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JACC. Heart Failure Nov 2022According to patterns of inheritance and incomplete penetrance, fewer than half of relatives to dilated cardiomyopathy probands will develop disease.
BACKGROUND
According to patterns of inheritance and incomplete penetrance, fewer than half of relatives to dilated cardiomyopathy probands will develop disease.
OBJECTIVES
The purpose of this study was to investigate the prevalence and incidence, and to identify predictors of developing familial dilated cardiomyopathy (FDC) in relatives participating in family screening.
METHODS
The study was a retrospective, longitudinal cohort study of families screened and followed from 2006 to 2020 at a regional assembly of clinics for inherited cardiomyopathies.
RESULTS
In total, 211 families (563 relatives, 50% women) were included. At baseline, 124 relatives (22%) were diagnosed with FDC. Genetic sequencing identified the etiology in 37% of screened families and classified 101 (18%) relatives as unaffected carriers (n = 43) or noncarriers (ie, not at risk of FDC [n = 58]). The combined clinical and genetic baseline yield was 30%. During follow-up (2,313 person-years, median 5.0 years), 45 developed FDC (incidence rate of 2.0% per person-year; 95% CI: 1.4%-2.8%), increasing the overall yield to 34%. The incidence rate of FDC was high in relatives with baseline abnormalities on electrocardiogram or echocardiography compared with relatives with normal findings (4.7% vs 0.4% per person-year; HR: 12.9; P < 0.001). In total, baseline screening identified 326 (58%) relatives to be at low risk of FDC.
CONCLUSIONS
Family screening identified a genetic predisposition to or overt FDC in 1 of 3 relatives at baseline. Genetic and clinical screening was normal in more than half of relatives, and these relatives had a low risk of developing FDC during follow-up. Thus, baseline screening identified a large proportion, in whom follow-up may safely be reduced, allowing focused follow-up of relatives at risk.
Topics: Humans; Female; Male; Cardiomyopathy, Dilated; Incidence; Prevalence; Follow-Up Studies; Retrospective Studies; Longitudinal Studies; Heart Failure
PubMed: 36328645
DOI: 10.1016/j.jchf.2022.07.009 -
Journal of Cardiovascular Magnetic... Dec 2023Despite the use of cardiovascular magnetic resonance (CMR) feature tracking (FT) imaging to detect myocardial deformation, the optimal strain index in dilated...
BACKGROUND
Despite the use of cardiovascular magnetic resonance (CMR) feature tracking (FT) imaging to detect myocardial deformation, the optimal strain index in dilated cardiomyopathy (DCM) is unclear. This study aimed to determine whether atrial and biventricular strains can provide the greatest or joint incremental prognostic value in patients with DCM over a long follow-up period.
METHODS
Four hundred-twelve DCM patients were included retrospectively. Comprehensive clinical evaluation and imaging investigations were obtained, including measurements of CMR-FT derived left atrial (LA) reservoir, conduit, booster strain (εs, εe, εa); left ventricular (LV) and right ventricular (RV) global longitudinal, radial, circumferential strain (GLS, GRS, GCS). All patients were followed up for major adverse cardiac events (MACE) including all-cause mortality, heart transplantation, and implantable cardioverter defibrillator discharge. The predictors of MACE were examined with univariable and multivariable Cox regression analysis. Subsequently, nested Cox regression models were built to evaluate the incremental prognostic value of strain parameters. The incremental predictive power of strain parameters was assessed by Omnibus tests, and the model performance and discrimination were evaluated by Harrell C-index and integrated discrimination improvement (IDI) analysis. Patient survival was illustrated by Kaplan-Meier curves and differences were evaluated by log-rank test.
RESULTS
During a median follow-up of 5.0 years, MACE were identified in 149 (36%) patients. LAεe, LVGLS, and RVGLS were the most predictive strain parameters for MACE (AUC: 0.854, 0.733, 0.733, respectively). Cox regression models showed that the predictive value of LAεe was independent from and incremental to LVGLS, RVGLS, and baseline variables (HR 0.74, 95% CI 0.68-0.81, P < 0.001). In reclassification analysis, the addition of LAεe provided the best discrimination of the model (χ 223.34, P < 0.001; C-index 0.833; IDI 0.090, P < 0.001) compared with LVGLS and RVGLS models. Moreover, LAεe with a cutoff of 5.3% further discriminated the survival probability in subgroups of patients with positive LGE or reduced LVEF (all log-rank P < 0.001).
CONCLUSION
LAεe provided the best prognostic value over biventricular strains and added incremental value to conventional clinical predictors for patients with DCM.
Topics: Humans; Prognosis; Cardiomyopathy, Dilated; Retrospective Studies; Magnetic Resonance Imaging, Cine; Predictive Value of Tests; Ventricular Function, Left; Stroke Volume
PubMed: 38057892
DOI: 10.1186/s12968-023-00967-4 -
Circulation Research Jan 2023Nuclear envelope proteins play an important role in the pathogenesis of hereditary cardiomyopathies. Recently, a new form of arrhythmic cardiomyopathy caused by a...
BACKGROUND
Nuclear envelope proteins play an important role in the pathogenesis of hereditary cardiomyopathies. Recently, a new form of arrhythmic cardiomyopathy caused by a homozygous mutation (p.L13R) in the inner nuclear membrane protein LEMD2 was discovered. The aim was to unravel the molecular mechanisms of mutant LEMD2 in the pathogenesis of cardiomyopathy.
METHODS
We generated a Lemd2 p.L13R knock-in mouse model and a corresponding cell model via CRISPR/Cas9 technology and investigated the cardiac phenotype as well as cellular and subcellular mechanisms of nuclear membrane rupture and repair.
RESULTS
Knock-in mice developed a cardiomyopathy with predominantly endocardial fibrosis, left ventricular dilatation, and systolic dysfunction. Electrocardiograms displayed pronounced ventricular arrhythmias and conduction disease. A key finding of knock-in cardiomyocytes on ultrastructural level was a significant increase in nuclear membrane invaginations and decreased nuclear circularity. Furthermore, increased DNA damage and premature senescence were detected as the underlying cause of fibrotic and inflammatory remodeling. As the p.L13R mutation is located in the Lap2/Emerin/Man1 (LEM)-domain, we observed a disrupted interaction between mutant LEMD2 and BAF (barrier-to-autointegration factor), which is required to initiate the nuclear envelope rupture repair process. To mimic increased mechanical stress with subsequent nuclear envelope ruptures, we investigated mutant HeLa-cells upon electrical stimulation and increased stiffness. Here, we demonstrated impaired nuclear envelope rupture repair capacity, subsequent cytoplasmic leakage of the DNA repair factor KU80 along with increased DNA damage, and recruitment of the cGAS (cyclic GMP-AMP synthase) to the nuclear membrane and micronuclei.
CONCLUSIONS
We show for the first time that the Lemd2 p.L13R mutation in mice recapitulates human dilated cardiomyopathy with fibrosis and severe ventricular arrhythmias. Impaired nuclear envelope rupture repair capacity resulted in increased DNA damage and activation of the cGAS/STING/IFN pathway, promoting premature senescence. Hence, LEMD2 is a new player inthe disease group of laminopathies.
Topics: Animals; Humans; Mice; Cardiomyopathy, Dilated; Fibrosis; Membrane Proteins; Mutation; Nuclear Envelope; Nuclear Proteins
PubMed: 36656972
DOI: 10.1161/CIRCRESAHA.122.321929 -
Circulation. Genomic and Precision... Feb 2023Lamin A/C gene ()-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of...
BACKGROUND
Lamin A/C gene ()-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with -related dilated cardiomyopathy.
METHODS
Patients with -related dilated cardiomyopathy in New York Heart Association class II-IIIA, on background heart failure treatment, received ARRY-371797 100 or 400 mg twice daily for 48 weeks. The primary end point was change from baseline in the 6-minute walk test distance at 12 weeks. Secondary end points included changes over time in 6-minute walk test distance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration, left ventricular ejection fraction, and quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire. Data from the 2 dose groups were combined.
RESULTS
Twelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified.
CONCLUSIONS
ARRY-371797 was well tolerated and resulted in potential increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients with -related dilated cardiomyopathy.
REGISTRATION
URL: https://clinicaltrials.gov; Unique identifier: NCT02057341.
Topics: Humans; Stroke Volume; Cardiomyopathy, Dilated; Ventricular Function, Left; Indazoles; Lamin Type A
PubMed: 36515663
DOI: 10.1161/CIRCGEN.122.003730 -
Circulation. Genomic and Precision... Aug 2023Genetic variants in (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular...
BACKGROUND
Genetic variants in (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function.
METHODS
We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including . We further performed burden testing of in the UK Biobank. For 2 novel variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.
RESULTS
We demonstrate enrichment of rare coding variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation.
CONCLUSIONS
Our findings demonstrate an increased burden of rare coding variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.
Topics: Humans; Cardiomyopathy, Dilated; Retrospective Studies; Arrhythmias, Cardiac; Genetic Testing; Cardiac Conduction System Disease; Protein Serine-Threonine Kinases
PubMed: 37199186
DOI: 10.1161/CIRCGEN.122.003975 -
ESC Heart Failure Aug 2023We assessed the diagnostic yield of genetic testing and the relationship of left ventricular (LV) reverse remodelling (LVRR) with the presence of DNA pathogenic (P) or...
AIMS
We assessed the diagnostic yield of genetic testing and the relationship of left ventricular (LV) reverse remodelling (LVRR) with the presence of DNA pathogenic (P) or likely pathogenic (LP) variants in patients with dilated cardiomyopathy (DCM).
METHODS AND RESULTS
From 680 outpatients followed at the Heart Failure Outpatient Clinic of our institution, we selected subjects with a diagnosis of DCM as defined by LV ejection fraction (LVEF) ≤40% and LV dilatation not explained by coronary artery disease or other causes. All patients were offered genetic investigation of 42 disease-associated DCM genes with next-generation sequencing. Seventy patients fulfilled the definition of DCM and 66 underwent genetic investigation. We identified 18 P/LP variants in 16 patients, with a diagnostic yield of 24%. The most common variants were truncating TTN variants (n = 7), followed by LMNA (n = 3), cytoskeleton Z-disc (n = 3), ion channel (n = 2), motor sarcomeric (n = 2), and desmosomal (n = 1) genes. After a median follow-up of 53 months (inter-quartile range 20-111), patients without P/LP variants exhibited higher systolic and diastolic blood pressure, lower plasma brain natriuretic peptide levels, and a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, P = 0.0008) and decrease in indexed LV end-diastolic diameter (-6.5 vs. -2 mm/m , P = 0.03) compared with patients with P/LP variants.
CONCLUSIONS
Our results confirm the high diagnostic yield of genetic testing in selected DCM patients and suggest that identification of P/LP variants in DCM portends poorer LVRR in response to guideline-directed medical therapy.
Topics: Humans; Cardiomyopathy, Dilated; Ventricular Remodeling; Ventricular Function, Left; Stroke Volume; Genetic Testing
PubMed: 37282787
DOI: 10.1002/ehf2.14395 -
Acta Pharmacologica Sinica Nov 2022Calpains have been implicated in heart diseases. While calpain-1 has been detrimental to the heart, the role of calpain-2 in cardiac pathology remains controversial. In...
Calpains have been implicated in heart diseases. While calpain-1 has been detrimental to the heart, the role of calpain-2 in cardiac pathology remains controversial. In this study we investigated whether sustained over-expression of calpain-2 had any adverse effects on the heart and the underlying mechanisms. Double transgenic mice (Tg-Capn2/tTA) were generated, which express human CAPN2 restricted to cardiomyocytes. The mice were subjected to echocardiography at age 3, 6, 8 and 12 months, and their heart tissues and sera were collected for analyses. We showed that transgenic mice over-expressing calpain-2 restricted to cardiomyocytes had normal heart function with no evidence of cardiac pathological remodeling at age 3 months. However, they exhibited features of dilated cardiomyopathy including increased heart size, enlarged heart chambers and heart dysfunction from age 8 months; histological analysis revealed loss of cardiomyocytes replaced by myocardial fibrosis and cardiomyocyte hypertrophy in transgenic mice from age 8 months. These cardiac alterations closely correlated with aberrant autophagy evidenced by significantly increased LC3BII and p62 protein levels and accumulation of autophagosomes in the hearts of transgenic mice. Notably, injection of 3-methyladenine, a well-established inhibitor of autophagy (30 mg/kg, i.p. once every 3 days starting from age 6 months for 2 months) prevented aberrant autophagy, attenuated myocardial injury and improved heart function in the transgenic mice. In cultured cardiomyocytes, over-expression of calpain-2 blocked autophagic flux by impairing lysosomal function. Furthermore, over-expression of calpain-2 resulted in lower levels of junctophilin-2 protein in the heart of transgenic mice and in cultured cardiomyocytes, which was attenuated by 3-methyladenine. In addition, blockade of autophagic flux by bafilomycin A (100 nM) induced a reduction of junctophilin-2 protein in cardiomyocytes. In summary, transgenic over-expression of calpain-2 induces age-dependent dilated cardiomyopathy in mice, which may be mediated through aberrant autophagy and a reduction of junctophilin-2. Thus, a sustained increase in calpain-2 may be detrimental to the heart.
Topics: Mice; Animals; Humans; Infant; Cardiomyopathy, Dilated; Calpain; Myocytes, Cardiac; Autophagy; Mice, Transgenic
PubMed: 35986214
DOI: 10.1038/s41401-022-00965-9 -
ESC Heart Failure Feb 2024Cardiomyopathies (CMPs) are a heterogeneous group of diseases that are defined by structural and functional abnormalities of the cardiac muscle. Dilated cardiomyopathy... (Observational Study)
Observational Study
AIMS
Cardiomyopathies (CMPs) are a heterogeneous group of diseases that are defined by structural and functional abnormalities of the cardiac muscle. Dilated cardiomyopathy (DCM), the most common CMP, is defined by left ventricular dilation and impaired contractility and represents a common cause of heart failure. Different phenotypes result from various underlying genetic and acquired causes with variable effects on disease development and progression, prognosis, and response to medical treatment. Current treatment algorithms do not consider these different aetiologies, due to lack of insights into treatable drivers of cardiac failure in patients with DCM. Our study aims to precisely phenotype and genotype the various subtypes of DCM and hereby lay the foundation for individualized therapy.
METHODS AND RESULTS
The Geno- And Phenotyping of PrImary Cardiomyopathy (GrAPHIC) is a currently ongoing prospective observational monocentric cohort study that recruits patients with DCM after exclusion of other causes such as coronary artery disease, valvular dysfunction, myocarditis, exposure to toxins, and peripartum CMP. Patients are enrolled at our heart failure outpatient clinic or during hospitalization at the University Hospital Hamburg. Clinical parameters, multimodal imaging and functional assessment, cardiac biopsies, and blood samples are obtained to enable an integrated genomic, functional, and biomarker analysis.
CONCLUSIONS
The GrAPHIC will contribute to a better understanding of the heterogeneous nature of primary CMPs focusing on DCM and provide improved prognostic approaches and more individualized therapies.
Topics: Humans; Cardiomyopathy, Dilated; Cohort Studies; Cardiomyopathies; Heart Failure; Genotype
PubMed: 37964758
DOI: 10.1002/ehf2.14544 -
Internal Medicine (Tokyo, Japan) 2021Objective It has been reported that anti-mitochondrial antibodies (AMAs) recognize mitochondrial antigens and are associated with some diseases involving multiple...
Objective It has been reported that anti-mitochondrial antibodies (AMAs) recognize mitochondrial antigens and are associated with some diseases involving multiple organs, such as primary biliary cholangitis, Sjögren syndrome, Hashimoto's thyroiditis, systemic sclerosis, interstitial pneumoniae, dilated cardiomyopathy, and tubulointerstitial nephritis. In the current study, we examined the prevalence of AMAs in patients with dilated cardiomyopathy (DCM) and their clinical characteristics. Methods We enrolled 270 patients with DCM. We measured serum AMAs and analyzed the associated factors. Out of the 270 patients, positive AMAs were detected in 3 patients (1.1%; mean age, 68 years old; 2 men). These three patients had a significantly higher prevalence of primary biliary cholangitis and myopathy and levels of alanine alkaline phosphatase than those who were negative for said antibodies. There were no significant differences in the levels of B-type natriuretic peptide, aspartate transaminase, and left ventricular ejection fraction between these groups of patients. During the follow-up period, two of the three patients died due to respiratory failure. The other patient survived but experienced type II respiratory failure. Conclusion The prevalence of AMAs in 270 DCM patients was only 1.1%, and these patients suffered from respiratory failure.
Topics: Aged; Cardiomyopathy, Dilated; Humans; Liver Cirrhosis, Biliary; Male; Natriuretic Peptide, Brain; Stroke Volume; Ventricular Function, Left
PubMed: 33456024
DOI: 10.2169/internalmedicine.5422-20 -
International Heart Journal 2022We are pleased to announce that the following 3 articles have been selected for the UEDA Heart Awards for the Year 2022.FIRST PLACEChronic HDAC6 Activation Induces...
We are pleased to announce that the following 3 articles have been selected for the UEDA Heart Awards for the Year 2022.FIRST PLACEChronic HDAC6 Activation Induces Atrial Fibrillation Through Atrial Electrical and Structural Remodeling in Transgenic MiceYohei Sawa, Naoko Matsushita, Sachiko Sato, Nanae Ishida, Maki Saito, Atsushi Sanbe, Yoshihiro Morino, Eiichi Taira, Mami Obara, Masamichi HiroseInt Heart J 2021; 62 (3): 616-626.SECOND PLACEA Novel Titin Truncation Variant Linked to Familial Dilated Cardiomyopathy Found in a Japanese Family and Its Functional Analysis in Genome-Edited Model CellsKayoko Hirayama-Yamada, Natsuko Inagaki, Takeharu Hayashi, Akinori KimuraInt Heart J 2021; 62 (2): 359-366.THIRD PLACECytokine Signaling and Matrix Remodeling Pathways Associated with Cardiac Sarcoidosis Disease Activity Defined Using FDG PET ImagingBryan D. Young, Hannah Moreland, Kelsie E. Oatmen, Lisa A. Freeburg, Zartashia Shahab, Erica Herzog, Edward J. Miller, Francis G. SpinaleInt Heart J 2021; 62 (5): 1096-1105.
Topics: Humans; Cardiomyopathy, Dilated; Heart Atria; Awards and Prizes; Myocarditis; Atrial Fibrillation
PubMed: 36450561
DOI: 10.1536/ihj.63-6_UEDA