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Abstract: Aims: Information on the prevalence and clinical, electrocardiographic and echocardiographic inter-relationships of mechanical dyssynchrony among patients with heart failure (HF) and left ventricular systolic dysfunction derives mainly from relatively small studies. The CARE-HF trial provides the opportunity to address these issues in a large population of patients with advanced HF. Methods and results: The CARE-HF trial enrolled patients with New York Heart Association (NYHA) class III or IV HF, with a QRS duration ≥120ms, left ventricular (LV) ejection fraction (EF) ≤35% and LV end diastolic diameter ≥30mm/m (height in m). Patients underwent a thorough echocardiographic evaluation, which included assessment of LV structure, systolic function, mitral inflow pattern, right ventricular (RV) dimensions and function, and interventricular mechanical delay (IVMD) as an index of interventricular dyssynchrony. Echocardiographic measurements were made in a Core Laboratory to ensure consistent quantitative analysis. Of the 813 patients enrolled, 735 had a baseline echocardiographic examination suitable for measurement. Overall patients had advanced LV dysfunction (mean EF 25.5%) but few had a restrictive mitral filling pattern (18%) and both the mean RV diameter and RV function were within normal limits. Interventricular dyssynchrony defined as IVMD >40ms was present in 455 patients (62%). Clinical, electrocardiographic and standard echocardiographic variables were only loosely associated with IVMD. Conclusions: Interventricular dyssynchrony appears to be an independent characteristic of patients with advanced HF, and is poorly related to clinical, electrocardiographic or standard echocardiographic variable. [Copyright &y& Elsevier]

Abstract: Background: Primary desminopathies are caused by desmin gene [DES (MIM*125660)] mutations. The clinical spectrum includes pure myopathies, cardiomuscular diseases and cardiomyopathies. Patients with restrictive cardiomyopathy (RCM) plus atrioventricular block (AVB) due to DES defects are frequently unrecognized unless desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study. Aims: To describe a cardiological phenotype characterized by RCM plus AVB due to desmin accumulation caused by DES defects. Methods and results: Desmin accumulation was diagnosed by means of ultrastructural and immunocytochemical studies of EMB in four unrelated probands with RCM and AVB. Candidate genes [DES and αB-crystallin (CRYAB)] were screened using sequence analysis. Four DES gene mutations were identified: three new (R16C, T453I and a 10 bp deletion at the exon–intron boundary of exon 3 disrupting the donor splice site) and one known (R406W). The disease was autosomal dominant in two families, recessive in one and associated with a de novo mutation in one. The mutations cosegregated with phenotype in all patients. CRYAB gene screening was negative. Conclusions: A cardiac phenotype characterized by RCM and AVB caused by desmin accumulation is associated with DES mutations. Although the mutations affected different domains, the cardiac phenotype was identical. [Copyright &y& Elsevier]

Aims To investigate celiac disease (CD) and related co-morbidity in patients with familial and sporadic cardiomyopathy and in their relatives.Methods and results We screened anti-human-tissue-transglutaminase (IgA and IgG anti-h-tTG) and anti-endomysial antibodies (AEAs) in 238 consecutive adult patients with inherited or sporadic dilated cardiomyopathy (DCM), 418 relatives, and 2000 healthy blood donors. HLADQ2-DQ8 was tested in tTG-positive subjects. The IgA-tTG-positive patients with cardiomyopathy underwent duodenal biopsy. Twenty-six subjects were tTG-positive: five DCM patients (2.1%), two of 28 (7.1%) and three of 390 (0.7%) relatives with and without echocardiographic abnormalities respectively, and 16 controls (0.8%). Twenty-two of 26 subjects were AEA-positive, and 25 HLA-positive. Of the five patients with cardiomyopathy and biopsy-proven CD, four suffered iron-deficiency anaemia. Two CD-positive DCM patients and two tTG-positive relatives were from families with inherited disease in which CD did not co-segregate with DCM.Conclusions The higher prevalence of CD in patients with sporadic or inherited DCM, and of tTG-positive serology in relatives with echocardiographic abnormalities, suggests that immune-mediated mechanisms are active in subsets of patients/families. However, gluten intolerance cannot be considered causative since CD seems to be associated but not co-segregated with DCM in familial cases. [ABSTRACT FROM PUBLISHER]

Background: The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the MT-TL1 m.3243A>G mutation of the mitochondrial DNA. Heart transplantation (HTx) is controversial and has rarely been performed with conflicting results.Objectives: We analyzed factors preventing HTx in consecutive adult patients with MELASMT-TL1:m.3243A>G cardiomyopathy diagnosed and followed during the last 23 years in our HTx referral center.Methods: The series consists of 14 unrelated adult probands who were referred for evaluation of cardiomyopathy from 1998 to 2021. None had a suspected diagnosis of MELAS before referral. All patients underwent clinical and genetic visit and counseling, mitochondrial DNA sequencing, cardiovascular investigation (including right heart catheterization and endomyocardial biopsy in 10), multidisciplinary assessment, and biochemical tests. Family screening identified 2 affected relatives.Results: The cardiac phenotype was characterized by hypertrophic, concentric, nonobstructive cardiomyopathy that often evolved into a dilated cardiomyopathy-like phenotype. Of the 14 probands, 7 were potential candidates for HTx, 2 for heart and kidney Tx, and 1 was on the active HTx list for 3 years. None of the 10 probands underwent HTx. One is currently being evaluated for HTx. All had diabetes, hearing loss, and myopathy, and 10 had chronic kidney disease and progressive encephalomyopathy. During follow-up, 10 died from heart failure associated with multiorgan failure within 5 years of the genetic diagnosis.Conclusions: High risk of stroke-like episodes, chronic kidney disease, and wasting myopathy in MELASMT-TL1:m.3243A>G patients prevents activation of plans for HTx. As a result, the management of their cardiomyopathy in this syndromic context remains an unmet clinical need. [ABSTRACT FROM AUTHOR]

The nuclear lamina is a proteinaceous layer apposed to the inner nuclear membrane. It is composed of a family of polypeptides, the lamins, highly conserved in evolution. In mammals, 3 lamins, A, B and C have been described with molecular weights ranging from 60,000 to 78,000 Da. Lamins A and C have close sequence homology. Lamins can be classified with the intermediate filament polypeptides and consist of a central rod domain flanked by globular and carboxyl domains. Lamins are synthesized into the cytoplasm: lamins B and C are transported from the cytoplasm into the nucleus and their sequences are not cleaved but remain a permanent feature of the mature polypeptide. Vice versa, lamin A is not synthesized as a large precursor polypeptide. The lamin A/C gene (LMNA) is mapped to 1q21.2-q21.3. Lamins are expressed in a wide range of tissues, including adult heart and skeletal muscle. Naturally occurring mutations in LMNA have been shown to be responsible for distinct diseases called laminopathies, including dilated cardiomyopathy with or without conduction defect and with or without variable skeletal muscle involvement. In the cardiological setting, conduction defects associated with dilated cardiomyopathy are now a reliable marker for LMNA gene molecular screening.

The definition of familial dilated cardiomyopathy (DCM) is clinically based on the presence, in the same family, of at least two members proven as affected. The prevalence of familial forms is about 25-30%. The approach to define the prevalence of familial diseases and to identify asymptomatic subjects is based on a clinical, non-invasive screening of family members of consecutive index patients. Familial DCM is commonly inherited as autosomal dominant trait; less frequently it is autosomal recessive, X-linked or matrilinear. The disease is clinically and genetically heterogeneous. Genes causally linked to this phenotype include dystrophin, dystrophin-associated glycoproteins, actin, desmin, beta-miosin heavy chain, cardiac troponin T, and mitochondrial DNA genes, mostly transfer RNAs. A peculiar phenotype is DCM associated with atrioventricular block, an autosomal dominant disorder that is causally linked to lamin A/C gene defects in a high proportion of cases. Although the knowledge on molecular genetics of DCM is progressively increasing, at present, the number of molecular diagnoses that can be provided to patients is limited to a few X-linked, autosomal dominant and matrilinear DCMs (overall, about 10% of DCMs). The new clinical approach to familial DCM studies, based on the screening of family members, will bring to the cardiologist's attention both patients and relatives, with extension of the clinical evaluation to subjects who are still healthy. On the other hand, molecular genetists will face a complex molecular field, for both high heterogeneity and poor phenotypical specificity. Therefore, interdisciplinary clinical and research projects are especially needed, hopefully coordinated by scientific societies.