**3.2. Models of right heart failure**

Understanding RV failure requires the use of animal models that are primarily or predominantly right-sided. Therefore, although the most common cause of RV failure in humans is left-sided heart failure, it is more helpful to study the RV in diseases and models in which it is primary. For reasons including methodological constraints, clinical relevance, and the sensitivity of the RV to increased afterload (compared to the insensitivity of the RV to volume overload), most groups use models of RV pressure overload. However, we should mention that other causes of RV failure include valvular insufficiency, congenital disease including tetralogy of fallot, pulmonary atresia, truncus arteriosus, and hypoplastic left heart syndrome, RV ischemia/infarct, and amyloid and sarcoid [44]. Below, we'll briefly overview common animal models of RV failure and how they recapitulate human disease, which are summarized in **Table 1**.

physiologically such as in response to exercise or pregnancy, pathophysiologic remodeling is a maladaptive process that occurs with stress such as myocardial infarction or hypertension (chronic pressure overload). Adaptations evidenced at the organ level can occur at the level of myocyte, as well as within other cardiac cell types including fibroblasts and endothelial cells. Typically, remodeling is not an acute event, but rather occurs as a continuum of changes both adaptive and maladaptive, first evidenced by ventricular hypertrophy, dysfunction and abnormalities in filling and contraction. In the continued face of stress and/or adverse signaling modalities the heart continues to remodel resulting in overt failure - the inability of the heart to supply sufficient circulation for the needs of the body. The response of the RV or LV to pathological stress is complex and is likely a cumulation of the nature, severity, and chronicity (acute versus chronic) of the insult. In addition, the timing of the insult (newborn, juvenile, adult, or aged) likely has a large impact on cardiac remodeling. Insults that are initiated early in life tend to be better tolerated than those in adulthood [44]. Though cardiac aging research and RV aging are understudied, the aged heart has been suggested to perform even poorer in

response to pathological stress, an area which warrants future research efforts.

discussed in greater detail below), often rapidly progress to right heart failure.

morphometric changes including RV/LV ratios and myocyte size.

**3.1. Right heart failure**

10 Mitochondrial Diseases

**3.2. Models of right heart failure**

It should come as no surprise given the physiological differences between ventricles, that the ability to adapt to pathological load greatly varies between the left and right heart. While it is generally accepted that the RV is able to tolerate volume overload well [45], it poorly tolerates pressure overload (afterload). Experimentally, an increase in pulmonary artery pressure of 20 mmHg compared to a similar increase in systolic afterload resulted in a 30% decline in RV stroke volume, compared to only a 10% reduction in LV stroke volume [46]. Mechanistically, the thin wall of the RV along with reduced elastance is thought to reflect this poor tolerance for increases in afterload. This observation is clinically highly relevant, as patients with systemic hypertension compensate for the increased load for many years before diagnosis or treatment of cardiac disease, but patients with pulmonary hypertension (PH, which will be

Right heart failure (RHF) is a syndrome reflecting the inability of the RV to fill or eject properly. Clinically, it manifests as fluid retention (peripheral edema) and decreased systolic reserve or cardiac output, which often presents as exercise intolerance [47]. In the case of RV geometry, the ventricle becomes more concentric, and the interventricular septum flattens. In humans, right heart failure is diagnosed through a combination of clinical findings, laboratory tests and imaging. Similarly, in larger animal models of RV failure (below), it can be measured by echocardiography, whereas in mouse models it is generally demonstrated by

Understanding RV failure requires the use of animal models that are primarily or predominantly right-sided. Therefore, although the most common cause of RV failure in humans is left-sided heart failure, it is more helpful to study the RV in diseases and models in which it is primary. For reasons including methodological constraints, clinical relevance, and the Pulmonary artery banding (PAB) involves surgical constriction of the pulmonary artery, in a manner equivalent to the commonly used transaortic constriction (TAC) model of LV pressure overload. Administration of a band around the pulmonary artery results in pulmonary constriction, increased afterload, RV hypertrophy, and eventually failure. While similar methodologically and conceptually to TAC, an RNA-seq experiment comparing the RV and LV in isolated TAC or PAB suggests that the two ventricles do not respond in an entirely similar manner [48]. Of the nearly 3600 genes identified, only 192 were commonly expressed in both ventricles, 565 were unique to the RV, and 327 were unique to the LV. Canonical pathway enrichment only revealed oxidative phosphorylation as similar between the two ventricles [48]. Therefore, despite being methodologically and conceptually equivalent models of isolated pressure overload, TAC and PAB do not elicit identical molecular signatures, again suggesting that important differences between the ventricles may explain disease trajectory and prognosis.

A more clinically relevant model of RV afterload is pulmonary hypertension (PH). The World Health Organization classifies five distinct groups of PH based on etiology, prognosis, and therapy. However, they're all linked by an increase in mean pulmonary artery pressure of >25 mmHg at rest [49]. The increased pulmonary pressures cause pressure overload in the RV, isolated RV


Legend: LV failure is the most common cause of RHF in humans. Pulmonary hypertension is a heterogenous disease, classified into five groups by the World Health Organization, but generally refers to an increase in pulmonary arterial pressure, causing increased RV afterload. Congenital diseases, amyloid, sarcoid, RV ischemia and infarct, and valvular disease (tricuspid, pulmonic) also contribute to RHF. In experimental RHF, pulmonary artery banding/constriction causes an isolated increased RV afterload, similar to transaortic banding in left heart failure. Animal models of PH (rats, mice, cows) are also frequently used to cause predominant RHF. MCT: monocrotaline, SuHx: Sugen hypoxia, BMP2R: bone morphogenetic peptide receptor models (BMP2R plays a critical role in the pathogenesis of familiar idiopathic PH).

**Table 1.** Selected causes of clinical right heart failure (RHF) and the corresponding experimental model.

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].

response to pathological load such as pressure overload, myocyte size increases via synthesis of new sarcomeres. Myocytes also reactivate a fetal program of gene expression, now often referred to as the hypertrophic gene program [61]. While initially characterized in the failing left heart, the fetal (hypertrophic) gene program has now been shown to also occur in RV failure [62]. While believed to be compensatory at first, over time this is maladaptive, and likely contrib-

Mitochondria and Metabolism in Right Heart Failure http://dx.doi.org/10.5772/intechopen.70450 13

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

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

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

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

utes to the energy deficit of the failing heart.

more ATP per mole of oxygen [64].

in development of the disease [72–74].

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 developing the least severe perivascular remodeling [50].

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