Late-onset Dilated Cardiomyopathy Research Articles

A CASE OF DILATED CARDIOMYOPATHY CAUSED BY TNNT2 MUTATION

Dilated cardiomyopathy is one of the leading causes of heart failure with high morbidity and mortality. Although more than 40 genes have been reported to cause dilated cardiomyopathy, the role of genetic testing in clinical practice is not well defined. Mutations in the troponin T (TNNT2) gene represent an important subset of known disease-causing mutations associated with dilated cardiomyopathy. Mutations in TNNT2, encoding cardiac troponin T, commonly shows early onset, aggressive dilated cardiomyopathy. This observation may influence the decision of whether to undertake clinical genetic testing for TNNT2 in later onset dilated cardiomyopathy. Further, the trigger for late onset dilated cardiomyopathy remains enigmatic. Here, we presented a case of dilated cardiomyopathy caused by TNNT2 mutation in 59-year-old male.

Association of Titin Variations With Late-Onset Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (ie, late-onset DCM). To investigate the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM. A population of patients with late-onset DCM who had undergone genetic testing in 7 international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants. The study outcome was all-cause mortality. A total of 184 patients older than 60 years (103 female [56%]; mean [SD] age, 67 [6] years; mean [SD] left ventricular ejection fraction, 32% [10%]) were studied. Sixty-six patients (36%) were carriers of a P/LP variant. Titin-truncating variants were the most prevalent (present in 46 [25%] of the total population and accounting for 46 [69%] of all genotype-positive patients). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers of P/LP variants, while 6 patients (5.1%) were genotype-negative. Late-onset DCM might represent a distinct subgroup characterized by and a high genetic variation burden, largely due to titin-truncating variants. Patients with a positive genetic test had higher mortality than genotype-negative patients. These findings support the extended use of genetic testing also in older patients.

An Adult Mouse Model of Dilated Cardiomyopathy Caused by Inducible Cardiac-Specific Bis Deletion.

BCL-2 interacting cell death suppressor (BIS) is a multifunctional protein that has been implicated in cancer and myopathy. Various mutations of the BIS gene have been identified as causative of cardiac dysfunction in some dilated cardiomyopathy (DCM) patients. This was recently verified in cardiac-specific knock-out (KO) mice. In this study, we developed tamoxifen-inducible cardiomyocyte-specific BIS-KO (Bis-iCKO) mice to assess the role of BIS in the adult heart using the Cre-loxP strategy. The disruption of the Bis gene led to impaired ventricular function and subsequent heart failure due to DCM, characterized by reduced left ventricular contractility and dilatation that were observed using serial echocardiography and histology. The development of DCM was confirmed by alterations in Z-disk integrity and increased expression of several mRNAs associated with heart failure and remodeling. Furthermore, aggregation of desmin was correlated with loss of small heat shock protein in the Bis-iCKO mice, indicating that BIS plays an essential role in the quality control of cardiac proteins, as has been suggested in constitutive cardiac-specific KO mice. Our cardiac-specific BIS-KO mice may be a useful model for developing therapeutic interventions for DCM, especially late-onset DCM, based on the distinct phenotypes and rapid progressions.

A combinatorial oligogenic basis for the phenotypic plasticity between late-onset dilated and arrhythmogenic cardiomyopathy in a single family.

Introduction:Primary dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are the two common and distinct forms of hereditary cardiomyopathies caused by defined pathogenic variants (PVs) typically in different sets of genes. DCM is characterized by left ventricular dilatation, dysfunction, and failure, whereas ARVC classically involves the right ventricle and is characterized by fibrofatty infiltration of the myocardium. DCM is caused primarily by the PVs in genes encoding sarcomere and cytoskeletal protein, while ARVC is mainly a disease of the desmosome proteins. DCM and ARVC exhibit partial phenotypic and genetic overlaps.Aim:To analyze the genetic basis of the phenotypic heterogeneity of cardiomyopathy in members of a single family.Methods and Results:We recruited, clinically characterized, and performed whole-exome sequencing in five affected, three probably affected, and two clinically unaffected members of a single family. The family members mainly exhibited late-onset DCM associated with conduction defects and arrhythmias. One family member who died suddenly was diagnosed with the classic ARVC at autopsy and another presented with isolated ventricular tachycardia. A novel splicing (truncating) and a rare missense variant in the TTN gene, likely in cis, co-segregated with the phenotype in all affected and probably affected family members and were likely the causal variants. Several PVs and LPVs in other genes involved in cardiomyopathies and arrhythmias were also identified that seem to modify the expression of the phenotype. Notably, LPVs in the DSP and PKP2 genes, which are known genes for ARVC, were identified in the family member who also carried the TTN variants but developed the classic ARVC.Conclusion:The findings indicate the causal role of the TTN variants, exhibiting an age-dependent penetrance in late-onset DCM, and highlight the potential modifying role of the concomitant LPVs in additional genes on the expression of the phenotype, including a phenotypic switch from the anticipated DCM to ARVC. The findings support an oligogenic basis of the cardiac phenotype in hereditary cardiomyopathies. A comprehensive genetic analysis involving all PVs and LPVs along with detailed phenotypic characterization is necessary to gain insights into the molecular pathogenesis of hereditary cardiomyopathies.

The late-onset dilated cardiomyopathy

Abstract Background Dilated Cardiomyopathy (DCM) represents a specific subgroup of non-ischemic cardiomyopathies. Little is known about the genotypic characterization of dilated cardiomyopathy (DCM) patients diagnosed over 60 years of age. Aim To investigate prevalence, characterization and prognostic impact of the genetic background of late-onset DCM patients. Methods We analyzed a study population of 566 DCM patients from two international referral centers. Genetic background was analyzed and patients were grouped into typical-onset DCM (<60 years of age at diagnosis) or late-onset DCM (>60 years of age at diagnosis). Results Approximately 12% of patients (n=70) had late-onset DCM and female sex was significantly more frequent in the late-onset DCM cohort (p<0.001). Diagnostic yield of genetic testing was comparable between typical- and late-onset DCM (53% vs 50%, respectively p=0.438) whereas the prevalence of Titin gene truncation variants (TTNtv) was higher in the late-onset DCM group compared to the younger cohort (23% vs 13% respectively; p<0.05). Notably, patients with late-onset genetic DCM had comparable long-term outcomes to those with typical-onset DCM. Conclusions Late-onset DCM patients have nearly double the rate of TTNtv mutations and are more likely to be female compared to younger DCM patients. These observed differences in mutational makeup and sex may reveal insights into age and sex dependent mechanisms for TTNtv and should prompt further study. Notably, the increased prevalence of TTNtv and female sex did not translate into noticeable differences in rates of measurable cardiac events. Funding Acknowledgement Type of funding source: None

Splicing mutation in LAMP2 gene leading to exon skipping and cardiomyopathy development

Mutations in LAMP2 (Xq24) encoding a lysosomal-associated membrane protein 2 crucial to the maintenance and adhesion of the lysosome cause a Danon disease. It is an X-linked glycogen storage disease that includes cardiomyopathy (hypertrophic or dilated), skeletal myopathy and mental retardation. Here, we report a woman, carrying the mutation c.864 + 1G > A (IVS6 + 1G > A, rs727503119) in heterozygosity and affected with late-onset dilated cardiomyopathy. We demonstrated the effects of the mutation on the splicing LAMP2 in cardiac muscle. The variant c.864 + 1G > A is located in the canonical splice donor site in intron 6. Functional analysis reveals that mutation c.864 + 1G > A leads to the skipping of exon 6 in cardiac muscle. The protein loses 41 amino acids in the second luminal domain of LAMP2 without frameshift and premature termination of protein synthesis. Using qRT-PCR we revealed a significantly low level of wild-type LAMP2 mRNA in patient that can be explained by X-inactivation.

A cardiac α-actin (ACTC1) p. Gly247Asp mutation inhibits SRF-signaling in vitro in neonatal rat cardiomyocytes

We recently identified a novel, heterozygous, and non-synonymous ACTC1 mutation (p.Gly247Asp or G247D) in a large, multi-generational family, causing atrial-septal defect followed by late-onset dilated cardiomyopathy (DCM). Molecular dynamics studies revealed possible actin polymerization defects as G247D mutation resides at the juncture of side-chain interaction, which was indeed confirmed by in vitro actin polymerization assays. Since polymerization/de-polymerization is important for the activation of Rho-GTPase-mediated serum response factor (SRF)-signaling, we studied the effect of G247D mutation using luciferase assay. Overexpression of native human ACTC1 in neonatal rat cardiomyocytes (NRVCMs) strongly activated SRF-signaling both in C2C12 cells and NRVCMs, whereas, G247D mutation abolished this activation. Mechanistically, we found reduced GTP-bound Rho-GTPase and increased nuclear localization of globular actin in NRVCMs overexpressing mutant ACTC1 possibly causing inhibition of SRF-signaling activation. In conclusion, our data suggests that human G247D ACTC1 mutation negatively regulates SRF-signaling likely contributing to the late-onset DCM observed in mutation carrier patients.

Cardiac α-Actin (ACTC1) Gene Mutation Causes Atrial-Septal Defects Associated With Late-Onset Dilated Cardiomyopathy.

Familial atrial septal defect (ASD) has previously been attributed primarily to mutations in cardiac transcription factors. Here, we report a large, multi-generational family (78 members) with ASD combined with a late-onset dilated cardiomyopathy and further characterize the consequences of mutant α-actin. We combined a genome-wide linkage analysis with cell biology, microscopy, and molecular biology tools to characterize a novel ACTC1 (cardiac α-actin) mutation identified in association with ASD and late-onset dilated cardiomyopathy in a large, multi-generational family. Using a genome-wide linkage analysis, the ASD disease locus was mapped to chromosome 15q14 harboring the ACTC1 gene. In 15 affected family members, a heterozygous, nonsynonymous, and fully penetrant mutation (p. Gly247Asp) was identified in exon 5 of ACTC1 that was absent in all healthy family members (n=63). In silico tools predicted deleterious consequences of this variant that was found absent in control databases. Ultrastructural analysis of myocardial tissue of one of the mutation carriers showed sarcomeric disarray, myofibrillar degeneration, and increased apoptosis, while cardiac proteomics revealed a significant increase in extracellular matrix proteins. Consistently, structural defects and increased apoptosis were also observed in neonatal rat ventricular cardiomyocytes overexpressing the mutant, but not native human ACTC1. Molecular dynamics studies and additional mechanistic analyses in cardiomyocytes confirmed actin polymerization/turnover defects, thereby affecting contractility. A combined phenotype of ASD and late-onset heart failure was caused by a heterozygous, nonsynonymous ACTC1 mutation. Mechanistically, we found a shared molecular mechanism of defective actin signaling and polymerization in both cardiac development and contractile function. Detection of ACTC1 mutations in patients with ASD may thus have further clinical implications with regard to monitoring for (late-onset) dilated cardiomyopathy.

A CARDIAC α-ACTIN (ACTC1) GENE MUTATION CAUSES ATRIAL-SEPTAL DEFECTS ASSOCIATED WITH DILATED CARDIOMYOPATHY

Atrial septal defect (ASD) is a common congenital heart defect. Its pathogenesis is not well defined, but mutations in cardiac transcription factor genes have been described in familial forms. Here, we report a large, multi-generational family with ASD combined with late-onset dilated cardiomyopathy

Incidence, risk factors, and mortality of neonatal and late-onset dilated cardiomyopathy associated with cardiac neonatal lupus

BackgroundDilated cardiomyopathy (DCM), a well-known complication of cardiac neonatal lupus, is associated with high mortality rate. Its risk factors remain unclear. MethodsWe analyzed occurrence of postnatal DCM among children with high-degree congenital heart block (CHB) and mothers with anti-SSA and/or anti-SSB antibodies. ResultsAmong 187 neonates with CHB, 35 (18.8%, one missing data) had DCM and 22 (11.8%) died during a median follow-up of 7years [range: birth–36years]. On multivariate analysis, factors associated with postnatal DCM were in utero DCM (P=0.0199; HR=3.13 [95% CI: 1.20–8.16]), non-European origin (P=0.0052; HR=4.10 [95% CI: 1.81–9.28]) and pacemaker implantation (P=0.0013; HR=5.48 [95% CI: 1.94–15.47]).Postnatal DCM could be categorized in two subgroups: neonatal DCM (n=13, diagnosed at a median age of 0day [birth–4days]) and late-onset DCM (n=22, diagnosed at a median age of 15.2months [3.6months–22.8years]). Factors associated with neonatal DCM were in utero DCM, hydrops, endocardial fibroelastosis and pericardial effusion, whereas those associated with late-onset DCM were non-European origin, in utero mitral valve insufficiency, and pacemaker implantation. Fluorinated steroids showed no protective effect against late-onset DCM (P=0.27; HR=1.65 [95% CI: 0.63–4.25]). Probability of survival at 10years was 23.1% for newborns diagnosed neonatally with DCM, 53.9% for those who developed late-onset DCM, and 98.6% for those without DCM. ConclusionNeonatal and late-onset DCM appear to be two different entities. None of the known risk factors associated with neonatal DCM predicted late-onset DCM. Long-term follow-up of cardiac function is warranted in all children with CHB.

330 - Doxorubicin-Mediated Toxic Effects Are Mediated Via NO/eNOS in a Novel 3D in Vitro Model of the Human Heart

Background Nitric oxide (NO●) and endothelial nitric oxide synthase (eNOS) play a dual role in the human heart by both preventing and mediating the toxic effects of chemotherapeutics such as doxorubicin (DOX). Treatment of cancer patients with DOX can result in severe late-onset dilated cardiomyopathy more than one year after completion of treatment. This cardiotoxicity has been linked to DOX-mediated upregulation of eNOS, peroxynitrous acid generation and caspase 3 activation. However, currently available models used to study this signalling pathway have limited potential to identify the cellular and molecular targets of DOX and the mechanism of toxicity in humans. Aims to use a novel in vitro 3D co-culture model, the “cardiac spheroid” (CS), generated from human endothelial cells (ECs), cardiac myocytes (CMs) and fibroblasts (CFs) to recapitulate biochemical and morphological features typical of the human heart and examine the mechanisms of DOX toxicity. Results DOX-mediated dose dependent toxic effects on CSs are shown to be dependent on NO● synthesis. Inhibition of NO● formation using L-NIO reduced DOX-mediated toxic effects in CSs at DOX concentrations detected in DOX-treated patients. Analysis at the cellular level showed that EC-derived NO● plays a protective role, whereas most of the toxic effects of DOX/NO was derived from CFs. Silencing of eNOS with lentiviral NOS3 shRNA particles in ECs confirmed a dual role of NO in mediating DOX-derived toxic effects in CSs., Genetic eNOS inhibition in CFs supported the toxic role played by these cells. Conclusions This study provides the first direct evidence for a dual role of NO. in mediating both toxic and protective DOX-mediated effects in the human heart, and cellular crosstalk responsible for this. Determining the molecular and cellular targets of novel drugs in CSs has the potential to prevent unexpected toxic effects.

Abstract 18: Coxsackievirus B3 Escapes Infected Cardiac Stem Cells via Ejected Autophagosomes

Many viruses have been shown to upregulate host autophagic processes during the course of infection. Originally this process was thought to be a response mechanism of the host cell in order to engulf viral particles and destroy them to prevent viral spread and host cell death. However, certain viruses have been shown to strategically hijack the autophagic pathway to evade host immunity and increase viral replication. Coxsackievirus B (CVB) is a non-enveloped picornavirus that most commonly causes a self-limited febrile illness in young children, but in rare severe cases can progress to myocarditis, pancreatitis, or meningo-encephalitis. It has also been associated with late-onset idiopathic dilated cardiomyopathy. CVB type 3 (CVB3) has previously been documented to upregulate host autophagic machinery upon infection, and we report here that the virus can infect cardiac stem cells and other muscle progenitors and allow itself to be engulfed in autophagosomes which later get shed from the surface of the host cell. This is a novel method of viral dissemination especially for a “naked” virus which would typically escape the infected host by triggering cytolysis. However, cytolytic viruses subsequently become exposed to neutralizing antibodies. The fact that CVB3 can hide itself in host membranes presents several fascinating possibilities. Not only could the ejected autophagosome mask the virus from adaptive immunity, but it may also bypass receptor-mediated endocytosis and infect cell-types that might lack CVB3 receptors. This mode of viral escape represents a unique evolutionary adaptation which obscures the line dividing enveloped and non-enveloped viruses.

Abstract 27: The Transcription Cofactor Eya4 Mediates the Development of Acquired Cardiac Hypertrophy

Introduction: Eyes absent 4 (Eya4) is a transcription cofactor involved in a number of cellular and developmental processes. We have previously shown that a mutation in Eya4 (E193) leads to late-onset familial dilated cardiomyopathy and heart failure. A precise role for Eya4 in the myocardium has not yet been identified. It appears to regulate the cyclin dependent kinase inhibitor p27 kip1 (p27), a protein shown to regulate hypertrophic responses in the adult cardiomyocyte. This study was aimed to explore the role of Eya4 in induced cardiac hypertrophy. Methods and results: We generated transgenic mice with cardiac-specific overexpression of HA-tagged Eya4 or E193 to elucidate the function of these proteins in the development of heart failure in vivo . These and wildtype littermates were challenged with angiotensin II (ATII) or subjected to transaortic constriction (TAC). Magnetic resonance imaging to visualize cardiac structures in detail showed that in response to sustained ATII stimulation and TAC, Eya4 mice exhibited a phenotype with significantly increased parameters of hypertrophy compared to WT and E193 overexpressing animals as judged by increases in heart weight and LV free wall diameter, cross-sectional cell surface areas and fibrosis. MRI also showed mild cardiac hypertrophy in Eya4 transgenic mice already under baseline conditions in an age dependent fashion. Moreover, Eya4 overexpression induced a significant suppression of p27 protein expression and resulted in increased levels of phosphorylated histone deacetylase 2 (HDAC2). E193 overexpression induced age dependent wall thinning and ventricular dilation under baseline conditions with no obvious structural or functional defects. ATII or TAC induced significant changes in HW/BW ratio, IVS, fibrosis, hemodynamic and cell size measurements, albeit to a lesser extent than seen with Eya4 mice. p27 expression and pHDAC2 levels were only slightly altered. Conclusion: In summary, we have demonstrated a mutation in Eya4 to disturb cardiac physiology. We now provide evidence that Eya4 is also involved in forms of acquired heart disease. It seems to suppress p27, which leads to phosphorylation and activation of HDAC2 and results in the development of cardiac hypertrophy.

Selective deletion of long but not short Cypher isoforms leads to late-onset dilated cardiomyopathy

Cypher long (CypherL) and short (CypherS) isoforms are distinguished from each other by the presence and absence of three C-terminal LIM domains, respectively. Cypher isoforms are developmentally regulated, and mutations affecting both long and short isoforms are linked to muscle disease in humans. Given these data, we hypothesized that various Cypher isoforms play overlapping and unique roles in striated muscle. To determine the specific role of Cypher isoforms in striated muscle, we generated two mouse lines in which either CypherS or CypherL isoforms were specifically deleted. Mice specifically, deficient in CypherS isoforms had no detectable muscle phenotype. In contrast, selective loss of CypherL isoforms resulted in partial neonatal lethality. Surviving mutants exhibited growth retardation and late-onset dilated cardiomyopathy, which was associated with cardiac fibrosis and calcification, leading to premature adult mortality. At a young age, preceding development of cardiomyopathy, hearts from these mutants exhibited defects in both Z-line ultrastructure and specific aberrations in calcineurin-NFAT and protein kinase C pathways. Earlier onset of cardiac dilation relative to control wild-type mice was observed in young CypherL isoform knockout mice consequent to pressure overload, suggesting a greater susceptibility to the disease. In summary, we have identified unique roles for CypherL isoforms in maintaining Z-line ultrastructure and signaling that are distinct from the roles of CypherS isoforms, while highlighting the contribution of mutations in the long isoforms to the development of dilated cardiomyopathy.

294 Clinical presentation and long-term outcome of non immune and isolated atrioventricular block when congenital or diagnosed during childhood: a French multicentric study on 141 patients

When isolated and non immune, prevalence of congenital and childhood atrioventricular blocks (AVB) is extremely low and little is known about their natural history. A multicentric study retrospective from 1980 to 2009 allowed inclusion of 141 children from 13 French referral centers. Included children presented an AVB diagnosed in utero, at birth or during childhood before the age of 15 years, without structural heart abnormalities and without maternal antibodies. 26 congenital and 114 childhood AVB were included. Symptoms lead to diagnosis in 15,6% whereas AVB was asymptomatic in 84,4%. 73% AVB were complete and 26,2% AVB were incomplete at first presentation. 21 of these incomplete blocks (56,7%) progressed to permanent complete AVB. Narrow QRS complexes were found in 69,2% congenital and 91,2% childhood AVB. In the 112 (79,4%) implanted children, mean duration between AVB diagnosis and pacemaker implantation was 35 months. Pacemaker primo-implantation occurred during the first year of life for 18 children and 90 children (63.8%) were paced before 10 years old. Pacing was required for symptomatic bradycardia in 37,5% whereas prophylactic cardiac pacing accounted for 61,6%. The median follow-up was 96 months (from 6 to 384 months). 85,1% experienced no complication and neither dilated cardiomyopathy nor death had occurred at last follow-up. Pacemaker-related complications appeared in 11,6%. We describe the largest reported experience with isolated and non immune congenital and childhood AVB. Such a block is a nodal damage from unknown origin that may postnatally progress in incomplete forms. Outcome is not influenced by age at diagnosis. Prognosis is very good with no late-onset dilated cardiomyopathy, a few pacemaker-related complications in the modern technological era and no death at last follow-up.

242 Clinical presentation and long-term outcome of non immune and isolated atrioventricular block when congenital or diagnosed during childhood: a French multicentric study on 141 patients

When isolated and non immune, prevalence of congenital and childhood atrioventricular blocks (AVB) is extremely low and little is known about their natural history. a multicentric study retrospective from 1980 to 2009 allowed inclusion of 141 children from 13 French referral centers. Included children presented an AVB diagnosed in utero, at birth or during childhood before the age of 15 years, without structural heart abnormalities and without maternal antibodies. 26 congenital and 114 childhood AVB were included. Symptoms lead to diagnosis in 15,6% whereas AVB was asymptomatic in 84,4%. 73% AVB were complete and 26,2% AVB were incomplete at first presentation. 21 of these incomplete blocks (56,7%) progressed to permanent complete AVB. Narrow QRS complexes were found in 69,2% congenital and 91,2% childhood AVB. In the 112 (79,4%) implanted children, mean duration between AVB diagnosis and pacemaker implantation was 35 months. Pacemaker primo-implantation occurred during the first year of life for 18 children and 90 children (63.8%) were paced before 10 years old. Pacing was required for symptomatic bradycardia in 37,5% whereas prophylactic cardiac pacing accounted for 61,6%. The median follow-up was 96 months (from 6 to 384 months). 85,1% experienced no complication and neither dilated cardiomyopathy nor death had occurred at last follow-up. Pacemaker-related complications appeared in 11,6%. We describe the largest reported experience with isolated and non immune congenital and childhood AVB. Such a block is a nodal damage from unknown origin that may postnatally progress in incomplete forms. Outcome is not influenced by age at diagnosis. Prognosis is very good with no late-onset dilated cardiomyopathy, a few pacemaker-related complications in the modern technological era and no death at last follow-up.

A nonsense mutation in the optic atrophy 3 gene ( OPA3) causes dilated cardiomyopathy in Red Holstein cattle

Cardiomyopathies are severe degenerative disorders of the myocardium that lead to heart failure. During the last three decades bovine dilated cardiomyopathy (BDCMP) was observed worldwide in cattle of Holstein–Friesian origin. In the Swiss cattle population BDCMP affects Fleckvieh and Red Holstein breeds. The heart of affected animals is enlarged due to dilation of both ventricles. Clinical signs are caused by systolic dysfunction and affected individuals die as a result of severe heart insufficiency. BDCMP follows an autosomal recessive pattern of inheritance and the disease-causing locus was mapped to bovine chromosome 18 (BTA18). In the present study we describe the successful identification of the causative mutation in the OPA3 gene located on BTA18 that was previously reported to cause 3-methylglutaconic aciduria type III in Iraqi-Jewish patients. We demonstrated conclusive genetic and functional evidence that the nonsense mutation c.343C>T in the bovine OPA3 gene causes the late-onset dilated cardiomyopathy in Red Holstein cattle.

Lysosomal, cytoskeletal, and metabolic alterations in cardiomyopathy of cathepsin L knockout mice

Although lysosomal proteases are expressed in the heart at considerable levels, their specific functions in this organ remain elusive. Mice deficient for the lysosomal cysteine protease cathepsin L (CTSL) develop a late onset dilated cardiomyopathy (DCM) that is characterized by cardiac chamber dilation, fibrosis, and impaired cardiac contraction at 12 month of age. Investigation of the pathogenic sequence of DCM in ctsl-/- mice revealed numerous dysmorphic lysosome-like structures in heart muscle as early as 3 days after birth, whereas skeletal muscle was not affected. Labeling of the acidic cell compartment of neonatal cardiomyocytes and detection of lysosomal markers after subcellular fractionation confirmed increased lysosome content in CTSL deficient myocardium; however, specific storage materials were not detected. The myocardium of ctsl+/+ and ctsl-/- mice revealed no differences in incidence of cell death, proliferation, and capillary density during DCM progression. However, an observed increase in mRNA expression of natriuretic peptides in young adult mice indicates the activation of the adaptive "fetal" gene program, while proteome analysis revealed decreased levels of the sarcomere-associated proteins alpha-tropomyosin, desmin, and calsarcin 1, as well as considerable changes of metabolic enzymes. Bioinformatic pathway analysis suggested a switch to anaerobic catabolism and impairment of mitochondrial respiration. This interpretation was supported by a 50% reduction in resting state oxygen consumption and impaired respiration capacity in ctsl-/- myocardial homogenates. In summary, the data indicate an essential role of CTSL in maintaining the structure of the endosomal/lysosomal compartment in cardiomyocytes. Lysosomal impairment in ctsl-/- hearts results in metabolic and sarcomeric alterations that promote DCM development.

Proposal for a new definition of congenital complete atrioventricular block.

The classic old definition of congenital heart block by Yater (1929) is still generally accepted: 'Heart block established in a young patient. There must be some evidence of the existence of the slow pulse at a fairly early age and absence of a history of any infection which might cause the condition after birth: notably diphtheria, rheumatic fever, chorea and congenital syphilis'. However, other definitions are used. We systematically reviewed 1825 cases from 38 separate studies. We conclude that complete AV blocks detected in utero in the absence of structural abnormalities differ from blocks detected later in life with respect to pathogenesis (they are generally associated with maternal anti-Ro/SSA antibodies), poorer childhood prognosis, increased risk of developing late-onset dilated cardiomyopathy, different maternal clinical features and increased risk of recurrence in future pregnancies. For these reasons we propose a new modern definition of congenital complete AV block which might be acceptable to cardiologists, rheumatologists, pediatricians and obstetricians: 'an AV block is defined as congenital if it is diagnosed in utero, at birth or within the neonatal period (0-27 days after birth)'.

Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela

OBJECTIVESWe report 16 infants with complete congenital heart block (CHB) who developed late-onset dilated cardiomyopathy despite early institution of cardiac pacing.BACKGROUNDIsolated CHB has an excellent prognosis following pacemaker implantation. Most early deaths result from delayed initiation of pacing therapy or hemodynamic abnormalities associated with congenital heart defects.METHODSA multi-institutional study was performed to identify common clinical features and possible risk factors associated with late-onset dilated cardiomyopathy in patients born with congenital CHB.RESULTSCongenital heart block was diagnosed in utero in 12 patients and at birth in four patients. Ten of 16 patients had serologic findings consistent with neonatal lupus syndrome (NLS). A pericardial effusion was evident on fetal ultrasound in six patients. In utero determination of left ventricular (LV) function was normal in all. Following birth, one infant exhibited a rash consistent with NLS and two had elevated hepatic transaminases and transient thrombocytopenia. In the early postnatal period, LV function was normal in 15 patients (shortening fraction [SF] = 34 ± 7%) and was decreased in one (SF = 20%). A cardiac pacemaker was implanted during the first two weeks of life in 15 patients and at seven months in one patient. Left ventricular function significantly decreased during follow-up (14 days to 9.3 years, SF = 9% ± 5%). Twelve of 16 patients developed congestive heart failure before age 24 months. Myocardial biopsy revealed hypertrophy in 11 patients, interstitial fibrosis in 11 patients, and myocyte degeneration in two patients. Clinical status during follow-up was guarded: four patients died from congestive heart failure; seven required cardiac transplantation; one was awaiting cardiac transplantation; and four exhibited recovery of SF (31 ± 2%).CONCLUSIONSDespite early institution of cardiac pacing, some infants with CHB develop LV cardiomyopathy. Patients with CHB require close follow-up not only of their cardiac rate and rhythm, but also ventricular function.