Primary Cardiomyopathy Research Articles

Iron Overload Cardiomyopathy in Clinical Practice

The cardiomyopathies are heart muscle diseases of primary or secondary origin. Primary cardiomyopathies are often of unknown cause, hence their treatment is limited to general heart failure management. In secondary cardiomyopathies, in contrast, the identification of the underlying cause allows for a more specific, hence effective, approach that, when applied early, may prevent the development of heart failure. The term iron overload cardiomyopathy (IOC) recently has been introduced to describe a secondary form of cardiomyopathy resulting from the accumulation of iron in the myocardium mainly because of genetically determined disorders of iron metabolism or multiple transfusions.1,2 This condition, although previously overlooked, has lately attracted the attention of investigators because iron overload is, on one hand, a frequently encountered condition, especially in association with certain hematologic conditions, and on the other hand, its accurate identification and effective management have now become possible. IOC has been recently described as a dilated cardiomyopathy, characterized by left ventricular (LV) remodeling with chamber dilatation and reduced LV ejection fraction (LVEF).1 However, primary hemochromatosis, a genetically determined condition leading to iron overload, is classically categorized as an infiltrative cause of restrictive cardiomyopathy.3 Moreover, secondary hemochromatosis may lead to severe diastolic LV dysfunction in the early stages of the disease, before LVEF is affected.4,5 In the present review, we describe the forms, pathophysiology, and phenotypic expression of IOC, focusing on ventricular geometry and function and describing the early diastolic abnormalities that lead ultimately to heart muscle dysfunction and heart failure. The clinical implications of the condition are also discussed. Iron overload is the accumulation of excess body iron in different organs as a result of increased intestinal absorption, parenteral administration, or increased dietary intake.6 Besides being a crucial component of hemoglobin with a key role in erythropoiesis, oxygen …

Predictors of Adverse Outcome in Adolescents and Adults With Isolated Left Ventricular Noncompaction

Isolated left ventricular noncompaction is a rare form of primary cardiomyopathy. Although increasingly diagnosed, data on the outcomes are limited. To define the predictors of adverse outcomes, we performed a retrospective analysis of a prospectively defined cohort of consecutive patients (age >14 years) diagnosed with left ventricular noncompaction at a single center. The baseline characteristics included presentation with a cardiovascular complication (i.e., decompensated heart failure, systemic embolic event, or sustained ventricular arrhythmia). The primary end point was survival free from cardiovascular death or transplantation. The predictors of survival were evaluated using the Kaplan-Meier method and Cox proportional hazards analysis. A total of 115 patients were included, 77% of whom were symptomatic at diagnosis. Compared to the asymptomatic patients, the symptomatic patients were significantly older and had larger left ventricular cavities and worse left ventricular ejection fraction. Of the 115 patients, 49 (43%) presented with a cardiovascular complication. During a median follow-up of 2.7 years (range 0.1 to 19.4), none of the asymptomatic patients died or underwent transplantation compared to 31% (27 of 88) of the symptomatic patients (p = 0.001). The major determinants of cardiovascular death or transplantation were presentation with a cardiovascular complication (hazard ratio 20.6, 95% confidence interval 4.9 to 87.5, p <0.0001) or New York Heart Association class III or greater (hazard ratio 8.8, 95% confidence interval 3.2 to 24.0, p <0.0001). Left ventricular dilation and systolic dysfunction were less strong predictors. In conclusion, in patients with left ventricular noncompaction, New York Heart Association class III or greater and cardiovascular complications at presentation are strong predictors for adverse outcome.

Coffin–Lowry syndrome and left ventricular noncompaction cardiomyopathy with a restrictive pattern

Coffin-Lowry syndrome (CLS) is an X-linked dominant condition characterized by moderate to severe mental retardation, characteristic facies, and hand and skeletal malformations. The syndrome is due to mutations in the gene that encodes the ribosomal protein S6 kinase-2, a growth factor-regulating protein kinase located on Xp22.2. Cardiac anomalies are known to be associated with CLS. Left ventricular noncompaction (LVNC) is a clinically heterogeneous disorder characterized by left ventricular (LV) myocardial trabeculations and intertrabecular recesses that communicate with the LV cavity. Patients may present with a variety of clinical phenotypes, ranging from a complete absence of symptoms to a rapid, progressive decline in LV systolic and diastolic function, resulting in congestive heart failure, malignant ventricular tachyarrhythmias, and systemic thromboembolic events. Restrictive cardiomyopathy is an uncommon primary cardiomyopathy characterized by biatrial enlargement, normal or decreased biventricular volume, impaired ventricular filling, and normal or near-normal systolic function. We describe a patient with CLS and LVNC with a restrictive pattern, as documented by echocardiography and cardiac catheterization. To our knowledge, there have been no previous reports of concomitant CLS and LVNC. On the basis of our case, we suggest that patients with CLS be screened not only for congenital structural heart defects but also for LVNC cardiomyopathy.

ACCESSMENT OF RIGHT VENTRICULAR SYSTOLIC FUNCTION USING TAPSE

Background: The prognostic importance of right ventricular (RV) dysfunction has been suggested in patients with systolic heart failure (due to primary or secondary dilated cardiomyopathy - DCM). Tricuspid annular plane systolic excursion (TAPSE) is a simple, feasible, reality, non-invasive measurement by transthoracic echocardiography for evaluating RV systolic function. Objectives: To evaluate TAPSE in patients with primary or secondary DCM who have left ventricular ejection fraction ≤ 40% and to find the relation between TAPSE and LVEF, LVDd, RVDd, RVDd/LVDd, RA size, severity of TR and PAPs. Materials and Methods: 61 patients (36 males, 59%) mean age 58.6 ± 14.4 years old with clinical signs and symtomps of chronic heart failure which caused by primary or secondary DCM and LVEF ≤ 40% and 30 healthy subject (15 males, 50%) mean age 57.1 ± 16.8 were included in this study. All patients and controls were underwent echocardiographic examination by M-mode, two dimentional, convensional Dopler and TAPSE. Results: TAPSE is significant low in patients compare with the controls (13.93±2.78 mm vs 23.57± 1.60mm, p&lt;0.001). TAPSE is linearly positive correlate with echocardiographic left ventricular ejection fraction (r= 0,43; p&lt;0,001) and linearly negative correlate with RVDd (r= -0.39; p&lt;0.01), RVDd/LVDd (r=-0.33; p&lt;0.01), RA size (r=-0.35; p&lt;0.01), TR (r=-0.26; p&lt;0.05); however, no correlation was found with LVDd and PAPs. Conclusions: 1. Decreased RV systolic function as estimated by TAPSE in patients with systolic heart failure primary and secondary DCM) compare with controls. 2. TAPSE is linearly positive correlate with LVEF (r= 0.43; p&lt;0.001) and linearly negative correlate with RVDd (r= -0.39; p&lt;0.01), RVDd/LVDd (r=-0.33; p&lt;0.01), RA size (r=-0.35; p&lt;0.01), TR (r=-0.26; p&lt;0.05); however, no correlation is found with LVDd and PAPs. 3. TAPSE should be used routinely as a simple, feasible, reality method of estimating RV function in the patients systolic heart failure DCM (primary and secondary).

Furthering the link between the sarcomere and primary cardiomyopathies: Restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy

Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

Requests for ICD and Pacemaker Deactivation: Characteristics of Affected Patients and Outcomes

no prior ventricular arrhythmias. Conclusions: Most ICDs in the VA system are implanted for the primary prevention of sudden death in the setting of underlying coronary artery disease and severely depressed left ventricular systolic function. Compared to other national registries, enrollees in the OVID registry are more likely to have an ICD placed for primary prevention and ischemic cardiomyopathy.

Assessing the global and regional impact of primary cardiomyopathies: The Global Burden of Diseases, Injuries and Risk Factors (GBD 2010) Study

Primary cardiomyopathies affect individuals of all ages and ethnic groups in all regions of the world and are associated with significant morbidity and mortality. Though these conditions are globally prevalent, lack of rigorous epidemiological analysis on a worldwide scale has prevented accurate estimates of the burden of this subset of cardiac diseases on regional populations. The Global Burden of Diseases, Injuries and Risk Factors (GBD 2010) Study was designed to address such analytical shortfalls by delivering data-driven estimates of epidemiological parameters for nearly 200 diseases and injuries, including the primary cardiomyopathies. The methodology utilized to generate GBD 2010 disease burden estimates for the primary cardiomyopathies is described. Preliminary epidemiologic data for the study's 21 global regions is then presented and discussed, along with evaluation of challenges and future opportunities in addressing the burden of primary cardiomyopathies.

Papel de la microcirculación coronaria en las enfermedades cardiacas

There is increasing evidence that the coronary microcirculation (CM) plays an important role in the pathophysiology of numerous cardiac diseases. The CM function, along with the endothelial function, are the cornerstone for understanding some diseases like the cardiac syndrome X, as well as some of the complications of obstructive coronary artery disease, such as the «no reflow» phenomenon or post-revascularization angina. CM dysfunction is also the basis of the most important theories about other diseases like Tako-Tsubo syndrome, and also seems to contribute to the perpetuation and progression of both primary and secondary cardiomyopathies. Therefore, understanding it accurately will enable new early screening methods to be developed for cardiovascular diseases (CVD), addressing many CVD from the beginning, as well as the development of new therapies.

Left ventricular noncompaction in Sotos syndrome

Sotos syndrome is an autosomal dominant condition characterized by pre- and postnatal overgrowth (tall stature and macrocephaly), a typical facial appearance, advanced bone age, and developmental delay. The syndrome is caused by mutations or deletions of the nuclear receptor binding SET domain protein 1 (NSD1) gene, which encodes a histone methyltransferase implicated in the regulation of chromatin. Left ventricular noncompaction (LVNC), also called left ventricular (LV) hypertrabeculation, is a rare disorder classified as a primary genetic cardiomyopathy by the American Heart Association. This condition is characterized by an altered myocardial wall due to arrest of embryonic compaction of the loose interwoven meshwork that makes up the fetal myocardial primordium. The cardiac manifestations of this cardiomyopathy are variable, ranging from an absence of symptoms to a progressive deterioration in cardiac function, with heart failure, arrhythmias, and systemic thromboemboli. We describe two unrelated patients who had LVNC, as based on echocardiographic findings, and Sotos syndrome, as based on physical features and molecular analysis. To our knowledge, the literature contains no previous reports of concomitant LVNC and Sotos syndrome. In the light of these two cases, we suggest that patients with Sotos syndrome be evaluated for LVNC cardiomyopathy when being screened for heart defects.

Presentation, echocardiographic findings and long-term outcomes in children with familial dilated cardiomyopathy

Background A potential genetic basis has been identified in around 30% of all childhood dilated cardiomyopathy (DCM). Despite this, the long-term outcomes for children with familial DCM have not been well characterized. This study examines the presentation, outcomes and echocardiographic findings for children with familial DCM enrolled in the National Australian Childhood Cardiomyopathy Study. Methods NACCS is a longitudinal, population based study which includes all children aged 0–10 years who were diagnosed with primary cardiomyopathy between 1987 and 1996. Details of clinical status at diagnosis, medical therapy and late outcomes were recorded. Serial echocardiographic indices of LV size, fractional shortening and ejection fraction were expressed as Z scores, based on BSA and age. Familial cardiomyopathy was defined as the presence of an affected first or second degree relative with a similar cardiomyopathy. All available echocardiograms were interpreted by a single observer. Results There were 175 subjects with DCM. Children with familial DCM (27 cases) were younger at diagnosis than those with sporadic DCM (median age 3.2 vs. 8.4 months ( p = .004) and were less likely to have congestive heart failure and to be hospitalised at presentation ( p ≤ .002 for both). Familial DCM subjects had a higher mortality (62.9% vs. 36.5%; p = .02) and were less likely to be free of medical therapy at latest follow-up (7.4% vs. 52.0%; p < .001). Echocardiographic measurements were similar at presentation but familial DCM subjects had a higher mean LVEDd Z score (4.15 vs. 2.25; p = .006) and a lower FS Z score (− 7.35 vs. − 3.40; p = .002) score at latest follow-up. Conclusions Familial DCM subjects are younger and are less likely to have symptomatic heart failure at the time of diagnosis. Despite this they have a higher mortality and worse ventricular function at late follow-up. This study underlines the differing presentations and outcomes among children with familial and sporadic DCM.

How Do Mutations in Contractile Proteins Cause the Primary Familial Cardiomyopathies?

In this article, the available evidence about the functional effects of the contractile protein mutations that cause hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) is assessed. The molecular mechanism of the contractile apparatus of cardiac muscle and its regulation by Ca(2+) and PKA phosphorylation have been extensively studied. Therefore, when a number of point mutations in the contractile protein genes were found to cause the well-defined phenotypes of HCM and DCM, it was expected that the diseases could be explained at the molecular level. However, the search for a distinctive molecular phenotype did not yield rapid results. Now that a substantial number of mutations that cause HCM or DCM have been investigated in physiologically relevant systems and with a range of experimental techniques, a pattern is emerging. In the case of HCM, the hypothesis that the major effect of mutations is to increase myofibrillar Ca(2+)-sensitivity seems to be well established, but the mechanisms by which an increase in myofibrillar Ca(2+)-sensitivity induces hypertrophy remain obscure. In contrast, DCM mutations are not correlated with a specific effect on Ca(2+)-sensitivity. It has recently been proposed that DCM mutations uncouple troponin I phosphorylation from Ca(2+)-sensitivity changes, albeit based on only a few mutations so far. A plausible link between uncoupling and DCM has been proposed via blunting of the response to α-adrenergic stimulation.

Indications and Outcome of Implantable Cardioverter‐Defibrillators for Primary and Secondary Prophylaxis in Patients with Noncompaction Cardiomyopathy

Noncompaction cardiomyopathy (NCCM) is a rare, primary cardiomyopathy, with initial presentation of heart failure, emboli, or arrhythmias, including sudden cardiac death. Implantable cardioverter-defibrillators (ICDs) are frequently used for primary and secondary prevention in different cardiomyopathy patients, but data about ICD in NCCM are scarce. The aim of this study was, therefore, to investigate ICD indications and outcomes in NCCM patients. We collected prospective data from our NCCM cohort (n = 77 pts, mean age: 40 ± 14 years). ICD was implanted in 44 (57%) patients with NCCM according to the current ICD guidelines for nonischemic cardiomyopathies: in 12 for secondary prevention (7 × ventricular fibrillation, 5 × sustained ventricular tachycardia [VT]) and in 32 patients for primary prevention (heart failure/severe LV dysfunction). During a mean follow-up of 33 ± 24 months, 8 patients presented with appropriate ICD shocks due to sustained VT after median 6.1 [1-16] months. This included 4 of 32 (13%) patients in the primary prevention group and 4 of 12 (33%) in the secondary prevention group (P = 0.04). 9 patients presented with inappropriate ICD therapy: 6 (19%) in the primary and 3 (25%) in the secondary prevention group, at a median follow-up of 4 (2-23) months. In our cohort of NCCM patients, an ICD was frequently implanted for primary or secondary prevention of sudden cardiac death. At follow-up, frequent appropriate ICD therapy was observed in both groups, supporting the application of current ICD guidelines for primary and secondary prevention of sudden cardiac death in NCCM.

Cardiac magnetic resonance in tropical endomyocardial fibrosis

Endomyocardial fibrosis (EMF) is a common cause of primary restrictive cardiomyopathy (RCM) in the tropics. Available studies on the role of CMR in diagnostic evaluation of EMF are confined to case reports. We describe the spectrum of CMR features in a group of patients with this disease.

Idiopathic Cardiomyopathies in Korean Children - 9-Year Korean Multicenter Study -

Idiopathic cardiomyopathies (CMPs) are an important heterogeneous group of diseases. With the advance of therapeutic strategies, epidemiologic data on CMP have become very important, but only a few have been reported in Asian children. We conducted a retrospective epidemiologic study of primary CMP in Korean children. Using a multicenter survey, we studied primary CMP among Korean children from January 1998 to December 2006 based on classification (2006) of CMP by the American Heart Association. A total of 277 primary CMP patients were reported from 17 cardiovascular centers. The average annual occurrence of new cases of primary CMP was 0.28 per 100,000 Korean children younger than 15 years of age (95% confidence interval (CI) 0.24-0.31). Dilated CMP (DCMP) was 66.43%, hypertrophic CMP (HCMP) 23.47%, restrictive CMP (RCMP) 6.50% and others 3.61%. The point prevalence of primary CMP at the end of the study was estimated as 2.11/100,000 (95%CI 1.83-2.43), DCMP 1.39/100,000, HCMP 0.51/100,000, RCMP 0.16/100,000 and others 0.04/100,000. Survival rates over 9 years were 69.8% in DCMP, 90.3% in HCMP, and 47.2% in RCMP. Recent point prevalence of childhood primary CMP in Korea was estimated as 2.11/100,000. Further epidemiologic study with a nationwide survey is necessary.

Subendocardial Fibrosis in Left Ventricular Hypertrabeculation-Cause or Consequence?

Left ventricular noncompaction has been classified as a primary cardiomyopathy with a genetic origin. This condition is morphologically characterized by a thickened, two-layered myocardium with numerous prominent trabeculations and deep, intertrabecular recesses. Recently, it has become clear that these pathological characteristics extend across a continuum with left ventricular hypertrabeculation at one end of the spectrum.The histological findings include areas of interstitial fibrosis.We present a case of left ventricular hypertrabeculation which presented as sudden infant death syndrome. Histologically areas of subendocardial fibrosis was prominent and we propose that this entity may be a hidden cause of arrhythmic death in some infants presenting as sudden infant death syndrome., with areas of subendocardial fibrosis as possible arrhythmogenic foci.

Unusual case of isolated biventricular non-compaction presenting with stroke

Prominent ventricular trabeculations are seen in a fetal heart. Isolated ventricular non-compaction (IVNC) is a rare form of primary cardiomyopathy. It usually presents with heart failure, arrhythmias and very rarely with thrombo-embolic manifestation. The left ventricle is involved in the majority of the cases. Echocardiography is the principal modality for the diagnosis of this condition. IVNC may be misdiagnosed as dilated or hypertrophic cardiomyopathy wherein the prognosis and management do differ significantly. We report a case of a 38-year-old male with IVNC involving both the ventricles, who presented very unusually as stroke resulting from a cardiogenic embolus.

Phenotypic Variability of Myosin Binding Protein C Gene Mutation Associated Cardiomyopathy: A Role for Cardiac Magnetic Resonance Imaging in Clinical Screening

Left ventricular non compaction (LVNC) and hypertrophic cardiomyopathy (HCM) are genetically mediated primary cardiomyopathies that have both been associated with mutations in sarcomere protein genes. We describe the first case of the MYBPC3 p.Arg502Trp mutation manifesting as an LVNC phenotype. In addition, we describe this occurring within a family where the phenotype had been expressed as HCM in other kindred. Clinical screening including repeated electrocardiograms and echocardiograms of the 27 year old son of a woman with previously diagnosed HCM revealed only borderline findings. Cardiac magnetic resonance (CMR) i g m

A misinterpretation of the left ventricular non-compactionadult patient with primary pulmonary hypertension

Non-compaction of the left ventricle is a rare cardiac malformation, defined as a primary cardiomyopathy caused by genetic malformations. Although the pathogenesis of this cardiomyopathy is unknown, there are two possible hypotheses (congenital and acquired) which lead to arrest in intrauterine endomyocardial morphogenesis. We are presenting a case of a 60-year-old woman, with a history of bradyarrhythmia, syncope and cyanosis. Two-dimensional echocardiography showed the thickened myocardium with prominent trabeculations and deep intertrabecular recesses in the two thirds of the apical part of left ventricle walls. The right side cavity was enlarged with hypertrophied wall. Tricuspid regurgitation was moderate. Systolic pressure in the right ventricle was 70mmHg. Catheterization of the right heart showed high pressure in the pulmonary artery. According to publications, this is a very rare case with the presence of possible primary pulmonary hypertension and non-compaction of the left ventricle.

Metabolomic distinction and insights into the pathogenesis of human primary dilated cardiomyopathy

Metabolomics, the comprehensive profile of small-molecule metabolites found in biological specimens, has the potential to provide insights into the pathogenesis of disease states and lead to the identification of new biomarkers. We analysed 451 plasma metabolites by liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy in 39 patients with primary dilated cardiomyopathy (DCM) and 31 age-, sex- and body mass index-matched controls. Sixty-one metabolites were significantly different between primary DCM and control individuals [false discovery rate (FDR) < 0·05]. Plasma levels of steroid metabolites, glutamine, threonine and histidine were reduced while levels of citric acid cycle intermediates and lipid β-oxidation products were increased in patients with primary DCM when compared to controls. Medications, particularly furosemide and angiotensin-1 converting enzyme-1 inhibitors, had significant effects on the plasma metabolites. Reduced levels of glutamine in conjunction with increased 3-methyhistidine and prolylhydroxyproline levels suggested enhanced myofibrillar and collagen degradation in DCM patients. Likewise, increased stachydrine and reduced indole-3-propionate implicated a role for intestinal-derived antioxidant molecules. Changes in steroid metabolites were notable for the loss of metabolic distinction between men and women in patients with primary DCM. Cortisol and cortisone levels were increased while androgen metabolites were decreased significantly, implying metabolic 'feminization' of men with primary DCM. Metabolomic profiling identifies biologically active metabolites that could serve as markers of primary DCM and impart protective or harmful effects on cardiac structure and function.

Unrecognized noncompaction on the internet

Recently we detected an image of an explanted or autopsied heart in two different publications on the internet (Fig. 1). The first one presented the figure under the header “Academic dictionaries and encyclopedias” in the chapter about primary cardiomyopathies (URL http://www.google.de/imgres?imgurl=http://de.academic.ru/pictures/dewiki/73/Idiopathic_cardiomyopathy__gross_pathology_20G0018_lores.jpg&imgrefurl). The second mentioning of the same image was found on Wikipedia under the term “cardiomyopathy” (URL: http://geneticpeople.com/?tag=cardiomyopathy).