**3.5. Genetic mitochondrial heart disease**

transits to HF, the expression of OPA1 is reduced and mitochondria become small and fragmented. Furthermore, in decompensated hypertrophy and HF, the mitochondrial biogenesis also declines due to depletion of ATP synthesis, which then halts the increase in new mito-

Moreover, cardiac hypertrophy also affects the energetic cross-talk between mitochondria and other organelles to transfer ATP. There is direct communication between the mitochondria and the ATPases of the myofibrils and the SR [119]. Muscle mitochondria in its ordered bundled organization around the myofibrils and the SR are highly clustered at regions of high-energy demand where there is a tightly regulated ATP/ADP ratio [69]. In the pressure overload–induced hypertrophic heart, the direct channeling of ATP within the high-energy demand sites becomes weakened due to the decrease in mitochondrial content and numbers [69, 119]. In addition, mitophagy is activated in pressure overloaded cardiomyocytes due to the increased cellular damage from mitochondrial dysfunction. The causative factors of autophagy in cardiac hypertrophy are complex. Although low baseline autophagy allows the cardiomyocytes to adapt to hypertrophic demands, exacerbation of autophagy promotes

In summary, pressure overload causes cardiac remodeling through disruption of the cell signaling pathway, altering the mitochondrial morphology in size, volume, and numbers, regulating the mitochondrial biogenesis and affecting the energetic cross-talk between mitochondria and other organelles to transfer ATP for utilization by the cardiomyocyte or mitoph-

Although coronary artery disease remains as the top cause of mortality and morbidity in western countries, the link between HF and diabetes is growing with the rising incidence of diabetes and prediabetes [121]. Based on epidemiological studies, diabetic individuals are likely to develop HF compared to those who have no diabetic history [122]. This link describes the term diabetic cardiomyopathy, which is due to the myocardium of chronic diabetes patients showing diastolic dysfunction and left ventricular hypertrophy, followed by later onset systolic dysfunction that regresses to decompensated HF [123]. Approximately 60% of type 2 diabetic patients have diabetic cardiomyopathy [124]. The causes of diabetic cardiomyopathy are multifactorial and complex. Cardiac mitochondrial abnormalities were found in both diabetic mouse models and human diabetic hearts. Diabetic cardiomyopathy has been linked to the increased myocardial oxygen consumption and increased oxidative stress. Mouse models of type 2 diabetes (*db/db* and *ob/ob*) showed dysfunctional mitochondrial state 3 respiration and decline in ATP production [125, 126]. In right atrial myofibers of diabetic patients, defects in respiratory complex were observed with the reduction of state 3 respiration on impairment in complex I alone [127]. Another respiration deficiency was detected in myofibers from diabetic patients that showed deficiency in respiration with substrate palmitoyl-L-carnitine [127].

Interestingly, opposite to the reduction of FAO in failing heart, diabetic hearts had more FAO and a reduction in glucose oxidation. The increase in FAO is attributed to the increased expression of PPARα, which increases the genes that are involved with cardiac FA utilization [128]. Additionally, in type 2 diabetes, reduction of cardiac efficiency is also caused by an increase in mitochondrial

chondria in the cardiomyocyte [109].

44 Mitochondrial Diseases

hypertrophic contractile dysfunction [120].

**3.4. Mitochondria and diabetic cardiomyopathy**

agy. These changes further lead to the failing of the myocardium.

Genetic MD can be caused by a mutation in either the mtDNA or the nDNA [130, 131]. MDs arising from mtDNA are more prevalent in adults, whereas diseases arising from nDNA tend to be more prevalent in infants and children [132]. MDs can also be classified by the function of the proteins involved in the disease. For example, MDs have been found to be associated with the mutations in genes that encode subunits of the ETC complexes [130] and ATP synthase [133, 134], ancillary proteins that participate in the assembly, transport, and function of the ETC complexes, or the regulatory proteins that control activities of the mitochondria [130, 131]. In addition, mutations have been described in gene-encoding proteins that synthesize cardiolipin, an integral part of the inner mitochondrial membrane [135, 136]. The most frequently identified biochemical abnormalities are deficiencies in NADH-coenzyme Q (CoQ) reductase (complex I) and cytochrome-c oxidase (complex IV) [135, 136].

The mitochondrion is a unique organelle as it possesses its own DNA system. While mutated DNA can affect any organ, the presence of the mtDNA mutations in highly metabolic tissues, such as brain, heart, skeletal muscle, and eyes, exhibits a more severe and progressive prognosis. Patients with the known mitochondrial mutation of m.3243A > G develop early death, whereas if this mutation has a cardiac cause, sudden deaths would occur [137]. A healthy individual may possess mutated DNA, but the onset of the disease will not be obvious until a certain mutation threshold of ~60–90% is present [138]. Inheritance of mtDNA occurs only through the maternal line with single, large-scale deletions being rare and the point mutations frequently transmitted [139].

Cross-sectional studies have shown that specific mitochondrial mutations have been presented with a certain cardiac phenotype, and cardiac disorders could inherit different mtDNA mutations [140]. For example, there are inherited familial cardiomyopathies (in both children and adult) linked to mutations in the mtDNA [139, 141]. Mutation m.1555A > G mt-rRNA has only been associated with restrictive cardiomyopathy [142]. Conversely, up to 40% of MD patients have HCM [143]; atrioventricular (AV) block is one of the manifestations of Kearns-Sayre syndrome (KSS) that is due to the large-scale deletions in the mtDNA [143]. The symptoms of HCM patients who have sarcomeric protein gene mutations differ from the those of MD patients who developed HCM. Generally, these MD patients who develop HCM have left ventricular dysfunction but no left ventricular outflow tract obstruction [144, 145]. Another cardiomyopathy-presenting phenotype that is less common in the MD patients is DCM. The echocardiographic findings showed slow progression of disease [146, 147].

Cardiac phenotype association with genetic MD is more common than realized; however, the mechanism of association of some mutations with specific cardiac phenotypes is not clearly understood. Since myocardial cells depend heavily upon mitochondria for its energy requirements, it is no wonder that specific MD involves specific cardiac pathology phenotype.

younger patients. Laboratory tests for the levels of creatine phosphokinase, pyruvate, albumin, lactate, transaminases, and blood count are also recommended [152]. An elevated postprandial lactate:pyruvate ratio (>20) is commonly found in MD patients; however, some MD patients may show normal ratio and thus other tests are required to confirm the disease [146]. Nextgeneration sequencing is also proposed for screening of the multiple mutations associated with MDs [152]. Additionally, fibroblast growth factor-21 (FGF-21) has been recently identified as a serum biomarker of MDs associated with both mtDNA and nDNA mutations [148], potentially

Mitochondria and Heart Disease

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

The cardiac presentation of MD patients varies; however, progressive cardiac conduction defects may develop into a complete heart block in KSS, while Wolff-Parkinson-White (WPW) syndrome can develop in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome owing to the m.3243A > G mutation [153, 154]. There is no characteristic manifestation of cardiomyopathy that differentiates MD, although HCM is common [150]. Cardiac imaging using cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) can be used to effectively evaluate the heterogeneous presentation of HCM, offering a more reliable measurement of all segments of the heart than echocardiography [155].

In the early stage of the diagnosis process of MD, 12-lead electrocardiogram results are useful to add to the diagnostic criteria [146]. ECG results will be variable depending on the kinds of syndrome the mitochondrial myopathy is associated with [156]. Ocular myopathy patients may in general show normal ECG profile, but two out of the six patients were presented with ST depression and inverted T wave [156]. Patients with MELAS/MERRF may show atrial or ventricular premature contraction (APC or VPC) with T-wave abnormalities such as inverted T wave, as well as ST depression [156]. These abnormalities can be present even without the presentation of left ventricular hypertrophy [146]. A profile of short PR, or WPW, was also found for a MELAS patient [146, 156]. Patients with KSS presented cardiac conduction abnormalities with a variation of ECG profile of AV blocks, complete right bundle branch block with inverted T, or left axis deviation (LAD) and prolonged His ventricular (HV) interval [156]. Though some patients may show normal ECG profile at diagnosis, performing another ECG every 1–3 years

may be important to detect uprise of cardiac abnormalities or complications [151].

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

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

simplifying the clinical diagnosis of MD.

*4.1.3. Cardiac imaging*

*4.1.4. Electrocardiogram*
