**1. Introduction**

Cardiovascular disease is the leading cause of death worldwide, of which heart failure (HF) constitutes a growing public health concern. In the United States alone, close to 6 million individuals currently suffer from HF, accounting for nearly one of out every nine deaths [1]. Morbidity and mortality from HF are high, with 50% mortality within the first 5 years of diagnosis. HF is also a financial burden on the healthcare system, with direct costs estimated at \$32 billion per year in the United States [2], roughly 2–3% of total global healthcare spending.

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

While HF constitutes a complex syndrome of diseases, it generally refers to the inability of the heart to pump sufficient blood to the periphery. As such, historically HF has been studied as a disease of the left ventricle (LV), and most treatments for HF are designed to improve function of the failing LV. Hallmarks of current HF therapies include neurohormonal targets, vasodilators, and/or reducing heart rate- all of which should reduce myocardial oxygen consumption and workload and rebalance energy supply and demand in the heart. However, these therapeutic approaches are largely based on symptom management and have not significantly changed the clinical course of the disease, as the staggering HF morbidity and mortality statistics have remained largely the same over the past 15 years [3]. These data suggest new therapeutic strategies are needed for successful HF therapy, and targeting the bioenergetic deficit through restoration of mitochondrial abnormalities has recently emerged as a promising strategy [4].

leading to an increase in RV compliance, regression of muscle mass, and shifting of the interventricular septum toward the RV, resulting in a concave shape of the ventricle in adulthood. Consequently, right sided pressures are significantly lower than the systemically-coupled left sided pressures. Due to its coupling to a low-pressure circuit, the RV is approximately 1/3 the thickness of the LV. As a result of lower pressures and wall stress, the RV has a lower O<sup>2</sup> requirement both at rest and during exercise. Consistent with a lower workload, coronary

oxygen uptake are important under periods of physiological or pathological stress, particularly those in which oxygen availability changes. Further, the ventricles can adapt to changes

increases coronary flow to match demand [13]. These data are consistent with the response of

In healthy states, the heart derives energy from multiple sources to match the demand of contractile function, and can serve as an energetic omnivore based on substrate availability. When given a choice, however, the heart prefers lipid, based on significantly higher ATP production per carbon molecule compared to glycolysis. The first report of the heart's preference for lipid was published in 1953 [14], with subsequent studies confirming that fatty acids constitute 60–90% of cardiac ATP sources with carbohydrates supplying the remaining 10–40% [15]. Fatty acids are transported into cardiomyocytes through fatty acid transporters and subsequently into the mitochondria by carnitine palmitoyltransferase-1 into the matrix where they undergo β-oxidation. The successive oxidation of fatty acid chains provides acetyl CoA that enters the Kreb's Cycle to produce energy to supply the demand of contraction. Glucose is transported into cardiomyocytes by facilitated diffusion mediated by glucose transporters GLUT1 and GLUT4 (insulin-dependent). Once inside the cell, glucose is phosphorylated by hexokinase as the first step in glycolysis. Nine steps later, pyruvate is either decarboxylated by pyruvate dehydrogenase (PDH) to form acetyl CoA to be transported into the mitochondria to begin

and the RV ~50% of the available coronary O<sup>2</sup>

in oxygen availability through different mechanisms, with the RV meeting O<sup>2</sup>

Kreb's Cycle, or reduced to form lactate and subsequent anaerobic metabolism.

as other metabolic genes (11 genes) significantly varying between ventricles [16].

Assuming similar metabolism and mechanisms of control of these pathways between the ventricles might be overly simplistic. As discussed above, the RV is thinner and has a different shape than the LV, which contributes to differential responses to pathological load (discussed below). Transcriptional profiles, including those which regulate metabolism, differ between ventricles, as a comparative gene expression of mRNA and microRNA between control RV and LV samples identified numerous genes with differential expression between the ventricles [16]. These genes spanned a wide variety of biological processes including metabolism, with carbohydrate metabolism (three differentially expressed genes), lipid, fatty acid and steroid metabolism (11 genes), nucleic acid (30 genes) and protein metabolism (22 genes), as well

**2.2. Mitochondrial function and metabolism in the healthy heart**

the ventricles to pathological insult, which will be discussed in greater detail below.

either increasing coronary flow or by increased O<sup>2</sup>

delivery to the RV are comparatively lower than the LV [11]. At rest, the LV

. These basal differences in

extraction [12], whereas the LV primarily

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

demands by

5

blood flow and O<sup>2</sup>

extracts 75% of O<sup>2</sup>

*2.2.1. Cardiac metabolism*

While LV-centered pathology constitutes the largest number of HF cases, it is ability of the right ventricle (RV) to function that predicts survival in many cardiovascular disease contexts including pulmonary hypertension [5], (which will be reviewed in much greater detail below), heart failure with preserved ejection fraction [6], and dilated cardiomyopathy [7]. However, no RV-directed therapies exist, and far less is known about the pathophysiology of the failing right heart than the LV. So, while considerable progress has been made to elucidate the metabolic and mitochondrial derangements that underlie LV failure, basic understanding of mitochondrial and metabolic derangements in RV dysfunction continues to be ill-defined. Here, we will present what is known about RV failure and the role of mitochondria and metabolism in models of experimental RV failure and in human populations with right HF. We believe successful HF therapies must target the failing RV for significant improvement in clinical and therapeutic outcomes.
