**4.2. Mitochondria as a drug target in heart disease**

Most standard-of-care pharmacological approaches to HF, such as β-blockers, ivabradine, a cyclic nucleotide-gated channel blocker, and antagonism of the renin-angiotensin-aldosterone system, focus on the reduction of the energy requirements of cardiac muscle, including modulation of neurohormonal abnormalities, unloading the heart (vasodilatation), and/or reducing the heart rate, which subsequently reduces myocardial oxygen consumption. Although these therapies have improved survival in patients over the past 2–3 decades, death and poor quality of life continue to adversely affect this ever-increasing patient population [94]. The search for more effective and complementary therapy for these patients must be focused on improving the intrinsic function of the cardiomyocytes [157, 158], such as finding ways to increase/restore the energy supply, in addition to reducing the energy demand of the heart [1].

will be expected to be an area of great advances in the future. Additionally, more preclinical and clinical studies are necessary to evaluate the effectiveness and toxicity of mitochondrial-targeted antioxidants. Furthermore, the identification of the mechanisms by which alterations in sub-

Mitochondria and Heart Disease

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http://dx.doi.org/10.5772/intechopen.72611

strate utilization cause cardiomyopathy is also a necessary area of intense research.

Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda

[1] Brown DA et al. Expert consensus document: Mitochondrial function as a therapeutic

[2] Marín-García J, Goldenthal MJ. The mitochondrial organelle and the heart. Revista

[3] Bisetto E et al. Proteomic analysis of F1F0-ATP synthase super-assembly in mitochondria of cardiomyoblasts undergoing differentiation to the cardiac lineage. Biochimica et

[4] Grossman LI, Lomax MI. Nuclear genes for cytochrome c oxidase. Biochimica et Biophy-

[5] Zhang YH. Nitric oxide signalling and neuronal nitric oxide synthase in the heart under

[6] Ma J et al. *O*-GlcNAcomic profiling identifies widespread *O*-linked beta-N-acetylglucosamine modification (*O*-GlcNAcylation) in oxidative phosphorylation system regulating cardiac mitochondrial function. The Journal of Biological Chemistry. 2015;

[7] Qiu H et al. H11 kinase/heat shock protein 22 deletion impairs both nuclear and mitochondrial functions of STAT3 and accelerates the transition into heart failure on cardiac

[8] Rashed E et al. Heat shock protein 22 (Hsp22) regulates oxidative phosphorylation upon its mitochondrial translocation with the inducible nitric oxide synthase in mammalian

[9] Lizano P et al. The valosin-containing protein is a novel mediator of mitochondrial respi-

[10] Eisner D. Calcium in the heart: From physiology to disease. Experimental Physiology.

ration and cell survival in the heart in vivo. Scientific Reports. 2017;**7**:46324

target in heart failure. Nature Reviews. Cardiology. 2017;**14**(4):238-250

Shaunrick Stoll, Christiana Leimena and Hongyu Qiu\*

Española de Cardiología. 2002;**55**(12):1293-1310

Biophysica Acta. 2013;**1827**(7):807-816

sica Acta. 1997;**1352**(2):174-192

stress. F1000Research. 2017;**6**:742

overload. Circulation. 2011;**124**(4):406-415

heart. PLoS One. 2015;**10**(3):e0119537

**290**(49):29141-29153

2014;**99**(10):1273-1282

\*Address all correspondence to: hqiu@llu.edu

University, Loma Linda, CA, USA

**Author details**

**References**

Since disruption of metabolic signaling pathways such as in FAO, glucose utilization, or ATP generation contributes to the development of heart dysfunction, proteins in these metabolic pathways have become attractive targets of novel therapeutic strategies for the prevention or early treatment of HF [159]. Selective agonists for each of the PPARs have been established and are currently used to treat hyperlipidemia (fibrates) and diabetes (thiazolidinediones). It must be noted that stimulation of the PPAR pathway in the heart or extra cardiac tissues, e.g., adipose or hepatic tissue, potentially diminishes cardiac lipotoxicity by reducing lipid delivery or increasing mitochondrial oxidation. However, chronic activation of PPARα could lead to deleterious effects, particularly in the context of diabetes, hyperlipidemic states, or the ischemic heart [159].

Additionally, although the molecular mechanisms responsible for mitochondria-mediated disease processes are not yet clear, oxidative stress seems to play an important role. Accordingly, strategies for the targeted delivery of antioxidants to mitochondria are being developed. A typical "mitochondrial cocktail," which may include coenzyme Q10 (CoQ10), creatine, L-carnitine, thiamine, riboflavin, folate, as well as other antioxidants such as vitamins C and E, has been reported to partially improve clinical manifestations, though others have disputed its effectiveness [160]. Although, L-carnitine supplementation may be highly effective in patients diagnosed with DCM secondary to primary systemic carnitine deficiency, supplementation has little effect on other types of mitochondrial cardiomyopathy [132]. Recent developments in mitochondrial-targeted antioxidants that concentrate on the matrix-facing surface of the IMM protect against mitochondrial oxidative damage and hold therapeutic potential for future treatment of cardiovascular diseases (CVDs) [161].

Because a cure for mitochondrial genetic defects is still not available, the management of genetic MD with presentation of cardiac pathology, β-blockers, ACE inhibitors, or angiotensin receptor blockers should be administered [146]. Providing rudimentary nutritional education along with nutritional assessment and exercise will be important for the patients to take preventative measures from further lifestyle disease complications [146, 162]. Should there be advanced second- and third-degree AV block coupled with neuromuscular disorders, a permanent pacemaker is highly recommended [163]. Depending on the severity of the mitochondrial cardiomyopathy, cardiac transplantation could be recommended depending on the presence of neuromuscular weakness as it can complicate anesthesia administration [164].
