Cardiomyopathy Patients Research Articles

Follow-Up Study of Percutaneous Intramyocardial Septal Radiofrequency Ablation in the Treatment of Hypertrophic Obstructive Cardiomyopathy With HFpEF.

The study aimed to evaluate the changes of left ventricular diastolic function and the improvement of clinical symptoms in hypertrophic cardiomyopathy (HCM) patients with heart failure with preserved ejection fraction (HFpEF) after percutaneous intramyocardial septal radiofrequency ablation (PIMSRA). This study enrolled 31 adult HCM patients with HFpEF who underwent PIMSRA treatment. Electrocardiogram, imaging, and blood biochemical examinations were performed on these patients during a 6-month follow-up. Compared with the baseline, at 6 months after PIMSRA, patients showed significant reductions in peak left ventricular outflow tract pressure gradients (resting gradient: from a mean of 83.24 to 23.40mmHg, p < 0.001; postexercise gradient: from a mean of 109.70 to 33.39mmHg, p< 0.001). The interventricular septal thickness reduced from a mean of 22.90 to 17.48mm, p < 0.001. The E/e' decreased from a median of 18.67 to 11.54, p < 0.001. The 6-minute walk distance (6MWD) increased from a mean of 359.03 to 435.81 m, p < 0.001. The Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ OS) increased from a mean of 57.57 to 71.93, p < 0.001. The number of HFpEF patients diagnosed according to the European Society of Cardiology's Heart Failure Association HFA-PEFF score decreased from 31 to 23. None of the patients had new-onset bundle branch block or complete heart block after PIMSRA. PIMSRA is a safe and effective treatment. It can improve left ventricular diastolic function and quality of life in HCM patients.

Exome sequencing data reanalysis of 200 hypertrophic cardiomyopathy patients: the HYPERGEN French cohort 5 years after the initial analysis

BackgroundApproximately half of hypertrophic cardiomyopathy (HCM) patients lack a precise genetic diagnosis. The likelihood of identifying clinically relevant variants increased over time.MethodsIn this study, we conducted a gene-centric reanalysis of exome data of 200 HCM cases 5 years after the initial analysis. This reanalysis prioritized genes with a matched HCM entry in the OMIM database and recently emerging HCM-associated genes gathered using a text mining-based literature review. Further classification of the identified genes and variants was performed using the Clinical Genome Resource (ClinGen) resource and American College of Medical Genetics and Genomics (ACMG) guidelines to assess the robustness of gene–disease association and the clinical actionability of the prioritized variants.ResultsAs expected, the majority of patients carried variants in MYBPC3 and MYH7 genes, 26% (n = 51) and 8% (n = 16), respectively, in accordance with the initial analysis. The vast majority of pathogenic (P) and likely pathogenic (LP) variants were found in MYBPC3 (22 out of 40 variants) and MYH7 (8 out of 16 variants) genes. Three genes—not included in the initial analysis—were identified: SVIL, FHOD3, and TRIM63. Considering only patients with unique variants in the last three genes, there was a 9% enhancement in variant identification. Importantly, SVIL variant carriers presented apical and septal HCM, aortopathies, and severe scoliosis for one patient. Ten patients (5%) carried variants in the FHOD3 gene, six in hotspot regions (exons 12 and 15). We identified seven variants within the TRIM63 gene in 12 patients (6%). Homozygous variants were detected in 2.5% of the cohort in MYBPC3 (n = 1), MYL3 (n = 1), and TRIM63 (n = 3) genes.ConclusionOur study revealed that no variants were found in the ACTC1, TPM1, and TNNI3 genes in the HYPERGEN cohort. However, we identified variants in five out of the eight HCM core genes, with a high prevalence in young patients. We identified variants in three recent HCM-associated genes (SVIL, FHOD3, and TRIM63) in 35 patients, with 18 patients carrying unique variants (9%). Our results further emphasize the usefulness of exome data reanalysis, particularly in genotype-negative patients.

Identification of fibrosis-associated lncRNAs in diabetic cardiomyopathy patients.

Our study endeavours to ascertain the plasma-derived long noncoding ribonucleic acids (lncRNA) and messenger RNA (mRNA) expression profiles through gene microarray analysis, aiming to elucidate their potential biological roles in the development and progression of diabetic cardiomyopathy (DCM), particularly with respect to myocardial fibrosis. We conducted gene chip experiments to discern differences in lncRNA and mRNA expression profiles between diabetic cardiomyopathy and type 2 diabetes mellitus (T2DM). Differentially expressed mRNAs were subjected to functional enrichment analysis, thereby enabling the identification of key genes. Subsequently, we established an interaction network connecting lncRNAs with mRNAs. To validate myocardial fibrosis-related mRNAs, we further developed a rat model of diabetic cardiomyopathy. We identified 688 differentially expressed lncRNAs and 341 differentially expressed mRNAs, which were primarily enriched in creatine metabolism, small guanosine triphosphate hydrolase (GTPase)-mediated signal transduction, and fatty acid degradation processes. Our analyses revealed 8 core genes (SMD11, DRG1, RPS26, EIF2S1, UBE3A, CEBPZ, NUP153, and EMD) associated with diabetic cardiomyopathy. An investigation into the lncRNA-mRNA coexpression network underscored 4 lncRNAs (lnc-NEK10-3, lnc-KDM4A-2, lnc-PCYOX1-3, and lnc-CDCP2-1) as significantly linked to differentially expressed fibrosis-associated mRNAs. The expression levels of transmembrane protein 173 (TMEM173) and toll-like receptor 7 (TLR7) were found to be significantly higher in DCM compared to normal controls, whereas cathepsin L1 (CTSL) and forkhead box O3 (FOXO3) displayed significantly lower expression levels relative to those of normal controls. Our study disclosed a subset of lncRNAs and mRNAs that are implicated in diabetic cardiomyopathy and myocardial fibrosis, thereby presenting themselves as promising biomarkers and therapeutic targets for the management of both diabetic cardiomyopathy and myocardial fibrosis.

Unraveling Marfan hearts: ultrastructural evidence for myocardial remodeling and cardiomyopathy

Abstract Background Despite improved life expectancy for patients with Marfan syndrome (MFS), significant morbidity and mortality persist. Although primarily attributed to aortic dissection and rupture, recent studies highlight the emerging role of arrhythmias and heart failure as additional contributors to morbidity and mortality in MFS. While severe valvular heart disease is an established cause of heart failure, there is a growing recognition of primary cardiomyopathy in patients with MFS. The mechanisms underlying cardiomyopathy in MFS remain poorly understood. Purpose This study aimed to reveal insights into the ultrastructural myocardial architecture in patients with MFS, thereby elucidating the role of cardiomyopathy in MFS. Methods This study enrolled 44 patients who underwent cardiac surgery at 2 centers (Marfan syndrome patients n=27 (MFS), ascending thoracic aortic aneurysm repair patients n=5 (non-MFS), patients post-orthotopic heart transplant n=12 (controls)). Myocardial biopsy samples were subjected to histopathological analysis using transmission electron microscopy and conventional histology. Results Conventional histological analysis revealed subtle abnormalities in the cardiomyocyte morphology of MFS patients, compared to non-MFS and controls. Overall, a slight increase in interstitial fibrosis and mild myocyte hypertrophy were observed in MFS patients. Ultrastructural examination of both MFS and non-MFS patients revealed significant structural remodeling and degenerative changes in the myocardium. These changes included: extensive myofibril lysis, compromised cell membrane integrity and nuclear chromatin condensation. Degenerative lesions were often accompanied by cytoplasmic debris, lysosomal residual bodies, autophagic vacuoles, and severe mitochondrial pathology. Dense accumulation of glycogen granules and lipofuscin was evident in areas of focal myofibril lysis. Notably, only MFS patients exhibited recruitment of granulocytes, including mast cells, eosinophils and neutrophils. A subset of MFS patients displayed advanced stages of myocardial degeneration. However, these changes did not correlate with clinical myocardial failure. Conclusions To the best of our knowledge, this study represents the first evidence of ultrastructural changes in the myocardium of patients with MFS. Our data indicate various degenerative changes in the myocardial architecture, including structural and metabolic myocardial remodeling, along with inflammatory cell infiltration. We believe that our findings of ultrastructural lesions reflect the complexity of myocardial disease in MFS and emphasize the importance of careful surveillance for cardiomyopathy in MFS patients. Further studies are warranted to confirm whether the observed granulocyte influx is specific to MFS and to clarify its role in MFS myocardial disease pathophysiology.Graphical abstract

Gene-echocardiography: unmasking the covert role of fatty acid metabolism gene mutations in adult cardiomyopathy

Abstract Background Although the role of fatty acid metabolic deficiencies in cardiomyopathy is established, the precise identity of causative genes and their respective phenotypes in adult cardiomyopathy remains unclear. Methods We implemented a combination of echocardiography and whole exome sequencing in clinically diagnosed cardiomyopathy patients to uncover this relationship. This involved recording cardiac phenotypes, identifying genes associated with disrupted fatty acid metabolism, and subsequently followed up with these patients. Results Out of 802 cardiomyopathy patients, 27 exhibited mutations in genes tied to fatty acid metabolism. Specifically, 16 patients demonstrated a hypertrophic cardiomyopathy (HCM) phenotype, and 11 showed a dilated cardiomyopathy (DCM) phenotype. The implicated genes were SLC22A5 (n=7), ACADVL (n=6), ACADS (n=4), ACADM (n=3), SLC25A20 (n=3), ACADL (n=2), HADH (n=1), and AGK (n=1), with a higher prevalence in males. Among these, the SLC22A5 mutation was predominant and correlated with HCM phenotype. Notably, compound mutations were frequently observed (16/27), leading to earlier disease onset and diminished aortic sinus dimension. Further investigation showed that smaller aortic sinus dimensions resulted from abnormal left ventricular myocardial work. HCM phenotype mutation carriers showed more consistent left ventricular hypertrophy and a higher probability of right ventricular hypertrophy, while DCM phenotype mutation carriers exhibited impaired contractile function across all left ventricle segments. After a 24-month follow-up, the DCM phenotype group demonstrated higher cardiovascular risk, including two fatalities. Conclusion Our investigation highlights the significant prevalence of mutations related to abnormal fatty acid metabolism in adult cardiomyopathy patients, underscoring the utility of a gene-echocardiography approach for diagnosis.

Gene-echocardiography: refining genotype-phenotype correlations in cardiomyopathy patients with restrictive phenotype

Abstract Background The restrictive phenotype, the least frequent and genetically complex form of cardiomyopathy, is the focus of this investigation. The aim is to clarify the association between restrictive phenotype and genetic variants in cardiomyopathy patient. Methods We utilized whole-exome sequencing in a cohort of 568 cardiomyopathy patients and performed echocardiographic evaluations to identify restrictive phenotypes. Comprehensive analysis of cardiac characteristics and functionality was also undertaken. Results Among the cohort, 33 patients exhibited a restrictive phenotype. These patients were distributed as follows: 7 within the restrictive cardiomyopathy group (RCM), 20 in the hypertrophic cardiomyopathy group (HRCM), and 6 in the dilated cardiomyopathy group (HDRCM). A notable prevalence of gene mutations, mainly in the MYBPC3 gene, was found in these individuals. We observed that mutation carriers, characterized by smaller aortic sinus dimension, demonstrated an association with the mutation and diminished myocardial work. Furthermore, MYBPC3 mutation carriers showed a thicker ventricular wall and a higher predisposition for septal hypertrophy. Both HRCM and HDRCM groups displayed consistent hypertrophic manifestations, with the latter demonstrating a higher frequency of interventricular septal hypertrophy. The 5-year survival rate was calculated at 54.5%, with gene mutations not significantly affecting longevity. Conclusion Genetic factors profoundly influence the restrictive phenotype of cardiomyopathy. There is a strong link between restrictive phenotype and genetic variants in cardiomyopathy, providing a foundation for more accurate genetic testing and personalized management of patients. The emerging "gene-echocardiography" concept may refine the accuracy and productivity of genetic counseling and testing in cardiomyopathy.

Utilization and safety of digoxin in patients with chronic heart failure and atrial fibrillation with rapid ventricular rate

Abstract Background Digoxin can reduce symptoms and the risk of tachycardia-induced cardiomyopathy in patients with heart failure (HF) and concomitant atrial fibrillation (AF) with rapid ventricular rate. The effect of digoxin in HF and AF has not been tested in randomized controlled trials, and observational data have shown conflicting results linking digoxin to increased mortality in AF, though the nature of observational data makes it prone to bias and results difficult to interpret. Purpose To assess the utilization of digoxin in patients with HF and AF, and its association with New York Heart Association (NYHA) functional class and survival. Methods We used data from the Norwegian HF registry that collected data from all Norwegian HF clinics between 2013-2022. Data was collected from the first and last visit during optimizization of HF medical therapy. Associations with mortality status from Statistics Norway were assessed in unadjusted time-to-event analysis, and after adjustment for age, sex, body mass index, estimated glomerular filtration rate, aldosterone antagonists, renin-angiotensin-aldosterone system inhibitors, and beta blockers. Results The study included 4,877 HF patients, consisting of 4,067 (83.4%) with ejection fraction (EF) ≤40% and 810 (16.6%) with EF &amp;gt;40%.. The mean age was 67.7±12.0 years; 25.1% were women, and 27.3% had NYHA functional class III/IV. At the first visit, 1,339 (27.5%) patients had AF and 829 (61.9%) of these were treated with ≥50% of the beta-blocker target dose. AF with a ventricular rate ≥100 bpm was present in 277 (20.1%) patients, and 188 (67.9%) of these were on ≥50% beta-blocker target dose. Similarly, 262 (19.6%) of all AF patients and 44 (15.9%) of those with a ventricular rate ≥100 bpm were treated with digoxin. After optimization of HF medical therapy (median duration 140 [Q1–Q3 82–237] days), 1,039 (21.3%) patients had AF. Among these, 227 (21.9%) were treated with digoxin, including 9 (18.0%) patients with ventricular rate ≥100 bpm. Patients with AF who were started on digoxin experienced during the optimization period a larger decline in heart rate compared to those who were not (mean change -23.7±17.2 vs. -5.7±16.7 bpm, p=0.001), and more often an improvement in NYHA functional class (45% vs 30%, p=0.018). During median 779 [Q1–Q3 386–1,334)] days of follow-up after the last optimization visit, digoxin use was associated with lower mortality in HF patients with AF in unadjusted analysis (HR 0.67 [0.46–0.97]). After adjustment for baseline characteristics and other HF medical therapies, the association with mortality was attenuated and no longer significant (HR 0.96 [0.65–1.42]). Conclusion Digoxin was infrequently used in patients with HF and AF with rapid ventricular rate but was associated with a greater decrease in heart rate and improvement in NYHA functional class. The use of digoxin appears safe and was not associated with increased mortality.

Incidence, definitions and outcomes of anthracycline induced subclinical and clinical left ventricular dysfunction: a systematic review and meta-analysis

Abstract Purpose To assess incidence and risk factors for anthracycline-induced left ventricular dysfunction, and associated mortality in order to inform patients and providers of the risk, as well as for clinical trial endeavours. Background Anthracyclines (ACs) are very effective cancer therapeutics, but their use is confronted by the risk of cardiotoxicity. Estimates of AC-induced cardiotoxicity based on systematic analyses are limited and have not recently been defined. We present here a systematic review and meta-analysis of the incidence of anthracycline induced subclinical (AC-LVD) and clinical LV dysfunction (AC-CHF) and AC-CHF related mortality in non-liposomal AC recipients over the last 3 decades. Methods We searched Ovid MEDLINE(R), Embase, Cochrane Database and other major databases from their inception until June 22, 2023 for studies examining the rate of AC induced cardiomyopathy in patients receiving ACs and anthraquinones for haematologic, breast (BC) and sarcomatous malignancies. Covidence was used to aid with the management of our systematic review. Screening of abstracts and data extraction was independently performed by 2 reviewers. Results 6,365 abstracts were reviewed, of which 74 were included in the final analysis. 72 studies (n=41,138) reported data on AC-LVD, and 47 studies (n=27,012) reported data on AC-CHF. The average age was 53 years and 50% of the patients were female. Data on cardiac function at baseline was available in only 70% of the studies. Overall, AC-LVD occurred in 8.2% (95% CI 6.8%-10.2% I2 97%) (Fig 1). AC-CHF was noted in 2.2% (95% CI 1.6% to 2.9%, I2 91%) (Fig 2A), mortality related to decompensated AC-CHF was 0.5% (95% CI 0.3%-0.9%, I2 88%) (Fig 2B) while total mortality rate among AC recipients was 24.9% (95% CI 14.8-38.7%, I2 99%). Incidence of AC-LVD was higher in doxorubicin recipients (vs other ACs 10.5% vs 5-5.6%), studies from North America &amp; Asia (vs other regions; 9.3-9.6% vs 6.7%), and prospective studies (vs retrospective studies; 8.7% vs 7.5%). AC-LVD was more common in BC patients (vs other cancers; 8.7% vs 3.5-7.2%) while AC-CHF was more common in lymphoma patients (8.5% vs 1.6-4.1%). AC-LVD was 4.6 times (95% CI 1.2-17.1, p=0.02) more likely in patients with a mean age &amp;gt;70 (vs &amp;lt;70). 21 definitions for AC-LVD were used across the studies. The most common definition (15 studies; n=7904) was "any decline in LVEF from baseline" resulting in a 5.8% rate of AC-LVD. Conclusions AC-LVD and AC-CHF has been reported in up to 10% and 3% of AC recipients, respectively. AC-CHF related mortality occurs in &amp;lt;1% of anthracycline recipients and has a 2-3% share in overall mortality among these patients. The type of malignancy and anthracycline can influence the rate of AC-LVD, AC-CHF and AC-CHF related mortality. Global region, age of the patient population and study design also seem to influence incidence rates. There is noteworthy heterogeneity in definitions for cardiotoxicity across studies.

Genotype-phenotype correlation of transthyretin cardiomyopathy in patients with stage C/D heart failure: atrial and myocardial mechanics and fibrosis

Abstract Objectives We sought to investigate: (1) the relationship between transthyretin (TTR) pathogenic variants and their corresponding echocardiographic atrial and ventricular strains in patients with TTR cardiomyopathy (TTR-CM) and clinical evidence of heart failure (HF), and (2) the relationship between TTR pathogenic variants and atrial fibrosis assessed by cardiac MRI. Methods and results Fifty Asian patients with biopsy or scintigraphy proven TTR-CM and stage C or D (C/D) HF were identified from an advanced HF clinic in a tertiary-care university hospital. Genetic testing for the pathogenic variants in the TTR genes associated with hereditary TTR-CM (hTTR-CM) was available in 22 patients (67 ±13 years; 77% were male). Of these, 3 different mutations were identified. The most prevalent pathogenic variant was Ala97Ser (67%) followed by Val30Met (27%), and Gly67Glu (6%). Wild-type TTR-CM was diagnosed in 32% of the cohort. Strain analysis was performed using the TomTec Arena 2D-cardiac performance analysis (CPA) software. Atrial and left ventricular (LV) late gadolinium enhancement (LGE) was quantified using a 9-segment and a 17-segment model, respectively. Patients with hTTR-CM had less impaired longitudinal strain (LS) (more negative strain values) than those with wild-type TTR-CM in the regional basal right ventricular free wall (RV-FW) (-21 ± -8.3 % vs.-12.6 ± -8.1%, p = 0.048) and LV basal inferoseptum (-7.3 ± -4.1 % vs.-3.1 ± -3.0 %, p = 0.045). In univariate analysis, more negative LS values in the basal LV inferoseptum and basal RV-FW were significant predictors of hTTR-CM (OR 5.1 and 2.3; p &amp;lt;0.05, respectively). However, MRI findings revealed similar regional LGE extent involving basal inferolateral segments between hTTR-CM and wild-type TTR-CM (38.3 ± 7.9 vs. 52.5 ± 34.5%, p =0.314). Left atrial (LA) and right atrial (RA) LGE was present in 90% and 81% of patients, respectively. Patients with hTTR-CM had reduced RA LGE when compared to those with wild-type TTR-CM (41% vs 67%, p =0.039). Conclusions In patients with TTR-CM and stage C/D HF, a reduced RA LGE extent and/or more preserved myocardial deformation in specific regions of basal LV and RV segments (basal LV inferoseptum and basal RV free wall) assessed by 2-D speckle tracking echocardiography were significantly more prevalent in patients with hTTR-CM than in wild-type TTR-CM. These echocardiographic and/or MRI findings may facilitate genotype testing in patients with TTR-CM, particularly in resource-limited settings. Further validation of these novel findings in patients with TTR-CM with HF is needed.

Prevalence of transthyretin amyloid cardiomyopathy in patients hospitalised for heart failure with preserved ejection fraction in an LATAM center

Abstract Introduction Transthyretin Amyloid cardiomyopathy (ATTR-CM) usually presents as heart failure with preserved ejection fraction (HFpEF). Its diagnosis has a significant clinical impact, as specific treatment is currently available. Purpose To assess the prevalence of ATTR-CM in patients hospitalised for HFpEF and increased septal thickness in our institution of general community hospital in Latin America (LATAM). Methods Cross-sectional study. Patients hospitalised for HFpEF (&amp;gt;50%) and septal thickness ≥ 12 mm during the period from 8/2019 to 1/2023 were prospectively included. Patients with pacemaker, significant left valve disease and end-stage renal failure (creatinine clearance &amp;lt; 30 ml/min/BSA) were excluded. A pyrophosphate bone scintigraphy (PYP) was planned to be performed in order to assess ATTR-CM. The prevalence of ATTR-CM and its 95% confidence interval were calculated. Results A PYP was performed in 59/82 patients hospitalised for HFpEF. Median age was 85 [IQR 78-88] years, and 54% were women. At admission, 61% (n=36) had atrial fibrillation and the median NT Pro-Bnp was 3536 [1700-7748] pg/mL. The mean left ventricle ejection fraction was 57% (+/- 5%). The prevalence of ATTR-CM diagnosed by PYP was 19% (95% CI 9.7-30.1, n=11). There were no significant clinical differences between patients who performed a PYP and did not. Patients with ATTR-CM had lower blood pressure and higher septal thickness, NT Pro-Bnp and troponin levels compared to patients without ATTR-CM (TABLE). Conclusion In patients admitted for HFpEF and increased septal thickness, the diagnosis of ATTR-CM was relatively common (one of five had ATTR-CM) in our region (LATAM). We believe that systemic assessment with PYP should be performed in patients hospitalised with HFpEF and increased wall thickness.

MicroRNA-145-5p restricts cardiac scar resolution during cardiac regeneration

Abstract Background Human hearts have a very limited capacity to renew cardiomyocytes following injury. The lost myocardium is permanently replaced with noncontractile fibrotic tissue, consequently leading to heart failure. In contrast, zebrafish retain cardiac regenerative capacity during their lifetime. After injury, zebrafish hearts undergo transient fibrotic scarring that subsequently resolves and is replaced with new cardiomyocytes over time. Thus, understanding the molecular mechanisms governing cardiac scar resolution in zebrafish could offer insights into enhancing the regenerative capacities of human hearts. Objective We aimed to decipher the molecular pathways associated with zebrafish cardiac scar resolution. Methods We investigated the mRNA and miRNA responses to injury at 14 days post-injury by high-throughput transcriptome profiling of RNAs isolated from healthy or cryoinjured hearts. The prediction of miRNA-mRNA interactions was performed to identify the most differentially expressed miRNAs and their target genes. These miRNAs and genes were validated in zebrafish regenerating hearts and in the left ventricles of ischemic cardiomyopathy or dilated cardiomyopathy patients. The potential role of identified miRNAs in cardiac scar resolution was investigated in human cardiac fibroblasts. Results Principal component analyses identify two distinct clusters in both the mRNAome and miRNAome corresponding to healthy and injured hearts, indicating significant changes in transcriptome profiles during zebrafish cardiac regeneration. Gene set enrichment analyses indicate that molecular pathways involved in extracellular matrix organization and inflammatory response are markedly activated whereas genes associated with mitochondrial organization and oxidative phosphorylation are downregulated in injured hearts. We observed the downregulation of miR-145-5p and the upregulation of procollagen V in the injured hearts. In contrast to zebrafish, in the left ventricles of ischemic cardiomyopathy patients, miR-145-5p is significantly upregulated and procollagen V α1 is downregulated. Theoretical prediction of miRNA-mRNA interactions indicates procollagen V α1 is negatively correlated with miR-145-5p. Overexpression of miR-145-5p in human cardiac fibroblasts downregulates collagen V α1 and alpha smooth muscle actin, upregulates procollagen I and matrix metalloproteinase 9, and inhibits cell proliferation and migration. In contrast, inhibition of miR-145-5p upregulates collagen V α1 and alpha smooth muscle actin, downregulates procollagen I and matrix metalloproteinase 9, and stimulates cell proliferation and migration. Conclusion Our study suggests that miR-145-5p may play a role in the suppression of myofibroblast transdifferentiation via collagen V α1, which restricts scar resolution and cardiac repair.

Integrated plasma proteomics and myocardial tissue transcriptomics reveal elevated fibrosis markers in arrhythmogenic cardiomyopathy patients

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is characterized by myocardial fibrofatty replacement and ventricular arrhythmias, with potential progression to heart failure. This study aims to identify ACM-specific biomarkers for improved prognosis and possible treatment strategies. Methods RNA sequencing and transcriptome analyses were performed in cardiomyocytes of 10 ACM patients, 10 dilated cardiomyopathy patients and 10 healthy controls. Analyses were performed using liquid chromatography and mass spectrometry. Additionally, plasma protein expression was assessed in 38 ACM patients and 24 healthy controls using the Proximity Extension Assay (Olink®). A standardized bicycle exercise test was performed in 11 ACM patients and controls and blood was obtained before and after exercise. Results Myocardial tissue transcriptomics identified several upregulated molecules associated with extracellular matrix formation and immune response in ACM. Plasma protein sequencing revealed upregulation of proteins involved in metabolic pathways, inflammation, and fibrosis. Integration of these analyses identified key soluble profibrotic markers such as Fibulin-3, Endostatin and C-X-C motif chemokine 10 (CXCL10) in plasma of ACM patients. After exercise, Fibulin-3 levels increased in ACM patients compared to controls. These findings were further validated using enzyme-linked immunosorbent assay (ELISA). Conclusion This comprehensive analysis revealed distinct proteomic and transcriptomic signatures in ACM patients' plasma and cardiomyocytes. The integrative analysis identified several upregulated profibrotic markers in ACM. Our Findings may advance diagnostic and prognostic strategies and offer potential therapeutic targets.

Mitral regurgitation improvement following left bundle branch pacing versus right ventricular septum pacing: a dedication to postoperative amelioration of mitral regurgitation

Abstract Background Mitral regurgitation (MR) is correlated with left ventricular (LV) remodeling and LV function in patients. Left bundle branch pacing (LBBP) exhibits a significant decline in MR in left bundle branch block (LBBB) and cardiomyopathy patients. This research aims to evaluate the influence of LBBP on MR in comparison to right ventricular septal pacing (RVSP) in patients with atrioventricular block (AVB) or sick sinus syndrome (SSS). Methods Sixty consecutive patients with SSS or AVB were enrolled if they underwent pacemaker implantation via LBBP or RVSP. Patients with a history of mitral valve surgery were excluded. Echocardiogram parameters were assessed to measure MR and LV remodeling as well as LV function at baseline and follow-up. Results Thirty-six patients (60 %; mean age: 70.39 ± 14.80 years; 61.1 % male) underwent successful LBBP, and 24 patients (40 %; mean age: 71.58 ± 10.91 years; 66.7 % male) underwent RVSP. The average follow-up duration was relatively comparable between the two groups. In comparison to RVSP, LBBP demonstrated significant changes in MR area, and severity at baseline and follow-up (P&amp;lt;0.05). LBBP independently predicted MR amelioration in patients who underwent pacemaker implantation (HR=0.289, CI=0.087–0.9961; P=0.043). At follow-up, the LBBP subgroup with moderate/severe MR exhibited significantly shorter lead-TVA-dist, higher left atrium (LA) diameters, and mitral E/A ratio (P&amp;lt;0.05) compared to the none/mild MR subgroup. In LBBP with MR amelioration, LV remodeling (ΔLVEDD) was significantly enhanced compared to baseline (P=0.016). Additionally, a non-significant trend toward better improvement in LV function (ΔLVEF and ΔE/A) was observed in patients with MR amelioration. Conclusion LBBP, considered an optimal pacing technique for SSS or AVB patients, may substantially reduce MR and subsequently enhance LV remodeling and function compared to RVSP. This open, observational pilot study warrants confirmation through further investigations.Comparison between LBBP and RVSPKaplan-Meier curves for MR amelioration

The dynamic increment of epicardial adipose tissue is associated with reverse remodeling after guideline-directed medical treatment in dilated cardiomyopathy patients

Abstract Background/Introduction Epicardial adipose tissue (EAT) accumulation is associated with adverse prognosis in patients with HFpEF and a better prognosis in HFrEF patients. Whether EAT is playing a protective role in dilated cardiomyopathy (DCM) patients have been described sparingly. Purpose Aim to explore whether the epicardial fat would change along with the dynamic changes in cardiac function and volumes after receiving guideline-directed medical therapy (GDMT) in patients with DCM. Methods We prospectively enrolled 232 DCM patients who underwent complete baseline and follow-up Cardiac magnetic resonance (CMR) examinations. The measurement of the epicardial fat composition includes epicardial fat thickness, paracardial fat thickness, and paracardial fat volume, while the measurement of body fat composition includes subcutaneous and visceral abdominal fat, while We used univariable and multivariable logistic regression to evaluate the association between different body and cardiac fat depots with the changes in bi-ventricular structure (delta indexed EDV) and function (delta EF). Results The study included 232 patients (mean age 46.1±14.1 years, 157 (67.7%) males). After GDMT, we found that the visceral fat thickness and EAT (thickness and volume) tend to significantly increase. The increase in the (left ventricular reverse remodeling) LVRR group was significantly higher compared with the non-LVRR group. Independently with the changes of BMI and body fat depots, the increment of EAT was associated with the improvement in bi-ventricular function and volumes (significantly positively correlated with the improvement of LVEF (r = 0.499, p &amp;lt; 0.001), and RVEF (r = 0.482, p &amp;lt; 0.001), negatively correlated with delta LVEDVi (r = -0.407, p &amp;lt; 0.001), delta RVEDVi (r = -0.305, p &amp;lt; 0.001)). Conclusions After GDMT, the increment of EAT was positively correlated with the improvement of bi-ventricular structure and function, independent of the changes in BMI and body fat depots.Graphic Abstract

Left atrial strain differences between hypertensive and sarcomeric left ventricular hypertrophy: a sign of sarcomeric auricular myopathy?

Abstract Introduction In clinical practice, left ventricular (LV) hypertrophy is a common finding that can be caused by physiologic or pathologic conditions. An etiologic diagnosis is extremely important because it may change the prognosis and management of the patient and his family. Left atrial (LA) dysfunction is common due to diastolic dysfunction but, in patients with sarcomeric LV hypertrophy, primary cardiomyopathy disease could also be present. Purpose To evaluate if there are differences in LA function between arterial hypertension (HT) and hypertrophic cardiomyopathy (HCM) patients. Methods 73 patients with HCM (according to ESC guidelines criteria) and 82 patients with HT (under treatment with ≥1 hypertensive drug for ≥3 months) and ≥13mm of LV hypertrophy underwent an echocardiography to assess LA function with strain analysis and LV diastolic function. Continuous normally distributed variables were compared with T-student test and categoric variables with square-chi or exact Fisher test if required, accepting as significant a p-value &amp;lt;0.05. Results Globally, HCM patients showed thicker LV walls and larger LA indexed volumes (18.7±4.7 vs. 13.3±0,8 mm and 44.9±20.7 vs. 30.7±8.8 ml/m2, p&amp;lt;0.000 for both). Also, HCM patients presented diastolic dysfunction and atrial fibrillation history in a higher frequency (31 vs. 7.6% and 16.4% vs. 0%, p&amp;lt;0.000 for both). LA strain was significantly lower in HCM patients as compared to the HT group (LA contractile 11.5±5.8 vs. 17.2±4.4, p&amp;lt;0.000; LA conduit 12.2±5.4 vs. 13.3±3.8, p=0.041; and LA reservoir 23.9±8.7 vs. 31.1±5.9, p&amp;lt;0.000). In the subgroup of patients with moderate-severe LV hypertrophy (&amp;lt;17mm) and no significant mitral regurgitation (n=103; HCM=21, HT=82), LA contractile strain remained lower in HCM as compared to HT patients (13.2±4.8% vs. 17.2±4.4%, p&amp;lt;0.000) (figure 1); without differences in diastolic dysfunction, LA volumes, significant mitral regurgitation or atrial fibrillation history. Conclusions Our results show that LA strain is more impaired in HCM patients as compared to HT patients. Specifically, contractile LA strain remained lower even in those patients with moderate-severe LV hypertrophy, despite having similar LV diastolic function, LA indexed volumes, significant mitral regurgitation, or atrial fibrillation history. These findings could be caused by HCM involvement of the LA myocytes. In the context of moderate-severe hypertrophy of unknown origin with non-significant mitral regurgitation, the detection of abnormally reduced LA strain could indicate the presence of an HCM.Figure 1

Nationwide trends in utilization and safety of ventricular arrythmia ablation in patients with hypertrophic cardiomyopathy

Abstract Background Catheter ablation for ventricular arrhythmias, including ventricular tachycardia (VT) and premature ventricular complexes (PVC) is increasingly utilized across the nation, while data on its safety in Hypertrophic Cardiomyopathy (HCM) patients is sparse. Purpose To analyze the nationwide trends in utilization and complications of inpatient ventricular arrhythmia ablations in patients with HCM. Methods This study is a retrospective analysis of hospitalizations, in HCM patients 18 years of age and older, who underwent an inpatient VA ablation in the U.S., between 2016 and 2020. We drew data from the National Inpatient Sample (NIS) database. Patients without HCM undergoing the CA for VA were used as controls. Baseline sociodemographic and clinical data, procedural complications, mortality and length of stay were analyzed. Multivariable analysis was performed to identify independent predictors of procedural complications. Results Among a weighted total of 2880 patients hospitalized between 2016 and 2020, who underwent VA ablations, the median age was 67 years (IQR 56-74), 60% were male, and 73% were white. The HCM group had similar age distribution but more women (64.5% vs 33.6%, p&amp;lt;0.001) and more African Americans (13.2% vs. 7.3%, p=0.03). The non-HCM cohort had significantly higher rates of prior myocardial infarction (22% vs 12.4%, p=0.026), ischemic cardiomyopathy (30.1% vs 0.8%, p&amp;lt;0.001), heart failure (70.5% vs 39.7%, p&amp;lt;0.001), and peripheral vascular disease (PVD, 42.9% vs 18.2%, p&amp;lt;0.001). This was reflected in higher Deyo Comorbidity Index in the non-HCM cohort (score of ≥ 2 in 66.6% vs 43%, p&amp;lt;0.001). Overall, the real-world peri-procedural complication rate in the entire cohort was 15.3%, including 6.4% hemorrhagic, 4.5% pericardial, and 2.3% vascular complications. There was a trend for lower complication rate in the HCM group (9.9% vs. 16.7%, p = 0.08). The in-hospital mortality didn’t defer (1.7% vs. 4.2%, p=0.28) and the length of stay was shorter in the HCM group (3.5 vs. 6.4 days, p &amp;lt; 0.001). Multivariable logistic regression analysis showed obesity (OR 2.06; 95%CI: 1.59 - 2.67; p&amp;lt;0.001) and PVD (OR 2.19; 95%CI: 1.34-3.53; p=0.001) to be independent predictors of complications while HCM was not (OR 0.76, 95% CI 0.51-1.14, p = 0.195). Conclusion Real-world data from a nationwide inpatient database shows comparable safety for VA ablation in HCM patients with similar mortality and lower length of stay, compared to non-HCM patients.

Dynamic changes of excessive trabeculation in dilated cardiomyopathy: a longitudinal cardiovascular magnetic resonance study

Abstract Background A portion of dilated cardiomyopathy (DCM) patients present with left ventricular (LV) excessive trabeculation at diagnosis. It remains unknown if the extent of trabeculation would be reduced after guideline-directed medical therapy (GDMT). Purpose To investigate the dynamic change of excessive trabeculation after GDMT in patients with DCM, and its relationship with that in LV structure and function. Methods A group of DCM patients with baseline and follow-up cardiovascular magnetic resonance (CMR) examination after 1-2 years of GDMT were enrolled. Trabeculation was assessed by Petersen method as measuring the thickness of the most prominent non-compacted (NC) layer and the corresponding compacted (C) segment at the apical long-axis view at end-diastole. Excessive trabeculation was defined as the NC/C ratio &amp;gt; 2.3, and a regression was reached if it decreased to ≤ 2.3. Major adverse cardiovascular events (MACE) consisted of cardiovascular death, heart transplantation, and heart failure readmission. Results Among 218 DCM patients (45 ± 14 years, 67.4% male), 58 (26.6%) met the excessive trabeculation criteria at baseline. Despite a similar LV ejection fraction (LVEF), patients with excessive trabeculation had a higher LV end-diastolic dimension (73.3 ± 9.0 vs. 70.5 ± 8.0mm) and native T1 (1325.3 ± 71.2 vs. 1305.5 ± 65.9mm) (both p&amp;lt;0.05) with a trend of more late gadolinium enhancement (51.7% vs. 39.4% of patients). After 15 months of GDMT, patients with excessive trabeculation (n=58) showed a decreased NC layer (12.7 ± 3.4 vs. 11.3 ± 3.0 mm) and NC/C ratio (3.1 ± 0.9 vs. 2.7 ± 0.9) (both p &amp;lt; 0.05), 25.9% of whom showed a regression of trabeculation. Patients with the regression had a lower NC/C ratio (1.8 ± 0.4 vs. 3.0 ± 0.8, p &amp;lt; 0.001) and LV end-diastolic volume index (LVEDVi) (121.5 ± 40.5 ml/m2 vs. 165.9 ± 67.8ml/m2, p=0.004) compared with those without. The change of (△) NC/C ratio was associated with that of LVEDVi (r = 0.323), and LVEF as well (r = -0.254) (both p &amp;lt; 0.001). Excessive trabeculation at baseline did not differentiate patients with a higher risk of MACE by Kaplan-Meier survival curve (p= 0.208), but its persistent presence at follow-up did (p= 0.004). However, when put △NC/C ratio, △LVEDVi, △LVEF and In NT-proBNP into multivariate cox regression model, only the △LVEDVi (HR, 0.963; 95% CI: 0.942, 0.985; P = 0.001) and In NT-proBNP (HR, 2.016; 95% CI: 1.288, 3.157; P = 0.002) were independent predictors of MACE. Conclusions Regression of excessive trabeculation occurred after GDMT in DCM patients that was related somewhat to LV reverse remodeling and not an independent predictor of MACE. It may also indicate the interconnection between LV remodeling and trabeculation.

Polygenic risk score for prediction of atrial fibrillation according to presence of the hypertrophic cardiomyopathy

Abstract Background The significance of genetic predisposition in predicting atrial fibrillation (AF) is well recognized, yet its role in hypertrophic cardiomyopathy (HCM) patients remains less clear. Objective In this study, we aimed to elucidate the impact of genetic risk on the development of AF in both HCM and non-HCM patients. Methods This retrospective analysis examined 1,180 HCM patients (mean age 61.1±7.1, 63.0% male) and 476,238 non-HCM patients (mean age 57.0±8.1, 45.3% male) from the UK Biobank. Participants were stratified based on their validated polygenic risk score (PRS) for AF: the bottom 10% constituted the low genetic risk group, the top 10% comprised the high genetic risk group, and the remainder fell into the intermediate genetic risk group. We assessed the incidence of AF and major cardiovascular events and analyzed predictors, including genetic risk. Results Among HCM patients, no significant differences in baseline characteristics were observed based on genetic risk, except for the rate of CIED implantation (P=0.036). Conversely, among non-HCM patients, variations in age, gender, and comorbidities were noted according to genetic risk. The HCM patients were categorized into three groups based on risk, with respective AF incidence rates of 2.4, 3.6, and 5.4 events per 100 person-years, respectively. In non-HCM patients, the incidence of AF per 100 person-years was 0.2, 0.5, and 1.0, respectively. Genetic risk emerged as a significant predictor of AF in both HCM and non-HCM patients, although with a higher hazard ratio observed in non-HCM patient (HR, 2.51; 95% CI, 1.59–3.98 vs. HR, 4.77; 95% CI, 4.47–5.09) (P=0.003 for interaction). In non-HCM patients, predictors of AF included age, male sex, body mass index, smoking history, and a history of hypertension, diabetes, heart failure, stroke, and myocardial infarction, in addition to PRS. However, in HCM patients, only age, diabetes, and a history of stroke were identified as independent predictors of AF. Moreover, high genetic risk was significantly associated with the risk of major adverse cardiovascular events. Conclusions In conclusion, our study indicates associations between genetic predisposition and AF occurrence in both HCM and non-HCM patients.

Reverse remodelling and clinical outcomes in patients with chagas cardiomyopathy with reduced ejection fraction

Abstract Introduction Chagas disease affects around 8 million individuals globally and about 30% develop cardiac manifestations and, in time, heart failure with reduced ejection fraction (HFrEF). Chagas cardiomyopathy (CC) patients often have a poorer prognosis compared to other causes of HFrEF, owing to a higher rate of ventricular arrhythmias and thromboembolic conditions. Reverse remodelling (RR) has been linked to enhanced mortality and morbidity outcomes in HFrEF due to non-Chagas causes, but the effect of RR on CC prognosis is still unclear. Methods This retrospective study assessed 1043 patients diagnosed with CC via positive serology for Trypanosoma cruzi infection coupled with cardiopathy and ventricular dysfunction [left ventricular ejection fraction (LVEF) &amp;lt; 40%] during the follow-up period from January 2006 to September 2021. The primary outcome measured included overall mortality and heart transplantation in relation to RR status. Propensity score matching was utilised to adjust for confounding factors. Positive reverse remodelling (PRR) was characterised as patients displaying improved LVEF, and negative reverse remodelling (NRR) as those with persistent ventricular dysfunction during follow-up. Results Initially, 221 (21.2%) were categorised as PRR and 822 (78.8%) as NRR. Participants in the PRR group were predominantly female (51.6% versus 41.4%; p &amp;lt; 0.001), older [59 years (53 – 66) versus 56 years (47 – 64); p = 0.007], more prone to hypertension (43.4% versus 35.8%; p = 0.036), and presented with higher initial heart rates [70 bpm (60 – 80) versus 65 bpm (60 – 75); p = 0.002], systolic blood pressure [120 mmHg (110 – 130) versus 110 mmHg (100 – 120); p &amp;lt; 0.001], diastolic blood pressure [80 mmHg (69 – 82) versus 70 mmHg (60 – 80); p &amp;lt; 0.001], and LVEF [30.0% (26.0 – 35.0) versus 29% (25.0 – 34.0); p &amp;lt; 0.001] compared to the NRR group. Moreover, the PRR group had a lower intake of beta-blockers (BB) (76.6% versus 87.0%; p = 0.004), spironolactone (38.5% versus 59.5%; p &amp;lt; 0.001), and triple therapy (30.9% versus 50.4%; p &amp;lt; 0.001). Following propensity score matching, 200 patients remained for the final analysis, with 100 in each group. Cox proportional hazards model analysis revealed PRR as an independent predictor [hazard ratio (HR): 0.367; 95% confidence interval (CI) 0.218 – 0.616; p &amp;lt; 0.001] of mortality from all causes or heart transplantation. The PRR group exhibited a longer event-free survival duration than the NRR group (10.332 years; 95% CI 9.557 – 11.107 versus 7.348 years; 95% CI 6.606 – 8.089; p &amp;lt; 0.001). Discussion This study suggests a positive association between the PRR and increased survival in patients with CHD and HFrEF. Previously published studies didn’t demonstrate this association, possibly due to the small number of patients included. Conclusion PRR predicts a better long-term survival free from all-cause mortality and cardiac transplantation in Chagas cardiomyopathy with LVEF &amp;lt; 40%.Kaplan-Meier event-free survival curve

Identification and validation of ventricular rhythmic risk subgroups in hypertrophic cardiomyopathy by clustering analysis including left ventricular strain analysis

Abstract Background The excess mortality in hypertrophic cardiomyopathy (HCM) patients is mainly attributed to the occurrence of ventricular arrhythmia (VA).The prediction of VA remains challenging and could be improved. Purpose The study aimed to characterize the VA risk profile in HCM patients through clustering analysis combining conventional parameters with information derived from left ventricular longitudinal strain analysis (LV-LS). Methods 434 HCM patients (65% men, mean age 56 years) were retrospectively included from two referral centers and followed longitudinally (mean duration 6 years). The validation cohort included 177 HCM patients from an other tertiary French center. Mechanical and temporal parameters were automatically extracted from the LV-LS segmental curves of each patient in addition to conventional clinical and imaging data. A total of 287 features were analyzed using a clustering approach (k-means). The first endpoint for VA included suspected SCD, aborted cardiac arrest, appropriate ICD therapy (AIT), sustained ventricular tachycardia (SVT) and non-sustained ventricular tachycardia (NSVT) during follow-up. Results From the derivation cohort, 4 clusters were identified with a higher rhythmic risk for clusters 1 and 4 (VA rates of 26%(28/108), 13%(13/97), 12%(14/120), and 31%(34/109) for cluster 1,2,3 and 4 respectively) (Figure 1). These 4 clusters differed mainly by the LV mechanics. Patients from cluster 4 had a severe and homogeneous decrease of myocardial deformation (global longitudinal strain (GLS) -11%, normal value ≥ -20%) associated with LV and left atrium (LA) remodeling (left atrial volume index (LAVI) 46.6 vs. 41.5 ml/m², p=0.04 and LVEF 59.7 vs. 66.3%, p &amp;lt; 0.001) and impaired exercise capacity (% predicted peak work 58.6 vs. 69.5%; p= 0.025). Patients from cluster 1 showed a marked deformation delay and temporal dispersion on the segmental analysis associated with a moderate decrease of the GLS (-15.3%; p &amp;lt;0.0001 for GLS comparison between clusters). Patients from clusters 2 and 3 had a small GLS decrease (GLS -17.2 and -16.3%, respectively) with a less severe phenotype for cluster 2 and older patients for cluster 3 (mean age 62.1 vs. 54.1 years; p &amp;lt; 0.0001). The clustering analysis in the validation population resulted in the creation of 4 clusters overlapping the derivation cohort with similar characteristics (Figure 2). Clusters 1’ and 4’ had a higher incidence of ventricular arrhythmia with a VA rate of 22%(5/23), 18%(16/88), 0%(0/17), and 20%(10/49) for clusters 1’,2’,3’ and 4’ respectively. Conclusion Machine-learning-based cluster analysis processing LV-LS parameters in HCM patients identified 4 clusters with specific LV-strain patterns and different rhythmic risk levels. In the future, the automatic extraction and analysis of LV strain parameters could help to improve the risk stratification for SCD in HCM patients.Clustering analysisExternal validation