First human implant of the cardiac contractility modulation in patient with dilated cardiomyopathy–related laminopathy
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SUBMITTER: D’Onofrio A
PROVIDER: S-EPMC10285176 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
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Project description:BackgroundCardiac contractility modulation (CCM) is a novel device-based therapeutic option in patients with heart failure with reduced ejection fraction who are not eligible for cardiac resynchronization therapy. Cardiac contractility modulation enhances cardiac contractility by delivering high-voltage non-excitatory electrical impulses during the absolute refractory period. Cardiac contractility modulation is known to improve left ventricular ejection fraction (LVEF), quality of life, and exercise capacity in heart failure (HF) patients.Case summaryWe present a case of a 77-years-old woman with a cardiomyopathy associated with a pathogenic PLN variant [p.(Arg14del), Dutch founder mutation]. Due to progressive deterioration of LVEF (25%) despite maximally tolerated guideline-directed medical therapy (GDMT), a CCM device was implanted. After implantation, the patient experienced a sharp thoracic and interscapular pain after stimulation of one of the two leads. This lead was turned-off and the output on the other lead was increased to maximal output of 7,5 V. After 3 months, there were less signs and symptoms of HF. New York Heart Association class improved from class III to II and the patient was free of thoracic pain. Echocardiography demonstrated further improvement of LVEF to 44% and a decrease in end-diastolic pressures.DiscussionWe describe a case of CCM therapy in a patient with HF related to a genetic cardiomyopathy due to a pathogenic variant in phospholamban (PLN), persistent symptoms despite maximally tolerated GDMT. Although it was necessary to deactivate one of the both leads due to thoracic pain, LVEF and HF symptoms significantly improved. Further research is needed to elaborate on the potential role of CCM therapy in genetic cardiomyopathies.
| S-EPMC11852272 | biostudies-literature
Project description:Cardiac troponin (cTn) acts as a pivotal regulator of muscle contraction and relaxation and is composed of three distinct subunits (cTnC: a highly conserved Ca(2+) binding subunit, cTnI: an actomyosin ATPase inhibitory subunit, and cTnT: a tropomyosin binding subunit). In this mini-review, we briefly summarize the structure-function relationship of cTn and its subunits, its modulation by PKA-mediated phosphorylation of cTnI, and what is known about how these properties are altered by hypertrophic cardiomyopathy (HCM) associated mutations of cTnI. This includes recent work using computational modeling approaches to understand the atomic-based structural level basis of disease-associated mutations. We propose a viewpoint that it is alteration of cTnC-cTnI interaction (rather than the Ca(2+) binding properties of cTn) per se that disrupt the ability of PKA-mediated phosphorylation at cTnI Ser-23/24 to alter contraction and relaxation in at least some HCM-associated mutations. The combination of state of the art biophysical approaches can provide new insight on the structure-function mechanisms of contractile dysfunction resulting cTnI mutations and exciting new avenues for the diagnosis, prevention, and even treatment of heart diseases.
| S-EPMC4899195 | biostudies-literature
Project description:To investigate the physiological characteristics of cardiac fibroblasts (CF) from pediatric dilated cardiomyopathy (DCM) patients, CFs were harvested from left ventricular free wall at the heart transplantation. We then performed RNA-seq for 7 different lines of CFs.
2023-09-12 | GSE223517 | GEO
Project description:BackgroundCardiac-resident or -enriched microRNAs (miRNAs) could be released into the bloodstream becoming circulating cardiac miRNAs, which are increasingly recognized as non-invasive and accessible biomarkers of multiple heart diseases. However, dilated cardiomyopathy (DCM)-associated circulating miRNAs (DACMs) and their roles in DCM pathogenesis remain largely unexplored.MethodsTwo human cohorts, consisting of healthy individuals and DCM patients, were enrolled for serum miRNA sequencing (10 vs. 10) and quantitative polymerase chain reaction validation (46 vs. 54), respectively. Rigorous screening strategy was enacted to define DACMs and their potentials for diagnosis. DCM mouse model, different sources of cardiomyocytes, adeno-associated virus 9 (AAV9), gene knockout, RNAscope miRNA in situ hybridization, mRFP-GFP-LC3B reporter, echocardiography and transmission electron microscopy were adopted for mechanistic explorations.ResultsSerum miRNA sequencing revealed a unique expression pattern for DCM circulating miRNAs. DACMs miR-26a-5p, miR-30c-5p, miR-126-5p and miR-126-3p were found to be depleted in DCM circulation as well as heart tissues. Their expressions in circulation and heart tissues were proven to be correlated significantly, and a combination of these miRNAs was suggested potential values for DCM diagnosis. FOXO3, a predicted common target, was experimentally demonstrated to be co-repressed within cardiomyocytes by these DACMs except miR-26a-5p. Delivery of a combination of miR-30c-5p, miR-126-5p and miR-126-3p into the murine myocardium via AAV9 carrying an expression cassette driven by cTnT promoter, or cardiac-specific knockout of FOXO3 (Myh6-CreERT2 , FOXO3 flox+/+ ) dramatically attenuated cardiac apoptosis and autophagy involved in DCM progression. Moreover, competitively disrupting the interplay between DACMs and FOXO3 mRNA by specifically introducing their interacting regions into murine myocardium crippled the cardioprotection of DACMs against DCM.ConclusionsCirculating cardiac miRNA-FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and excessive autophagy in DCM development, which may provide serological cues for DCM non-invasive diagnosis and shed light on DCM pathogenesis and therapeutic targets.
| S-EPMC10157268 | biostudies-literature
Project description:Dilated cardiomyopathy (DCM) is characterized by decreased systolic function and dilation of one or both ventricles, often leading to heart failure or sudden death. Two 10-month-old sibling Nova Scotia Duck Tolling Retrievers (NSDTR) died acutely with evidence of dilated cardiomyopathy with myocardial fibrosis. Association analysis using two cases and 35 controls identified three candidate regions homozygous in the two cases. Whole genome sequencing identified a frameshift deletion in the LMNA gene (NC_049228.1:g.41688530del, NP_001274080:p.(Asp576ThrfsTer124)). Three retrospectively identified NSDTRs with sudden death before 2 years of age and severe myocardial fibrosis were also homozygous for the deletion. One 5 year old with sudden death and myocardial fibrosis was heterozygous for the deletion. This variant was not identified in 722 dogs of other breeds, nor was it identified to be homozygous in 784 NSDTR. LMNA codes for lamin A/C proteins, which are type V intermediate filaments that provide structural support to the nuclear membrane. In humans, LMNA variants can cause DCM with sudden death as well as diseases of striated muscles, lipodystrophy, neuropathies, and accelerated aging disorders. This frameshift deletion is predicted to affect processing of prelamin A into lamin A. Pedigree analysis in the NSDTR and functional evaluation of heterozygotes is consistent with a predominantly recessive mode of inheritance and possibly low penetrance in heterozygotes in contrast to people, where most pathogenic LMNA variants are dominantly inherited.
| S-EPMC10625583 | biostudies-literature
Project description:Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 (Val66Met), which might be correlated with increased risk of cardiovascular events. We previously showed that BDNF correlates with better cardiac function in Duchenne muscular dystrophy (DMD) patients. However, the effect of the Val66Met polymorphism on cardiac function has not been determined. The goal of the current study was to determine the effects of rs6265 on BDNF biomarker suitability and DMD cardiac functions more generally. We assessed cardiovascular and skeletal muscle function in human DMD patients segregated by polymorphic allele. We also compared echocardiographic, electrophysiologic, and cardiomyocyte contractility in C57/BL-6 wild-type mice with rs6265 polymorphism and in mdx/mTR (mDMD) mouse model of DMD. In human DMD patients, plasma BDNF levels had a positive correlation with left ventricular function, opposite to that seen in rs6265 carriers. There was also a substantial decrease in skeletal muscle function in carriers compared to the Val homozygotes. Surprisingly, the opposite was true when cardiac function of DMD carriers and non-carriers were compared. On the other hand, Val66Met wild-type mice had only subtle functional differences at baseline but significantly decreased cardiomyocyte contractility. Our results indicate that the Val66Met polymorphism alters myocyte contractility, conferring worse skeletal muscle function but better cardiac function in DMD patients. Moreover, these results suggest a mechanism for the relative preservation of cardiac tissues compared to skeletal muscle in DMD patients and underscores the complexity of BDNF signaling in response to mechanical workload.
| S-EPMC7593910 | biostudies-literature
Project description:Background Pediatric dilated cardiomyopathy (DCM) is a well-known clinical entity; however, phenotype-genotype correlations are inadequately described. Our objective was to provide genotype associations with life-threatening cardiac outcomes in pediatric DCM probands. Methods and Results We performed a retrospective review of children with DCM at a large pediatric referral center (2007-2016), excluding syndromic, chemotherapy-induced, and congenital heart disease causes. Genetic variants were adjudicated by an expert panel and an independent clinical laboratory. In a cohort of 109 pediatric DCM cases with a mean age at diagnosis of 4.2 years (SD 5.9), life-threatening cardiac outcomes occurred in 47% (42% heart transplant, 5% death). One or more pathogenic/likely pathogenic variants were present in 40/109 (37%), and 36/44 (82%) of pathogenic/likely pathogenic variants occurred in sarcomeric genes. The frequency of pathogenic/likely pathogenic variants was not different in patients with familial cardiomyopathy (15/33 with family history versus 25/76 with no family history, P=0.21). TTN truncating variants occurred in a higher percentage of children diagnosed as teenagers (26% teenagers versus 6% younger children, P=0.01), but life-threatening cardiac outcomes occurred in both infants and teenagers with these TTN variants. DCM with left ventricular noncompaction features occurred in 6/6 patients with MYH7 variants between amino acids 1 and 600. Conclusions Sarcomeric variants were common in pediatric DCM. We demonstrated genotype-specific associations with age of diagnosis and cardiac outcomes. In particular, MYH7 had domain-specific association with DCM with left ventricular noncompaction features. Family history did not predict pathogenic/likely pathogenic variants, reinforcing that genetic testing should be considered in all children with idiopathic DCM.
| S-EPMC9075202 | biostudies-literature
Project description:Dilated cardiomyopathy (DCM) has a genetic cause in up to 40% of cases, with differences in disease penetrance and clinical presentation, due to different exogeneous triggers and implicated genes. Cardiac inflammation can be the consequence of an exogeneous trigger, subsequently unveiling a phenotype. The study aimed to determine cardiac inflammation in a cohort of genetic DCM patients and investigate whether it associated with a younger disease onset. The study included 113 DCM patients with a genetic etiology, of which 17 had cardiac inflammation as diagnosed in an endomyocardial biopsy. They had a significant increased cardiac infiltration of white blood, cytotoxic T, and T-helper cells (p < 0.05). Disease expression was at a younger age in those patients with cardiac inflammation, compared to those without inflammation (p = 0.015; 50 years (interquartile range (IQR) 42-53) versus 53 years (IQR 46-61). However, cardiac inflammation was not associated with a higher incidence of all-cause mortality, heart failure hospitalization, or life-threatening arrhythmias (hazard ratio 0.85 [0.35-2.07], p = 0.74). Cardiac inflammation is associated with an earlier disease onset in patients with genetic DCM. This might indicate that myocarditis is an exogeneous trigger unveiling a phenotype at a younger age in patients with a genetic susceptibility, or that cardiac inflammation resembles a 'hot-phase' of early-onset disease.
| S-EPMC10299389 | biostudies-literature
Project description:BackgroundGenetic studies of cardiomyopathy and heart failure have limited throughput in mammalian models. Adult zebrafish have been recently pursued as a vertebrate model with higher throughput, but genetic conservation must be tested.Methods and resultsWe conducted transcriptome analysis of zebrafish heart and searched for fish homologues of 51 known human dilated cardiomyopathy-associated genes. We also identified genes with high cardiac expression and genes with differential expression between embryonic and adult stages. Among tested genes, 30 had a single zebrafish orthologue, 14 had 2 homologues, and 5 had ≥3 homologues. By analyzing the expression data on the basis of cardiac abundance and enrichment hypotheses, we identified a single zebrafish gene for 14 of 19 multiple-homologue genes and 2 zebrafish homologues of high priority for ACTC1. Of note, our data suggested vmhc and vmhcl as functional zebrafish orthologues for human genes MYH6 and MYH7, respectively, which are established molecular markers for cardiac remodeling.ConclusionsMost known genes for human dilated cardiomyopathy have a corresponding zebrafish orthologue, which supports the use of zebrafish as a conserved vertebrate model. Definition of the cardiac transcriptome and fetal gene program will facilitate systems biology studies of dilated cardiomyopathy in zebrafish.
| S-EPMC4406804 | biostudies-literature
Project description: Not available
| S-EPMC8160050 | biostudies-literature