreased ATP synthesis and measurements of mitochondrial number in a rat model of chronic hypoxia in both ventricles, however, the effect was slightly delayed in the right compared to LV [91]. Data from our lab in the neonatal calf model of PH-induced RV dysfunction also demonstrated similar changes to mitochondrial function in both ventricles, with no additional impact of pressure overload on the RV [92]. In these models of PH and RV dysfunction, the hypoxic stimulus is administered systemically using a hypobaric chamber. Thus, the LV experiences similar degrees of hypoxia as the RV, yet does not show signs of contractile or relaxation deficits until much later in disease progression. It's possible that interventricular differences in oxygen supply and demand explain the similar findings in both ventricles, and support the need for better mechanistic understanding of the similarities and differences in oxygen delivery and metabolism in the RV exposed to pathological load.

Mitochondrial dynamics are not well-described in the failing right heart. However, in a study by Marsboom et al., administration of the Drp1 inhibitor Mdivi-1 regressed PH in rodents by arresting proliferation of pulmonary artery smooth muscle cells, resulting in improved exercise capacity and RV function. Therefore, while not described in the RV, modulation of mitochondrial dynamics may be therapeutically viable for right heart failure [93]. Even less has been described on the role of mitophagy in the setting of right heart failure. However, one group has attempted to elucidate the impact of autophagy on remodeling following PAB. p62 and LC3 II/I were both increased in the hypertrophied RV [94]. These data support similar findings in MCT-induced RV dysfunction, with increased autophagy signaling and autophagosome formation by EM [95]. Expression of these markers temporally increased post MCT injection, which the authors suggest indicates a causal role for autophagy during the progression from hypertrophy to failure. Future work is needed to elucidate the changes that occur with mitochondrial dynamics and mitophagy in the failing right heart, and future investigations should

test myocyte-specific deletion of Mfn1, Mfn2, and Drp1 in experimental RV failure.

Our understanding of mitochondrial abnormalities in human RV failure is equally as understudied. Although availability of human samples is methodologically limiting, the use of pediatric congenital heart explants has shed some light on changes which underlie human RHF. One study of RV samples obtained from 31 pediatric patients undergoing cardiac surgery for congenital heart disease classified patients based on compensated RV function or failure based on echocardiography, right heart catheterization and MRI. Citrate synthase activity was maintained

**5.2. Mitochondrial dysfunction in right heart failure**
