Adult-onset Dilated Cardiomyopathy Research Articles

Who should be prioritized for screening for adult onset dilated cardiomyopathy among first degree relatives?

Abstract Introduction Familial genetic and cardiovascular screening is highly recommended to detect dilated cardiomyopathy (DCM) in first-degree relatives (FDRs). Consequently, questions arise regarding the prioritization of screening among FDRs especially in Asian populations. Purpose To investigate prevalence and proportion of FDRs of DCM patients presenting with DCM. Methods Patients with DCM and their FDRs who underwent genetic counseling between April 2017 and March 2023 at a single tertiary center were retrospectively enrolled. The study collected baseline demographics and conducted sequential echocardiograms, along with genetic cascade sequencing for 36 genes clinically relevant to DCM. A positive DCM phenotype in FDRs was determined based on the presence of a decreased left ventricular ejection fraction (LVEF) with left ventricular enlargement, with a full phenotype containing both criteria and a partial phenotype containing either of them. Results A total of 122 probands (median age 59 years) and 241 FDRs (median age 43 years) participated in the study. Out of 72 FDRs (29.9%) with P/LP proband variants, only 18.6% of FDRs showed a positive DCM-phenotype. Overall, 29 individuals (15.5%) exhibited a positive DCM-phenotype, with 2.7% displaying a full DCM-phenotype and 12.8% displaying a partial DCM-phenotype. Among them, 69% exhibited heart failure (HF) with preserved EF, 20.7% had HF with mildly reduced EF, and 10.3% had HF with reduced EF. Siblings tended to be older compared to offspring (52.1 years vs. 35.5 years), aligning with the tendency shown in the more fulminant manifestation of the positive phenotype. Accordingly, a higher prevalence was observed among siblings (n=4, 80%) with a full phenotype and in those with a partial phenotype. Conclusion This study demonstrated higher prevalence of phenotype-positive DCM among siblings of probands. Given disease’s manifestation in adulthood, it is essential to prioritize the screening of all FDRs with emphasis on the siblings.

Abstract Tu086: Repairing nuclear envelope ruptures to ameliorate Lamin-related cardiomyopathy

Heterozygous loss-of-function mutations in LMNA , encoding nuclear lamina protein Lamin A/C, cause severe adult-onset dilated cardiomyopathy. A prevailing hypothesis posits that LMNA insufficiency causes nuclear envelope structural defects that ultimately cause the disease. However, the mechanisms linking defective nuclear envelopes to cardiomyopathy remain undefined. To determine specific nuclear envelope defects and their consequences, we deleted Lmna in cardiomyocytes in adult mice ( Lmna CKO ). Strikingly, a modest (50%) reduction of Lamin A/C caused widespread localized ruptures of the nuclear envelope in cardiomyocytes (En et al. bioRxiv 2023). The nuclear envelope ruptures did not cause immediate cell death, but accompanied a strong inflammatory response in the heart, prior to fatal cardiomyopathy. We hypothesized that DNA leaked from ruptured nuclei might elicit the cGAS-STING cytosolic DNA sensing pathway of innate immunity. Contrary to this hypothesis, we did not observe cGAS-STING activation in Lmna CKO cardiomyocytes. This lack of cGAS-STING activation was likely due to the near absence of cGAS protein in adult cardiomyocytes. To investigate the mechanism underlying cardiac inflammation in Lmna CKO mice, we conducted time-course single-nucleus RNA-seq. This analysis nominated cardiac fibroblasts as the central mediator of the inflammatory response, receiving ECM-mediated signaling from Lmna CKO cardiomyocytes and recruiting immune cells to the mutant hearts. Finally, we found evidence suggesting that nuclear envelope repair activity counteracts nuclear envelope ruptures in Lmna CKO mice. We found that the envelope ruptured sites co-localized with the ESCRT-III membrane remodeling complex, previously implicated in nuclear envelope repair. We further found that overexpression of DNA-binding protein BANF1 promoted ESCRT-III recruitment to the ruptured sites. We are currently investigating whether facilitated nuclear envelope repair ameliorates cardiomyopathy in Lmna CKO mice. If it does, nuclear envelope repair may be a potential therapeutic strategy for LMNA -related dilated cardiomyopathy.

A spectrum of clinical severity of recessive titinopathies in prenatal.

Variants in TTN are associated with a broad range of clinical phenotypes, from dominant adult-onset dilated cardiomyopathy to recessive infantile-onset myopathy. However, few foetal cases have been reported for multiple reasons. Next-generation sequencing has facilitated the prenatal identification of a growing number of suspected titinopathy variants. We investigated six affected foetuses from three families, completed the intrauterine course of the serial phenotypic spectrum of TTN, and discussed the genotype-phenotype correlations from a broader perspective. The recognizable prenatal feature onset at the second trimester was started with reduced movement, then contracture 3-6 weeks later, followed with/without hydrops, finally at late pregnancy was accompanied with polyhydramnio (major) or oligohydramnios. Two cases with typical arthrogryposis-hydrops sequences identified a meta-only transcript variant c.36203-1G>T. Deleterious transcriptional consequences of the substitution were verified by minigene splicing analysis. Case 3 identified a homozygous splicing variant in the constitutively expressed Z-disc. It presented a milder phenotype than expected, which was presumably saved by the isoform of corons. A summary of the foetal-onset titinopathy cases implied that variants in TTN present with a series of signs and a spectrum of clinical severity, which followed the dosage/positional effect; the meta-only transcript allele involvement may be a prerequisite for the development of fatal hydrops.

Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein that is dispensable for mitochondrial division yet essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in a fatal, adult-onset dilated cardiomyopathy accompanied by extensive mitochondrial and cardiac remodeling during the transition to heart failure. Prior to the onset of disease, knockout cardiac mitochondria displayed specific IMM defects: futile proton leak dependent upon the adenine nucleotide translocase and an increased sensitivity to the opening of the mitochondrial permeability transition pore, with which MTFP1 physically and genetically interacts. Collectively, our data reveal new functions of MTFP1 in the control of bioenergetic efficiency and cell death sensitivity and define its importance in preventing pathogenic cardiac remodeling.

Understanding the genetics of adult-onset dilated cardiomyopathy: what a clinician needs to know.

There is increasing understanding of the genetic basis to dilated cardiomyopathy and in this review, we offer a practical primer for the practising clinician. We aim to help all clinicians involved in the care of patients with dilated cardiomyopathy to understand the clinical relevance of the genetic basis of dilated cardiomyopathy, introduce key genetic concepts, explain which patients and families may benefit from genetic testing, which genetic tests are commonly performed, how to interpret genetic results, and the clinical applications of results. We conclude by reviewing areas for future research in this dynamic field.

MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy.

The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of the MEF2C gene results in dilated cardiomyopathy (DCM). However, in humans, the association of MEF2C variation with DCM remains to be investigated. The coding regions and splicing boundaries of the MEF2C gene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identified MEF2C mutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped for MEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier's family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM. This study indicates MEF2C as a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.

Propionic acidemia as a cause of adult-onset dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is extremely heterogeneous with a large proportion due to dominantly inherited disease-causing variants in sarcomeric genes. Recessive metabolic diseases may cause DCM, usually with onset in childhood, and in the context of systemic disease. Whether metabolic defects can also cause adult-onset DCM is currently unknown. Therefore, we performed an extensive metabolic screening in 36 consecutive adult-onset DCM patients. Diagnoses were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Measurement of propionyl-CoA carboxylase (PCC) activity was done in fibroblasts. Whole exome sequencing (WES) data of 157 additional DCM patients were analyzed for genetic defects. We found a metabolic profile characteristic for propionic acidemia in a patient with severe DCM from 55 years of age. Genetic analysis demonstrated compound heterozygous variants in PCCA. Enzymatic activity of PCC in fibroblasts was markedly reduced. A targeted analysis of the PCCA and PCCB genes using available WES data from 157 further DCM patients subsequently identified another patient with propionic acidemia. This patient had compound heterozygous variants in PCCB, and developed severe DCM from 42 years of age. Adult-onset DCM can be caused by propionic acidemia, an autosomal recessive inheritable metabolic disorder usually presenting as neonatal or childhood disease. Current guidelines advise a low-protein diet to ameliorate or prevent detrimental aspects of the disease. Long-term follow-up of a larger group of patients may show whether this diet would also ameliorate DCM. Our results suggest that diagnostic metabolic screening to identify propionic acidemia and related disorders in DCM patients is justified.

Hematopoietic Id Deletion Triggers Endomyocardial Fibrotic and Vascular Defects in the Adult Heart

Inhibitor of DNA binding (Id) proteins play important roles in regulating cardiac development via paracrine signaling. Id1/Id3 knockout mice die at mid-gestation with multiple cardiac defects. Single Id knockout studies have not reported cardiomyopathies. To bypass embryonic lethality we used Tie2CRE-mediated recombination to conditionally delete Id1 against global Id3 ablation (Id cDKOs), which develops adult-onset dilated cardiomyopathy. We confirm upregulation of thrombospondin-1 (TSP1) in Id cDKO hearts. Colocalization studies reveal increased TSP1 expression in the vicinity of endothelial cells and near regions of endocardial fibrosis/disruption. Downstream fibrotic molecules were upregulated. Endocardial capillary density was reduced with evidence of vascular distention. Treatment of Id cDKO cardiac explants with LSKL, a peptide antagonist of TSP1 activation of TGFβ, reversed the increased expression of fibrotic molecules. We conducted bone marrow transplant experiments in which we transferred bone marrow cells from Id cDKO mice into lethally irradiated WT mice. The majority of WT recipients of Id cDKO bone marrow cells phenocopied Id cDKO cardiac fibrosis 4 months post-transplantation. Injection of LSKL into adult Id cDKO mice led to downregulation of fibrotic molecules. The results prompt caution when bone marrow transfers from individuals potentially carrying mutations in the Id axis are applied in clinical settings.

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients.

A novel TBX20 loss‑of‑function mutation contributes to adult‑onset dilated cardiomyopathy or congenital atrial septal defect.

Dilated cardiomyopathy (DCM) is the most prevalent form of primary cardiomyopathy in humans and is a leading cause of heart failure and sudden cardiac death. Genetic abnormalities have been demonstrated to be a major contributor to the development of DCM. However, DCM is a genetically heterogeneous disease, and the genetic basis underlying DCM in a significant proportion of patients remains unclear. In the current study, the coding exons and splicing junction sites of the T‑Box20 (TBX20) gene, which encodes a T‑box transcription factor essential for cardiac morphogenesis and structural remodeling, were sequenced in 115unrelated patients with idiopathic DCM, and a novel heterozygous mutation, p.E143X, was identified in one patient. Genetic analysis of the mutation carrier's pedigree indicated that the nonsense mutation was present in all the living family members with DCM, and also in a female patient with a congenital atrial septal defect. The mutation, which was predicted to generate a truncated protein with only the N‑terminus and a fraction of the T‑box domain remaining, was absent in 800control chromosomes. Functional assays using a dual‑luciferase reporter assay system revealed that the truncated TBX20 protein had no transcriptional activity in contrast to its wild‑type counterpart. Furthermore, the mutation abolished the synergistic activation between TBX20 and NK2 homeobox5, or between TBX20 and GATA binding protein4. The observations of the current study expand the mutation spectrum of TBX20 associated with DCM and congenital heart disease (CHD), which provide novel insight into the molecular mechanisms underlying DCM and CHD, suggesting the potential implications for the effective and personalized treatment of these diseases.

G.P.34: The expanding spectrum of congenital titinopathies

Congenital core myopathies (CM) remain genetically unexplained in many cases. Heart disease is not considered part of the typical CM spectrum. Childhood-onset dilated cardiomyopathy (DCM) was reported in two families with minicores and homozygous TTN mutations. TTN encodes the giant sarcomere protein titin. Relatively few titin mutations (mostly heterozygous and associated to adult-onset cardiac or skeletal muscle disease) have been reported, TTN size and complexity precluding full screening before NGS. Thus, the prevalence and spectrum of titinopathies is probably underestimated. Here we report the analysis of 23 families with CM and primary heart disease using TTN M-line targeted sequencing followed in selected patients by whole-exome sequencing and functional studies. We found 7 novel homozygous or compound heterozygous TTN mutations (5 in the M-line, 5 truncating) in 5 patients. All heterozygous parents were healthy. We identified 4 novel phenotypes previously unreported or non-associated with TTN , including several congenital cardiopathies. The first antenatal-onset titinopathy presented with multi-minicore disease (MmD), arthrogryposis, left ventricular non-compaction and ventricular septal defect, and was associated with the first-reported absence of a functional titin kinase domain in humans. Other novel phenotypes associate MmD with auricular and/or ventricular septal defects, Rigid Spine, Emery-Dreifuss phenotype and/or adult-onset DCM. The histological pattern consistently showed minicores, central nuclei and structural lesions. Conversely, the spectrum of severity and heart disease was large. Thus, we demonstrate that TTN M-line truncating mutations are typically recessive and represent a significant cause of MmD with heart disease. Our results represent the first series of recessive titinopathies, expand TTN mutational and phenotypic spectrum, and identify TTN as a candidate gene in arthrogryposis, EDMD and pediatric heart defects.

Adult-onset dilated cardiomyopathy as the primary manifestation of mitochondrial m.3243A > G mutation with heart-specific high mutation load

Adult-onset dilated cardiomyopathy as the primary manifestation of mitochondrial m.3243A > G mutation with heart-specific high mutation load

Congenital posterior pole cataract and adult onset dilating cardiomyopathy: expanding the phenotype of αB‐crystallinopathies

Mutations in the αB-crystallin gene (CRYAB) have been reported in desmin-related myopathies, with or without cardiac involvement. Mutations in this gene have also been documented in large multi-generation families with autosomal dominant congenital posterior pole cataract (CPPC). In these congenital cataract families no cardiac or muscular phenotype was reported. This report describes a family with an unusual read-through mutation in CRYAB, leading to the elongation of the normal αB-crystallin protein with 19 amino acid residues. Affected family members combine a CPPC with an adult onset dilated cardiomyopathy (DCM), thereby expanding the αB-crystallinopathy phenotype. Repolarisation abnormalities preceded the onset of cardiomyopathy and were already present in childhood. No skeletal myopathy was observed. This report illustrates that congenital cataract can be a prelude to more severe disease even outside the context of inborn errors of metabolism. The identification of a CRYAB mutation in this family supports the notion that mutations in this gene are a rare cause of genetically determined DCM. The combined congenital cataract/cardiomyopathy phenotype adds to our understanding of the complex phenotypic spectrum of αB-crystallinopathies.

Functional Characterization of a Novel Mutation in NKX2-5 Associated With Congenital Heart Disease and Adult-Onset Cardiomyopathy

The transcription factor NKX2-5 is crucial for heart development, and mutations in this gene have been implicated in diverse congenital heart diseases and conduction defects in mouse models and humans. Whether NKX2-5 mutations have a role in adult-onset heart disease is unknown. Mutation screening was performed in 220 probands with adult-onset dilated cardiomyopathy. Six NKX2-5 coding sequence variants were identified, including 3 nonsynonymous variants. A novel heterozygous mutation, I184M, located within the NKX2-5 homeodomain, was identified in 1 family. A subset of family members had congenital heart disease, but there was an unexpectedly high prevalence of dilated cardiomyopathy. Functional analysis of I184M in vitro demonstrated a striking increase in protein expression when transfected into COS-7 cells or HL-1 cardiomyocytes because of reduced degradation by the Ubiquitin-proteasome system. In functional assays, DNA-binding activity of I184M was reduced, resulting in impaired activation of target genes despite increased expression levels of mutant protein. Certain NKX2-5 homeodomain mutations show abnormal protein degradation via the Ubiquitin-proteasome system and partially impaired transcriptional activity. We propose that this class of mutation can impair heart development and mature heart function and contribute to NKX2-5-related cardiomyopathies with graded severity.

Dilated Cardiomyopathy-Associated <i>FHOD3</i> Variant Impairs the Ability to Induce Activation of Transcription Factor Serum Response Factor

Dilated cardiomyopathy (DCM) is characterized by a dilated left ventricular cavity with systolic dysfunction manifested by heart failure. It has been revealed that mutations in genes for cytoskeleton or sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in far less than half of patients with a family history, indicating that there should be other disease genes for DCM. Formin homology 2 domain containing 3 (FHOD3) is a sarcomeric protein expressed in the heart that plays an essential role in sarcomere organization during myofibrillogenesis. The purpose of this study was to explore a possible novel disease gene for DCM. We analyzed 48 Japanese familial DCM patients for mutations in FHOD3, and a missense variant, Tyr1249Asn, which was predicted to modify the 3D structure and damage protein function, was found in a case with adult-onset DCM. Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of FHOD3. The DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly.

Mitochondrial dysfunction in myocardium obtained from clinically normal dogs, clinically normal anesthetized dogs, and dogs with dilated cardiomyopathy

To compare mitochondrial complex I and complex IV activity in myocardial mitochondria of clinically normal dogs, clinically normal dogs exposed to inhalation anesthesia, and dogs affected with dilated cardiomyopathy. Myocardial samples obtained from 21 euthanized dogs (6 clinically normal [control] dogs, 5 clinically normal dogs subjected to inhalation anesthesia with isoflurane prior to euthanasia, 5 dogs with juvenile-onset dilated cardiomyopathy, and 5 dogs with adult-onset dilated cardiomyopathy). Activity of mitochondrial complex I and complex IV was assayed spectrophotometrically in isolated mitochondria from left ventricular tissue obtained from the 4 groups of dogs. Activity of complex I and complex IV was significantly decreased in anesthetized dogs, compared with activities in the control dogs and dogs with juvenile-onset or adult-onset dilated cardiomyopathy. Inhalation anesthesia disrupted the electron transport chain in the dogs, which potentially led to an outburst of reactive oxygen species that caused mitochondrial dysfunction. Inhalation anesthesia depressed mitochondrial function in dogs, similar to results reported in other species. This effect is important to consider when anesthetizing animals with myocardial disease and suggested that antioxidant treatments may be beneficial in some animals. Additionally, this effect should be considered when designing studies in which mitochondrial enzyme activity will be measured. Additional studies that include a larger number of animals are warranted.

Altered neddylation in the heart of a mouse model for cardiomyopathy

We reported that a strain (4C30 strain) of mice with sialyltransferase (ST3GalII) transgenes would be a new mouse model for adult‐onset dilated cardiomyopathy (Proc Jpn Acad Ser B Phys Biol Sci. 2011; 87(8):550–562). Overexpression of ST3GalII perturbed protein glycosylation in 4C30 hearts, suggesting alteration of folding, translocation, and degradation of various proteins in 4C30 hearts. To study a possible involvement of protein degradation mechanisms in the cardiomyopathy, we compared neddylation statuses of heart proteins in our cardiomyopathic 4C30 mice with those in normal controls (C57BL/6NCr). Quantitative Western blots (QWB) for NEDD8 with GAPDH as a loading control revealed that two bands (100 and 105 kDa), but not four additional bands (90, 70, 60, or 40 KDa), were significantly denser in 4C30 hearts than in control hearts (p<0.05). QWB for culins with GAPDH indicated that culin‐2, but not culin‐1 or ‐3, was significantly more abundant (p<0.05). These results suggest that the protein degradation is altered in cardiomyopathic hearts.

Dilated cardiomyopathy-associatedBAG3mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes

Dilated cardiomyopathy (DCM) is characterized by dilation of left ventricular cavity with systolic dysfunction. Clinical symptom of DCM is heart failure, often associated with cardiac sudden death. About 20-35% of DCM patients have apparent family histories and it has been revealed that mutations in genes for sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in about 17% of Japanese patients with familial DCM. Bcl-2-associated athanogene 3 (BAG3) is a co-chaperone protein with antiapoptotic function, which localizes at Z-disc in the striated muscles. Recently, BAG3 gene mutations in DCM patients were reported, but the functional abnormalities caused by the mutations are not fully unraveled. In this study, we analyzed 72 Japanese familial DCM patients for mutations in BAG3 and found two mutations, p.Arg218Trp and p.Leu462Pro, in two cases of adult-onset DCM without skeletal myopathy, which were absent from 400 control subjects. Functional studies at the cellular level revealed that the DCM-associated BAG3 mutations impaired the Z-disc assembly and increased the sensitivities to stress-induced apoptosis. These observations suggested that BAG3 mutations present in 2.8% of Japanese familial DCM patients caused DCM possibly by interfering with Z-disc assembly and inducing apoptotic cell death under the metabolic stress.

Rare variant mutations identified in pediatric patients with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) in infants and children can be partially explained by genetic cause but the catalogue of known genes is limited. We reviewed our database of 41 cases diagnosed with DCM before 18 years of age who underwent detailed clinical and genetic evaluation and have summarized here the evidence for mutations causing DCM in these cases from 15 genes ( PSEN1, PSEN2, CSRP3, LBD3, MYH7, SCN5A, TCAP, TNNT2, LMNA, MYBPC3, MYH6, TNNC1, TNNI3, TPM1, and RBM20). Thirty-five of the 41 pediatric cases had relatives with adult-onset DCM. More males (66%) were found among children diagnosed after 1 year of age with DCM. Nineteen mutations in 9 genes were identified among 15 out of 41 patients; 3 patients (diagnosed at ages 2 weeks, 9 and 13 years) had multiple mutations. Of the 19 mutations identified in 12 families, mutations in TPM1 (32%) and TNNT2 (21%) were the most commonly found. Of the 6 patients diagnosed before 1 year of age, 3 had mutations in TPM1 (including a set of identical twins), 1 in TNNT2, 1 in MYH7, and 1 with multiple mutations ( MYH7 and TNNC1). Most DCM was accompanied by advanced heart failure and need for cardiac transplantation. We conclude that in some cases, pediatric DCM has a genetic basis, which is complicated by allelic and locus heterogeneity as seen in adult-onset DCM. We suggest that future prospective comprehensive family-based genetic studies of pediatric DCM are indicated to further define mutation frequencies in known genes and to discover novel genetic cause.

Effects of Mechanical Stress and Carvedilol in Lamin A/C–Deficient Dilated Cardiomyopathy

Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking. Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna(+/-)) mice. Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna(+/-) mice develop adult-onset DCM with relatively more severe disease in males. Lmna(+/-) cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna(+/-) mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna(+/-) mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna(+/-) mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna(+/-) mice from 12 to 40 weeks with the beta-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice. These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts.