**3. Cardiac remodeling and heart failure**

*2.2.3. Non-energy producing roles for mitochondria in the healthy heart*

ventricle. White bars: RV; black bars: LV. Adapted from Bruns, DR et al. AJP-lung, 2014.

the active site (MnSOD, or SOD2) [38]. SOD2 dismutates O<sup>2</sup>

each site to total O<sup>2</sup>

8 Mitochondrial Diseases

damage to mtDNA.

ducer of ROS within the cell [36]. Several labs have identified superoxide (O<sup>2</sup>

Mitochondria are a major source of cardiac reactive oxygen species (ROS), and the largest pro-

**Figure 1.** Mitochondrial content, dynamics, and activity in healthy right ventricle (RV) and left ventricle (LV) from neonatal cows. (A) Representative electron micrographs of the mid-RV and LV of control cows. (B) Expression of electron transport chain complexes does not differ in the healthy ventricles. OXPHOS complex expression was assessed by immunoblotting using an antibody against one subunit of each complex. (C) Representative image. (D) Mitochondrial content, as assessed by mt/nDNA copy number, is slightly different between ventricles, as COX1 copy number is higher in the RV than the LV. (E) Mitofusin-1 (Mfn1) expression is significantly higher in the RV than the LV, with no differences in other mitochondrial dynamics markers. (F) Complex I and V activity do not differ between healthy RV and LV, as assessed by spectrophotometric assay. All comparisons were assessed by Student's t-test. \*p < 0.05, n = 10 in each

mitochondrial source of ROS. Superoxide formation occurs on the outer mitochondrial membrane, in the matrix, and on both sides of the inner membrane. The relative contribution of

tion [37]. When mitochondria are functioning normally, ROS production is low. Although a physiological amount of ROS are produced for oxidant-sensitive cell signaling, these ROS are balanced by both mitochondrial and cytosolic scavenging systems to prevent oxidative damage. The matrix contains a specific form of superoxide dismutase (SOD) with manganese in

which is catalyzed to water and molecular oxygen by catalase, a major detoxifying enzyme present in heart mitochondria [39]. In addition to these enzymes, other enzymes including glutathione peroxidases, as well as non-enzymatic molecules like vitamins C and E, help to attenuate excess ROS production. However, if ROS production exceeds the ability to remove them, oxidant damage occurs in the form of lipid peroxidation (including oxidation of both inner and outer membranes, and cardiolipin), mitochondrial protein oxidation, and oxidant

chondria. In heart mitochondria, complex III appears to be most responsible for O<sup>2</sup>

•− varies from tissue to tissue and depends on respiration state of the mito-

•−) as the primary

•− into hydrogen peroxide (H2

•− forma-

O2 ),

> In response to pathological stress, the heart remodels, resulting in changes in structure, shape, or physiology of the heart and its cellular components. While remodeling can occur

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.

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

Mitochondria and Metabolism in Right Heart Failure http://dx.doi.org/10.5772/intechopen.70450 11

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

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

Pulmonary hypertension Pulmonary hypertension: chronic hypoxia, MCT,

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).

SuHx, BMP2R

Not available

**Human RHF Experimental RHF**

Valvular disease Not available

Congenital disease: hypoplastic left heart syndrome, tetralogy of

LV failure Pulmonary artery banding (PAB)

Amyloid sarcoid Microbial infection, genetic knockout RV Ischemia/infarct Right coronary ligation (sheep)

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

summarized in **Table 1**.

prognosis.

fallot, pulmonary atresia

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