Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder that characterized by marked thickening of the left ventricular wall that occurs in the absence of increased external load. HCM is the most common cause of sudden cardiac death under 35 years and in addition causes heart failure. HCM is usually inherited as an autosomal dominant mutation in genes that encode protein constituents of the sarcomere. To date, more than 450 different mutations have been identified within 13 myofilament-related genes. This review focuses current research involved in the discovery of other causative genes, investigation of the mechanisms by which sarcomere genes mutations produce hypertrophy and arrhythmia, and identification of modifying factors that influence clinical expression in HCM patients. The clinical implications of molecular advances in HCM are discussed.     

An update on cirrhotic cardiomyopathy

Introduction: Cirrhosis with portal hypertension and related complications are associated with a high mortality. Excess of circulating vasodilators and cardiodepressive substances lead to a hyperdynamic circulation with changed myocardial structure and function. The entity cirrhotic cardiomyopathy seems to be involved in different aspects of hepatic decompensation, which focuses on new targets of treatment.

Areas covered: This review deals with contemporary aspects of cirrhotic cardiomyopathy, and the literature search was undertaken by PubMed with ‘cirrhotic’ and ‘cardiomyopathies’ as MeSH Terms. Cirrhotic cardiomyopathy is defined as the presence of systolic and diastolic dysfunction and electrophysiological abnormalities. The diagnosis is based on contemporary Doppler/Echocardiography measurements or quantitative magnetic resonance imaging. Cirrhotic cardiomyopathy is independent of the etiology of the liver disease but related to severity and survival.

Expert commentary: The outcome of invasive procedures and liver transplantation is influenced by the presence of cardiac dysfunction. Therefore, a cautious cardiac evaluation should be included in the patient evaluation prior to liver transplantation. Liver transplantation ameliorates most of the abnormalities seen in cirrhotic cardiomyopathy, but no specific treatment can yet be recommended.     

Reversal of dilated to hypertrophic cardiomyopathy after alcohol abstinence

Left ventricular dilatation and systolic dysfunction develop in 14-16% of patients with hypertrophic cardiomyopathy. Such findings may easily be misdiagnosed as dilated cardiomyopathy. It is unknown whether left ventricular dilatation and systolic dysfunction in patients with hypertrophic cardiomyopathy are reversible. A 35-year-old man had been a heavy drinker for 13 years and was abstinent for 1 year. Five years previously he suffered cardiac arrest and, based on echocardiographic, radionuclide, and cardiac catheterization findings, the diagnosis of alcohol-induced dilated cardiomyopathy was established. At presentation the heart was of normal size, with concentric left ventricular hypertrophy and only slightly reduced systolic function. Hypertrophic cardiomyopathy was diagnosed since no other cause for left ventricular hypertrophy could be detected. In hypertrophic cardiomyopathy, alcohol may induce reversible systolic dysfunction and left ventricular dilatation.     

超声评价原发性扩张型心肌病舒张功能障碍及其与收缩功能的关系

目的 :探讨原发性扩张型心肌病 （DCM）是否存在主动舒张功能障碍及舒张功能障碍与收缩功能障碍的关系。方法 :DCM患者 5 6例 ,彩色超声诊断仪常规方法测量 L VEDD,L AD,L VEF,L VEDV,L VESV,E,A,E/ A ,IVRT,DT。结果 :1仅有舒张功能障碍 8例 （14%） ,收缩功能障碍和舒张功能障碍并存者 48例 （86 %）。 2主动舒张功能障碍 ,即 IVRT≥ 10 0 m s者 2 1例 （38%） ,IVRT<10 0 ms者 35例 （6 2 %） ,两组比较 ,前者 L VEF高 ,L AD小 ,E低 ,A高 ,E/ A大 （P<0 .0 5 ）。IVRT≥ 10 0 ms时 ,控制变量 L VEF情况下 ,IVRT与 L VEDD呈正相关 （r=0 .39,P<0 .0 5 ） ,未发现 L VEF与 E/ A或 E相关 （均 r=- 0 .2 2 ,P>0 .0 5 ） ;以 IVRT 110 ms为分界点分成两组 ,IVRT≥110 ms组较 <110 ms组 L VEDD大 （74± 9vs 6 6± 10 m m,P<0 .0 5 ） ,而 L VEF无显著差别。 3DT≥ 15 0 m s者 2 1例 ,DT<15 0 m s者 35例 ,两组比较 ,前者 IVRT长 ,L VEDV小 （P<0 .0 5 ） ,而 L VEF,L AD,L VEDD,E,A,E/ A,L VESV无显著差别。结论 :DCM存在主动舒张功能障碍 ,随着主动舒张功能障碍加重 ,收缩功能下降增剧。     

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扩张型心肌病是一组心肌的异质性疾病,其特点是在没有异常负荷状态或没有导致心肌收缩力下降的缺血因素存在的前提下,表现为心室扩大和心肌收缩力下降。扩张型心肌病病因复杂多样,临床表现近似,诊断和鉴别诊断困难,治疗效果差异较大,预后有别。     

Diabetic cardiomyopathy

Summary Diabetic cardiomyopathy as a distinct entity was first recognized by Rubler et al. in diabetics with congestive heart failure (CHF), who had no evidence of coronary atherosclerosis. The Framingham study showed a 2.4-fold increased incidence of CHF in diabetic men and a 5.1-fold increase in diabetic women over 18 years. Pathological studies show left ventricular hypertrophy and fibrosis with varying degrees of small vessel disease, the functional significance of which is uncertain. Hypertension was recognized as an important cofactor in the development of fatal congestive heart failure in diabetics. On cardiac catheterization, in patients symptomatic of heart failure, either congestive or restrictive patterns have been observed. In contrast, asymptomatic diabetics had decreased left ventricular compliance but normal systolic function on hemodynamic study. Noninvasive studies show alterations in systolic and especially diastolic function, particularly in diabetics with microvascular complications and/or coexistent hypertension. Using load-independent measures of contractility, however, systolic function was generally found to be normal in asymptomatic normotensive diabetics. Experimental studies have focused on the mildly diabetic dog and the severely diabetic rat. Decreased left ventricular compliance and increased interstitial connective tissue were observed in chronically diabetic dogs. In contrast, ventricular myocardium from diabetic rats exhibits a reversible decrease in the speed of contraction, prolongation of contraction, and a delay in relaxation. These mechanical changes are associated with a decreased myosin ATPase, a shift in myosin isoenzyme distribution, alterations in a variety of Ca²⁺ fluxes, and changes in responses to alpha- and beta-adrenergic and cholinergic stimulation. These biochemical changes may be secondary to alterations in carbohydrate, lipid, and adenine nucleotide metabolism in the diabetic heart. When drug induced diabetes was combined with hypertension, a lethal cardiomyopathy with increased left ventricular hypertrophy and fibrosis, increased microvascular pathology and pulmonary congestion were observed. Compared to animals with isolated diabetes or hypertension, greater changes in papillary muscle function, isolated perfused heart performance, cellular electrophysiology, and contractile protein biochemistry were observed. Several studies suggest a protective effect of calcium channel blockers (verapamil and diltiazem) in experimental diabetic cardiomyopathy. Currently the clinical approach to this disorder emphasizes control of hyperglycemia and coexistent hypertension.     

Dilated versus nondilated cardiomyopathy in the elderly population treated with guideline-based medical therapy for systolic chronic heart failure

BACKGROUND: Although the process by which the left ventricular (LV) remodels in response to an injury generally leads to dilatation, in patients with heart failure (HF) the recognition of a small or mildly dilated left ventricle is not uncommon. We investigated the prevalence and the characteristics of elderly patients with traditional dilated and nondilated cardiomyopathy (CMP). We also assessed the response to the guideline-based medical therapy and the prognosis based on LV dilatation in this population. METHODS AND RESULTS: We selected 243 patients >70 years of age with HF and LV ejection fraction <40% who underwent clinical and echocardiographic evaluations at baseline and after 12 months. They were subdivided into 2 groups according to baseline LV end-diastolic volume (LVEDV) (values < or =78 mL/m(2) identified nondilated CMP). Nondilated CMP was recognized in 64 patients (26%) who showed at baseline better clinical status, less severe mitral regurgitation, and higher LV ejection fraction than those with dilated CMP. At the final evaluation, favorable changes in clinical and echocardiographic parameters could be detected in both groups. The magnitude of these variations did not differ between the groups. The risk of hospitalization for worsening HF was 2.4-fold higher in patients with nondilated than dilated CMP. Mortality was 11% and 20%, respectively (P = .06). Statistical analysis revealed a direct, approximately linear relationship between LVEDV and outcomes in this population. CONCLUSIONS: A total of 1 of 4 elderly patients with systolic HF had a nondilated left ventricle. These patients had a better clinical presentation than did counterparts with dilated left ventricles. After HF therapy is optimized, the likelihood of improvement is independent of LV size in this population, whereas the risk of death or worsening HF linearly increases with LV dilatation.     

Non-ischaemic dilated cardiomyopathy: recognising the genetic links

The landscape of genetically related cardiac disease continues to evolve. Heritable genetic variants can be a primary cause of familial or sporadic dilated cardiomyopathy (DCM). There is also increasing recognition that genetic variation is an important determinant of susceptibility to acquired causes of DCM. Genetic forms of DCM can show a wide variety of phenotypic manifestations. Identifying patients who are most likely to benefit from genetic testing is paramount. The objective of this review is to highlight the importance of recognising genetic DCM, key genotype–phenotype correlations and the value of genetic testing in clinical management for both the individual and their family. This is likely to become more relevant as management strategies continue to be refined with genotype-specific recommendations and disease-modifying therapies.     

Dilated cardiomyopathy: Pathogenesis and the recognition of early disease

Idiopathic dilated cardiomyopathy causes longterm morbidity in young people and results in premature death. The underlying cause remains unknown, but there is now evidence of humoral and cellular immune activation in a proportion of patients and their asymptomatic relatives, raising the possibility of future targeted immunotherapy.     

Dilated cardiomyopathy associated with Chlamydia trachomatis infection

A 26-year-old man was admitted to hospital with acute myocarditis complicated by congestive heart failure, and atrial and ventricular arrhythmias. Detailed investigations to determine the aetiological factors involved yielded negative results, except for serological evidence of infection with Chlamydia trachomatis. During the follow-up period, dilated cardiomyopathy developed. To the best of our knowledge a similar case has not been reported previously.     

Left Ventricular Untwisting in Restrictive and Pseudorestrictive Left Ventricular Filling: Novel Insights into Diastology

Background: Conceptually, an ideal therapeutic agent should target the underlying mechanisms that cause left ventricular (LV) diastolic dysfunction. The objective of our study was to gain further insight into the mechanics of diastology by comparison of LV untwisting measured by speckle tracking echocardiography (STE) in young healthy adults with normal and “pseudorestrictive” LV filling, and dilated cardiomyopathy (DCM) patients with “true restrictive” LV filling. Methods: The study comprised 20 healthy volunteers with a Doppler LV‐inflow pattern compatible with restrictive LV filling but a diastolic early phase filling velocity/early diastolic velocity of the mitral annulus (E/Em) ratio <8 (“pseudorestrictive”), 20 for age and gender‐matched healthy volunteers with normal LV filling and an E/Em ratio <8, and 10 DCM patients with “true restrictive” LV filling and an E/Em ratio >15. LV untwisting parameters were determined by STE. Results: Compared to healthy subjects, DCM patients had decreased peak diastolic untwisting velocity (−62 ± 33 degrees/s vs −113 ± 25 degrees/s, P < 0.01) and untwisting rate (−15 ± 9 degrees/s vs −51 ± 24 degrees/s, P < 0.01). Compared to healthy subjects with normal LV filling, healthy subjects with “pseudorestrictive” LV filling had increased peak diastolic untwisting velocity (−123 ± 25 degrees/s vs −104 ± 30 degrees/s, P < 0.05) and untwisting rate (−59 ± 23 degrees/s vs −44 ± 22 degrees/s, P < 0.05). Conclusion: Faster LV untwisting plays a pivotal role in the rapid early diastolic filling occasionally seen in young healthy individuals. In contrast, in DCM patients untwisting is severely delayed and this impairment to utilize suction may reduce LV filling. (Echocardiography 2010;27:269‐274)     

Sarcomeric Protein Mutations in Dilated Cardiomyopathy

This review aims to provide a concise summary of the DCM associated mutations identified in the proteins of the sarcomere and cytoskeleton, and discuss the reported effects of the mutations, as determined by functional studies, and in relation to the known structure of the protein affected. The mechanisms by which single missense mutations in the proteins of the sarcomere can lead to similar diseases as those caused by mutations in the proteins of the sarcolemma and cytoskeleton, are still unknown. However, a wide variety of mutations being associated with DCM suggests a complex mechanism shared by the proteins affected. The DCM mutations reviewed here are those of the β-myosin heavy chain (β-MHC), myosin binding protein-C (MyBP-C), actin, α- tropomyosin (Tm), troponin T (TnT), troponin I (TnI), troponin C (TnC), of the sarcomere, and titin, T-cap, desmin, vinculin, and muscle LIM protein (MLP) of the cytoskeleton. This work was supported by NIH Grants HL67415 and HL-42325     

Prognosis in Dilated Myocardial Disease: Influence of Diastolic Dysfunction and Anatomical Changes

A prospective study has been conducted, in patients with dilated myocardial disease, in order to examine the relation between echocardiographic variables and mortality rate. Patients were divided into two major groups: (1) group A—designed to evaluate the influence of the ventricular filling pattern in the mortality rate. It included 95 patients, followed-up for a period ranging from 1–23 months (mean = 12.6 months), divided into three subgroups: AF (atrial filling predominant pattern, n = 22); N (normal or "normalized" filling pattern, n = 40), and RF (rapid filling predominant pattern, n = 33); and (2) group B—designed to correlate echocardiographic variables to the 1-year mortality rate. It included 52 patients divided into two subgroups: survivors (n = 40) and nonsurvivors (n = 12). In group A, a progressive decrease in survival rate was noted on comparing subgroups N to AF to RF. At the 14 months follow-up a survival rate of 89% was noted in N, 75% in AF, and 50% in RF. Univariate analysis in group B showed high 1-year mortality rate associated with mitral flow deceleration time ≤ 140 msec (50%, P = 0.003), left ventricular diastolic diameter/thickness ratio ≥ 3.4 (35.3%, P = 0.002), and left atrial index ≥ 25 mm/m² (40.7%, P = 0.001). The highest mortality rate (61.5%, P = 0.0004) was observed in patients with increased left atrial index and decreased deceleration time. Thus, diastolic dysfunction and anatomical changes, as evaluated by echocardiography, are confident parameters to estimate the prognosis in dilated myocardial disease.     

The Prevalence and Prognostic Effects of Subclinical Thyroid Dysfunction in Dilated Cardiomyopathy Patients: A Single-Center Cohort Study

BackgroundSubclinical thyroid dysfunction may be a risk factor for mortality in patients with heart failure and may be associated with dilated cardiomyopathy (DCM). This was a cohort study to examine the possible association between subclinical thyroid dysfunction and all-cause mortality in DCM patients, because the current evidence on this association remains elusive.Methods and ResultsA total of 963 DCM patients were evaluated for thyroid function. Of these patients, 7.1% (n = 68) had subclinical hyperthyroidism (defined as serum thyroid-stimulating hormone [TSH] <0.35 μIU/mL), 84.7% (n = 816) had euthyroidism (TSH 0.35-5.5 μIU/mL), and 8.2% (n = 79) had subclinical hypothyroidism (TSH >5.5 μIU/mL). There was a significant difference in all-cause mortality rates between patients with euthyroidism and patients with subclinical hyper- and hypothyroidism (21%, 38.2%, and 26.6%, respectively; log-rank χ² = 13.104; P = .001) with mean follow-up of 3.5 years. After adjustment for other confounding factors at baseline, QRS duration, N-terminal pro–B-type natriuretic peptide, New York Heart Association functional class, left atrial diameter, and subclinical hyperthyroidism (hazard ratio 1.793, 95% CI 1.010–3.183; P = .046) emerged as significant predictors of all-cause mortality.ConclusionDCM patients with subclinical hyper- and hypothyroidism had higher all-cause mortality rates. However, only subclinical hyperthyroidism, not subclinical hypothyroidism, was an independent predictor for increased risk of all-cause mortality.     

Electrocardiographic features differentiating dilated cardiomyopathy from hypertrophic cardiomyopathy

To determine the usefulness of electrocardiographic (ECG) features in differentiating between hypertrophic cardiomyopathy with features mimicking dilated cardiomyopathy (D-HCM) and true dilated cardiomyopathy (DCM), we compared ECGs of 52 consecutive patients (11 with D-HCM, 41 with DCM). Left atrial dimension, left ventricular internal dimension, and septal and posterior wall thickness were employed as echocardiographic indexes, while QRS duration, amplitude of RV₅ or V₆ + SV₁, number of abnormal Q waves, P-terminal force in V₁, and frontal plane QRS axis were used as ECG parameters. The patients with D-HCM demonstrated a larger number of abnormal Q waves (P < .0001), greater prolongation of QRS duration (P < .0001), and lower amplitude of RV₅ or V₆ + SV₁ (P < .0001). In all cases of D-HCM, atrial overload was observed and abnormal QRS axis in 9 (82%) of the 11 patients. These features were noted in 21 (51%) and 17 (41%), respectively, of the 41 DCM patients (P < .005 and P < .05, respectively). Despite significant differences in the echocardiographic parameters between D-HCM and DCM, excluding left ventricular end-diastolic dimension, ECG abnormalities were more significant between the two groups. The results indicate that ECG features are extremely useful in differentiation between DCM and D-HCM.     

Stress cardiomyopathy in a Caucasian man

Stress cardiomyopathy is increasingly being described as a form of reversible left ventricular systolic dysfunction, with a characteristic shape on left ventriculography. The acute clinical, electrocardiographic and laboratory abnormalities are reminiscent of acute coronary syndrome, with nonobstructive coronary arteries on angiography. Wall motion abnormalities typical of this disease exhibit apical akinesis with compensatory basal hyperkinesis, resulting in the characteristic systolic apical ballooning. Stress cardiomyopathy is much more common in women than men, especially postmenopausal women, and it is typically triggered by intense medical, emotional or physical stress. The pathogenesis of the disease is not well understood, with current evidence favouring catecholamine myocardial injury. Until prospective distinction can be made between stress car-diomyopathy and acute coronary syndrome, the diagnosis should be that of exclusion. In addition to long-term beta-blockers, angiotensin-converting enzyme inhibitors and diuretics as needed, treatment is generally supportive, with recovery of baseline left ventricular function within a few weeks to a month.