Cardiac Complications in Inherited Mitochondrial Diseases

Heart Failure Reviews https://doi.org/10.1007/s10741-020-10009-1

Cardiac complications in inherited mitochondrial diseases

Mohaddeseh Behjati1 & Mohammad Reza Sabri2 & Masood Etemadi Far3 & Majid Nejati4,5

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract Maternally mitochondrial dysfunction includes a heterogeneous group of genetic disorders which leads to the impairment of the final common pathway of energy metabolism. Coronary heart disease and coronary venous disease are two important clinical manifestations of mitochondrial dysfunction due to abnormality in the setting of underlying pathways. Mitochondrial dysfunction can lead to cardiomyopathy, which is involved in the onset of acute cardiac and pulmonary failure. Mitochondrial diseases present other cardiac manifestations such as left ventricular noncompaction and cardiac conduction disease. Different clinical findings from mitochondrial dysfunction originate from different mtDNA mutations, and this variety of clinical symptoms poses a diagnostic challenge for cardiologists. Heart transplantation may be a good treatment, but it is not always possible, and other complications of the disease, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome, should be considered. To diagnose and treat most mitochondrial disorders, careful cardiac, neurological, and molecular studies are needed. In this study, we looked at molecular genetics of MIDs and cardiac manifestations in patients with mitochondrial dysfunction.

Keywords Mitochondrial dysfunction . mtDNA . Cardiac . Atrioventricular

Abbreviations ND1 NADH-ubiquinone oxidoreductase chain 1 ANT Adenine nucleotide translocator NDUFAF1 NADH dehydrogenase [ubiquinone] 1 alpha BSCL2 Berardinelli-Seip congenital lipodystrophy subcomplex assembly factor 1 CMP Cardiomyopathy OXPHOS Oxidation-phosphorylation COX Cytochrome c oxidase ROS Reactiveoxygenspecies ECMP Encephalocardiomyopathy MELAS Mitochondrial encephalopathy lactic acidosis and stroke-like episodes Introduction MERRF Myoclonus epilepsy red ragged fibers MID Mitochondrial dysfunction Mitochondria are involved in various fundamental cellular pro- MRP Mitochondrial ribosomal protein cesses like apoptosis, calcium signaling, and generation of reac- MTO Mitochondrial tRNA translation optimization tive oxygen species (ROS), but the most principal action of mitochondria is the synthesis of adenosine triphosphate (ATP) through oxidative phosphorylation pathway. Electron transfer * Majid Nejati between respiratory chain enzymes occurs through an electro- [email protected] chemical slope in the inner mitochondrial membrane [1, 2]. 1 Echocardiography Research Center, Rajaie Cardiovascular Medical Defects in the oxidative phosphorylation pathway cause a and Research Center, Iran University of Medical Sciences, variety of diseases ranging from the involvement of one tissue Tehran, Iran to the involvement of multiple organs with high-energy de- 2 Pediatric Cardiovascular Research Center, Cardiovascular Research mands such as the heart and brain. Mutations or gene variation Institute, Isfahan University of Medical Sciences, Isfahan, Iran can play a role in the onset and severity of the disease [3, 4]. 3 Department of Neurosurgery, Isfahan University of Medical Mitochondrial DNA in neonatal heart cells has a simple, amor- Sciences, Isfahan, Iran phous and double-stranded structure. Branched forms appear in 4 Anatomical Sciences Research Center, Institute for Basic Sciences, adults as mitochondrial DNA copy number increases in early Kashan University of Medical Sciences, Kashan, Iran childhood [5]. Adult human mitochondrial DNA has a complex 5 Core Research Lab, Kashan University of Medical Sciences, organization with a large number of dimer molecules, four-way Kashan, Iran junction, and branching structures [6]. Heart Fail Rev

In adults, mtDNA mutations are the most common cause of different from nuclear gene mutations. Mitochondrial gene mu- mitochondriopathy or mitochondrial dysfunction (MID). tations can be heterogeneous or homogeneous and cause a More than 300 mtDNA have been recognized so far. The disease phenotype when mutations exceed threshold levels. number of mtDNA molecules in the oocyte is remarkably Often, there is a correlation between the rate of mutation and diminished during the development of the female germ cells the expression of the disease phenotype, and sometimes differ- before re-amplification to final count (less than 100,000) [7]. ent mutations occur in different tissues [3]. Some pathways in The ratio of mutated to normal mtDNA can change over time, the pathogenesis of MID-induced cardiac disorders are also affecting the prevalence and severity of the disorder. Thus observed in the natural aging process by increased cardiac mi- inter-genetic shifts in mtDNA mutation with subsequent var- tochondrial ROS and decreased mitochondrial and nuclear iation in clinical disease severity are due to this germ cell DNA integrity [19, 20]. bottleneck [8]. Due to the deficiency of DNA repair mechanisms and proximity to the OXPHOS system, 10–17-fold mitochondrial mutations higher than nuclear DNA mutations Mitochondrial genetics result in MIDs [9, 10]. Cellular OXPHOS dysfunction due to primary genetic de- Mitochondria have been implicated in important cellular pro- fects (mitochondrial or nuclear DNA) leads to MIDs [11]. The cesses such as apoptosis and calcium signaling, but cellular precise extent and range of MIDs in the general population respiration and adenosine triphosphate (ATP) synthesis is their have yet to be determined [12]. The actual prevalence of these main function. ATP production is accomplished by the elec- defects is underestimated, probably due to regional referral trons transmission between the respiratory chain enzymatic patterns. In the general population, there is a 1/300 G complexes and transfer of proton into the mitochondrial inner m.3243A>G mutation [13]. Diseases related to mtDNA mu- membrane and the creation of an electrochemical gradient. As tation appear to be more common than previously thought well as 13 import polypeptides of the OXPHOS enzyme com- (about 1/5000) because many people may have low mutation- plexes, the mitochondrial genome encodes 22 transfer RNA al burden and are asymptomatic [14]. In a broad spectrum of (mt-tRNA) and two ribosomal RNA (mt-rRNA). Other struc- MIDs, point mutations in mitochondrial DNA have been iden- tural and functional proteins of mitochondria are expressed by tified. Increasing the mutant mtDNA ratio (60–90%) affects the nucleus genome. The mitochondrial genome has unique the MID and its onset and severity. A small fraction of the features and complex inheritance. The maternal inheritance of mitochondrial genome (< 1%) is mutated in the general mitochondrial DNA differs from that of the Mendelian model populatio. [15]. There are different phenotypes of MID, but of nuclear DNA mutations. There are several copies of mtDNA one of their main features is heterogeneity due to the presence in each cell, and a small percentage of them may have a muta- of both normal and mutant mtDNA in the cell population [16]. tion. The rate and threshold of mtDNA mutation may affect In cardiac muscle cells, mitochondrial number, topological clinical disease incidence and extent [21]. The identification arrangement, and replication mode are linked together [8]. of pathogenic mtDNA mutations, that commonly result in iso- By now, more than 250 pathogenic mtDNA mutations have lated organ phenotypes such as cardiomyopathy (CMP), re- been identified which many are associated with cardiac mani- veals the fact that other genetic (e.g., expression of festations. Maternally transmitted MIDs comprise a heteroge- aminoacyl-tRNA synthetase) or environmental factors can neous group of genetic disorders that disrupt the pathway of the modulate the phenotype [22, 23]. Since the inheritance of hu- final metabolism of energy production. The major components man mitochondrial diseases is purely from the mother’sside, of the respiratory chain are affected by mitochondrial DNA the presence of the disease in maternal relatives increases the mutations, which include most for a majority of mitochondrial suspicion of mitochondrial disease, so diagnosis through genet- DNA deletion syndromes. Clinical presentations of MIDs are ic counseling is quite different from nuclear genetic diseases varied from oligo-symptomatic (migraine, type 2 diabetes [24]. Depending on the type of mutation, the probability of mellitus (DM)) to very complex syndrome [10]. In summary, transfer from mother to child varies. Large and single deletions clinical phenotype of MIDs include mitochondrial encephalop- are less likely to be transmitted, while point mutations are more athy, lactic acidosis and stroke-like episodes (MELAS), myoc- likely to be inherited from mothers. The number of mtDNA in lonus, epilepsy, red ragged fibers (MERRF), Leber hereditary each oocyte decreases greatly during the development of female optic neuritis with acute or sub-acute visual loss), Leigh (sub- germ cells. The variation in the severity of hereditary diseases acute necrotizing encephalopathy and basal ganglion lesions), can partly be explained by this “genetic bottleneck” and change mitochondrial myopathy-cardiomyopathy, Wolfram syndrome in the rate of mtDNA mutation across generations [25]. The (diabetes insidious, optic atrophy, and deafness), and Pearson’s percentage of mutations in the mitochondrial genome is higher marrow pancreas syndrome (sideroblastic anemia, exocrine than that of the nuclear genome due to a lack of DNA repair pancreatic insufficiency, hepatopathy, and nephropathy) [17, mechanisms. High levels of mtDNA mutation in patients can 18]. Expression and segregation of mitochondrial diseases are lead to clinical progression of the disease. The ability of Heart Fail Rev continuous replication causes mutant mtDNA molecules to in- transfer and ATP production. Recent studies indicated that com- crease with colonic proliferation even after mitosis of cells, plexes III, IV, and V in mitochondria are inhibited by miR-210, including cardiomyocytes [15, 24]. miR-181c, and miR-141, respectively [48]. It has also been shown that miR-181c has a role in the remodeling of the electron chain complex IV in rat cardiomyocytes [49]. In Epigenetic in MIDs cardiomyocytes, miRNAs interfere with the mitochondrial net- work by regulating Mfn1. In adult cardiac myocytes, mitochon- Alongside with genetic alterations, epigenetic modifications, drial fusion is essential for maintaining mitochondrial morphol- i.e., DNA methylation, histone modifications, and noncoding ogy and for normal contractile and respiratory function [50]. RNAs have very important roles in various disorders such as cancer, diabetes, viral infections, and the cardiac complications due to mitochondrial diseases. Like nuclear DNA, Cardiac involvement in MIDs mtDNA, can be methylated by mechanisms present within mitochondria. Epigenetic patterns of mtDNA may vary by Cardiac involvement (CI) is one of the major problems of tissue and cell type, because the number of mitochondria MIDs, but cardiologists rarely consider these defects in the and their activity in different cells varies [26]. However, low etiology of heart disease. The prevalence of cardiac involve- levels of mtDNA methylation and low sensitivity to conven- ment in MIDs is due to the complete dependence of the heart tional measurement methods have questioned the effective- on oxidative metabolism and may occur as a major clinical ness of using mtDNA methylation as a biomarker. However, complication or part of a multi-systemic disease [51]. The sensitive techniques, including the bisulfite pyrosequencing, incidence of mtDNA carriers’ mutations and at-risk individ- are used to measure mtDNA methylation levels [27, 28]. uals for the mitochondrial disease was estimated at 1:10,000 Recently, mitochondrial DNA methylation has been investi- adults [17]. The importance of diagnosing CI in MIDs is be- gated in many genes, including MT-ATP6, MT-APT8, MT- cause earlier diagnosis helps better treatment. Studies have ND2, MT-ND4, MT-ND5, MT-ND6, MT-CO1, MT-CO2, shown that life expectancy in CI patients is significantly re- and MTCO3. These genes encode effective molecules and duced if MID is present. This is because the supply of energy enzyme in the electron transport chain such as ATP synthesis, to the heart is the same as the muscle and the brain depends on NADH dehydrogenase, and cyclooxygenase [29, 30]. aerobic respiration [52]. Organs such as the heart that have Baccarelli et al. also showed that the level of methylation of high aerobic metabolism are more susceptible to damage several mitochondrial genes in people with CVD is higher caused by MIDs. Continuous pulse causes cardiomyocytes than in healthy people. Furthermore, the expression of leucine to need more energy than skeletal muscle and differences in 1 (MT-TL1) tRNA gene in CVD patients is different from that respiratory ratios [53, 54]. in healthy people. Therefore examination of mitochondrial gene methylation in platelets and blood cells can be considered as a biomarker in people at risk for CVD [29]. Myocardial abnormalities Noncoding RNAs are very important classes of epigenetic regulators that play crucial roles in different diseases [31–36]. Cardiomyopathy (CMP) is a major cardiac problem of mito- MicroRNAs (miRNAs) are short noncoding single-stranded chondrial disorders (MIDs) that divided into restrictive, hy- RNA molecules that epigenetically regulate gene expression pertrophic, dilated, and unclassified CMP. The hypertrophic after transcription by destroying or inhibiting mRNA translation CMP (hCMP) is the most common cardiac abnormality in [37–40]. It has been showed that deregulation of miRNAs are MIDs (Table 1). Some syndromic MIDs include Leigh-syn- associated with several disorders such as various cancers, and drome, MERRF, MELAS, NARP, and CPEO are associated cardiovascular diseases [41–45]. About 150 miRNAs have been with hCMP, (Table 2). detected in mitochondria so far, but the characteristics and per- formance of many of them are not well known [46]. Among Coronary artery disease them, miR-23a, miR-23b, miR24, miR-92 miR-103, miR-106a, miR-125a, miR-125b, miR-133, miR-193, miR-221, miR-365, Coronary artery disease (CAD) might occur due to coronary and miR-423 are some better-known microRNA in mitochon- abnormalities mainly in small vessels which have been report- dria [47]. Mitochondria dysfunction can cause cell damage by ed rarely in the setting of MIDs but angina due to these coro- producing active oxygen species (ROS), which is abundant in nary involvements have not been yet reported [122]. C3256T the CVD. Various miRNAs are involved in endothelial and heteroplasmy level, as a biomarker of MID, is a predisposing vascular dysfunction and CVD through oxidative stress and factor for atherosclerosis, coronary artery disease, and myo- overproduction of ROS. Some miRNAs can regulate the cardial infarction [11]. Indeed, CAD may be caused by the OXPHOS in mitochondria by affecting molecules in electron simultaneous presence of classical risk factors for heart Heart Fail Rev

Table 1 Phenotypes of mitochondrial and nuclear gene mutation Table 2 Cardiac abnormalities and affected gene in MIDs

Gene/defect Phenotype Ref Cardiac abnormality Involved gene Ref mtDNA Myocardial fibrosis arrhythmias mtDNA deletion [81] ATP 8 hCMP, neuropathy [55] Systolic dysfunction heart failure ND5 [82] ND1 Variable [56] Leu-tRNA [83] ND5 Leigh syndrome, hCMP [57] Sinus arrhythmia Leu-tRNA [84] 12s RNA Variable [51] AFIB/AFLU mtDNA depletion [85] rRNA hCMP [58] Ventricular tachycardia Leu-tRNA [86] Single mtDNA deletion [87] Leu-tRNA hCMP, infantile CMP [59] AV block Leu-tRNA [88] Gly-tRNA Infantile CMP [60] Single mtDNA deletion [81] Val-tRNA Variable [51] Restrictive cardiomyopathy ND5 [2][89] Lys-tRNA NS, variable [61] mtDNA deletion [90] nDNA Sudden cardiac death Lys-tRNA [91] Ala-tRNA synthesize Infantile CMP [62] Leu-tRNA [92] ANT1 CMP, myopathy [63] Bundle branch block Leu-tRNA [93] ATPase 8 Infantile CMP [64] Single mtDNA deletion [94] ATP synthesize ECMP [65] Dilated cardiomyopathy POLG1 [95] BSCL2 Generalized lipodystrophy [66] ND1 [96] mtDNA deletion [97] COX3 Variable [67] Val-tRNA [51] MRPS 22 NS, ECMP [68] Lys-tRNA [98] MRPL44 Infantile CMP [69] Leu-tRNA [99] MRPL3 CMP [70] Ile-tRNA [100] MTO1 hCMP, lactic acidosis [71] Glu-tRNA [101] NDUFAF1 Infantile CMP [72] Non compaction Cyt b [102] NDUFS2 Leigh syndrome [73] ND1 [103] NDUFV2 Early-onset hCMP [74] tRNA (m.8381A N G) [104] NFU1 Infantile encephalopathy [75] Leu-tRNA [105] RCC1 mutation Syndromic MIDs, NS [76] WPW ND5 [93] Leu-tRNA [106] SCO1 Infantile encephalopathy [77] Lys-tRNA [98] SCO2 ECMP [78] QT prolongation Single mtDNA deletion [107] TMEM70 ECMP [79] Pulmonary hypertension TMEM70 [76] YARS2 MLASA [80] MFN2 136 [108] Glu-tRNA [101] Leu-tRNA [109] diseases such as DM, hypertension, hyperlipidemia, or ciga- COX7B [110] rette smoking independently or MID dependent. Among en- SARS2 [111] docrine problem, DM is more common while hepatic, renal, NFU1 [75] and other endocrine disorders are rare [123–125]. Renal im- Single mtDNA deletion [112] pairment is seen in MELAS, MERRF, Pearson syndrome, Ventricular cavity obstruction 12sRNA, ND1, ND4, ND6 [113] Leigh syndrome, and kerns Sayre syndrome (KSS) [126]. In Ventricular septal defect mtDNA depletion [114] a study, DM, arterial hypertension, atherosclerosis, pulmonary Hypoplastic left heart syndrome mtDNA depletion [114] hypertension, hyperlipidemia, and severe cardiac diseases Autonomic nerve fibers Leu-tRNA [115] were reported in a 72-year-old woman with MID. Dilation of aortic root mtDNA deletion, depletion [116] Apparently, after the occurrence of an acute coronary event, Noonan syndrome MYBPC3 [113] Patent foramen ovale BSCL2 [66] MID has been involved in the development and progression of DNA2 [117] ischemia/reperfusion (I/R) injury [127, 128]. Leu-tRNA [118] Coronary heart disease Thr-tRNA [119] Cerebrovascular disease Pericardial effusion HDHA, HDHB [120] Lys-tRNA [121] Autonomic nerve fibers Leu-tRNA [86] A stroke in myopathies is often with cardio-embolic origin which may be due to atrial fibrillation/flutter or dilated Heart Fail Rev cardiomyopathy of the left ventricular noncompaction [129, Heart failure (HF) is the end stage of all CMPs, but it could 130]. Low-flow infarcts can be caused by severe heart failure be attributed to some specific genetic disorders. In one study due to cardiomyopathy. Angiopathy from atherosclerosis or vas- of untreated patients with Barthes syndrome, HF or septicemia culitis is the second most frequent cause of stroke in myopathies was the leading cause of death. Left-sided dilation and hyper- as a factor of inflammatory myopathies [131–133]. Stroke-like trophy or both are seen in boys [147]. Myocardial fibrosis and episodes often occur in mitochondrial encephalopathy, lactic combination of circular and tubular crista and spherical mito- acidosis, and stroke-like episode syndrome and are rarely seen chondria were seen under electron microscopy examination of in Leigh syndrome and other MIDs. Stroke-like episodes can be myocardial tissue [146]. Formation and destruction of recently a manifestation of metabolic or vascular processes and are dif- described inter-mitochondrial junction (IMJ) are involved in ferent from ischemic strokes [134]. The neurological symptoms compensatory adaptive reactions. An animal study demon- of MELAS are due to respiratory chain deficiencies (RCD) re- strated that an overload of heart decreased the number of lated to vascular cytochrome c oxidase deficiency. RCD could IMJs or completely destroyed the IMJs and mitochondria, present in various clinical manifestations. Minimizing substrate leading to acute heart failure and death [148]. Pulmonary hy- deficiencies in RCD by pharmacological supplement such as pertension can develop in long-standing CMPs but may also coenzyme Q10 could be useful [135, 136]. occur initially. Persistent pulmonary arterial hypertension in the newborn apical hypertrophic cardiomyopathy is a rarely Cardiomyopathy reported manifestation associated with mitochondrial dysfunction associated with TMEM70 deficiency even in the ab- Cardiomyopathies (CMPs) are a wide genetically and clinical- sence of overt cardiomyopathy and represents an early sign for ly heterogeneous group of cardiac disorders with primary in- the diagnosis [149]. volvement of myocardial tissue [137]. MIDs are known as the second most common cases of CMPs. Infantile cardiomyop- Left ventricular hypertrophy and hypertrophic athies are disastrous disorders of the neonatal period and first cardiomyopathy year of life. MID is a common cause of this disease entity. However, gene defect have been recognized in a small pro- Normally, the energy needed for the heart to function is ob- portion of these patients [62]. The exact prevalence of MID- tained from the breakdown of fatty acids [150]. Various mol- related CMP is unknown. CMP may be the only complication ecules such as glucose, pyruvate, ketone bodies, and FFA or one of the problems. CMP may be the only complication or produce energy in various metabolic processes. In some path- one of the symptoms. In patients with idiopathic primary car- ological conditions, heart changes its source of energy produc- diomyopathy, specific mtDNA mutation has been identified tion from FFA to glucose and pyruvate similar to the fetal [138]. Senescent mitochondria often have large size, defect in period. In the hypertrophic heart, the role of glycolysis in ATP synthesis, high ROS production, and reduced inner energy production is higher. Heart functional overload such membrane potential. In end-stage mtDNA-related CMPs, re- as myocardial hyper-functioning provides adequate energy markable induction of mitochondrial biogenesis with a detri- supplies through mitochondrial hyperplasia and IMJ forma- mental effect on cardiomyocytes is observed [139, 140]. tion [151, 152]. Hypertrophic remodeling is reported in However, adverse cardiac remodeling is attributed to the pro- myocytes of patients with MIDs which mimics hypertrophic liferation of mitochondrial inter-myofibrils which interferes cardiomyopathy (HCM). Since MID is a potential cause of with the sarcomere function [140–142]. Oxygen consumption HCM, cardiologists should differentiate these disease through is enhanced in mitochondrial-related CMPs due to the induc- presence of noncardiac symptoms and maternal inheritance. tion of genes participating in mitochondrial biogenesis [54]. The main point mutation related to HCM is TMEM70 which This is in contrast with other pathogenesis such as left ventric- is the most common cause of nuclear ATP synthesis deficien- ular hypertrophy (LVH) in which energy metabolism is cy [153]. In cases harboring m.3243A>G mutation, the rate of shifted from free fatty acid (FFA) to glucose oxidation LVH has been reported to be 38–56%. There is a correlation [143]. In the absence of antioxidants, mutations in mitochon- between LV mass and skeletal muscle mutation load. CMP is dria lead to ROS generation. Also, the role of ROS in muta- the result of both sporadic and maternally inherited point mu- tions in nuclear genes is well known, but mtDNA mutations tations in mtDNA [86, 154]. LVH may be a cardiac sign of have not yet been confirmed [144, 145]. Cardiomyopathy is mutations in other than mtDNA gene such as mt-RNA genes an important clinical manifestation of Refsum disease. In this (m.8344A>G in MTTK, m.4264A>G and m.4317A>G in disease, phytanic acid accumulates in tissues and biological MTTI) or polypeptide genes (m.8993T>G and m.8528T>C fluids, but pathophysiological mechanism of heart damage is in MTATP6/MTATP8 overlap regions) [10, 98]. mt-RNA poorly understood. Disturbance of cellular energy and redox genes are sensitive to mutations related to hypertrophic geno- hemostasis induced by phytanic acid are likely to contribute to type. Mutations in mt-RNA and polypeptides are common in the development of cardiomyopathy in Refsum disease [146]. development of LVH. In cardiac diseases, homoplasmic Heart Fail Rev mtDNA mutations with organ-specific phenotypes such as Pavlakis et al. The disease characterized by red ragged fiber m.4300A>G mutations in MTTI gene in patients with isolated (RRF) on muscle biopsy and hemiparesis, seizure, hemianopia, mtDNA-related cardiomyopathy have been reported. The cortical blindness, lactic acidosis, short stature, and normal early likelihood of progression to LV dilation and HF in mtDNA- development [161]. A common point mutation of mitochondrial related LVH is higher than hypertrophic cardiomyopathy. In myopathy is stroke-like lactic acidosis encephalopathy with a individuals harboring m.3243A>G mutation, degree of LVH transmission of A to G at 3243 of untranslated reign (UTR) of is positively related to chamber dilation and negatively with RNA [162]. Mitochondrial microangiopathy has not been re- cardiac systolic function. Mutations in m.3343A>G or ported in cardiac rather than cerebral manifestation of MELAS m.8344A>G are related to both HF and LV systolic dysfunc- syndrome. Mutations in Lucine tRNA (3243 positions) is re- tion in patients with LVH [10, 98]. Left ventricular outflow sponsible for 80% of cases with MELAS syndrome [163]. tract obstruction and apical hypertrophic cardiomyopathy Echocardiographic evaluation shows an initial abnormal thick have also been reported with regard to MIDs. In taken biopsy of left ventricle wall progressing to severe dilation and poor samples from affected hearts, red ragged fibers are seen. HCM ventricular contraction [164]. is most commonly seen as a feature of KSS and in association with atrioventricular block which is attributed to a single Dilated cardiomyopathy Dilated cardiomyopathy (DCM) in large-scale defect in mtDNA. Leigh’ssyndromeisoccasion- MIDs is most commonly due to pre-existing hypertrophy as ally manifested by hypertrophic cardiomyopathy and asym- alatephenomenon[165]. Lack of data about the history of metric septal hypertrophy [10, 92]. patients with MIDs and DCMP may be due to the rarity of this CMP is a life-threatening presentation of Friedreich ataxia phenotype. Due to progressive skeletal myopathy and restrict- (FA). FA is a genetic disorder of the central nervous system ed physical activity, cardiac symptoms are limited in cases with cardiac involvement and endocrine disturbance in some with multi-systemic MIDs. DCM is also seen in Barth syn- cases. Cardiac involvement is a major determinant of the FA drome, an X-linked recessive syndrome, with neutropenia and disease that is the most mortal complications of the disease. skeletal myopathy [166] . Alcoholic CMP which is manifested Up to 20% of cases with FA are conflicted by cardiac disor- as DCM has been reported to be linked with acquired MID. ders [155]. Unstable GAA nucleotides repeat expansion (> The most prominent feature of alcoholic CMP is the mega- 120 repeats) in the primary intron of the frataxin gene (9q13) mitochondrial formation by the fusion of dilated crista. in both alleles lead to the development of FA, as autosomal Swollen mitochondria with disorganized crista directly related recessive disorder manifested mainly as spinocerebellar de- to decreased activity of oxidative phosphorylation system and generation [156]. suppression of ATP synthesis [167]. Cardiac involvement is a major determinant of the FA disease. Although cardiac involvement is usually followed by Restrictive cardiomyopathy degeneration of the nervous system, it is not a secondary disease and is not associated with the severity and duration of Restrictive cardiomyopathy (RCMP) is the only sign of mu- neurological diseases [157]. tation in the m.1555A>G mt-rRNA gene [168]. MID-related The most common recognized cardiac involvement in FA is RCMP is associated with m.3243A>G mutation and is the concentric LVH [156]. Intraventricular septal hypertrophy and mere manifestation of m.1555A>G mutation [10]. frataxin repeat length in smaller alleles is remarkably correlated. Histiocytoid CMP is characterized by the pathogenic Indeed, the septal to posterior wall thickness ratio is highly re- histiocyte-like cells within sub endocardium and aggregation lated to GAA repeat size on the smaller alleles. Degree but not of structurally abnormal mitochondria, linked to m.8344A>G the severity of LVH is correlated to GAA repeat size in smaller mutation in MTCYB gene which encoded complex III en- allele [158]. LV mass index is diminished by age in the setting zyme subunit [10]. Fabry disease is a rare lysosomal storage of FA. Thus, hypertrophy would be seen in a minority of adult disorder with X-linked recessive inheritance that results from patients with FA. These cardiac manifestations are attributed to a deficiency of alpha-galactosidase as a lysosomal enzyme. deficiency of the frataxin, a mitochondrial protein which its Deficiency of this enzyme leads to accumulation of sufficient amounts are required for maintenance of proper cellu- globotriaosylceramide (GL-3) in vascular and endothelial tis- lar iron hemostasis [159]. In some cases, no cardiac symptom sues, which one of the symptoms can be RCMP. Thus, mito- could be established and cardiac involvement could be detected chondrial cytopathic disorders involve several organs but just by electrocardiography (ECG) and echocardiography eval- heart failure may not occur in childhood [10, 169]. uation. For accurate assessment of cardiac anatomy in FA, mag- netic resonance imaging is recommended [127, 160]. Rarely, Left ventricular noncompaction mitral valve prolapse without LVH is seen in cases with FA [129]. MELAS syndrome is a multi-organ disease that usually Abnormal myofibril compaction during cardiogenesis leads to begins in early childhood and was first described in 1984 by left ventricular noncompaction (LVNC). LVNC is one of the Heart Fail Rev cardiac manifestations in MIDs particularly in the pediatric preoperatively. Some of the side effects after cardiac trans- population [170]. LVNC has been reported in adults with plantation could be related to their MELAS syndrome. m.3398T>C mtDNA variants [138]. These patients are susceptible to the development of acidosis; thus, maintenance of stable cardiovascular function is essen- Electrocardiographic abnormalities tial. Indeed, the administration of common cardiac drugs in cases with MELAS syndrome needs lots of precaution due to In patients with MIDs, electrocardiographic (ECG) abnormal- their possible disadvantages in MIDs like statins (reduced co- ities as prolongation of QTc (> 440 ms), widening of corrected enzyme Q), B-blockers (inhibited ATPase activity), and QRS interval, bundle branch block, premature atrial and ven- acetylsalicylic acid (inhibited respiratory chain electron trans- tricular contraction, and wolf Parkinson white syndrome have port). In addition, immunosuppressive drugs have not yet been been reported [171]. ECG abnormalities have also been re- approved for MELAS syndrome. But despite of these obsta- ported in cases with MERRF syndrome [102]. Thus, active cles, some successful cases of heart transplantation in cases screening with ECG has been suggested in patients with MIDs with MIDs have been reported [178]. even in cases without overt cardiac manifestations [135]. Arrhythmia Cardiac conduction disease Torsade de points, as the mere manifestation of cardiac in- The prevalence of cardiac conduction disease in MIDs involvement has been reported in a case of FA [178]. creases with age. Atrioventricular block as a part of diagnostic criteria of KSS occurs in 84% of cases. KSS is defined by the Sudden cardiac arrest triad of pigmentary retinopathy, progressive external ophthalmopathy, and onset before age 20 years old [98, Neurological and cardiologic disorders are the major cause of 172]. Specific cardiac symptoms have been reported in nearly early death in MIDs cases with the m.3243A>G mutation. In 60% of patients with KSS [173]. KSS develop fascicular these cases, suspected sudden cardiac death has been frequent- blocks, complete or partial right bundle branch block, com- ly reported [179]. Cardiac involvement in MIDs is progressive plete heart block, and nonspecific intraventricular conduction in nature. In fact, molecular events related to mtDNA defects delays [172]. Progression of atrioventricular block to its high and cardiac disorders are not fully understood due to the low grade is often unpredictable which requires prompt identifica- frequency of the disorder, lack of access to human heart tissue, tion of this condition and early interventions. Early premature and incompatibility of genotype and phenotype. Different car- death in cases with KSS is directly attributed to infra-nodal diac presentations may be seen in the specific mtDNA muta- block [174, 175]. The frequency of mutations in tissue is a tions. Vice versa, different mitochondrial DNA (mtDNA) mu- determining factor in the clinical manifestations of MIDs. tations could be seen in the same cardiac presentations. Lack Excessive mutations and deletion in mtDNA in the His- of a reliable animal model is also a great obstacle. Thus, the Purkinje system and AV node have been reported in a patient development of cardiomyocyte cell line derived from affected with KSS after death, which is a reason for the sensitivity of patients might be useful and a step forward. Therefore, a deep the conduction system to mtDNA mutation and mitochondrial understanding of the range of clinical symptoms and genetic function [10]. Intra-atrial block (IAB) which is s a predictor of causes of cardiac disorders in MIDs helps cardiologists to atrial arrhythmia is observed in FA [176]. By early recognition properly manage patients [180]. of IAB, asymptomatic FA patients who are susceptible to the development of potentially life-threatening arrhythmia could be identified [177]. In the patient with cardiac conduction Conclusion blocks, the placement of cardiac pacemaker is effective. ECG and echocardiography surveillance every 6–12 months Lack of unique cardiac phenotype and a variety of cardiac is recommended in these cases. Application of antioxidants complications of MIDs is a challenge for cardiologists. could ameliorate injury derived by ROS [62]. Since early reports of cardiac involvement in MIDs depict a phenotype with severe complications, early recognition of Post-transplantation cases with MIDs is essential. It has been notable that minor ECG abnormalities are the most common cardiac manifesta- For mitochondrial cardiomyopathy, heart transplantation is a tion. High-grade atrioventricular block and progression of sys- variable treatment. It should be noted that cardiac transplanta- tolic dysfunction occur in at least every 5 beats. But this can be tion is absolutely contraindicated in cases with significant co- done by genetic screening of family to identify asymptomatic morbid disorders [178]. Thus, the degree of extra-cardiac in- or oligo-symptomatic adults. Finally, interdisciplinary volvement and predicted quality of life could be assessed neurologic-cardiologic cooperation is required for the Heart Fail Rev treatment of most of MIDs. Fortunately, the management of 17. Chinnery PF (2015) Mitochondrial disease in adults: what's old ’ – cardiac diseases related to MIDs is, as usual, cardiologist care, and what s new? EMBO Mol Med 7:1503 1512 18. Di Donato S (2009) Multisystem manifestations of mitochondrial but earlier recognition and close follow-up are essential. In disorders. J Neurol 256:693–710 conclusion, the crucial problem that is associated with MIDs 19. Hamilton GC, Eilers MA, Pacholka R, Brooks T (1991) is cardiac complications. More understanding about genetics Objectives to direct the training of emergency medicine residents and epigenetics factors involved in MIDs that lead to cardiac on off-service rotation: otolaryngology. J Emerg Med 9:75–80 complications can provide new treatment strategies for the 20. Dai D-F, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS (2014) Mitochondrial oxidative stress in aging and healthspan. management of MIDs. Longev Healthspan 3:1–22 21. Choi B-O, Hwang JH, Cho EM, Jeong EH, Hyun YS, Jeon HJ, Seong KM, Cho NS, Chung KW (2010) Mutational analysis of whole mitochondrial DNA in patients with MELAS and MERRF diseases. Exp Mol Med 42:446–455 References 22. Taylor RW, Giordano C, Davidson MM, d’Amati G, Bain H, Hayes CM, Leonard H, Barron MJ, Casali C, Santorelli FM, 1. Osellame LD, Blacker TS, Duchen MR (2012) Cellular and mo- Hirano M, Lightowlers RN, DiMauro S, Turnbull DM (2003) A lecular mechanisms of mitochondrial function. Best Pract Res homoplasmic mitochondrial transfer ribonucleic acid mutation as Clin Endocrinol Metab 26:711–723 a cause of maternally inherited hypertrophic cardiomyopathy. J – 2. Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Am Coll Cardiol 41:1786 1796 Mitochondria as sensors and regulators of calcium signalling. 23. Perli E, Giordano C, Tuppen HA, Montopoli M, Montanari A, NatRevMolCellBiol13:566 Orlandi M et al (2011) Isoleucyl-tRNA synthetase levels modulate 3. Jacobs L, de Wert G, Geraedts J, De Coo I, Smeets H (2005) The the penetrance of a homoplasmic m. 4277T> C mitochondrial transmission of OXPHOS disease and methods to prevent this. tRNAIle mutation causing hypertrophic cardiomyopathy. Hum – Hum Reprod Update 12:119–136 Mol Genet 21:85 100 24. Krishnan KJ, Reeve AK, Samuels DC, Chinnery PF, Blackwood 4. Nejati M, Atlasi MA, Karimian M, Nikzad H, Tameh AA (2018) JK, Taylor RW et al (2008) What causes mitochondrial DNA Lipoprotein lipase gene polymorphisms as risk factors for stroke: a computational and meta-analysis. Iran J Basic Med Sci 21:701 deletions in human cells? Nat Genet 40:275 25. Carling PJ, Cree LM, Chinnery PF (2011) The implications of 5. DiMauro S, Hirano M (2011) Mitochondrial encephalomyopathies: mitochondrial DNA copy number regulation during embryogene- an update. Neuromuscul Disord 15:276–286 sis. Mitochondrion. 11:686–692 6. Pohjoismäki JL, Goffart S, Taylor RW, Turnbull DM, 26. Shock LS, Thakkar PV, Peterson EJ, Moran RG, Taylor SM Suomalainen A, Jacobs HT et al (2010) Developmental and path- (2011) DNA methyltransferase 1, cytosine methylation, and cyto- ological changes in the human cardiac muscle mitochondrial sine hydroxymethylation in mammalian mitochondria. Proc Natl DNA organization, replication and copy number. PLoS One 5: Acad Sci 108:3630–3635 e10426 27. Byun H-M, Panni T, Motta V, Hou L, Nordio F, Apostoli P, 7. Shoubridge EA, Wai T (2007) Mitochondrial DNA and the mam- Bertazzi P, Baccarelli AA (2013) Effects of airborne pollutants malian oocyte. Curr Top Dev Biol 77:87–111 on mitochondrial DNA methylation. Part Fibre Toxicol 10:18 8. Johns DR (1995) Mitochondrial DNA and disease. N Engl J Med 28. Liu B, Du Q, Chen L, Fu G, Li S, Fu L et al (2016) CpG methyl- 333:638–644 ation patterns of human mitochondrial DNA. Sci Rep 6:1–10 9. Wallace DC, Chalkia D (2013) Mitochondrial DNA genetics and 29. Baccarelli AA, Byun H-M (2015) Platelet mitochondrial DNA the heteroplasmy conundrum in evolution and disease. Cold methylation: a potential new marker of cardiovascular disease. Spring Harb Perspect Biol 5:a021220 Clin Epigenetics 7:44 10. Bates MG, Bourke JP, Giordano C, d'Amati G, Turnbull DM, 30. Iacobazzi V, Castegna A, Infantino V, Andria G (2013) Taylor RW (2012) Cardiac involvement in mitochondrial DNA Mitochondrial DNA methylation as a next-generation biomarker disease: clinical spectrum, diagnosis, and management. Eur Heart and diagnostic tool. Mol Genet Metab 110:25–34 – J 33:3023 3033 31. Saeedi Borujeni MJ, Esfandiary E, Baradaran A, Valiani A, 11. Niyazov DM, Kahler SG, Frye RE (2016) Primary mitochondrial Ghanadian M, Codoñer-Franch P, Basirat R, Alonso-Iglesias E, disease and secondary mitochondrial dysfunction: importance of Mirzaei H, Yazdani A (2019) Molecular aspects of pancreatic β- – distinction for diagnosis and treatment. Mol Syndromol 7:122 cell dysfunction: oxidative stress, microRNA, and long noncoding 137 RNA. J Cell Physiol 234:8411–8425 12. Chinnery P, Johnson M, Wardell T, Singh-Kler R, Hayes C, 32. Hashemian SM, Pourhanifeh MH, Fadaei S, Velayati AA, Mirzaei Brown D et al (2000) The epidemiology of pathogenic mitochon- H, Hamblin MR (2020) Non-coding RNAs and exosomes: their – drial DNA mutations. Ann Neurol 48:188 193 role in the pathogenesis of sepsis. Mol Ther Nucleic Acids 21:51– 13. Pankuweit S, Richter A (2015) Mitochondrial disorders with car- 74 diac dysfunction: an under-reported aetiology with phenotypic 33. Yousefi F, Shabaninejad Z, Vakili S, Derakhshan M, heterogeneity. Eur Heart J 36:2894–2897 Movahedpour A, Dabiri H et al (2020) TGF-β and WNT signal- 14. Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF ing pathways in cardiac fibrosis: non-coding RNAs come into (2008) Pathogenic mitochondrial DNA mutations are common focus. Cell Commun Signal 18:87 in the general population. Am J Hum Genet 83:254–260 34. Naeli P, Pourhanifeh MH, Karimzadeh MR, Shabaninejad Z, 15. Tuppen HA, Blakely EL, Turnbull DM, Taylor RW (2010) Movahedpour A, Tarrahimofrad H, Mirzaei HR, Bafrani HH, Mitochondrial DNA mutations and human disease. Biochim Savardashtaki A, Mirzaei H, Hamblin MR (2020) Circular Biophys Acta Bioenerg 1797:113–128 RNAs and gastrointestinal cancers: epigenetic regulators with a 16. Luft JH (1961) Improvements in epoxy resin embedding methods. prognostic and therapeutic role. Crit Rev Oncol Hematol 145: J Cell Biol 9:409–414 102854 Heart Fail Rev

35. Shabaninejad Z, Vafadar A, Movahedpour A, Ghasemi Y, 54. Meyers DE, Basha HI, Koenig MK (2013) Mitochondrial cardio- Namdar A, Fathizadeh H et al (2019) Circular RNAs in cancer: myopathy: pathophysiology, diagnosis, and management. Tex new insights into functions and implications in ovarian cancer. J Heart Inst J 40:385 Ovarian Res 12:84 55. Jonckheere AI, Hogeveen M, Nijtmans L, Van Den Brand M, 36. Vafadar A, Shabaninejad Z, Movahedpour A, Mohammadi S, Janssen A, Diepstra J et al (2008) A novel mitochondrial ATP8 Fathullahzadeh S, Mirzaei HR, Namdar A, Savardashtaki A, gene mutation in a patient with apical hypertrophic cardiomyopa- Mirzaei H (2019) Long non-coding RNAs as epigenetic regulators thy and neuropathy. J Med Genet 45:129–133 in Cancer. Curr Pharm Des 25:3563–3577 56. He R, Ding C, Yin P, He L, Xu Q, Wu Z, Shi Y, Su L (2019) MiR- 37. Mirzaei H, Yazdi F, Salehi R, Mirzaei HR (2016) SiRNA and 1a-3p mitigates isoproterenol-induced heart failure by enhancing epigenetic aberrations in ovarian cancer. J Cancer Res Ther 12: the expression of mitochondrial ND1 and COX1. Exp Cell Res 498–508 378:87–97 38. Khani P, Nasri F, Khani Chamani F, Saeidi F, Sadri Nahand J, 57. Mkaouar-Rebai E, Chamkha I, Mezghani N, Ayed IB, Fakhfakh F Tabibkhooei A et al (2019) Genetic and epigenetic contribution to (2013) Screening of mitochondrial mutations in Tunisian patients astrocytic gliomas pathogenesis. J Neurochem 148:188–203 with mitochondrial disorders: an overview study. Mitochondrial – 39. Mirzaei H (2017) Stroke in women: risk factors and clinical bio- DNA 24:163 178 markers. J Cell Biochem 118:4191–4202 58. Liu Z, Song Y, Li D, He X, Li S, Wu B et al (2014) The novel mitochondrial 16S rRNA 2336T> C mutation is associated with 40. Pourhanifeh MH, Mahjoubin-Tehran M, Karimzadeh MR, hypertrophic cardiomyopathy. J Med Genet 51:176–184 Mirzaei HR, Razavi ZS, Sahebkar A, Hosseini N, Mirzaei H, 59. Palecek T, Tesarova M, Kuchynka P, Dytrych V, Elleder M, Hamblin MR (2020) Autophagy in cancers including brain tu- Hulkova H et al (2012) Hypertrophic cardiomyopathy due to the mors: role of MicroRNAs. Cell Commun Signal 18:88 mitochondrial DNA mutation m. 3303C> T diagnosed in an adult 41. Nahand JS, Taghizadeh-Boroujeni S, Karimzadeh M, Borran S, male. Int Heart J 53:383–387 Pourhanifeh MH, Moghoofei M et al (2019) microRNAs: new 60. Zarrouk-Mahjoub S, Mehri S, Ouarda F, Finsterer J, Boussaada R prognostic, diagnostic, and therapeutic biomarkers in cervical can- – (2015) Mitochondrial tRNA glutamine variant in hypertrophic cer. J Cell Physiol 234:17064 17099 cardiomyopathy. Herz. 40:436–441 42. Salarinia R, Sahebkar A, Peyvandi M, Mirzaei HR, Jaafari MR, 61. Bates MG, Nesbitt V, Kirk R, He L, Blakely EL, Alston CL et al Riahi MM et al (2016) Epi-drugs and Epi-miRs: moving beyond (2012) Mitochondrial respiratory chain disease in children under- – current cancer therapies. Curr Cancer Drug Targets 16:773 788 going cardiac transplantation: a prospective study. Int J Cardiol 43. Sadri Nahand J, Moghoofei M, Salmaninejad A, Bahmanpour Z, 155:305–306 Karimzadeh M, Nasiri M, Mirzaei HR, Pourhanifeh MH, 62. Götz A, Tyynismaa H, Euro L, Ellonen P, Hyötyläinen T, Ojala T, Bokharaei-Salim F, Mirzaei H, Hamblin MR (2020) Pathogenic Hämäläinen RH, Tommiska J, Raivio T, Oresic M, Karikoski R, role of exosomes and microRNAs in HPV-mediated inflammation Tammela O, Simola KOJ, Paetau A, Tyni T, Suomalainen A and cervical cancer: a review. Int J Cancer 146:305–320 (2011) Exome sequencing identifies mitochondrial alanyl-tRNA 44. Aghdam AM, Amiri A, Salarinia R, Masoudifar A, Ghasemi F, synthetase mutations in infantile mitochondrial cardiomyopathy. Mirzaei H (2019) MicroRNAs as diagnostic, prognostic, and ther- Am J Hum Genet 88:635–642 apeutic biomarkers in prostate Cancer. Crit Rev Eukaryot Gene 63. Echaniz-Laguna A, Chassagne M, Ceresuela J, Rouvet I, Padet S, Expr 29:127–139 Acquaviva C, Nataf S, Vinzio S, Bozon D, Mousson de Camaret 45. Mirzaei H, Ferns GA, Avan A, Mobarhan MG (2017) Cytokines B (2012) Complete loss of expression of the ANT1 gene causing and MicroRNA in coronary artery disease. Adv Clin Chem 82:47– cardiomyopathy and myopathy. J Med Genet 49:146–150 70 64. Ware SM, El-Hassan N, Kahler S, Zhang Q, Miller E, Wong B 46. Geiger J, Dalgaard LT (2017) Interplay of mitochondrial metabo- et al (2009) Infantile cardiomyopathy caused by a mutation in the lism and microRNAs. Cell Mol Life Sci 74:631–646 overlapping region of mitochondrial ATPase 6 and 8 genes. J Med 47. Barrey E, Saint-Auret G, Bonnamy B, Damas D, Boyer O, Gidrol Genet 46:308–314 X (2011) Pre-microRNA and mature microRNA in human mito- 65. Hejzlarova K, Mráček T, Vrbacký M, Kaplanova V, Karbanova chondria. PLoS One 6:e20220 V, Nůsková H et al (2014) Nuclear genetic defects of mitochon- – 48. Bienertova-Vasku J, Sana J, Slaby O (2013) The role of drial ATP synthase. Physiol Res 63:sS57 S71 microRNAs in mitochondria in cancer. Cancer Lett 336:1–7 66. Rahman OU, Khawar N, Khan MA, Ahmed J, Khattak K, Al- 49. Das S, Ferlito M, Kent OA, Fox-Talbot K, Wang R, Liu D, Aama JY et al (2013) Deletion mutation in BSCL2 gene underlies Raghavachari N, Yang Y, Wheelan SJ, Murphy E, Steenbergen congenital generalized lipodystrophy in a Pakistani family. Diagn C (2012) Nuclear miRNA regulates the mitochondrial genome in Pathol 8:78 the heart. Circ Res 110:1596–1603 67. Krzywanski DM, Moellering DR, Fetterman JL, Dunham-Snary KJ, Sammy MJ, Ballinger SW (2011) The mitochondrial para- 50. Chen Y, Liu Y, Dorn GW (2011) Mitochondrial fusion is essential digm for cardiovascular disease susceptibility and cellular func- for organelle function and cardiac homeostasis. Circ Res 109: tion: a complementary concept to Mendelian genetics. Lab 1327–1331 Investig 91:1122 51. Villar P, Bretón B, García-Pavía P, González-Páramos C, 68. Van den Heuvel L, Smits P, Saada A, Wortmann S, Heister A, Blázquez A, Gómez-Bueno M et al (2013) Cardiac dysfunction Miller C, et al. (2010) Mutation in mitochondrial ribosomal pro- in mitochondrial disease. Circ J 77:279–286 tein MRPS22 leads to Cornelia de Lange-like phenotype, brain ’ 52. Limongelli G, Masarone D, D Alessandro R, Elliott PM (2012) abnormalities and hypertrophic cardiomyopathy. Eur J Hum Mitochondrial diseases and the heart: an overview of molecular Genet 19:394–399 – basis, diagnosis, treatment and clinical course. Futur Cardiol 8:71 69. Carroll CJ, Isohanni P, Pöyhönen R, Euro L, Richter U, Brilhante 88 V, Götz A, Lahtinen T, Paetau A, Pihko H, Battersby BJ, 53. Park S-Y, Gifford JR, Andtbacka RH, Trinity JD, Hyngstrom JR, Tyynismaa H, Suomalainen A (2013) Whole-exome sequencing Garten RS et al (2014) Cardiac, skeletal, and smooth muscle mi- identifies a mutation in the mitochondrial ribosome protein tochondrial respiration: are all mitochondria created equal? Am J MRPL44 to underlie mitochondrial infantile cardiomyopathy. J – Phys Heart Circ Phys 307:H346 HH52 Med Genet 50:151–159 Heart Fail Rev

70. Galmiche L, Serre V, Beinat M, Assouline Z, Lebre AS, Chretien 84. Shikata C, Nemoto M, Ebisawa T, Nishiyama A, Takeda N (2011) D, Nietschke P, Benes V, Boddaert N, Sidi D, Brunelle F, Rio M, Mitochondrial DNA and heart disease. Genes and Cardiovascular Munnich A, Rötig A (2011) Exome sequencing identifies MRPL3 Function. Springer, Boston, p 79–84 mutation in mitochondrial cardiomyopathy. Hum Mutat 32:1225– 85. Peretto G, Durante A, Limite LR, Cianflone D (2014) 1231 Postoperative arrhythmias after cardiac surgery: incidence, risk 71. Baruffini E, Dallabona C, Invernizzi F, Yarham JW, Melchionda factors, and therapeutic management.Cardiol Res Pract 2014: L, Blakely EL, Lamantea E, Donnini C, Santra S, Vijayaraghavan 615987 S, Roper HP, Burlina A, Kopajtich R, Walther A, Strom TM, 86. Majamaa-Voltti K, Peuhkurinen K, Kortelainen M-L, Hassinen Haack TB, Prokisch H, Taylor RW, Ferrero I, Zeviani M, IE, Majamaa K (2002) Cardiac abnormalities in patients with mi- Ghezzi D (2013) MTO 1 mutations are associated with hypertro- tochondrial DNA mutation 3243A>G. BMC Cardiovasc Disord 2: phic cardiomyopathy and lactic acidosis and cause respiratory 12 chain deficiency in humans and yeast. Hum Mutat 34:1501–1509 87. Wilmin S, De Bels D, Knecht S, Gottignies P, Gazagnes M-D, 72. Fassone E, Taanman J-W, Hargreaves IP, Sebire NJ, Cleary MA, Devriendt J (2012) Torsade de pointes in Kearns–Sayre syndrome. Burch M et al (2011) Mutations in the mitochondrial complex I Pract Neurol 12:199–201 assembly factor NDUFAF1 cause fatal infantile hypertrophic car- 88. Berardo A, Musumeci O, Toscano A (2011) Cardiological mani- diomyopathy. J Med Genet 48:691–697 festations of mitochondrial respiratory chain disorders. Acta Myol 73. Ngu LH, Nijtmans LG, Distelmaier F, Venselaar H, van Emst-de 30:9 Vries SE, van den Brand MA et al (2012) A catalytic defect in 89. Zhou N, Tang L, Jiang Y, Qin S, Cui J, Wang Y et al (2019) mitochondrial respiratory chain complex I due to a mutation in Whole-exome sequencing reveals a novel mutation of MT-ND5 NDUFS2 in a patient with Leigh syndrome. Biochim Biophys gene in a mitochondrial cardiomyopathy pedigree: patients who Acta Mol Basis Dis 1822:168–175 show biventricular hypertrophy, hyperlactacidemia, pulmonary 74. Liu H-Y, Liao P-C, Chuang K-T, Kao M-C (2011) Mitochondrial hypertension, and decreased exercise tolerance. Anatol J Cardiol targeting of human NADH dehydrogenase (ubiquinone) flavopro- 21:18 tein 2 (NDUFV2) and its association with early-onset hypertro- 90. Khullar M, Thangaraj K. Mitochondrial DNA variations associat- phic cardiomyopathy and encephalopathy. J Biomed Sci 18:29 ed with hypertrophic cardiomyopathy. 2013 75. Navarro-Sastre A, Tort F, Stehling O, Uzarska MA, Arranz JA, 91. Vallance H, Jeven G, Wallace D, Brown M (2004) A case of del Toro M, Labayru MT, Landa J, Font A, Garcia-Villoria J, sporadic infantile histiocytoid cardiomyopathy caused by the Merinero B, Ugarte M, Gutierrez-Solana LG, Campistol J, A8344G (MERRF) mitochondrial DNA mutation. Pediatr Garcia-Cazorla A, Vaquerizo J, Riudor E, Briones P, Elpeleg O, Cardiol 25:538–540 Ribes A, Lill R (2011) A fatal mitochondrial disease is associated 92. Finsterer J (2009) Manifestations of the mitochondrial A3243G with defective NFU1 function in the maturation of a subset of mutation. Int J Cardiol 137:60–62 mitochondrial Fe-S proteins. Am J Hum Genet 89:656–667 93. Wang S-B, Weng W-C, Lee N-C, Hwu W-L, Fan P-C, Lee W-T 76. Fassone E, Rahman S (2012) Complex I deficiency: clinical fea- (2008) Mutation of mitochondrial DNA G13513A presenting with tures, biochemistry and molecular genetics. J Med Genet 49:578– Leigh syndrome, Wolff-Parkinson-White syndrome and cardio- 590 myopathy. Pediatr Neonatol 49:145–149 77. Leary SC, Antonicka H, Sasarman F, Weraarpachai W, Cobine 94. Riera ARP, Kaiser E, Levine P, Schapachnik E, Dubner S, PA, Pan M et al (2013) Novel mutations in SCO 1 as a cause of Ferreira C et al (2008) Kearns-Sayre syndrome: electro- fatal infantile encephalopathy and lactic acidosis. Hum Mutat 34: vectorcardiographic evolution for left septal fascicular block of 1366–1370 the his bundle. J Electrocardiol 41:675–678 78. Joost K, Rodenburg R, Piirsoo A, van den Heuvel B, Zordania R, 95. Verhoeven WM, Egger JI, Kremer BP, de Pont BJ, Marcelis CL Õunap K (2010) A novel mutation in the SCO2 gene in a neonate (2011) Recurrent major depression, ataxia, and cardiomyopathy: with early-onset cardioencephalomyopathy. Pediatr Neurol 42: association with a novel POLG mutation? Neuropsychiatr Dis 227–230 Treat 7:293 79. Atay Z, Bereket A, Turan S, Haliloglu B, Memisoglu A, Khayat 96. Planavila A, Dominguez E, Navarro M, Vinciguerra M, Iglesias M, Shalev SA, Spiegel R (2013) A novel homozygous TMEM70 R, Giralt M, Lope-Piedrafita S, Ruberte J, Villarroya F (2012) mutation results in congenital cataract and neonatal mitochondrial Dilated cardiomyopathy and mitochondrial dysfunction in Sirt1- encephalo-cardiomyopathy. Gene. 515:197–199 deficient mice: a role for Sirt1-Mef2 in adult heart. J Mol Cell – 80. Shahni R, Wedatilake Y, Cleary MA, Lindley KJ, Sibson KR, Cardiol 53:521 531 Rahman S (2013) A distinct mitochondrial myopathy, lactic aci- 97. Vernengo L, Lilienbaum A, Agbulut O, Rodríguez M-M (2013) dosis and sideroblastic anemia (MLASA) phenotype associates The role of genetics in cardiomyopathy. Cardiomyopathies, with YARS2 mutations. Am J Med Genet A 161:2334–2338 IntechOpen 81. Kabunga P, Lau AK, Phan K, Puranik R, Liang C, Davis RL, Sue 98. Wahbi K, Larue S, Jardel C, Meune C, Stojkovic T, Ziegler F, CM, Sy RW (2015) Systematic review of cardiac electrical disease Lombes A, Eymard B, Duboc D, Laforet P (2010) Cardiac in- in Kearns–Sayre syndrome and mitochondrial cytopathy. Int J volvement is frequent in patients with the m.8344A>G mutation Cardiol 181:303–310 of mitochondrial DNA. Neurology. 74:674–677 82. Ayalon N, Flore LA, Christensen TG, Sam F (2013) 99. Jain-Ghai S, Cameron JM, Al Maawali A, Blaser S, MacKay N, — Mitochondrial encoded NADH dehydrogenase 5 (MT-ND5) Robinson B et al (2013) Complex II deficiency a case report and – gene point mutation presents as late onset cardiomyopathy. Int J review of the literature. Am J Med Genet A 161:285 294 Cardiol 167:e143–e1e5 100. Giordano C, Perli E, Orlandi M, Pisano A, Tuppen HA, He L, 83. Hollingsworth KG, Gorman GS, Trenell MI, McFarland R, Taylor Ierinò R, Petruzziello L, Terzi A, Autore C, Petrozza V, Gallo P, RW, Turnbull DM, MacGowan GA, Blamire AM, Chinnery PF Taylor RW, d'Amati G (2013) Cardiomyopathies due to (2012) Cardiomyopathy is common in patients with the mitochon- homoplasmic mitochondrial tRNA mutations: morphologic and – drial DNA m.3243A>G mutation and correlates with mutation molecular features. Hum Pathol 44:1262 1270 load. Neuromuscul Disord 22:592–596 101. Van Hove JL, Freehauf C, Miyamoto S, Vladutiu GD, Pancrudo J, Bonilla E et al (2008) Infantile cardiomyopathy caused by the Heart Fail Rev

T14709C mutation in the mitochondrial tRNA glutamic acid gene. 118. Johnson EC, West TW, Ko NU, Strober JB (2011) A 41-year-old Eur J Pediatr 167:771–776 man with new headache and altered mental status. 102. Tang S, Batra A, Zhang Y, Ebenroth ES, Huang T (2010) Left Neurohospitalist 1:48–54 ventricular noncompaction is associated with mutations in the mi- 119. Jia Z, Wang X, Qin Y, Xue L, Jiang P, Meng Y, Shi S, Wang Y, tochondrial genome. Mitochondrion. 10:350–357 Qin Mo J, Guan MX (2013) Coronary heart disease is associated 103. Mahjoub SZ, Mehri S, Ourda F, Boussaada R, Mechmeche R, with a mutation in mitochondrial tRNA. Hum Mol Genet 22: Arab SB et al (2011) Transition m. 3308T> C in the ND1 gene 4064–4073 is associated with left ventricular hypertrabeculation/ 120. Choi J-H, Yoon H-R, Kim G-H, Park S-J, Shin Y-L, Yoo H-W noncompaction. Cardiology. 118:153–158 (2007) Identification of novel mutations of the HADHA and 104. Liu S, Bai Y, Huang J, Zhao H, Zhang X, Hu S, Wei Y (2013) Do HADHB genes in patients with mitochondrial trifunctional protein mitochondria contribute to left ventricular non-compaction cardio- deficiency. Int J Mol Med 19:81–87 myopathy? New findings from myocardium of patients with left 121. Yajima N, Yazaki Y, Yoshida K, Sano K, Takahashi W, Sasaki Y, ventricular non-compaction cardiomyopathy. Mol Genet Metab Ikeda U (2009) A case of mitochondrial cardiomyopathy with 109:100–106 pericardial effusion evaluated by 99m Tc-MIBI myocardial scin- 105. Finsterer J (2007) Genetic, pathogenetic, and phenotypic implica- tigraphy. J Nucl Cardiol 16:989–994 tions of the mitochondrial A3243G tRNALeu (UUR) mutation. 122. Mackenzie RM, Salt IP, Miller WH, Logan A, Ibrahim HA, Acta Neurol Scand 116:1–14 Degasperi A et al (2012) Mitochondrial reactive oxygen species 106. Malfatti E, Laforêt P, Jardel C, Stojkovic T, Behin A, Eymard B enhance AMP-activated protein kinase activation in the endothe- et al (2013) High risk of severe cardiac adverse events in patients lium of patients with coronary artery disease and diabetes. Clin Sci with mitochondrial m.3243A>G mutation. Neurology. 80:100– 124:403–411 105 123. Ferres-Sanchez P, Subirana-Domenech M, Torner-Soler M (1995) 107. Karanikis P, Korantzopoulos P, Kountouris E, Dimitroula V, Chest pain during exercise as first manifestation of Friedreich’s Patsouras D, Pappa E, Siogas K (2005) Kearns–Sayre syndrome ataxia. Heart. 74:464–467 associated with trifascicular block and QT prolongation. Int J 124. Sobenin IA, Sazonova MA, Ivanova MM, Zhelankin AV, Cardiol 101:147–150 Myasoedova VA, Postnov AY et al (2012) Mutation C3256T of 108. Ryan JJ, Marsboom G, Fang Y-H, Toth PT, Morrow E, Luo N, mitochondrial genome in white blood cells: novel genetic marker Piao L, Hong Z, Ericson K, Zhang HJ, Han M, Haney CR, Chen of atherosclerosis and coronary heart disease. PLoS One 7:e46573 CT, Sharp WW, Archer SL (2013) PGC1α-mediated mitofusin-2 125. Chow J, Rahman J, Achermann JC, Dattani MT, Rahman S deficiency in female rats and humans with pulmonary arterial hy- (2017) Mitochondrial disease and endocrine dysfunction. Nat pertension. Am J Respir Crit Care Med 187:865–878 Rev Endocrinol 13:92–104 109. Hung P-C, Wang H-S, Chung H-T, Hwang M-S, Ro L-S (2012) 126. Schaefer AM, Walker M, Turnbull DM, Taylor RW (2013) Pulmonary hypertension in a child with mitochondrial A3243G Endocrine disorders in mitochondrial disease. Mol Cell point mutation. Brain and Development 34:866–868 Endocrinol 379:2–11 110. Indrieri A, Van Rahden VA, Tiranti V, Morleo M, Iaconis D, 127. Finsterer J, Strobl W (2012) Brachydactylia as a phenotypic fea- Tammaro R et al (2012) Mutations in COX7B cause ture of mitochondrial disorder. Acta Med Iran 50:831–835 microphthalmia with linear skin lesions, an unconventional mito- 128. Kalogeris T, Bao Y, Korthuis RJ (2014) Mitochondrial reactive chondrial disease. Am J Hum Genet 91:942–949 oxygen species: a double edged sword in ischemia/reperfusion vs 111. Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, preconditioning. Redox Biol 2:702–714 Feinstein S, Zeligson S, Segel R, Elpeleg O, Nassar S, Frishberg 129. Brown DA, Sabbah HN, Shaikh SR (2013) Mitochondrial inner Y (2011) Mutations in the mitochondrial seryl-tRNA synthetase membrane lipids and proteins as targets for decreasing cardiac cause hyperuricemia, pulmonary hypertension, renal failure in ischemia/reperfusion injury. Pharmacol Ther 140:258–266 infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 88: 130. Mirzaei H, Momeni F, Saadatpour L, Sahebkar A, Goodarzi M, 193–200 Masoudifar A, Kouhpayeh S, Salehi H, Mirzaei HR, Jaafari MR 112. Fijołek J, Wiatr E, Wiechecka A, Torbicki A, Biederman A, (2018) MicroRNA: relevance to stroke diagnosis, prognosis, and Mickielewicz A et al (2003) Pulmonary thromboembolism as a therapy. J Cell Physiol 233:856–865 late complication of mitochondrial myopathy (Kearns-Sayer syn- 131. Ahmed S, Khan H, Mirzaei H (2019) Mechanics insights of drome). Pneumonol Alergol Pol 71:449–457 curcumin in myocardial ischemia: where are we standing? Eur J 113. Prasad GN, Vanniarajan A, Emmanuel C, Cherian KM, Singh L, Med Chem 183:111658 Thangaraj K (2006) Novel mitochondrial DNA mutations in a rare 132. Hoseini Z, Sepahvand F, Rashidi B, Sahebkar A, Masoudifar A, variety of hypertrophic cardiomyopathy. Int J Cardiol 109:432– Mirzaei H (2018) NLRP3 inflammasome: its regulation and in- 433 volvement in atherosclerosis. J Cell Physiol 233:2116–2132 114. Cave D, Ross DB, Bahitham W, Chan A, Sergi C, Adatia I (2013) 133. Rashidi B, Hoseini Z, Sahebkar A, Mirzaei H (2017) Anti- Mitochondrial DNA depletion syndrome-an unusual reason for atherosclerotic effects of vitamins D and E in suppression of ath- interstage attrition after the modified stage 1 Norwood operation. erogenesis. J Cell Physiol 232:2968–2976 Congenit Heart Dis 8:E20–E23 134. Finsterer J (2012) Stroke and stroke-like episodes in muscle dis- 115. Majamaa-Voltti K, Majamaa K, Peuhkurinen K, Mäkikallio T, ease. Open Neurol J 6:26–36 Huikuri H (2004) Cardiovascular autonomic regulation in patients 135. Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R (2009) with 3243A>G mitochondrial DNA mutation. Ann Med 36:225– A modern approach to the treatment of mitochondrial disease. 231 Curr Treat Options Neurol 11:414–430 116. Brunetti-Pierri N, Pignatelli R, Fouladi N, Towbin JA, Belmont 136. DiMauro S, Tanji K, Schon EA (2012) The many clinical faces of JW, Craigen WJ, Wong LJ, Jefferies JL, Scaglia F (2011) Dilation cytochrome c oxidase deficiency. Adv Exp Med Biol 341–357 of the aortic root in mitochondrial disease patients. Mol Genet 137. Chevallier JA, Koenig MK (2012) Friedreich-like ataxia as an Metab 103:167–170 initial manifestation of mitochondrial DNA 8344A>G mutation. 117. Ronchi D, Di Fonzo A, Lin W, Bordoni A, Liu C, Fassone E et al J Child Neurol 27:1056–1058 (2013) Mutations in DNA2 link progressive myopathy to mito- 138. El-Hattab AW, Scaglia F (2016) Mitochondrial cardiomyopathies. chondrial DNA instability. Am J Hum Genet 92:293–300 Front Cardiovasc Med 3:25 Heart Fail Rev

139. Terman A, Kurz T, Gustafsson B, Brunk UT (2008) The involve- 156. Bit-Avragim N, Perrot A, Schöls L, Hardt C, Kreuz FR, Zühlke C, ment of lysosomes in myocardial aging and disease. Curr Cardiol Bubel S, Laccone F, Vogel HP, Dietz R, Osterziel KJ (2001) The Rev 4:107–115 GAA repeat expansion in intron 1 of the frataxin gene is related to 140. Sebastiani M, Giordano C, Nediani C, Travaglini C, Borchi E, the severity of cardiac manifestation in patients with Friedreich's Zani M, Feccia M, Mancini M, Petrozza V, Cossarizza A, Gallo ataxia. J Mol Med 78:626–632 P, Taylor RW, d’Amati G (2007) Induction of mitochondrial bio- 157. Albano LMJ, Nishioka SAD, Moysés RL, Wagenführ J, Bertola genesis is a maladaptive mechanism in mitochondrial cardiomy- D, Sugayama SMM, Chong AK (2002) Friedreich's ataxia: cardi- opathies. J Am Coll Cardiol 50:1362–1369 ac evaluation of 25 patients with clinical diagnosis and literature 141. Hansson A, Hance N, Dufour E, Rantanen A, Hultenby K, review. Arq Bras Cardiol 78:448–451 Clayton DA, Wibom R, Larsson NG (2004) A switch in metabo- 158. Koeppen AH, Michael SC, Knutson MD, Haile DJ, Qian J, Levi lism precedes increased mitochondrial biogenesis in respiratory S, Santambrogio P, Garrick MD, Lamarche JB (2007) The dentate chain-deficient mouse hearts. Proc Natl Acad Sci 101:3136–3141 nucleus in Friedreich’s ataxia: the role of iron-responsive proteins. 142. Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Acta Neuropathol 114:163–173 Saffitz JE et al (2004) Cardiac-specific induction of the transcrip- 159. Regner SR, Lagedrost SJ, Plappert T, Paulsen EK, Friedman LS, tional coactivator peroxisome proliferator-activated receptor γ Snyder ML, Perlman SL, Mathews KD, Wilmot GR, Schadt KA, coactivator-1α promotes mitochondrial biogenesis and reversible Sutton MSJ, Lynch DR (2012) Analysis of echocardiograms in a cardiomyopathy in a developmental stage-dependent manner. Circ large heterogeneous cohort of patients with Friedreich ataxia. Am Res 94:525–533 J Cardiol 109:401–405 143. Lehman JJ, Kelly DP (2002) Gene regulatory mechanisms 160. Meyer C, Schmid G, Görlitz S, Ernst M, Wilkens C, Wilhelms I governing energy metabolism during cardiac hypertrophic et al (2007) Cardiomyopathy in Friedreich's ataxia-assessment by growth. Heart Fail Rev 7:175–185 cardiac MRI. Mov Disord 22:1615–1622 144. Li Y, Huang T-T, Carlson EJ, Melov S, Ursell PC, Olson JL, 161. Sproule DM, Kaufmann P (2008) Mitochondrial encephalopathy, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, lactic acidosis, and strokelike episodes: basic concepts, clinical Epstein CJ (1995) Dilated cardiomyopathy and neonatal lethality phenotype, and therapeutic management of MELAS syndrome. in mutant mice lacking manganese superoxide dismutase. Nat Ann N Y Acad Sci 1142:133–158 Genet 11:376–381 162. Al-Enezi M, Al-Saleh H, Nasser M (2008) Mitochondrial disor- 145. Dai DF, Chen T, Wanagat J, Laflamme M, Marcinek DJ, Emond ders with significant ophthalmic manifestations. Middle East Afr J MJ, Ngo CP, Prolla TA, Rabinovitch PS (2010) Age-dependent Ophthalmol 15:81–86 cardiomyopathy in mitochondrial mutator mice is attenuated by 163. O’Toole JF (2014) Renal manifestations of genetic mitochondrial overexpression of catalase targeted to mitochondria. Aging Cell 9: disease. Int J Nephrol Renov Dis 7:57 536–544 164. Finsterer J, Zarrouk-Mahjoub S (2016) Mitochondrial vasculopa- 146. Grings M, Tonin AM, Knebel LA, Zanatta Â, Moura AP, Dutra thy. World J Cardiol 8:333–339 Filho CS et al (2012) Phytanic acid disturbs mitochondrial homeo- 165. Lorenzoni PJ, Werneck LC, Kay CSK, Silvado CES, Scola RH stasis in heart of young rats: a possible pathomechanism of car- (2015) When should MELAS (mitochondrial myopathy, enceph- diomyopathy in Refsum disease. Mol Cell Biochem 366:335–343 alopathy, lactic acidosis, and stroke-like episodes) be the diagno- 147. Spencer CT, Bryant RM, Day J, Gonzalez IL, Colan SD, sis? Arq Neuropsiquiatr 73:959–967 Thompson WR, Berthy J, Redfearn SP, Byrne BJ (2006) 166. Diegoli M, Grasso M, Favalli V, Serio A, Gambarin FI, Klersy C, Cardiac and clinical phenotype in Barth syndrome. Pediatrics. Pasotti M, Agozzino E, Scelsi L, Ferlini A, Febo O, Piccolo G, 118:e337–ee46 Tavazzi L, Narula J, Arbustini E (2011) Diagnostic work-up and 148. Paukov V, Protsenko D (1996) The intermitochondrial contacts of risk stratification in X-linked dilated cardiomyopathies caused by cardiomyocytes during cardiac adaptation under pathological con- dystrophin defects. J Am Coll Cardiol 58:925–934 ditions. Arkh Patol 58:43–50 167. White KL, Chen JM, Margot NA, Wrin T, Petropoulos CJ, Naeger 149. Catteruccia M, Verrigni D, Martinelli D, Torraco A, Agovino T, LK, Swaminathan S, Miller MD (2004) Molecular mechanisms of Bonafé L, D'Amico A, Donati MA, Adorisio R, Santorelli FM, tenofovir resistance conferred by human immunodeficiency virus Carrozzo R, Bertini E, Dionisi-Vici C (2014) Persistent pulmonary type 1 reverse transcriptase containing a diserine insertion after arterial hypertension in the newborn (PPHN): a frequent manifes- residue 69 and multiple thymidine analog-associated mutations. tation of TMEM70 defective patients. Mol Genet Metab 111:353– Antimicrob Agents Chemother 48:992–1003 359 168. Clarke SL, Bowron A, Gonzalez IL, Groves SJ, Newbury-Ecob R, 150. Singh RB, Dandekar SP, Elimban V, Gupta SK, Dhalla NS (2004) Clayton N et al (2013) Barth syndrome. Orphanet J Rare Dis 8:23 Role of proteases in the pathophysiology of cardiac disease. Mol 169. Laurent D, Edwards JG (2014) Alcoholic cardiomyopathy: multi- Cell Biochem 263:241–256 genic changes underlie cardiovascular dysfunction. J Cardiol Clin 151. Shao D, Tian R (2011) Glucose transporters in cardiac metabolism Res 2:1 and hypertrophy. Compr Physiol 6:331–351 170. Finsterer J, Llberger CS (2009) Neuromuscular disorders associ- 152. Bulthuis EP, Adjobo-Hermans MJ, Willems PH, Koopman WJ ated with apical hypertrophic cardiomyopathy. Acta Cardiol 64: (2019) Mitochondrial morphofunction in mammalian cells. 85–89 Antioxid Redox Signal 30:2066–2109 171. Buda P, Wieteska-Klimczak A, Ksiazyk J, Smorczewska-Kiljan 153. Spiegel R, Khayat M, Shalev SA, Horovitz Y, Mandel H, A, Gietka P, Czartoryska B, Tylki-Szymańska A (2011) Hershkovitz E, Barghuti F, Shaag A, Saada A, Korman SH, Diagnostic problems in a 17-year-old patient with gastrointestinal Elpeleg O, Yatsiv I (2011) TMEM70 mutations are a common manifestations of Fabry disease. Med Wieku Rozwoj 15:69–72 cause of nuclear encoded ATP synthase assembly defect: further 172. Baik R, Chae JH, Lee YM, Kang HC, Lee JS, Kim HD (2010) delineation of a new syndrome. J Med Genet 48:177–182 Electrocardiography as an early cardiac screening test in children 154. Vydt TC, de Coo RF, Soliman OI, Folkert J, van Geuns R-JM, with mitochondrial disease. Korean J Pediatr 53:644–647 Vletter WB et al (2007) Cardiac involvement in adults with 173. Berkman N, Henderson J, Fiordalisi C, Hartling L, Newberry S, m.3243A>G MELAS gene mutation. Am J Cardiol 99:264–269 Guise J et al (1993–2019) In: Adam MP, Ardinger HH, Pagon RA, 155. Rahman S (2015) Emerging aspects of treatment in mitochondrial Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) disorders. J Inherit Metab Dis 38:641–653 GeneReviews®[Internet]. University of Washington, Seattle, Heart Fail Rev

Seattle. Available from http://www.ncbi.nlm.nih.gov/books/ resynchronization therapy: the task force for cardiac pacing and NBK1116/PubMed Mol Imaging Biol. 2012;14:4–13 cardiac resynchronization therapy of the European Society of 174. Gobu P, Karthikeyan B, Prasath A, Santhosh S, Balachander J Cardiology. Developed in collaboration with the European Heart (2010) Kearns Sayre syndrome (KSS)-a rare cause for cardiac Rhythm Association. Eur Heart J 28:2256–2295 pacing. Indian Pacing Electrophysiol J 10:547 178. Panas M, Gialafos E, Spengos K, Papaioannou TG, Aggeli K, 175. Puri A, Pradhan A, Chaudhary G, Singh V, Sethi R, Narain VS Kladi A et al (2010) Prevalence of interatrial block in patients with (2012) Symptomatic complete heart block leading to a diagnosis Friedreich’s ataxia. Int J Cardiol 145:386–387 of Kearns–Sayre syndrome. Indian Heart J 64:515–517 179. Fayssoil A (2009) Heart diseases in mitochondrial encephalomy- 176. Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB, Estes opathy, lactic acidosis, and stroke syndrome. Congest Heart Fail NM et al (2013) 2012 ACCF/AHA/HRS focused update incorpo- 15:284–287 rated into the ACCF/AHA/HRS 2008 guidelines for device-based 180. Dedkova EN, Blatter LA (2012) Measuring mitochondrial func- therapy of cardiac rhythm abnormalities: a report of the American tion in intact cardiac myocytes. J Mol Cell Cardiol 52:48–61 College of Cardiology Foundation/American Heart Association Task Force on practice guidelines and the Heart Rhythm Publisher’snote Society. J Am Coll Cardiol 61:e6–e75 Springer Nature remains neutral with regard to jurisdic- 177. Vardas PE, Auricchio A, Blanc J-J, Daubert J-C, Drexler H, Ector tional claims in published maps and institutional affiliations. H et al (2007) Guidelines for cardiac pacing and cardiac