Search

X-linked dilated cardiomyopathy (XLDC) is a familial heart disease presenting in young males as a rapidly progressive congestive heart failure, without clinical signs of skeletal myopathy. This condition has recently been linked to the dystrophin gene in some families and deletions encompassing the genomic region coding for the first muscle exon have been detected. In order to identify the defect responsible for this disease at the molecular level and to understand the reasons for the selective heart involvement, a family with a severe form of XLDC was studied. In the affected members, no deletions of the dystrophin gene were observed. Analysis of the muscle promoter, first exon and intron regions revealed the presence of a single point mutation at the first exon-intron boundary, inactivating the universally conserved 5' splice site consensus sequence of the first intron. This mutation introduced a new restriction site for Msel, which cosegregates with the disease in the analyzed family. Expression of the major dystrophin mRNA isoforms (from the muscle-, brain- and Purkinje cell-promoters) was completely abolished in the myocardium, while the brain- and Purkinje cell- (but not the muscle-) isoforms were detectable in the skeletal muscle. Immunocytochemical studies with anti-dystrophin antibodies showed that the protein was reduced in quantity but normally distributed in the skeletal muscle, while it was undetectable in the cardiac muscle. These findings indicate that expression of the muscle dystrophin isoform is critical for myocardial function and suggest that selective heart involvement in dystrophin-linked dilated cardiomyopathy is related to the absence, in the heart, of a compensatory expression of dystrophin from alternative promoters.

Objectives The aim of our study was to investigate the benefit of antiarrhythmic drugs (AAD) - beta-blockers, sotalol or amiodarone - in a cohort of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) patients with long-term longitudinal follow up. Background AAD are prescribed in ARVC to prevent ventricular arrhythmias and control symptoms. However, there are no controlled clinical trials and knowledges regarding the efficacy of AAD in ARVC are limited. Methods The study population included 123 patients with definite diagnosis of ARVC and ≥ 2 clinical evaluations. The primary outcome was a composite of sudden cardiac death (SCD)/recurrent major ventricular arrythmias (MVA): sudden cardiac arrest, sustained ventricular tachycardia (VT) and appropriate implantable cardioverter defibrillator interventions, including recurrent events in patients with >1 MVA. Time to first event (SCD or MVA) was considered as secondary composite endpoint. Results Sixteen patients were taking AAD at baseline and 75 started at least one AAD during a median follow-up of 132 months [61–255]. A total of 37 patients experienced ≥1 MVA with a total count of 83 recurrent MVA. After adoption of a propensity score analysis, no AAD were associated with lower risk of recurrent MVA. However, if dosage of AAD was considered, beta-blockers at >50% target dose were associated with a significant reduction in the risk of MVA compared to patients not taking beta-blockers (HR 0.10, 95% CI 0.02–0.46, p = 0.004). Conclusions In a large cohort of ARVC patients with a long-term follow-up, only beta-blockers administrated at >50% target dose were associated with lower risk of SCD/recurrent MVA.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease. Funding Agencies|Marianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB Project

The term dilated cardiomyopathy (DCM) defines a heterogeneous group of cardiac disorders, which are characterized by left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. In approximately one third of cases, DCM is familial with a genetic pathogenesis and various patterns of inheritance. Although the electrocardiogram (ECG) has been considered traditionally non-specific in DCM, the recently acquired knowledge of the genotype-phenotype correlations provides novel opportunities to identify patterns and abnormalities that may point toward specific DCM subtypes. A learned ECG interpretation in combination with an appropriate use of other ECG-based techniques including ambulatory ECG monitoring, exercise tolerance test and imaging modalities, such as echocardiography and cardiovascular magnetic resonance, may allow the early identification of specific genetic or acquired forms of DCM. Furthermore, ECG abnormalities may reflect the severity of the disease and provide a useful tool in risk stratification and management. In the present review, we discuss the current role of the ECG in the diagnosis and management of DCM. We describe various clinical settings where the appropriate use and interpretation of the ECG can provide invaluable clues, contributing to the important role of this basic tool as cardiovascular medicine evolves.

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.ObjectiveFilamin C gene truncations (FLNCtv) have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that FLNCtv could be a novel gene associated with ARVC.MethodsOne hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for FLNC variants. Available family members were tested for cosegregation.ResultsWe identified two unique FLNCtv variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling ‘definite’ diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.ConclusionThe identification of FLNCtv as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC non-desmosome disease genes for this disorder. Our findings should prompt inclusion of FLNC genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

Article, see p 1595 Arrhythmogenic cardiomyopathy (AC) is a genetic disorder characterized by high risk of life-threatening ventricular arrhythmias, sudden cardiac death, and progressive heart failure. Currently, there is evidence that AC includes a spectrum of cardiomyopathy phenotypes, ranging from the classical form of arrhythmogenic right ventricular cardiomyopathy (ARVC) to more recently identified forms of arrhythmogenic left ventricular cardiomyopathy.1,2 ARVC is considered a disease of the desmosome, because in the majority of cases, it is caused by mutations in genes encoding proteins of the cardiac desmosomes.3 However, mutations in nondesmosomal genes have also been found in ARVC, such as the genes encoding the cardiac ryanodine receptor 2 ( RYR2 ), the transforming growth factor β-3 ( TGFB3 ), the nuclear transmembrane protein 43 ( TMEM43 ), and desmin ( DES ). Mutations in LMNA , encoding the nuclear envelope protein lamin A/C, known to cause dilated cardiomyopathy with an arrhythmic phenotype, was reported to cause also an ARVC phenotype,3 even though the association between LMNA and ARVC is still questioned. In the left dominant form, which clinically presents as an arrhythmogenic dilated cardiomyopathy, the same desmosomal genes causing ARVC can be found,1 as well as LMNA and the more recently identified filamin C gene ( FLNC ), encoding an actin …

PURPOSE OF REVIEW: This review aims to summarize the current knowledge on the genetic background of dilated cardiomyopathy (DCM), with particular attention to the genotype-phenotype correlations and the possible implications for clinical management. RECENT FINDINGS: Next generation sequencing (NGS) has led to the identification of an increasing number of genes and mutations responsible for DCM. This genetic variability is probably related to the extreme heterogeneity of disease manifestation. Important findings have associated mutations of Lamin A/C (LMNA) and Filamin C (FLNC) to poor prognosis and the propensity to cause an arrhythmic phenotype, respectively. However, a deeper understanding of the genotype-phenotype correlation is necessary, because it could have several implications for the clinical management of the patients. Furthermore, the correct interpretation of pathogenicity of mutations and the clinical impact of genetic testing in DCM patients still represent important fields to be implemented. A pathogenic gene mutation can be identified in almost 40% of DCM patients. The recent discoveries and future research in the field of genotype-phenotype correlation may lead to a more personalized management of the mutation carriers towards the application of precision medicine in DCM.

Pathophysiology and treatment of pediatric heart failure (HF) is poorly understood. A growing body of literature demonstrates age-related differences in mechanisms and in therapies efficacy. HF results from ventricular dysfunction due to volume or/and pressure overload. Circulatory, neurohormonal, and molecular alterations promote the progression of HF and ventricular remodeling; they include inflammation, oxidative stress, mitochondrial dysfunction, loss of cardiomyocytes, and fibrosis. Children and young affected by cardiomyopathies have the greatest risk of HF and heart transplantation. Genetic mutations of sarcomere, cytoskeleton, cell membrane proteins, and ion channels have been recognized as the main causes of many cardiomyopathy phenotypes. In particular, sarcomeric and cytoskeleton genes mutations seem to have an important role in the progression of HF. Prognostic stratification and clinical management could benefit from identification of biomarkers such as inflammatory mediators or microRNA (miRNA). miRNA and myocardial regenerative strategies are under investigations as potential novel therapeutic approaches.

Aims We sought to examine the clinical presentation and natural history and to identify long-term prognostic predictors in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) as information concerning the natural history and risk stratification of ARVC is still incomplete. Methods and results A cohort of 96 ARVC patients (68% males, 35 ± 15 years) was enrolled and underwent structured diagnostic protocol and follow-up. Primary study endpoints were death and heart transplantation (HTx). Clinical and echo-Doppler data were assessed as prognostic indicators. Sixty-five per cent of patients had right ventricular (RV) systolic dysfunction (RV fractional area change < 33%) and 24% had left ventricular (LV) systolic dysfunction (LV ejection fraction

Aims Familial screening of patients with dilated cardiomyopathy (DCM) allows an early diagnosis of the disease in family members. It is unclear if familial forms (FDC) have a different long-term outcome compared with sporadic DCM. Our aim was to compare the long-term prognosis of FDC and sporadic forms in order to assess the role of familial screening. Methods and results Between 1988 and 2007, 637 DCM patients were consecutively enrolled. Of these, 130 patients (20.4%) had FDC, including 82 (12.9%) probands and 48 (7.5%) non-proband FDC patients (NP-FDC), identified by family screening. We compared the 48 NP-FDC patients with a sample of 96 patients with sporadic DCM, who were randomly matched by year of enrolment in a 2:1 ratio. At enrolment the NP-FDC patients were younger (40 ± 16 vs. 48 ± 13 years, P = 0.002), less symptomatic [New York Heart Association, (NYHA) III–IV: 8 vs. 28%, P = 0.006], had higher left ventricular ejection fraction (35 ± 10 vs. 30 ± 9%, P = 0.005) and were less intensively treated with evidence-based drugs than the sporadic DCM patients. Survival free from heart transplant at 2, 5 and 10 years was 93, 91 and 82%, respectively, in NP-FDC patients compared with 86, 76 and 62% in sporadic forms (P = 0.04). After stratification for NYHA classes, no difference in survival was observed between sporadic and NP-FDC patients. Conclusion Our study demonstrates that family screening can effectively identify DCM patients at an earlier stage of disease and can improve survival. The possibility of changing the prognosis of DCM needs to be verified in patients intensively treated with tailored medical treatment. Family screening should be recommended for all DCM patients.

BACKGROUND: To evaluate the role of nonsustained ventricular tachycardias (NSVT) for the prediction of major ventricular arrhythmias (MVA) in patients with idiopathic dilated cardiomyopathy (DCM) after optimization of medical treatment. METHODS AND RESULTS: Three hundred nineteen consecutive DCM patients were evaluated after adequate stabilization on optimal angiotensin-converting enzyme (ACE) inhibitor (88%) and beta-blocker (82%) therapy. Frequency, length, and rate of NSVT at 24-hour Holter monitoring were analyzed to assess their values in predicting MVA (unexpected sudden death, SVT, ventricular fibrillation, and appropriate implantable cardioverter defibrillator interventions). During follow-up (median 96 months, 1(st)-3(rd) interquartile range 52-130), MVA incidence was low, and not statistically different between patients with and without NSVT (3 and 2 per 100 patient-years, respectively, P = nonsignificant [NS] at log-rank analysis). At multivariable analysis, the number of NSVT was predictive of MVA only if left ventricular ejection fraction (LVEF) was > 0.35 (two NSVT/day vs no NSVT/day: hazard ratio [HR] 5.3, 95% confidence interval [CI] 1.59-17.85 in LVEF > 0.35 vs HR 0.93, 95% CI 0.3-2.81 in LVEF < or = 0.35). Consequently, in patients with LVEF < or = 0.35, MVA incidence rates were similar regardless of NSVT (3.6 and 4.1 patient-years, respectively, in those with and without NSVT, P = NS), while in patients with LVEF > 0.35, MVA incidence (3.1 per 100 patient-years vs 0.9 per 100 patient-years, P = 0.003) was significantly higher when NSVT were present. CONCLUSIONS: After medical stabilization, NSVT did not increase the risk of MVA in patients with DCM and LVEF < or = 0.35. Conversely, the number and length of NSVT runs were significantly related to the occurrence of MVA in the patients with LVEF > 0.35.

Some patients diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) are eventually found to have cardiac sarcoidosis (CS). Accurate differentiation between these 2 conditions has implications for immunosuppressive therapy and familial screening. We sought to determine whether cardiac magnetic resonance imaging (MRI) could be used to identify the characteristic findings to accurately differentiate between CS and ARVC. Consecutive patients with a diagnostic MRI scan indicating CS and/or ARVC constituted the cohort. All patients diagnosed with CS had histologic confirmation of sarcoidosis, and all patients with ARVC met the diagnostic task force criteria. The cardiac MRI data were retrospectively analyzed to identify possible differentiating characteristics. Of the patients, 40 had CS and 21 had ARVC. Those with CS were older and had more left ventricular scar. The presence of mediastinal lymphadenopathy or left ventricular septal involvement was seen exclusively in the patients with CS (p

Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size.We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics.We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P=3×10(-16)) or controls (7 of 249 [3%], P=9×10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10(-5)).TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.).

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin ( TTN ) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks. Methods and Results— All 312 titin exons known to be expressed in human cardiac titin and the complete 3′ untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families, including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in 1 large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain) located in the spring region of titin. Native gel electrophoresis, nuclear magnetic resonance, intrinsic fluorescence, and proteolysis assays of wild-type and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity for degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by a history of sudden death (5 of 7 families), progressive myocardial dysfunction causing death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14), and incomplete penetrance (86%). Conclusions— Our data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.

Barth syndrome is an X-linked genetic condition featuring neutropenia, skeletal myopathy, and dilated cardiomyopathy in boys due to tafazzin (TAZ) mutations. Pure dilated cardiomyopathy without other features of Barth syndrome may also result from TAZ mutations and survival into adulthood has been described. Although TAZ testing is routinely included in dilated cardiomyopathy panels in adults, the prevalence of TAZ mutations in the adult population, including women who may be at risk to develop later onset disease due to TAZ mutations, has not been measured. We screened 292 families with dilated cardiomyopathy (209 male and 83 female probands) for TAZ mutations using denaturing high-performance liquid chromatography and sequence analysis. Putative mutations were evaluated based on standard criteria including screening available relatives and healthy controls and for effects on splicing efficiency in the case of one intronic variant. Two variants suspicious for being pathogenic were found in two unrelated families (c.387T>C, Phe128Ser and c.507C>T, Leu169Leu). The Phe128Ser variant had been previously reported as a pathogenic mutation; however we determined that this variant is instead a rare polymorphism restricted to African Americans. The Leu169Leu variant was detected in a male patient and altered RNA processing in our minigene assay supporting a pathogenic role. No mutations in female subjects were detected. Tafazzin mutations were rare in our population of adults with dilated cardiomyopathy and none were found in females. Our findings indicate that genetic testing for tafazzin should not be routinely performed in dilated cardiomyopathy as suggested by current guidelines. Furthermore, the Phe128Ser variant is not pathogenic, but likely represents a benign polymorphism in persons of African American ancestry.

Hypertrophic cardiomyopathy (HCM) is the most frequent autosomal dominant genetic heart muscle disease and the most common cause of sudden cardiac death in young people (under 30 y of age), who are often unaware of their underlying condition. Genetic screening is now considered a fundamental tool for clinical management of HCM families. However, the high genetic heterogeneity of HCM makes genetic screening very expensive. Here, we propose a new high-throughput genotyping method based on a HCM 96-well sequencing plate for the analysis of 8 of the most frequent HCM-causing sarcomeric genes by automating several processes required for direct sequencing, using a commercially available robotic systems and routinely used instruments. To assess the efficiency of the robot-assisted method, we have analyzed the entire coding sequence and flanking intronic sequences of the 8 sarcomeric genes in samples from 18 patients affected by HCM and their relatives, which revealed 9 different mutations, 3 of which were novel. The automated, robot-assisted assembling of polymerase chain reaction, purification of polymerase chain reaction products, and assembly of sequencing reactions resulted in a substantial saving of time, reagent costs, and reduction of human errors, and can therefore be proposed as a primary strategy for mutation identification in HCM genetic screening in many medical genetic laboratories.

Background— Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin ( DES ) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known. Methods and Results— Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic staining of desmin, causing clumping of the desmin protein. A tail domain mutation (Val459Ile) showed milder effects on desmin cytoplasmic network formation and appears to be a low-penetrant mutation restricted to black subjects. Conclusions— The prevalence of DES mutations in DCM is between 1% and 2%, and mutations in the 1A helical domain, as well as the 2B rod domain, are capable of causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM.

Background— Mutations in the β-myosin heavy-chain (βMyHC) gene cause hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy. In failing human hearts, downregulation of αMyHC mRNA or protein has been correlated with systolic dysfunction. We hypothesized that mutations in αMyHC could also lead to pleiotropic cardiac phenotypes, including HCM and DCM. Methods and Results— A cohort of 434 subjects, 374 (134 affected, 214 unaffected, 26 unknown) belonging to 69 DCM families and 60 (29 affected, 30 unaffected, 1 unknown) in 21 HCM families, was screened for αMyHC gene ( MYH6 ) mutations. Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L, A1004S, and E1457K; 4.3% of probands). A Q1065H mutation was detected in 1 of 21 HCM probands and was absent in 2 unaffected offspring. All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of αMyHC, and were absent in at least 300 control chromosomes from an ethnically similar population. The DCM carrier phenotype was characterized by late onset, whereas the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure. Conclusions— This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM.

The etiology of dilated cardiomyopathy (DC), a disease of the myocardium characterized by dilatation and impaired contraction of the left ventricle or both ventricles, has been actively investigated for several decades. Unfortunately, the cause of DC is still mostly unknown and the diagnosis mainly based on the exclusion of any specific heart muscle disease, that is any disease associated with known cardiac or systemic disorders. However, it is expected that with the increasing understanding of the etiology and the pathogene-sis of DC, the difference between a true primary cardiomyopathy and specific heart muscle diseases will become indistinguishable in the future [1].

To evaluate the occurrence of familial cases of dilated cardiomyopathy (DC), 165 consecutive patients were studied. Diagnosis of myocardial disease was based on clinical, hemodynamic, bioptic, postmortem or a combination of these criteria. Twelve patients (7% of cases) showed evidence of myocardial disease in greater than or equal to 1 relative; 27 patients with myocardial disease were detected in the 12 families, but a suspected history of myocardial involvement was present in a further 16 cases. In 6 families proband and relatives were affected by DC (total 14 cases); in 1 of these families the disease began with an atrioventricular block. In 4 families the relatives showed the presence of myocarditis at the endomyocardial biopsy. In 2 families the relatives presented a right ventricular cardiomyopathy. The mode of inheritance was autosomal dominant in 7 families, recessive in 4; X-linked pattern may be hypothesized in 1. Nine patients died under the age of 45 years: 2 of sudden death, 6 of chronic heart failure and 1 of cerebral embolism. Familial transmission is not rare. Different modes of genetic transmission (autosomal dominant, recessive and X-linked) and different forms of myocardial disease suggest that familial DC may be a multifactorial disease.

Many studies on the natural history of dilated cardiomyopathy show high probability of death or of cardiac transplantation in a large percentage of patients. These studies have several methodological limitations. Our prospective study, carried out from 1971, and which evaluated 120 patients, showed improved survival in more recent years. Survival 3 years after diagnosis changed from 30% (1971–67sol;1981) to 88·4% (7/1986–1/1989). Thirty patients were investigated by haemodynamic exercise test to assess their haemodynamic behaviour during exercise, to evaluate the effects of pharmacological treatment and to define parameters of prognostic value. Different haemodynamic behaviours were observed. Haemodynamic investigation during exercise is useful to assess the effect of treatment and may have prognostic value. Myocarditis presents a spectrum of clinical symptoms and echocardiographic abnormalities. In patients with congestive heart failure left ventricular dysfunction is common. Patients with atrioventricular block or chest pain usually have good left ventricular function. During follow-up, improvement is possible but persistent left ventricular dysfunction is associated with a high mortality rate. When left ventricular function is good at presentation and does not deteriorate during follow-up the prognosis is good.