Sleep fragmentation induces heart failure in a hypertrophic cardiomyopathy mouse model by altering redox metabolism.
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ABSTRACT:
SUBMITTER: Bose K
PROVIDER: S-EPMC10867644 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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Sleep fragmentation induces heart failure in a hypertrophic cardiomyopathy mouse model by altering redox metabolism.
Bose Karthikeyan K Agrawal Radhika R Sairam Thiagarajan T Mil Jessenya J Butler Matthew P MP Dhandapany Perundurai S PS
iScience 20240201 3
Sleep fragmentation (SF) disrupts normal biological rhythms and has major impacts on cardiovascular health; however, it has never been shown to be a risk factor involved in the transition from cardiac hypertrophy to heart failure (HF). We now demonstrate devastating effects of SF on hypertrophic cardiomyopathy (HCM). We generated a transgenic mouse model harboring a patient-specific myosin binding protein C3 (MYBPC3) variant displaying HCM, and measured the progression of pathophysiology in the ...[more]
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Project description:Aims: We aimed to assess diabetes outcomes in heart failure (HF) patients with hypertrophic cardiomyopathy (HCM). Methods: The National Inpatient Sample database was analyzed to identify records from 2005 to 2015 of patients hospitalized for HF with concomitant HCM. We examined the prevalence of diabetes in those patients, assessed the temporal trend of in-hospital mortality, ventricular fibrillation, atrial fibrillation, and cardiogenic shock and compared diabetes patients to their non-diabetes counterparts. Results: Among patients with HF, 0.26% had HCM, of whom 29.3% had diabetes. Diabetes prevalence increased from 24.8% in 2005 to 32.7% in 2015. The mean age of patients with diabetes decreased from 71 ± 13 to 67.6 ± 14.2 (p < 0.01), but the prevalence of cardiovascular risk factors significantly increased. In-hospital mortality decreased from 4.3% to 3.2% between 2005 and 2015. Interestingly, cardiogenic shock, VF, and AF followed an upward trend. Age (OR = 1.04 [1.03-1.05]), female gender (OR = 1.50 [0.72-0.88]), and cardiovascular risk factors were associated with a higher in-hospital mortality risk in diabetes. Compared to non-diabetes patients, the ones with diabetes were younger and had more comorbidities. Unexpectedly, the adjusted risks of in-hospital mortality (aOR = 0.88 [0.76-0.91]), ventricular fibrillation (aOR = 0.79 [0.71-0.88]) and atrial fibrillation (aOR 0.80 [0.76-0.85]) were lower in patients with diabetes, but not cardiogenic shock (aOR 1.01 [0.80-1.27]). However, the length of stay was higher in patients with diabetes, and so were the total charges per stay. Conclusion: In total, we observed a temporal increase in diabetes prevalence among patients with HF and HCM. However, diabetes was paradoxically associated with lower in-hospital mortality and arrhythmias.
| S-EPMC9691891 | biostudies-literature
Project description:Study objectivesSleep fragmentation (SF) has been reported to be associated with cardiovascular risk. The aim of this study was to explore the relationship between SF and congestive heart failure (CHF).MethodsA total of 4,887 participants (2,256 males and 2,631 females; mean age of 63.6 ± 11.0 years) from the Sleep Heart Health Study were included in this study. Incident CHF was defined as the first occurrence of CHF between baseline in-home polysomnography (PSG) and the end of follow-up. Objective assessments for SF, including sleep fragmentation index (SFI), arousal index (ArI), sleep efficiency (SE), and wake after sleep onset (WASO), were determined based on in-home PSG records. Multivariate Cox regression analysis was used to investigate the relationship between SF and incident CHF.ResultsDuring an average of 10 years of follow-up, 543 participants with CHF (11.1%) were observed. Individuals with CHF had a significantly higher SFI, total ArI, and WASO and a lower SE than controls. After multivariate Cox regression analysis, SE (odds ratio [OR], 0.967; 95% confidence interval [CI], 0.955-0.978; P < .001), WASO (OR, 1.009; 95% CI, 1.006-1.012; P < .001), SFI (OR, 1.046; 95% CI, 1.007-1.086; P = .021), and total ArI (OR, 1.018; 95% CI, 1.000-1.035; P = .044) were found to be associated with the incidence of CHF in participants without hypertension.ConclusionsObjectively measured SF was associated with the incidence of CHF. The role of SFI, total ArI, SE, and WASO deserves further investigation.Clinical trial registrationRegistry: ClinicalTrials.gov; Name: Sleep Heart Health Study (SHHS) Data Coordinating Center (SHHS); URL: https://clinicaltrials.gov/ct2/show/NCT00005275; Identifier: NCT00005275.CitationYan B, Wu Y, Fan X, Lu Q, Ma X, Bai L. Sleep fragmentation and incidence of congestive heart failure: the Sleep Heart Health Study. J Clin Sleep Med. 2021;17(8):1619-1625.
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| S-EPMC8155292 | biostudies-literature
Project description:ObjectiveHeart failure (HF) is one of the most common and lifestyle-limiting complications of hypertrophic cardiomyopathy (HCM). Prediction of worsening HF using clinical measures alone remains limited. Moreover, the mechanisms by which patients with HCM develop worsening HF have not been elucidated. Therefore, the aim of this study was to develop a plasma proteomics-based model to predict worsening HF among patients with HCM and to identify signalling pathways that are differentially regulated in those who subsequently develop worsening HF.MethodsIn this multi-centre, prospective cohort study of 389 patients with HCM, plasma proteomics profiling of 4986 proteins was performed at enrolment. A proteomics-based random forest model was developed to predict worsening HF using data from one institution (training set, n=268). This model was externally validated in patients from a different institution (test set, n=121). Pathway analysis of proteins significantly dysregulated in patients who subsequently developed worsening HF compared with those who did not was executed, using a false discovery rate (FDR) threshold of <0.001.ResultsUsing the 11-protein proteomics-based model derived from the training set, the area under the receiver-operating characteristic curve to predict worsening HF was 0.87 (95% CI: 0.76 to 0.98) in the test set. Pathway analysis revealed that the Ras-MAPK pathway (FDR<0.00001) and related pathways were dysregulated in patients who subsequently developed worsening HF.ConclusionsThe present study with comprehensive plasma proteomics profiling demonstrated a high accuracy to predict worsening HF in patients with HCM and identified the Ras-MAPK and related signalling pathways as potential underlying mechanisms.
| S-EPMC10843738 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) is a disease, which is difficult to diagnose at an early stage and for which there is a pressing need for more effective treatment options. The purpose of this study was to compare the molecular profile of HCM to that of ischaemic cardiomyopathy (ISCM) and dilated cardiomyopathy (DCM) for identification of protein and pathway targets that could support the development of better diagnostic and treatment options for HCM. A high-throughput mass spectrometry workflow was applied to achieve deep quantitative coverage of left ventricular tissue from HCM, DCM, ISCM and non-heart-failure control patients. HCM had a diverse proteomic profile compared to that of DCM and ISCM. Differentially expressed proteins unique to HCM were identified based on an observed fold change of ≥1.5 or ≤0.67 and q-value ≤ 0.05. Candidate proteins of interest were found to be significantly associated with clinical features of HCM. The significant association between these proteins and HCM was validated in an independent dataset. This represents one of the largest and deepest proteomic datasets for myocardial tissue reported to date. The dataset highlights the diverse proteomic profile of HCM, relative to other cardiomyopathies, and reveals disease-relevant pathways and promising biomarker candidates that are uniquely associated with HCM.
| S-EPMC11351942 | biostudies-literature
Project description:ObjectiveSome patients with obstructive hypertrophic cardiomyopathy may remain limited after surgical relief of the subaortic obstruction. In this report, we describe experience in surgical management of patients with advanced diastolic heart failure symptoms after adequate transaortic septal myectomy for obstructive hypertrophic cardiomyopathy.MethodsWe identified adult patients who presented with heart failure symptoms after previous transaortic septal myectomy for obstructive hypertrophic cardiomyopathy and underwent repeat sternotomy for transapical myectomy to enlarge a small left ventricular cavity. Functional recovery after hospital dismissal was assessed through a questionnaire-based survey.ResultsSix patients with previous septal myectomy presented with New York Heart Association functional class III symptoms. Preoperative transthoracic Doppler echocardiography confirmed adequate relief of subaortic outflow tract obstruction with only trivial or mild mitral valve regurgitation; left atrial volume index was increased at 46 mL/m2 (range, 44-47 mL/m2). Following transapical myectomy, the left ventricular diameter was enlarged from 23 mm (range, 21-27 mm) to 29 mm (range, 27-31 mm) at end-systole and from 40 mm (range, 38-42 mm) to 43 mm (range, 42-50 mm) at end-diastole. All the patients were alive after a median follow-up of 0.6 years (range, 0.4-3.5 years), and 5 patients responded to a postoperative survey and indicated improvement in their heart condition compared with functional status before the repeat myectomy.ConclusionsPatients with diastolic heart failure after septal myectomy for obstructive hypertrophic cardiomyopathy may present with systolic cavity obliteration due to excessive myocardial hypertrophy. Repeat transapical myectomy can enlarge the left ventricular chamber and augment the diastolic volume, which results in improved physical capacity and patient-perceived functional status.
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| S-EPMC7255654 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) is the most common cardiovascular disease that is inherited from a single gene. Its clinical manifestations range from asymptomatic mutant gene carriers to patients with severe left ventricular effluent tract obstruction and end-stage HCM with motor restriction. In this case, we present a patient with the main presentation of heart failure and ST-segment elevation of the lateral wall, as determined by electrocardiogram. The patient was finally diagnosed with HCM because of genetic testing and the presentation of extensive myocardial fibrosis with reduced systolic function on cardiac magnetic resonance imaging. The patient's clinical findings, electrocardiogram, and cardiac magnetic resonance imaging were different from those of typical patients with HCM.
| S-EPMC9871721 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) is a disease, which is difficult to diagnose at an early stage and for which there is a pressing need for more effective treatment options. The purpose of this study was to compare the molecular profile of HCM to that of ISCM and DCM for identification of protein and pathway targets that could support development of better diagnostic and treatment options for HCM. A high throughput mass spectrometry workflow was applied to achieve deep quantitative coverage of left ventricular tissue from HCM, DCM, ISCM and non-heart failure control patients. HCM had a diverse proteomic profile compared to that of DCM and ISCM. Dif-ferentially expressed proteins unique to HCM were identified based on an observed fold change of ≥ 1.5 or ≤-1.5 and q-value ≤ 0.005. Candidate proteins of interest were found to be significantly associated with clinical features of HCM. The significant association between these proteins and HCM was validated in an independent dataset. This represents one of the largest and deepest proteomic datasets for myocardial tissue reported to date. The dataset highlights the diverse proteomic profile of HCM, relative to other cardiomyopathies, and reveals disease-relevant pathways and promising biomarker candidates that are uniquely associated with HCM.
2024-08-08 | PXD054266 | Pride
Project description:BackgroundHypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant-negative fashion. However loss-of-function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3, suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis. Here, we investigate MYBPC3 complete deletion as a disease mechanism in HCM by analyzing two unrelated patients with confirmed diagnosis of HCM that tested negative by Sanger sequencing analysis.MethodsMYBPC3 complete deletion was investigated by Multiplex ligation-dependent probe amplification (MLPA) and microarray analyses. The mechanism of deletion was investigated by interrogating the SINEBase database.ResultsPatient-1 was diagnosed with nonobstructive HCM in his mid-40s while undergoing assessment for palpitations, and patient-2 with obstructive HCM in his late-20s while undergoing systolic heart murmur assessment for an unrelated illness. MLPA testing revealed a heterozygous deletion of all MYBPC3 exons in both patients. Subsequent microarray testing confirmed these deletions which extended beyond the 5' and 3' ends of MYBPC3. Genomic assessment suggested that these deletions resulted from Alu/Alu-homologous recombination.ConclusionOur results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM.
| S-EPMC6978237 | biostudies-literature