Familial Dilated Cardiomyopathy Patients Research Articles

Association of rs505080 Single Nucleotide Polymorphism in Lamin-A Gene with Familial Dilated Cardiomyopathy in Iranian Population; A Case-Control Study

Background: Dilated cardiomyopathy (DCM) is among the most prevalent causes of heart failure and sudden cardiac death worldwide. Nuclear lamin protein coding genes are believed to have a definitive role in the DCM phenotype. The rs505058 thymine (T) to cytosine (C) polymorphism in the lamin-A gene is one of the most common mutations reported in familial DCM in previous studies. Objectives: We aimed to demonstrate the possible role of this SNP in the lamin A and C (LMNA) gene in the incidence of DCM among the south of Iran population. Methods: This case-control study included 65 patients with familial DCM and 70 healthy participants in south Iran. DNA was extracted from nucleated blood cells, and polymerase chain reaction (PCR) was performed. First, the sequence of the LMNA gene was investigated. Then the frequency of alleles C (mutated allele) and T (normal) of the LMNA gene (rs505058) was compared between the case and controls. Results: No notable differences were seen in gender and age between the case and controls. The genotype frequencies of the LMNA rs505058 T/C polymorphism were 6% (CC), 31% (CT), and 63% (TT) amongst cases, and 1% (CC), 13% (CT) and 86% (TT) in controls. For allele level comparison, the LMNA rs505058 C allele has been shown to have a statistically significant association with an enhancement in the risk of dilated cardiomyopathy (OR = 2.92; 95% CI = 1.05 to 8.15, P-value = 0.034) Conclusions: The results indicated that the rs505058 T/C SNP of the LMNA gene is associated with familial DCM patients in the Iranian population.

Abstract 14750: Mechanical Circulatory Support Devices Among Patients With Familial Dilated Cardiomyopathy

Introduction: With increasing disease recognition and widespread availability of genetic testing, it is important to characterize the clinical outcomes and prognosis among familial dilated cardiomyopathy (DCM) patients with stage D heart failure requiring a mechanical circulatory support device (MCSD). INTERMACS (INTEragency Registry for Mechanical Assisted Circulatory Devices) was examined to assess the clinical characteristics and outcomes of familial DCM patients who received an MCSD. Methods: DCM patients who received an MCSD between June 2005-December 2017 were classified according to their etiology. The primary outcome was death (with heart transplant as a competing risk) and the secondary outcome was heart transplant (with death as a competing risk). Multivariable-adjusted Cox regression analyses were used to assess the risk of study outcomes across DCM etiologies. Results: Among 19,928 DCM patients, 8,622 (43.3%), 7,091 (35.6%), 568 (2.9%), and 3,647 (18.3%) had ischemic DCM, idiopathic DCM, familial DCM, and DCM due to other causes respectively. Familial DCM patients had the lowest median age at implantation [46 (34, 56) years] compared with other DCM etiologies. Bridge to transplant was the most common device strategy (78.4%) in the familial DCM group (45.6% were listed and an additional 32.8% were eligible for a heart transplant). Familial DCM patients had the lowest adverse events of bleeding, device thrombosis, infection, and respiratory failure post-MCSD implantation. Over a median follow-up of 1.0 (0.4, 2.0) years, familial DCM patients had the lowest risk of death [HR adj : 0.68 (95% CI: 0.55-0.83)] and the highest likelihood of heart transplantation [HR adj : 1.47 (95% CI: 1.28-1.69)] compared with the other DCM groups. Conclusions: Among DCM patients receiving MCSDs, familial DCM patients had the lowest adverse events, the lowest risk of death, and the highest likelihood of heart transplantation, compared with other DCM etiologies.

Circulating circRNA as biomarkers for dilated cardiomyopathy etiology

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure. The multidisciplinary nature of testing — involving genetics, imaging, or cardiovascular techniques — makes its diagnosis challenging. Novel and reliable biomarkers are needed for early identification and tailored personalized management. Peripheral circular RNAs (circRNAs), a leading research topic, remain mostly unexplored in DCM. We aimed to assess whether peripheral circRNAs are expressed differentially among etiology-based DCM. The study was based on a case–control multicentric study. We enrolled 130 subjects: healthy controls (n = 20), idiopathic DCM (n = 30), ischemic DCM (n = 20), and familial DCM patients which included pathogen variants of (i) LMNA gene (n = 30) and (ii) BCL2-associated athanogene 3 (BAG3) gene (n = 30). Differentially expressed circRNAs were analyzed in plasma samples by quantitative RT-PCR and correlated to relevant systolic and diastolic parameters. The pathophysiological implications were explored through bioinformatics tools. Four circRNAs were overexpressed compared to controls: hsa_circ_0003258, hsa_circ_0051238, and hsa_circ_0051239 in LMNA-related DCM and hsa_circ_0089762 in the ischemic DCM cohort. The obtained areas under the curve confirm the discriminative capacity of circRNAs. The circRNAs correlated with some diastolic and systolic echocardiographic parameters with notable diagnostic potential in DCM. Circulating circRNAs may be helpful for the etiology-based diagnosis of DCM as a non-invasive biomarker.Key messagesThe limitations of cardiac diagnostic imaging and the absence of a robust biomarker reveal the need for a diagnostic tool for dilated cardiomyopathy (DCM).The circular RNA (circRNA) expression pattern is paramount for categorizing the DCM etiologies.Our peripheral circRNAs fingerprint discriminates between various among etiology-based DCM and correlates with some echocardiographic parameters.We provide a potential non-invasive biomarker for the etiology-based diagnosis of LMNA-related DCM and ischemic DCM.

Genetic analysis using targeted next-generation sequencing of sporadic Chinese patients with idiopathic dilated cardiomyopathy

BackgroundInherited dilated cardiomyopathy (DCM) contributes to approximately 25% of idiopathic DCM cases, and the proportion is even higher in familial DCM patients. Most studies have focused on familial DCM, whereas the genetic profile of sporadic DCM in Chinese patients remains unknown.MethodsBetween June 2018 and September 2019, 24 patients diagnosed with idiopathic DCM without a family history were included in the present study. All patients underwent genetic screening for 80 DCM-related genes using targeted next-generation sequencing.ResultsBy in silico analysis, 10 of 99 detected variants were considered pathogenic or likely-pathogenic, including seven TTN truncating variants (TTNtv), one in-frame deletion in TNNT2, one missense mutation in RBM20, and one frameshift deletion variant in FLNC. Of these variants, eight are reported for the first time.ConclusionsUsing targeted next-generation sequencing, potential genetic causes of idiopathic DCM were identified. Sarcomere mutations remained the most common genetic cause of inherited DCM in this cohort of sporadic Chinese DCM.

A Novel Titin Truncation Variant Linked to Familial Dilated Cardiomyopathy Found in a Japanese Family and Its Functional Analysis in Genome-Edited Model Cells

Dilated cardiomyopathy (DCM) is a common cause of heart failure. TTN, which encodes titin protein, is a representative causative gene of DCM, and is presented mainly as a truncation variant. However, TTN truncation variants are also found in healthy individuals, and it is therefore important to evaluate the pathogenicity of each variant. In this study, we analyzed 67 cardiomyopathy-associated genes in a male Japanese patient who was hospitalized for recurrent severe heart failure and identified a novel truncation variant, TTN Ser17456Arg fs*14. This TTN truncation variant was located in the A-band region. Moreover, the patient's mother with heart failure harbored the same variant, whereas the father and brother without heart failure did not harbor the variant. To examine the functional changes associated with the truncation variant, H9c2 cells were subjected to genome editing to generate cells with a homologous truncation variant. The cells were differentiated using all-trans-retinoic acid, and the mRNA expression of skeletal actin and cardiac actin were found to be increased and decreased, respectively, consistent with known changes in patients with DCM or heart failure. In contrast, another cell with the titin truncation variant used as a control showed no changes in heart failure-related genes. In summary, we found a novel TTN truncation variant in familial DCM patients and confirmed its functional changes using a relatively simple cell model. The novel truncation variant was identified as a pathogenic and disease-causing mutation.

Contemporary characteristics and outcomes of adults with familial dilated cardiomyopathy listed for heart transplantation.

BACKGROUNDFamilial dilated cardiomyopathy (FDCM) account for 20%-30% of non-ischemic cardiomyopathies (NICM). Previous published data showed that some patients with FDCM tend to have rapidly progressive disease; however, five-year mortality was not significantly different in the familial and non-familial forms of NICM with optimal medical therapy.AIMTo better define the characteristics and clinical outcomes of FDCM patients listed for heart transplantation (HT).METHODSWe queried the United Network for Organ Sharing Registry to identify FDCM patients listed for HT between January 2008 and September 2015 and compared them to NICM and ischemic cardiomyopathy (ICM) patients. We included all patients ≥ 18 years old and we separated patients to three groups: FDCM, NICM and ICM. Chi-square test was used to compare between categorical variables, the t-test was used to compare between continues variables, and Cox-proportional hazards model was used to perform time-dependent survival analyses.RESULTSOf the 24809 adults listed for HT, we identified 677 patients (2.7%) with the diagnosis of FDCM. Compared to patients with NICM and ICM, FDCM patients were younger (FDCM 43.9 ± 13.5 vs NICM 50.9 ± 12.3, P < 0.001, vs ICM 58.5 ± 8.1, P < 0.001), more frequently listed as status 2 (FDCM 35.2% vs NICM 26.5%, P < 0.001), with significantly lower left ventricular assist device (LVAD) utilization (FDCM 18.4% vs NICM 25.1%, P < 0.001; vs ICM 25.6%, P < 0.001), but higher use of total artificial heart (FDCM 1.3% vs NICM 0.6%, P = 0.039; vs ICM 0.4%, P = 0.002). Additionally, patients with FDCM were less frequently delisted for clinical deterioration or death and more likely to be transplanted compared to those with NICM [hazard ratio (HR): 0.617, 95% confidence interval (CI): 0.47-0.81; HR: 1.25, 95%CI: 1.14-1.37, respectively], and ICM (HR: 0.5, 95%CI: 0.38-0.66; HR: 1.18, 95%CI: 1.08-1.3, respectively). There was more frequent rejection among patients with FDCM (FDCM 11.4% vs NICM 9.8%, P = 0.28; vs ICM 8.4%, P = 0.034). One, three, and five post-transplant survival of patients with FDCM (91%, 88% and 80%) was similar to those with NICM (91%, 84%, 79%, P = 0.225), but superior to those with ICM (89%, 82%, 75%, P = 0.008), respectively.CONCLUSIONEnd-stage FDCM patients are more likely to be transplanted, more likely to have early rejection, and have similar or higher survival than patients with other cardiomyopathies.

Identification of a Novel LMNA Mutation in a Family with Dilated Cardiomyopathy and Sinus Bradycardia

Background: Dilated cardiomyopathy (DCM), the most common form of cardiomyopathy, is characterized by left ventricular dilatation and systolic dysfunction. The aetiology of DCM remains unclear; however, accumulating evidence indicates that gene mutations account for some of the cases of DCM. Methods: Four affected female subjects from a three-generation Chinese family with DCM and sinus bradycardia are included in the present study; there were no affected male family members identified after cardiovascular examinations. The proband and her family members for genetic analysis and exome sequencing was used to analyze the exomes of two patients, II:5 and III:11. Results: The proband patient (II:5) was diagnosed with DCM and sinus bradycardia, the affected family member presented with sinus bradycardia and all were female, no male family members were affected. A heterozygous variant, c.T686C, p.I229T, in the LMNA gene was identified as the causative mutation in this family. Subsequently, this variant was verified in all family members by Sanger sequencing. No co-segregation of mutations was detected by mitochondrial sequencing of three affected female family members. Conclusions: To the best of our knowledge, the present study is the first report of sinus bradycardia in familial DCM patients with an LMNA mutation, as LMNA mutations are usually clinically associated with cardiac conduction disease. Therefore, our findings extend the mutation spectrum of the LMNA gene and have important implications for genetic counselling for the family.

Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation

Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx has been poorly characterized. We sought to determine the genetic basis of familial DCM HTx and to establish the yield of modern next generation sequencing (NGS) technologies in this setting. Fifty-two heart-transplanted patients due to familial DCM underwent NGS genetic evaluation with a panel of 126 genes related to cardiac conditions (59 associated with DCM). Genetic variants were initially classified as pathogenic mutations or as variants of uncertain significance (VUS). Final pathogenicity status was determined by familial cosegregation studies. Initially, 24 pathogenic mutations were found in 21 patients (40%); 25 patients (48%) carried 19 VUS and 6 (12%) did not show any genetic variant. Familial evaluation of 220 relatives from 36 of the 46 families with genetic variants confirmed pathogenicity in 14 patients and allowed reclassification of VUS as pathogenic in 17 patients, and as non-pathogenic in 3 cases. At the end of the study, the DCM-causing mutation was identified in 38 patients (73%) and 5 patients (10%) harbored only VUS. No genetic variants were identified in 9 cases (17%). The genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and involves multiple genes. NGS technology plus detailed familial studies allow identification of causative mutations in the vast majority of familial DCM cases. Detailed familial studies remain critical to determine the pathogenicity of underlying genetic defects in a substantial number of cases.

Targeted Next-Generation Sequencing Reveals Hot Spots and Doubly Heterozygous Mutations in Chinese Patients with Familial Cardiomyopathy.

As a common cardiac disease mainly caused by gene mutations in sarcomeric cytoskeletal, calcium-handling, nuclear envelope, desmosomal, and transcription factor genes, inherited cardiomyopathy is becoming one of the major etiological factors of sudden cardiac death (SCD) and heart failure (HF). This disease is characterized by remarkable genetic heterogeneity, which makes it difficult to screen for pathogenic mutations using Sanger sequencing. In the present study, three probands, one with familial hypertrophic cardiomyopathy (FHCM) and two with familial dilated cardiomyopathy (FDCM), were recruited together with their respective family members. Using next-generation sequencing technology (NGS), 24 genes frequently known to be related to inherited cardiomyopathy were screened. Two hot spots (TNNI3-p.Arg145Gly, and LMNA-p.Arg190Trp) and double (LMNA-p.Arg190Trp plus MYH7-p.Arg1045His) heterozygous mutations were found to be highly correlated with familial cardiomyopathy. FDCM patients with doubly heterozygous mutations show a notably severe phenotype as we could confirm in our study; this indicates that the double mutations had a dose effect. In addition, it is proposed that genetic testing using NGS technology can be used as a cost-effective screening tool and help guide the treatment of patients with familial cardiomyopathy particularly regarding the risk of family members who are clinically asymptomatic.

A New Functional Measure of Contractility in Human Cardiomyopathies

Hypertrophic and familial dilated cardiomyopathies are arguably the most common forms of inherited myocardial dysfunction. Both disease states result in deterioration of cardiac function and quality of life as a consequence of extensive remodelling of the chamber walls.Here we use a novel technique SPontaneous Oscillatory Contractions - or SPOCs to assess changes in contraction and relaxation phases using a range of explanted human heart samples. We examine left ventricle (LV) samples from: (1) patients with hypertrophic cardiomyopathy (HCM); (2) patients with familial dilated cardiomyopathy (FDCM); and (3) and aged-matched non-failing donors. The SPOC parameters of interest are: (i) SPOC amplitudes; (ii) the rates of lengthening (relaxation); (iii) the rates of shortening (contraction); and (iv) their respective SPOC periods.On average, samples from HCM patients exhibited significantly slower rates of lengthening and shorter SPOC periods, while FDCM patients displayed significantly longer lengthening and shortening SPOC periods, compared to donors. Impaired shortening is indicative of diastolic dysfunction while impaired shortening indicates a systolic dysfunction. We observed extensive changes in SPOC parameters that were mutation-specific. The MYBPC3 mutation exhibited shorter SPOC period and faster shortening rates while the samples with the TNNI3 mutation had a higher amplitude and slower shortening rates. Their SPOC data are consistent with the relatively mild phenotype associated with their respective mutations. Furthermore, SPOC is also sensitive to the progressive deterioration in LV ejection fraction.SPOC analysis is a promising tool that provides a quantitative insights into cardiac contractility. It may allow us to unravel other significant differences between familial cardiomyopathies and donor hearts. The SPOC data agree well with patient clinical phenotypes.

Dilated Cardiomyopathy-Associated &lt;i&gt;FHOD3&lt;/i&gt; 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.

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.

Health status of cardiac genetic disease patients and their at-risk relatives

BackgroundHealth status is an important outcome measure that incorporates multiple dimensions of health, including symptoms, functional status, and psychosocial factors. While health status has been shown to be a predictor for hospital readmission, morbidity and mortality in the heart failure setting, there are limited data in cardiac genetic disease. We examined health status in a number of cardiac genetic disease groups compared to the general Australian population. MethodsA total of 409 individuals were assessed. Individuals with inherited cardiomyopathies [hypertrophic cardiomyopathy (HCM), familial dilated cardiomyopathy (FDC), arrhythmogenic right ventricular cardiomyopathy (ARVC)] and primary arrhythmogenic disorders [long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT)], as well as their first-degree relatives, completed the Medical Outcomes Survey Short Form-36 (SF-36). The physical and mental component scores (PCS and MCS) and SF-6D utility score were assessed. ResultsPatients with HCM (p<0.001), FDC (p<0.05), and CPVT (p<0.05) were found to have a significantly lower PCS, while patients with LQTS (p<0.01) had a lower MCS. Individuals at risk of HCM (p<0.0001) and genotype positive–phenotype negative HCM patients (p<0.01) both had a higher PCS and utility scores compared to the clinically affected HCM population. Individuals at risk of LQTS had significantly higher PCS than those with a clinical diagnosis of LQTS (p<0.05) and similarly individuals at risk of FDC had significantly higher PCS than FDC patients (p<0.05). In HCM, female gender (p=0.002), presence of co-morbidities (p<0.0001) and higher NYHA functional class (p<0.0001) were predictors of a lower PCS. ConclusionsPatients with a clinical diagnosis of a genetic heart disease have an impaired health status, related to both physical and mental function. Clinical management strategies in such patient groups need to consider health status as an important outcome measure.

Health Status of Cardiac Genetic Disease Patients and Their At-risk Relatives

Background: Health status is an important outcome measure incorporating multiple dimensions of health. While health status has been shown to be a predictor for hospital readmission, morbidity and mortality in the heart failure setting, there are limited data in cardiac genetic disease. This study sought to examine the health status in a number of cardiac genetic disease groups compared to the general population. Methods: Individuals with inherited cardiomyopathies [hypertrophic cardiomyopathy (HCM), familial dilated cardiomyopathy (FDC), arrhythmogenic right ventricular cardiomyopathy] and primary arrhythmogenic disorders [long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia], as well as their first-degree relatives, completed the Medical Outcomes Survey Short Form-36 (MOS SF-36v2). The physical and mental component scores (PCS and MCS) and SF-6D utility score were assessed. Results: A total of 409 individuals were assessed. Patients with HCM (p < 0.001), FDC (p < 0.05), and CPVT (p < 0.05) were found to have a significantly lower PCS, while patients with LQTS (p < 0.01) had a lower MCS. Individuals at risk of HCM (p < 0.0001) and genotype positive-phenotype negative HCM patients (p < 0.01) both had a higher PCS and utility scores compared to the HCM group. Individuals at risk of LQTS had significantly higher PCS than those with clinical LQTS (p < 0.05) and similarly individuals at risk of FDC had significantly higher PCS than FDC patients (p < 0.05). In HCM, female gender (p = 0.002), presence of co-morbidities (p < 0.0001) and higher NYHA functional class (p < 0.0001) were predictors of a lower PCS. Conclusions: Patients with a clinical diagnosis of a genetic heart disease have an impaired health status, related to both physical and mental function. Clinical management strategies need to consider health status as an important outcome measure.

Cardiac magnetic resonance imaging of myocardial contrast uptake and blood flow in patients affected with idiopathic or familial dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) is characterized by left ventricular (LV) enlargement with systolic dysfunction, other causes excluded. When inherited, it represents familial dilated cardiomyopathy (FDC). We hypothesized that IDC or FDC would show with cardiac magnetic resonance (CMR) increased myocardial accumulation of gadolinium contrast at steady state and decreased baseline myocardial blood flow (MBF) due to structural alterations of the extracellular matrix compared with normal myocardium. CMR was performed in nine persons affected with IDC/FDC. Healthy controls came from the general population (n = 6) or were unaffected family members of FDC patients (n = 3) without signs or symptoms of IDC/FDC or any structural cardiac abnormalities. The myocardial partition coefficient for gadolinium contrast (lambda(Gd)) was determined by T1 measurements. LV shape and function and MBF were assessed by standard CMR methods. lambda(Gd) was elevated in IDC/FDC patients vs. healthy controls (lambda(Gd) = 0.56 +/- 0.15 vs. 0.41 +/- 0.06; P = 0.002), and correlated with LV enlargement (r = 0.61 for lambda(Gd) vs. end-diastolic volume indexed by height; P < 0.01) and with ejection fraction (r = -0.80; P < 0.001). The extracellular volume fraction was higher in IDC patients than in healthy controls (0.31 +/- 0.05 vs. 0.24 +/- 0.03; P = 0.002). Resting MBF was lower in IDC patients (0.64 +/- 0.13 vs. 0.91 +/- 0.22; P = 0.01) than unaffected controls and correlated with both the partition coefficient (r = -0.57; P = 0.012) and the extracellular volume fraction (r = -0.56; P = 0.019). The expansion of the extracellular space correlated with reduced MBF and ventricular dilation. Expansion of the extracellular matrix may be a key contributor to contractile dysfunction in IDC patients.

Knock-In Mouse Model of Dilated Cardiomyopathy Caused by Troponin Mutation

We created knock-in mice in which a deletion of 3 base pairs coding for K210 in cardiac troponin (cTn)T found in familial dilated cardiomyopathy patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca(2+) sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca(2+) transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from that of wild-type mice, suggesting that Ca(2+) transient was augmented to compensate for decreased myofilament Ca(2+) sensitivity. Nevertheless, mutant mice developed marked cardiac enlargement, heart failure, and frequent sudden death recapitulating the phenotypes of dilated cardiomyopathy patients, indicating that global functional defect of the heart attributable to decreased myofilament Ca(2+) sensitivity could not be fully compensated by only increasing the intracellular Ca(2+) transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca(2+) sensitivity, had profound effects of preventing cardiac enlargement, heart failure, and sudden death. These results verify the hypothesis that Ca(2+) desensitization of cardiac myofilament is the absolute cause of the pathogenesis of dilated cardiomyopathy associated with this mutation and strongly suggest that Ca(2+) sensitizers are beneficial for the treatment of dilated cardiomyopathy patients affected by sarcomeric regulatory protein mutations.

Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a cardiac disease characterized by dilated ventricle and systolic dysfunction. Most of the DCM patients are sporadic cases, but a certain population of DCM patients can be familial cases caused by mutations in genes for sarcomere/Z-disc components including titin/connectin. However, disease-causing mutations could be identified only in a part of the familial DCM patients, suggesting that there should be other disease causing genes for DCM. To explore a novel disease gene for DCM, we searched for mutations in FHL2, encoding for four and half LIM protein 2 (FHL2) in DCM patients, because FHL2 is known to associate with titin/connectin. A missense mutation, Gly48Ser, was identified in a patient with familial DCM. Functional analysis demonstrated that the FHL2 mutation affected the binding to titin/connectin. Because FHL2 protein is known to tether metabolic enzymes to titin/connectin, these observations suggest that the Gly48Ser mutation may be involved in the pathogenesis of DCM via impaired recruitment of metabolic enzymes to the sarcomere.

A novel mutation, Ser143Pro, in the lamin A/C gene is common in finnish patients with familial dilated cardiomyopathy.

The mutations most frequently associated with dilated cardiomyopathy (DCM) have been reported in the lamin A/C gene. The role of variants of the lamin A/C gene was investigated in patients with DCM from eastern and southern Finland. All 12 exons of the lamin A/C gene were screened in 18 well-characterised familial DCM patients from eastern and southern Finland and in 72 sporadic DCM patients from eastern Finland using the PCR-SSCP method. A novel mutation, Ser143Pro (S143P), was detected in the lamin A/C gene in 24 subjects from 5 unrelated families and in one sporadic case of DCM. Sinus or atrioventricular nodal dysfunction occurred in the majority of the affected subjects, many of which required pacemaker implantation. Seven patients (28%) with the S143P mutation died suddenly or from progressive heart failure, or underwent heart transplantation. The haplotypes 5-5-5-3, 5-5-5-2, and 5-5-5-1 co-segregated with the Ser143Pro mutation, suggesting a founder effect of this mutation. A novel mutation S143P in the lamin A/C gene was found to be common among Finnish DCM patients. Haplotype analysis strongly suggests a founder effect of this mutation. The phenotype is characterised by severe heart failure, progressive atrioventricular conduction defects, and sudden death. Screening for the lamin A/C gene and, particularly, the S143P mutation seems warranted when patients with DCM have conduction system disturbances.

Familial dilated cardiomyopathy: Evidence for genetic and phenotypic heterogeneity

Abstract OBJECTIVES This study was performed to evaluate the characteristics, mode of inheritance and etiology of familial dilated cardiomyopathy (FDC). BACKGROUND A genetic form of disease transmission has been identified in a relevant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased frequency of cardiac antibodies have been reported. An analysis of FDC may improve the understanding of the disease and the management of patients. METHODS Of 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, electrocardiography, echocardiography and blood sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and 21 were due to sporadic DCM. Clinical features, histology, mode of inheritance and autoimmune serology were examined, molecular genetic studies were undertaken and the difference between familial and sporadic forms was analyzed. RESULTS Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic DCM. However, a number of distinct subtypes of FDC were identified: 1) autosomal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; the forms with isolated cardiomyopathy had an increased frequency of organ-specific cardiac autoantibodies. Histologic signs of myocarditis were frequent and nonspecific. CONCLUSIONS Familial dilated cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic basis and requires family screening for identification. The phenotypic heterogeneity, different patterns of transmission, different frequencies of cardiac autoantibodies and the initial molecular genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC.

Familial dilated cardiomyopathy: Evidence for genetic and phenotypic heterogeneity

OBJECTIVESThis study was performed to evaluate the characteristics, mode of inheritance and etiology of familial dilated cardiomyopathy (FDC).BACKGROUNDA genetic form of disease transmission has been identified in a relevant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased frequency of cardiac antibodies have been reported. An analysis of FDC may improve the understanding of the disease and the management of patients.METHODSOf 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, electrocardiography, echocardiography and blood sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and 21 were due to sporadic DCM. Clinical features, histology, mode of inheritance and autoimmune serology were examined, molecular genetic studies were undertaken and the difference between familial and sporadic forms was analyzed.RESULTSOnly a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic DCM. However, a number of distinct subtypes of FDC were identified: 1) autosomal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; the forms with isolated cardiomyopathy had an increased frequency of organ-specific cardiac autoantibodies. Histologic signs of myocarditis were frequent and nonspecific.CONCLUSIONSFamilial dilated cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic basis and requires family screening for identification. The phenotypic heterogeneity, different patterns of transmission, different frequencies of cardiac autoantibodies and the initial molecular genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC.