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Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies

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Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies Journal of Clinical Medicine Review Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies 1, 2,3, 2,3 4 Chia-Jung Li y , Chien-Sheng Chen y, Giou-Teng Yiang , Andy Po-Yi Tsai , Wan-Ting Liao 5,6,* and Meng-Yu Wu 2,3,* 1 Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan; [email protected] 2 Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan; [email protected] (C.-S.C.); [email protected] (G.-T.Y.) 3 Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien 970, Taiwan 4 Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan; [email protected] 5 Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan 6 Chinese Medicine Department, Show Chwan Memorial Hospital, Changhua 500, Taiwan * Correspondence: [email protected] (W.-T.L.); [email protected] (M.-Y.W.); Tel.: +886-4-725-6166 (W.-T.L.); +886-2-6628-42752 (M.-Y.W.) These authors contributed equally to this work. y Received: 7 March 2019; Accepted: 12 April 2019; Published: 16 April 2019 Abstract: Cardiomyopathy is a group of heterogeneous cardiac diseases that impair systolic and diastolic function, and can induce chronic heart failure and sudden cardiac death. Cardiomyopathy is prevalent in the general population, with high morbidity and mortality rates, and contributes to nearly 20% of sudden cardiac deaths in younger individuals. Genetic mutations associated with cardiomyopathy play a key role in disease formation, especially the mutation of sarcomere encoding genes and ATP kinase genes, such as titin, lamin A/C, myosin heavy chain 7, and troponin T1. Pathogenesis of cardiomyopathy occurs by multiple complex steps involving several pathways, including the Ras-Raf-mitogen-activated protein kinase-extracellular signal-activated kinase pathway, G-protein signaling, mechanotransduction pathway, and protein kinase B/phosphoinositide 3-kinase signaling. Excess biomechanical stress induces apoptosis signaling in cardiomyocytes, leading to cell loss, which can induce myocardial fibrosis and remodeling. The clinical features and pathophysiology of cardiomyopathy are discussed. Although several basic and clinical studies have investigated the mechanism of cardiomyopathy, the detailed pathophysiology remains unclear. This review summarizes current concepts and focuses on the molecular mechanisms of cardiomyopathy, especially in the signaling from mutation to clinical phenotype, with the aim of informing the development of therapeutic interventions. Keywords: cardiomyopathy; genetic mutations; cardiac remodeling; apoptosis; fibrosis 1. Introduction Cardiomyopathy refers to a group of heterogeneous genetic or idiopathic cardiac diseases that feature myocardial structural and functional abnormalities that occur due to myocyte injuries [1]. The anatomic changes and cell death induce electrical dysfunction contraction abnormalities of the heart, causing arrhythmia and heart failure. The reported etiologies include chronic hypertension, valvular heart disease, and toxin exposure [2]. Ischemic heart diseases and induced myocardial disorders are also included. Genetic mitochondrial dysfunction has been a focus of study [3]. However, clinical and basic studies carried out over a long time have not clarified details of the pathophysiology. Recent studies have focused on the molecular and genetic aspects of cardiomyopathy, including local J. Clin. Med. 2019, 8, 520; doi:10.3390/jcm8040520 www.mdpi.com/journal/jcm J. Clin. Med. 2019, 8, 520 2 of 23 J. Clin. Med. 2019, 8, x; doi: FOR PEER REVIEW 2 of 23 inflammation,inflammation, reperfusion injury, injury, death, remodeling, and recovery of myocardia, with the goal of informing novelnovel approaches approaches for for clinical clinical and prognosticand prognostic assessments assessments [4,5]. In [4,5]. this review, In this we review, summarize we thesummarize current conceptsthe current concerning concepts the cellconcerning biology and th moleculare cell biology regulation and ofmolecular cardiomyopathy regulation with theof aimcardiomyopathy of informing with the development the aim of informing of therapeutic the development interventions. of therapeutic interventions. 2. Clinical Features of Genetic Cardiomyopathy The heterogeneous conditions that encompass ca cardiomyopathyrdiomyopathy feature myocardial dysfunction with structuralstructural and and functional functional abnormalities, abnormalities, and and are broadlyare broadly classified classified as familial as familial types andtypes non-familial and non- typesfamilial [6 ].types Based [6]. on Based structural on structural and functional and functional abnormalities, abnormalities, these types these can types be further can be classified further intoclassified four majorinto four categories: major categories: dilated cardiomyopathy dilated cardiomyopathy (DCM), hypertrophic(DCM), hypertrophic cardiomyopathy cardiomyopathy (HCM), restrictive(HCM), cardiomyopathyrestrictive cardiomyopathy (RCM), and arrhythmogenic (RCM), and right arrhythmogenic ventricular cardiomyopathy right ventricular/dysplasia (ARVCcardiomyopathy/dysplasia/D) (Figure1). In familial (ARVC/D) types (Figure of cardiomyopathy, 1). In familial lefttypes ventricular of cardiomyopathy, non-compaction left ventricular (LVNC) isnon-compaction considered an unclassified(LVNC) is type.considered Takotsubo an unclassified cardiomyopathy type. andTakotsubo tachycardiomyopathy cardiomyopathy are twoand commontachycardiomyopathy cardiomyopathies are two that common are classified cardiomyopathies as non-familial that are types classified [7]. The as primarynon-familial causes types of the[7]. diThefferent primary types causes of cardiomyopathies of the different are types heterogeneous, of cardiomyopathies but they share are heterogeneous, a final common pathwaybut they leadingshare a tofinal cardiac common dysfunction. pathway leading to cardiac dysfunction. Figure 1. RiskRisk factors factors of of the the four major types of cardiomyopathy. 3. DCM DCM isis characterizedcharacterized by by the the structural structural dilation dilation of ventricles of ventricles associated associated with poorwith contraction.poor contraction. DCM isDCM the mostis the commonmost common cardiomyopathy, cardiomyopathy, with with an incidence an incidence ranging ranging from from 5–8 cases5–8 cases per per 100,000 100,000 people people [8]. Similar[8]. Similar to the to other the other three majorthree typesmajor oftypes cardiomyopathies, of cardiomyopathies, DCM is classifiedDCM is classified as primary as or primary secondary or types.secondary In primary types. In DCM, primary genetic DCM, causes genetic that causes are independent that are independent of age include of age Titin include (TTN), Titin Lamin (TTN A/C), (LaminLMNA A/C), Myosin (LMNA heavy), Myosin chain 7heavy (MYH7 chain), and 7 ( TroponinMYH7), and T2 (TNNT2Troponin) mutations. T2 (TNNT2 The) mutations. familial DCM The accountsfamilial DCM for 20–48% accounts of total for DCM 20–48% [9]. Mutationsof total DCM that a ff[9].ect sarcomericMutations andthat intrasarcomericaffect sarcomeric proteins and canintrasarcomeric induce decreased proteins contraction can induce force via decrease calciumd signalingcontraction in mechanotransduction force via calcium pathwayssignaling [10in]. Mutationmechanotransduction of LMNA, whichpathways encodes [10]. nuclearMutation lamin of LMNA A and, which nuclear encodes lamin C,nuclear is important lamin A in and the pathogenesisnuclear lamin of C, DCM. is importantLMNA-related in the pathogenesis DCM may present of DCM. with LMNA left ventricular-related DCM enlargement may present and poorwith systolicleft ventricular function, enlargement promoting and significant poor systolic conduction function, system promotin dysfunctiong significant and arrhythmiasconduction system [11,12]. Petersdysfunction et al. and [13] arrhythmias reported 11 genes[11,12]. associated Peters et al. with [13] DCM reported and 11 ventricular genes associated arrhythmias, with DCM including and LMNA,ventricularsodium arrhythmias, voltage-gated including channel LMNA, alpha sodium subunit voltage-gated 5 (SCN5A), channelRNA bindingalpha subunit motif 5 protein (SCN5A), 20 (RBM20),RNA bindingfilamin motif C (FLNC) protein, and20 (RBM20),TTN. In these filamin populations, C (FLNC) in, and which TTN the. In mortality these populations, rate can be in high, which the the mortality rate can be high, the implantable cardioverter-defibrillator (ICD) may provide benefit for the primary prevention of sudden cardiac death. J. Clin. Med. 2019, 8, 520 3 of 23 implantable cardioverter-defibrillator (ICD) may provide benefit for the primary prevention of sudden cardiac death. Etiologies reported in secondary DCM include myocarditis, Kawasaki disease, Churg-Strauss syndrome, drug-related toxicity, endocrine disturbance, hypophosphatemia, hypocalcemia, and tachycardiomyopathy [6,14,15]. Dilated cardiomyopathy from ischemic cardiomyopathy is an important etiology. Patients with ischemia-induced DCM may present with left ventricular dysfunction and wall motion hypokinesia. Iskandrian et al. [16] described the assessment of right ventricular function to rule out ischemic cardiomyopathy, based on the knowledge that preserved right ventricular function is a characteristic in ischemia-induced DCM. The detailed mechanism has been investigated. Ischemic events may trigger the accumulation
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