Mutations in genes for sarcomeric proteins

Idiopathic cardiomyopathy(ICM) is by definition of unknown etiology. There are four clinical types of ICM; hypertrophic cardiomyopathy(HCM) characterized by ventricular hypertrophy associated with reduced compliance of the heart and accompanied by myofibrillar disarray, dilated cardiomyopathy(DCM) characterized by dilated ventricles associated with systolic dysfunction, restricted cardiomyopathy (RCM) and arrhythmogenic right ventricular cardiomyopathy(ARVC). Recent molecular genetic analyses have now revealed disease-associated mutations in ICM, especially in familial HCM and familial DCM. Mutations in 9 different disease genes (MYH7, TNNT2, TPM1, MYBPC3, MYL3, MYL2, TNNI3, CACT and TTN) cause HCM, while mutations in 3 different genes(CACT, DES and DMD) cause DCM in adults. In this review, I will summarize our current data on sarcomere mutations found in Japanese ICM, especially in HCM and DCM.     

基于深度学习的1.5T心脏磁共振Cine序列在肥厚型心肌病和扩张型心肌病患者左心室功能评估中的应用

目的:探讨一种基于深度学习的1.5T心脏磁共振Cine序列自动量化不同心肌病左心室功能的性能。方法:回顾性分析2014年3月至2019年11月393例心脏MRI受检者的相关临床资料。对肥厚型心肌病(HCM)患者(HCM组,n=125)、扩张型心肌病(DCM)患者(DCM组,n=133)和健康个体(对照组,n=135)的左心室功能,分别通过手动和自动测量进行评估。手动分析由2位经验丰富的医师完成;自动分析后,从左心室分割精度和左心室功能参数准确性两方面对卷积神经网络(CNN)的性能进行评价。采用Pearson相关分析、Bland-Altman分析和受试者工作特征曲线(ROC),评价手动与自动方法诊断HCM和DCM的相关性与一致性。结果:CNN评估左心室功能时,在HCM组中与手动分析的一致性最好,对照组次之,在DCM中表现最差。HCM组左心室功能4个参数的自动分析与手动分析结果具有较高的相关性(P0.01);DCM组所有参数自动与手动分析的相关性均弱于HCM,特别是射血分数和每搏输出量。ROC曲线分析表明,自动分割算出的射血分数对DCM、HCM的诊断灵敏度分别为92.31%和78.05%,特异度分别为82.96%和54.07%。结论:在不同心肌疾病中,基于CNN的心功能分析性能可能不同,在HCM中表现优于DCM,但对DCM的诊断价值优于HCM。     

Energetics and function of the failing human heart with dilated or hypertrophic cardiomyopathy

BACKGROUND: Impaired energy metabolism in the failing human heart could be an important mechanism of functional deterioration. The purpose of this study was to assess the changes of myocardial energy metabolism in the human heart at end-stage heart failure. MATERIALS AND METHODS: The left ventricular myocardium of patients undergoing heart transplantation due to dilated (DCM, n = 14) or hypertrophic cardiomyopathy (HCM, n = 5) and non-diseased donor heart samples (n = 4) were analysed for citrate synthase (CS), enzymes of the glycolytic pathway as well as concentrations of phosphocreatine (PCr), creatine (Cr), adenine and guanine nucleotides. RESULTS: Total creatine levels (phosphocreatine + creatine) were significantly decreased (P < 0.05) in both groups of diseased hearts (3.87 +/- 0.57 in DCM, 5.09 +/- 1.23 in HCM compared with control 10. 7 +/- 3.5 micromol g-1 wet weight). There was a trend for higher guanine nucleotide content in failing hearts, but no significant differences were observed in total adenine nucleotides and total NAD content. CS was markedly reduced (P < 0.05) in both groups of diseased hearts: in the DCM to 13.8 +/- 1.3 micromol min-1 g-1 wet weight, and in HCM to 11.9 +/- 2.4 compared with the control 29.2 +/- 2.2. Glycolytic enzymes were decreased compared with the control, and this decrease was greater in DCM than in HCM. Echocardiographic indices of contractility were considerably better in hypertrophic cardiomyopathy. CONCLUSION: Despite the different mechanisms of cardiac failure and the differences in contractility of the heart we have observed, metabolic changes are very similar in hypertrophic and dilated cardiomyopathy. Depletion of the creatine pool suggests an alteration in the intracellular energy reserves and transfer, whereas the decrease in citrate synthase activity suggests reduced oxidative capacity in both dilated and hypertrophic cardiomyopathy.     

Molecular and Clinical Aspects of Inherited Cardiomyopathies

Hypertrophic cardiomyopathy (HCM) is phenotypically and genotypically a heterogeneous disease. Since 1989, four chromosomal loci have been identified for HCM and the genes residing on three of these have been identified as β-myosin heavy chain (β-MHC), cardiac troponin-T and α-tropomyosin. These genes code for sarcomere proteins and exhibit the same phenotype, suggesting that HCM is a disease of the sarcomere. Over 40 missense mutations and one deletion of the β-MHC gene have been identified. Similarly, missense mutations in the α-tropomyosin gene and the cardiac troponin-T gene have been identified. From genetic studies, including de novo mutations, it is established that these mutations are indeed responsible for HCM. The molecular basis of the pathogenesis of the cardiac hypertrophy appears to be a compensatory response to the primary defect. In addition to providing a definitive presymptomatic diagnosis, studies correlating β-MHC mutations with clinical prognosis suggest they have significant predictive value and can be helpful in genetic counselling and medical management.

Dilated cardiomiopathies (DCM), the most common form of cardiomyopathies, have an estimated prevalence of nearly 40 per 100000 individuals, and are the most common cause for cardiac transplantation in the United States. Familial dilated cardiomyopathy is thought to account for approximately 20% of the so-called cases of idiopathic DCM.     

Prognosis of hypertrophic and dilated cardiomyopathy

Hypertrophic and dilated cardiomyopathies are a heterogeneous disease, both clinically and genetically. Hypertrophic cardiomyopathy(HCM) is important causes of sudden cardiac death and death from congestive heart failure, although HCM has a relatively benign prognosis. The prognosis of dilated cardiomyopathy(DCM) has improved due to advances in earlier diagnosis and therapy, however, sudden cardiac death and death from congestive heart failure still occur in DCM. Accordingly, it is of importance to know possible risk factors on risk stratification for a high-risk group in HCM and DCM. Possible risk factors may contribute to the construction of therapeutic strategies for the prevention of sudden cardiac death or death from congestive heart failure in patients with HCM and DCM.     

HLA and hepatitis C virus positive cardiomyopathy

The relationship between HCV (hepatitis C virus) and the susceptibility of cardiomyopathy has been indicated, but the detailed mechanism for close association is still unknown. It is well known that the human leukocyte antigen (HLA) may regulate the development of chronic hepatitis in HCV positive patients. We have analyzed the distribution of HLA class II alleles in Japanese patients with HCV antibody positive dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), and HLA-DPB1*0901 was significantly increased in HCV Ab positive DCM, and the HLA-DRB1*0901-DQB1*0303 haplotype was in HCV Ab positive HCM. These results suggested that molecular mechanism for the development of cardiomyopathy mediated by HCV is different between DCM and HCM.     

Genetic mutations and mechanisms in dilated cardiomyopathy

Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are “private” or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia.     

磁共振T1 mapping成像评价肥厚型和扩张型心肌病弥漫性心肌纤维化

目的 探讨磁共振纵向弛豫时间定量(T1 mapping)成像评价肥厚型心肌病(HCM)和扩张型心肌病(DCM)心肌纤维化的价值,及心肌纤维化与左心室射血分数的关系。方法 收集经临床诊断证实的30例HCM患者(HCM组)、27例DCM患者(DCM)和符合纳入标准的33例患者(对照组)。对所有受检者均行心脏电影成像、对比增强前、后T1 mapping成像、延迟对比增强(LGE)成像。测量不同受检者增强前、后左心室平均T1值及心功能参数并进行统计学分析,分析心肌平均T1值与心功能指标的相关性。结果 HCM组22例(22/30,73.33%)患者存在延迟强化,DCM组15例(15/27,55.56%)患者存在延迟强化,对照组无延迟强化。比增强前,HCM组[(1294.79±85.22)ms]、DCM组[(1312.88±59.57)ms]左心室心肌T1值均较对照组[(1266.56±57.33)ms]显著增加(P均<0.05);对比增强后,HCM组[(491.31±121.59)ms]、DCM组[(466.77±126.34)ms]左心室心肌T1均值较对照组[(534.09±92.73)]显著减低(P均<0.05)。HCM患者左心室心肌增强前T1值与左心室射血分数呈负相关(r=-0.58,P<0.05),增强后T1值与其呈正相关(r=0.59,P<0.05);DCM患者左心室心肌增强前T1值与左心室射血分数呈负相关(r=-0.55,P<0.05),增强后T1值与其呈正相关(r=0.51,P<0.05)。结论 HCM和DCM患者心肌纤维化与心功能相关;T1 mapping成像有助于评价HCM和DCM患者心肌纤维化。     

Diagnostic algorithm of idiopathic cardiomyopathy

In this review, diagnostic algorithm of idiopathic cardiomyopathy is discussed. In the primary care, most of the patients with cardiomyopathy are initially found by signs and symptoms of systolic/diastolic cardiac dysfunction and arrhythmia, and the myocardial involvement is recognized by chest roentgenogram and electrocardiogram. In the next step, echocardiography is extremely useful to confirm cardiac size, ventricular hypertrophy, systolic/diastolic function and structural abnormalities. After this examination, detailed diagnostic approaches including invasive strategy can be planned to each type of cardiomyopathy(DCM, HCM, RCM, ARVC). In each case, any etiology to develop myocardial disorder should be carefully examined to exclude secondary cardiomyopathy.     

Athlete’s heart or hypertrophic cardiomyopathy?

Intensive endurance training is able to cause a distinct pattern of functional and structural changes of the cardiovascular system. In an unknown proportion of athletes a so called “athlete’s heart” develops. There is an overlap between this type of physiologic cardiac hypertrophy and mild forms of hypertrophic cardiomyopathy (HCM), the most common genetic disorder of the cardiovascular system with a prevalence of 0.2%. HCM is caused by mutations in 14 genes coding for sarcomere proteins. In the literature up to 50% of cases of sudden cardiac death (SCD) in younger sportsmen were connected to hypertrophic cardiomyopathy. It is therefore the most common cause of SCD in highly trained young athletes. Because of this data a great interest in distinguishing these two diagnoses exists. Apart from clinical examination and some non-specific ECG-changes, Echocardiography is the method of choice. The athlete’s heart shows an eccentric biventricular hypertrophy with wall thicknesses under 15 mm and a moderately dilated left ventricle (LVEDD up to 58 mm). HCM is commonly characterized by asymmetric left ventricular hypertrophy with a reduced LV-diameter. In up to 70% of cases left ventricular outflow tract obstruction is evident during stress echocardiography. Systolic function is normal in highly trained athletes and the majority of HCM patients as well. There are important differences regarding diastolic filling patterns. Physiological hypertrophy is consistent with a normal diastolic function with even increased early diastolic filling. In case of HCM diastolic dysfunction (mostly relaxation disturbances) occurs in the majority of patients and is therefore inconsistent with an athlete’s heart. If the diagnosis could not be stated using echocardiography, methods like cardiac-MRI, metabolic exercise testing, histological studies of endomyocardial biopsies and genetic testing can provide further information. A correct diagnosis may on the one hand prevent some athletes from sudden cardiac death. On the other hand sportsmen with an athlete’s heart are reassured and able to continue as competitors. New insights into electrophysiological changes during physiological hypertrophy could probably change this view.     

Cardiac magnetic resonance and galectin-3 level as predictors of prognostic outcomes for non-ischemic cardiomyopathy patients

This study was aimed at determining whether late gadolinium enhancement (LGE) in conjunction with Galectin-3 (Gal-3) level offered more precise prognosis of non-ischemic cardiomyopathy (NICM) in comparison to LGE alone. Results of LGE and Gal-3 expression in 192 patients with NICM, including 85 subjects with dilated cardiomyopathy (DCM) and 107 with hypertrophic cardiomyopathy (HCM), were examined. As suggested by the characteristics of LGE and Gal-3 levels, patients were divided into four groups: LGE positive?+?low Gal-3 (n?=?10 for DCM, n?=?15 for HCM), LGE positive?+?high Gal-3 (n?=?25 for DCM, n?=?51 for HCM), LGE negative?+?low Gal-3 (n?=?32 for DCM, n?=?29 for HCM), LGE negative?+?high Gal-3 (n?=?18 for DCM, n?=?12 for HCM). Primary endpoints over the follow-up period included major adverse cardiac events (MACEs). Kaplan–Meier survival analysis and univariate Cox proportional hazard models were used to analyze the survival status of patients with NICM. The optimal cut-off value of Gal-3 level for two types of NICM was determined by receiver operating characteristic analysis (13.38 U/L for DCM and 14.40 U/L for HCM). The combination of LGE and Gal-3 levels offered a more significant prognostic value than using LGE alone for both DCM and HCM (DCM P?=?0.001?<?0.012; HCM P?=?0.037?<?0.040). Moreover, the Cox proportional hazard model suggested that both LGE status [Hazard ratio (HR)?=?2.62, P?=?0.017] and Gal-3 level (HR?=?1.16, P?=?0.013) were significant predictors of MACEs in DCM, while they did not appear to have significant prognostic values for HCM (P?=?0.06 and 0.64). Furthermore, the multivariate analysis only confirmed LGE as an independent element in predicting prognosis of DCM (HR?=?12.19, P?=?0.026). In conclusion, LGE status was an independent indicator of DCM prognosis, yet the insignificant role of LGE in HCM prognosis could be limited by sample size.     

Secondary diseases of the heart muscle and their differential diagnosis in childhood

Possible causes of specific cardiac muscle disease, diagnosis, follow-up and the therapeutic management are discussed on the basis of a series of cases. 8 out of 30 patients who showed the clinical picture of dilative cardiomyopathy (DCM) were found to have a specific cardiac muscle disease. 4 patients had DCM following adriamycin therapy. Fibromuscular dysplasia with renal hypertension, thalassaemia major with secondary haemosiderosis, long-overlooked and untreated athyroidism each caused one case of dilative specific cardiac muscle disease. Once DCM was preceded by the Kawasaki syndrome for over 2 years. Amongst 47 patients with hypertrophic cardiomyopathy there were two children who had undergone ACTH treatment, 6 children born of diabetic mothers, 4 cases of Pompe's disease, and one patient with hypothyroidism resulting in reversible hypertrophy of the cardiac muscle. Different neurodegenerative diseases were associated with cardiac muscle disease in 4 cases, partly dictating the clinical course. Extremely rare was the development over 6 years of cardiac hypertrophy following a burns injury.     

Taking a bite out of hypertrophic cardiomyopathy: soy diet and disease

Some forms of hypertrophic cardiomyopathy (HCM) are caused by mutations in cardiac sarcomeric genes, but environmental factors are believed to influence the hypertrophic response. A highly variable but potentially significant environmental factor is diet. Since soy-rich diets have been speculated to confer protection against cardiovascular disease, Stauffer et al. have explored the influence of a soy diet on cardiac growth and function in a transgenic mouse model of HCM. They report that mice fed a soy diet exhibited significantly worse HCM than mice fed a soy-free (milk protein) diet. This study provides the first evidence of an environmental modifier--diet--on the hypertrophic phenotype and has implications for the way in which disease phenotypes are assessed in genetically altered murine models of disease.     

Genetic causes of inherited cardiac hypertrophy: Robert L. Frye Lecture

Cardiac hypertrophy is well recognized as a cardiac manifestation of systemic disorders such as hypertension or intrinsic myocardial disease, but it can also reflect an underlying genetic defect. Molecular studies of inherited forms of cardiac hypertrophy have defined 2 novel pathways that lead to cardiac remodeling in adults, discoveries that increasingly provide insights relevant for both diagnosis and management. This article reviews the genetic studies that led to the current molecular understanding of hypertrophic cardiomyopathy and discusses more recently discovered causes of inherited cardiac hypertrophy.     

An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice

The response of cardiomyocytes to biomechanical stress can determine the pathophysiology of hypertrophic cardiac disease, and targeting the pathways regulating these responses is a therapeutic goal. However, little is known about how biomechanical stress is sensed by the cardiomyocyte sarcomere to transduce intracellular hypertrophic signals or how the dysfunction of these pathways may lead to disease. Here, we found that four-and-a-half LIM domains 1 (FHL1) is part of a complex within the cardiomyocyte sarcomere that senses the biomechanical stress–induced responses important for cardiac hypertrophy. Mice lacking Fhl1 displayed a blunted hypertrophic response and a beneficial functional response to pressure overload induced by transverse aortic constriction. A link to the Gαq (Gq) signaling pathway was also observed, as Fhl1 deficiency prevented the cardiomyopathy observed in Gq transgenic mice. Mechanistic studies demonstrated that FHL1 plays an important role in the mechanism of pathological hypertrophy by sensing biomechanical stress responses via the N2B stretch sensor domain of titin and initiating changes in the titin- and MAPK-mediated responses important for sarcomere extensibility and intracellular signaling. These studies shed light on the physiological regulation of the sarcomere in response to hypertrophic stress.     

Immunoregulatory lymphocyte subpopulations in patients with dilated and hypertrophic cardiomyopathies

Forty patients with dilatation cardiomyopathy (DCM) and 30 patients with hypertrophic cardiomyopathy (HCM) were examined immunologically. Immunoregulatory lymphocytes (T1B) and their subpopulations (T helpers, T suppressors, natural killers--NK) were studied quantitatively and functionally. The patients with DCM showed inhibition of the number of T suppressors in part of the cases, attended by a decrease in non-specific (spontaneous) and mitogenin-induced suppressor activity, the lowering of the amount and activity of NK in the overwhelming majority of the cases. Study of the immunological characteristics in the patients with HCM did not reveal any substantial changes as compared to those in health. Immune disorders in the patients with DCM form the basis for conducting goal-oriented immunocorrection.     

Diastolic ventricular dysfunction as a marker for hypertrophic cardiomyopathy in a family with a novel alpha-tropomyosin mutation.

BACKGROUND: Early identification of familial cases of hypertrophic cardiomyopathy (HCM) depends on screening echocardiography, but hypertrophy may not be the most sensitive marker for the disease. We report the echocardiographic findings of a family with HCM and a newly reported mutation in the gene (TPM1) encoding alpha-tropomyosin.Methods and results An 8-year-old girl had sudden cardiac death, and was found to have HCM and a novel L185R-TPM1 mutation on postmortem examination. Screening echocardiograms and DNA analyses were performed on her family. Of the 5 remaining family members, 3 were genetically affected. Those without the TPM1 mutation had normal echocardiographic results. The only echocardiographic finding that identified all 3 of the gene-positive family members was an abnormal left ventricular diastolic filling pattern. CONCLUSION: Abnormal left ventricular diastolic filling patterns, indicating diastolic dysfunction, may provide an early marker for the diagnosis of familial HCM in children, even in the absence of left ventricular hypertrophy.     

Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. Evidence for a dominant negative action.

Mutations in the beta-myosin heavy chain gene are believed to cause hypertrophic cardiomyopathy (HCM) by acting as dominant negative alleles. In contrast, a truncated cardiac troponin T (TnT) that causes HCM implies that altered stoichiometry of contractile proteins may also cause cardiac hypertrophy. Wild-type and HCM-mutant (truncated) TnT were studied in a novel quail myotube expression system. Unexpectedly, antibody staining demonstrated incorporation of both forms of human cardiac TnT into the sarcomeres of quail myotubes. Functional studies of wild type and mutant transfected myotubes of normal appearance revealed that calcium-activated force of contraction was normal upon incorporation of wild type TnT, but greatly diminished for the mutant TnT. These findings indicate that HCM-causing mutations in TnT and beta-myosin heavy chain share abnormalities in common, acting as dominant negative alleles that impair contractile performance. This diminished force output is the likely stimulus for hypertrophy in the human heart.     

Uncommon cause of a common disease

Myocardial infarction is a common life-threatening condition. Multiple agents can be used to treat acute coronary syndrome (ACS). These therapeutic agents pose potential life-threatening complications when used outside the realm of the acute coronary syndrome. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder, occurring in 1 in 500 individuals, which may mimic ACS. The hypertrophy most typically involves the septum in patients with HCM. As many as 25% of Japanese patients with HCM have predominately apical involvement. Apical hypertrophic cardiomyopathy (AHC) occurs in only 1 to 2% of the non-Japanese population. Despite its low incidence, physicians caring for patients with chest pain need to consider AHC in their differential diagnosis. We present the case of a patient with chest pain and electrocardiographic changes suggestive of ACS who was later found to have AHC.     

Hypertrophic cardiomyopathy and ultra-endurance running - two incompatible entities?

Regular and prolonged exercise is associated with increased left ventricular wall thickness that can overlap with hypertrophic cardiomyopathy (HCM). Differentiating physiological from pathological hypertrophy has important implications, since HCM is the commonest cause of exercise-related sudden cardiac death in young individuals. Most deaths have been reported in intermittent ''start-stop'' sports such as football (soccer) and basketball. The theory is that individuals with HCM are unable to augment stroke volume sufficiently to meet the demands of endurance sports and are accordingly ''selected-out'' of participation in such events. We report the case of an ultra-endurance athlete with 25 years of > 50 km competitive running experience, with genetically confirmed HCM; thereby demonstrating that these can be two compatible entities.