Relationship between obesity and hypertrophic or dilated cardiomyopathy: The role of sex.

Evidence suggests an association between obesity and the risk for cardiomyopathy development; however, robust evidence is still lacking. In this study we sought to explore the relationship of obesity with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) and possible interactions with sex using large-scale epidemiological real-world data. We analysed data from the Nationwide Inpatient Sample of US hospitalisations for the years 2015-2019. There were a total of 46 934 admissions with diagnosis of HCM and 170 924 with DCM. There was a significant interaction between cardiomyopathies' diagnosis with sex and age subgroups; the rates of both DCM and HCM increased with age (p < .001 for both); DCM diagnosis was significantly higher in males compared with females (0.85% vs. 0.35%, p < .001). After adjustment for age, sex, race and presence of arterial hypertension there was a significant stepwise positive association between obesity and the population rates of both cardiomyopathy subtypes. For hospitalised patients with a body mass index (BMI) ≥30 kg/m2 there was an odds ratio (OR) of 1.68 (95% CI: 1.55-1.81, p < .001) for HCM and OR = 1.82 (95% CI: 1.79-1.84, p < .001) for DCM. More importantly, the positive relationship between a cardiomyopathy diagnosis (HCM or DCM) with increasing BMI was driven by the male sex (p < .001 for both) and it was non-significant in females. The findings from this nationwide observational analysis support a sexual dimorphism in the relationship between obesity and HCM or DCM, which should be further investigated.

Subcutaneous versus transvenous implantable cardioverter defibrillator in hypertrophic cardiomyopathy: a systematic review and meta-analysis.

Background: A subcutaneous implantable cardioverter-defibrillator (S-ICD) is an alternative to a transvenous implantable cardio defibrillator (TV-ICD). An S-ICD reduces the risk of transvenous lead placement. However, further research is required to determine how S-ICDs affect patients with hypertrophic cardiomyopathy (HCM). In this study, we investigated the comparative efficacy and safety of S-ICDs versus TV-ICDs in HCM. Methods: On December 6th, 2023, we performed a comprehensive search of the PubMed, Embase, Scopus, and Cochrane databases to identify randomized clinical trials (RCTs) and observational studies comparing S-ICDs with TV-ICDs in HCM patients published from 2004 until 2023. No language restrictions were applied. The primary outcome was appropriate shocks (AS), with inappropriate shocks (IAS), and device-related complications considered as secondary outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using a random effects model. The ROBINS-I tool was used to assess the risk of bias of the studies. Results: The search yielded 1,114 records. Seven studies comprising 4,347 HCM patients were included, of whom 3,325 (76.0%) had TV-ICDs, and 1,022 (22.6%) had S-ICDs. There were 2,564 males (58.9%). The age range was from 39.1 to 49.4 years. Compared with the TV-ICD group, the S-ICD cohort had a significantly lower incidence of device-related complications (OR 0.52; 95% CI: 0.30-0.89; P=0.02; I2=4%). Contrastingly, there were no statistically significant differences in the occurrences of AS (OR 0.49; 95% CI: 0.22-1.08; P=0.08; I2=75%) and IAS (OR 1.03; 95% CI: 0.57-1.84; P=0.93; I2=65%) between the two device modalities. In the analysis of the overall risk of bias in the studies, we found 42% of them with several, 28% with moderate, and 14% with low risk of bias. Conclusions: In HCM patients, S-ICDs were associated with a lower incidence of device-associated problems than TV-ICDs. AS and IAS incidence rates were similar between groups. These findings may assist clinicians in determining the most suitable device for treating patients with HCM.

Is Type 2 Diabetes Mellitus an Independent Risk Factor for Mortality in Hypertrophic Cardiomyopathy?

Background: The mortality rate of hypertrophic cardiomyopathy (HCM) has decreased between 1999 and 2020. The risk factors for sudden cardiac death (SCD) in HCM were updated in the American Heart Association (AHA)/American College of Cardiology Foundation (ACCF) 2020 guidelines by adding new risk factors, like the late gadolinium enhancement on cardiac magnetic resonance imaging (MRI). Type 2 diabetes mellitus (T2DM) is a major risk factor for most cardiac diseases; however, it is not included in these guidelines due to a lack of strong evidence of a correlation between T2DM and mortality in HCM. Therefore, we sought to investigate if T2DM increases the 5-year risk rate for adverse outcomes, such as heart failure and all-cause mortality in patients with HCM. Methods: We collected patient data from January 1, 2018, to March 1, 2023, using the TriNetX database. The sample included 80,502 individuals with HCM, then divided into two cohorts based on the absence (58,573; cohort 1) or presence (15,296; cohort 2) of T2DM. The two matched groups then underwent survival and risk analyses for all-cause mortality or the first incidence of heart failure diagnosis within 5 years from the point in time when the selection criteria were first met. Results: We found a statistically significant increase in all-cause mortality and new-onset heart failure in HCM patients with diabetes compared to those without diabetes after adjusting for major risk factors. Conclusions: This is one of the largest retrospective cohort studies that examined the correlation between T2DM and adverse outcomes in patients with HCM. This underlines the need for future prospective studies investigating the effects of T2DM on HCM outcomes.

Hypertrophic Cardiomyopathy: From Medical Treatment to Advanced Heart Failure Therapies.

PURPOSE OF REVIEW: There has been much debate surrounding novel medical therapies and heart transplantation listing challenges in patients with hypertrophic cardiomyopathy (HCM). RECENT FINDINGS: Recent clinical trials led to FDA approval of mavacamten (a cardiac myosin inhibitor), offering symptom relief and potentially delaying/avoiding invasive septal reduction therapies for some patients with HCM and left ventricular outflow obstruction (LVOTO). For those with refractory symptoms and end-stage heart failure, heart transplantation remains the gold standard. However, the concern for the organ allocation system failing to prioritize those individuals persists. HCM is a heterogeneous genetic condition with variable penetration and clinical presentation. Even though a large portion of patients remain asymptomatic, an important minority develops debilitating symptoms refractory to medical therapy. Post-HT short- and long-term outcomes are favorable. However, HT waitlist mortality remains high. For highly selected patients with HCM, a left ventricular assist device is a viable option.

Causal relationship between gut microbiota and pathological scars: a two-sample Mendelian randomization study.

Background: Pathological scars, including keloids and hypertrophic scars, represent a significant dermatological challenge, and emerging evidence suggests a potential role for the gut microbiota in this process. Methods: Utilizing a two-sample Mendelian randomization (MR) methodology, this study meticulously analyzed data from genome-wide association studies (GWASs) relevant to the gut microbiota, keloids, and hypertrophic scars. The integrity and reliability of the results were rigorously evaluated through sensitivity, heterogeneity, pleiotropy, and directionality analyses. Results: By employing inverse variance weighted (IVW) method, our findings revealed a causal influence of five bacterial taxa on keloid formation: class Melainabacteria, class Negativicutes, order Selenomonadales, family XIII, and genus Coprococcus2. Seven gut microbiota have been identified as having causal relationships with hypertrophic scars: class Alphaproteobacteria, family Clostridiaceae1, family Desulfovibrionaceae, genus Eubacterium coprostanoligenes group, genus Eubacterium fissicatena group, genus Erysipelotrichaceae UCG003 and genus Subdoligranulum. Additional sensitivity analyses further validated the robustness of the associations above. Conclusion: Overall, our MR analysis supports the hypothesis that gut microbiota is causally linked to pathological scar formation, providing pivotal insights for future mechanistic and clinical research in this domain.

Safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy: A 36-week analysis from FOREST-HCM.

AIMS: The aim of this study was to report safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) over 36 weeks in the ongoing FOREST-HCM trial. METHODS AND RESULTS: Patients were started on aficamten 5 mg daily, with doses adjusted in 5-mg increments (5-20 mg) at ≥2-week intervals according to site-read left ventricular ejection fraction (LVEF). Aficamten dose was increased if LVEF ≥55%, maintained if LVEF 50-54%, decreased if LVEF 40-<50%, and temporarily interrupted if LVEF <40%. Safety and efficacy were assessed over 36 weeks. Overall, 34 patients were enrolled (mean age 57.2 ± 15.3 years, 62% female, 41% in New York Heart Association [NYHA] class III). Over 36 weeks, 82.3% achieved 15-20 mg daily dose and there was a modest reduction in LVEF by -4.3% ± 5.2 from 70% ± 6.1 (p < 0.0001). At Week 36, NYHA class improved by ≥1 class in 27 (79.4%) patients. Mean Kansas City Cardiomyopathy Questionnaire clinical summary score improved by 13.8 ± 12.5 points relative to baseline. Median (interquartile range) levels of N-terminal pro-B-type natriuretic peptide were significantly improved from baseline (-665.5 pg/ml [-1244.0, -232.0]; p < 0.0001), while high-sensitivity cardiac troponin I was unchanged (-2.7 ng/L [-11.3, 1.6]; p = 0.25). There were no drug discontinuations due to adverse events. LVEF <50% occurred in 2 (5.9%) patients, one following pulmonary vein isolation and one associated with atrial fibrillation. CONCLUSIONS: Over 36 weeks, aficamten appeared safe and effective in the studied patients with nHCM.

Analysis of risk factors for complications in echocardiography-guided percutaneous intramyocardial septal radiofrequency ablation.

BACKGROUND: The feasibility of percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) for the treatment of hypertrophic obstructive cardiomyopathy (HOCM) has been previously reported. However, limited investigation has been conducted regarding the complications associated with this procedure. OBJECTIVE: This study aims to analyze the risk factors affecting the occurrence of complications during PIMSRA, such as pericardial effusion, ventricular premature beats, and interventricular septal perforation. In this study, the optimal cut-off values for these risk factors are also explored, and corresponding strategies for prevention are proposed. METHODS: A total of 101 patients diagnosed with HOCM who underwent the PIMSRA procedure from 2021 to 2022 were included in this retrospective analysis. Patients were classified into subgroups with or without complications based on procedural records. Univariate and multivariate regression analyses were conducted to identify independent risk factors for complications during the PIMSRA procedure. RESULTS: There were 48 patients with complications and 53 patients without complications. The heart rate at the start of the procedure and the maximum left ventricular outflow tract gradient (LVOTG) were independent risk factors related to PIMSRA complications. The optimal cut-off values for predicting complication occurrence were a heart rate > 49 bpm at the start of the procedure (OR: 3.79, 95% CI: 1.64-8.78, p = 0.002) and a maximum LVOTG > 92 mmHg (OR: 2.57, 95% CI: 1.15-5.75, p = 0.022), respectively. CONCLUSIONS: The occurrence of PIMSRA complications is primarily associated with the heart rate at the start of the procedure and the maximum LVOTG. It is recommended to establish a comprehensive control plan to minimize the risk of complications during PIMSRA procedures.

The Presence and Severity of Inferior Turbinate Hypertrophy in Patients with Hypertrophic Scars.

Objectives: This study aimed to investigate the presence and severity of inferior turbinate hypertrophy (ITH) in patients with hypertrophic scars (HTS). Methods: This case-control study was conducted with patients diagnosed with HTS during dermatologic examination and a control group without HTS. An otolaryngologist evaluated the presence and severity of inferior turbinate hypertrophy by anterior rhinoscopy. Results: ITH was more common in patients with HTS compared to the control group (64%, and 34%, respectively) (p=0.014). In the HTS group, 48% of patients had grade 2, and 16% had grade 3 ITH; in the control group, 24% had grade 2, and 10% had grade 3 ITH (p=0.046). Also, ITH was higher in patients who complained of pruritus or pain (83%, and 80%, respectively) in the HTS than in asymptomatic HTS patients (p=0.020). Conclusion: A higher number of patients with HTS had ITH compared to the control group, especially those who reported pruritus or pain associated with scar. Given the limited understanding of the full pathogenesis and treatment of HTS and ITH, their association potentially provides new insights into these related conditions.

Spectrum and genotype-phenotype relationship of ALPK3 variants in Chinese patients with hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, and it has obvious genetic and clinical heterogeneity. Recently, heterozygous ALPK3 truncating variants (ALPK3tv) have been shown to cause HCM. However, the spectrum of ALPK3 variants and their relationships with the clinical characteristics of Chinese patients with HCM remain to be elucidated. Methods and results: Whole-exome sequencing data from 986 patients with HCM and 761 controls without HCM were utilized to analyze ALPK3 variants. Eleven ALPK3tv were detected in 18 patients with HCM (1.8 %), while no such variants were identified in controls. We also detected 21 rare ALPK3 missense variants in 16 patients with HCM (1.6 %) and 8 controls (1.1 %), respectively. ALPK3tv were significantly enriched in patients with HCM (P < 0.001), whereas the prevalence of missense variants was comparable between the HCM and control groups (P = 0.309). Patients with ALPK3tv exhibited a significantly lower left ventricular outflow tract gradient (P = 0.011) and a higher prevalence of apical HCM (27.8 %; P = 0.008). Conclusions: Our study supports that heterozygous ALPK3tv, but not APLK3 missense variants, are a genetic cause of HCM. Patients with HCM carrying ALPK3tv have a greater likelihood of developing apical HCM.

Scar outcomes for conservatively managed children post burn injury: A retrospective study.

Hypertrophic scarring is a significant complication post burn injury, especially for delayed healing after 3 weeks. Burn injuries healing prior to 3 weeks also have the potential to develop hypertrophic scarring, even when prescribed prophylactic conservative scar interventions. A retrospective chart audit reviewed 326 burn patients treated at a paediatric tertiary hospital from 2014 to 2019 who sustained a partial thickness burn, healed >14 days and did not receive skin grafting. A scar was deemed hypertrophic if >1 mm in height. Early hypertrophic scar prevalence was defined as 3-6 months post burn, while persistent hypertrophic scarring was defined as 12-18 months post burn. Median days to wound closure was 18. The prevalence of early and persistent hypertrophic scarring was 56.1% and 16.3%, respectively. Seventeen (5.2%) children underwent medical interventions for scar modulation. Early signs of hypertrophic scarring were seen in just over half the patients presenting to burn therapy and despite scar intervention, persistent hypertrophic scarring was seen in 16.3%. At both time points, just over half of the children presenting healed between 14 and 21 days. Therefore, children healing prior to 21 days have potential to develop hypertrophic scarring.

The D-HCM score, a new diagnostic tool for distinguishing hypertrophic cardiomyopathy from hypertensive cardiopathy.

AIM: The diagnosis of hypertrophic cardiomyopathy (HCM) with moderate hypertrophy is challenging. Hypertensive heart disease (HHD) is the most common differential diagnosis that mimics the LVH of HCM. The aim of this study was to compare the QRS duration in HCM and HHD to create a novel diagnostic tool to identify primary HCM. METHODS AND RESULTS: We conducted an international retrospective multicentre study enrolling patients with true HCM and HHD. A total of 547 individuals with HCM and 139 with HHD were included. The median QRS duration was significantly shorter in HCM than in HHD (88 ms [80-94] vs. 98 ms [88-108]; P < 0.01). Multivariable logistic regression identified for the novel diagnostic HCM (D-HCM) score: absence of antihypertensive drugs (+2); family history of unexplained sudden death (+2); QRS duration [<95 ms] = +1; maximum wall thickness (mm) [≥17] = +1. A cumulative QRS-HCM score ≥2 supports the diagnostic certainty of true HCM with a sensitivity of 79%, specificity of 99%, negative predictive value (NPV) of 55%, and positive predictive value (PPV) of 99%. CONCLUSION: The QRS duration in patient with HCM is significantly shorter compared with patients with HHD-related LVH. QRS duration can be used as a diagnosis marker to distinguish between HCM and HHD. The D-HCM score is a novel, simple, and accurate diagnosis tool for HCM patients with mild to moderate phenotypes.

Metabolic remodeling and calcium handling abnormality in induced pluripotent stem cell-derived cardiomyocytes in dilated phase of hypertrophic cardiomyopathy with MYBPC3 frameshift mutation.

Hypertrophic cardiomyopathy (HCM) is an inherited disorder characterized by left ventricular hypertrophy and diastolic dysfunction, and increases the risk of arrhythmias and heart failure. Some patients with HCM develop a dilated phase of hypertrophic cardiomyopathy (D-HCM) and have poor prognosis; however, its pathogenesis is unclear and few pathological models exist. This study established disease-specific human induced pluripotent stem cells (iPSCs) from a patient with D-HCM harboring a mutation in MYBPC3 (c.1377delC), a common causative gene of HCM, and investigated the associated pathophysiological mechanisms using disease-specific iPSC-derived cardiomyocytes (iPSC-CMs). We confirmed the expression of pluripotent markers and the ability to differentiate into three germ layers in D-HCM patient-derived iPSCs (D-HCM iPSCs). D-HCM iPSC-CMs exhibited disrupted myocardial sarcomere structures and an increased number of damaged mitochondria. Ca2+ imaging showed increased abnormal Ca2+ signaling and prolonged decay time in D-HCM iPSC-CMs. Cell metabolic analysis revealed increased basal respiration, maximal respiration, and spare-respiratory capacity in D-HCM iPSC-CMs. RNA sequencing also showed an increased expression of mitochondrial electron transport system-related genes. D-HCM iPSC-CMs showed abnormal Ca2+ handling and hypermetabolic state, similar to that previously reported for HCM patient-derived iPSC-CMs. Although further studies are required, this is expected to be a useful pathological model for D-HCM.

Identification of differentially expressed genes to predict the risk of heart failure in older patients with hypertrophic cardiomyopathy.

AIM: Hypertrophic cardiomyopathy (HCM) is a common heart disease. Old people with HCM are at high risk of heart failure (HF). This study aimed to identify differentially expressed genes (DEGs) to evaluate the risk of HF in older patients with HCM. METHODS: GSE89714 and GSE116250 were downloaded from Gene Expression Omnibus (GEO) database, and DEGs were identified by using limma R package with P < 0.05 and logFC> 1 as cut off. Protein-protein interaction (PPI) network, Genome Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for the identified DEGs. NetworkAnalyst online tool was applied for Gene Set Enrichment Analysis (GSEA) analysis. RESULTS: We identified 124 overlap DEGs from the 2 datasets. PPI network showed that COL1A1, COL3A1, COL1A2, BGN, COL5A1, LUM, TGFB2, FMOD, ASPN, and COL14A1 were the top ten genes related to HCM and HF compared with control. Functional and pathway analyses showed that the overlap genes were mainly related to ECM-receptor interaction, ECM organization, Focal adhesion, PI3K-Akt signaling, TGF-beta signaling, and Platelet activation signaling and aggregation. Among the overlap genes, COL5A1 and LUM were significantly upregulated, while TGFB2, FMOD, ASPN, and COL14A1 were significantly downregulated in HF dataset compared with HCM dataset. CONCLUSIONS: Bioinformatics-based analysis revealed potential genes associated with HCM and HF, which could be utilized to evaluate the risk of HF in older patients with HCM.

Graphene Quantum Dots Reduce Hypertrophic Scar by Inducing Myofibroblasts To Be a Quiescent State.

Contrary to the initial belief that myofibroblasts are terminally differentiated cells, myofibroblasts have now been widely recognized as an activation state that is reversible. Therefore, strategies targeting myofibroblast to be a quiescent state may be an effective way for antihypertrophic scar therapy. Graphene quantum dots (GQDs), a novel zero-dimensional and carbon-based nanomaterial, have recently garnered significant interest in nanobiomedicine, owing to their excellent biocompatibility, tunable photoluminescence, and superior physiological stability. Although multiple nanoparticles have been used to alleviate hypertrophic scars, a GQD-based therapy has not been reported. Our in vivo studies showed that GQDs exhibited significant antiscar efficacy, with scar appearance improvement, collagen reduction and rearrangement, and inhibition of myofibroblast overproliferation. Further in vitro experiments revealed that GQDs inhibited α-SMA expression, collagen synthesis, and cell proliferation and migration, inducing myofibroblasts to become quiescent fibroblasts. Mechanistic studies have demonstrated that the effect of GQDs on myofibroblast proliferation blocked cell cycle progression by disrupting the cyclin-CDK-E2F axis. This study suggests that GQDs, which promote myofibroblast-to-fibroblast transition, could be a novel antiscar nanomedicine for the treatment of hypertrophic scars and other types of pathological fibrosis.

Distal Ventricular Pacing for Drug-Refractory Mid-Cavity Obstructive Hypertrophic Cardiomyopathy: A Randomized, Placebo-Controlled Trial of Personalized Pacing.

BACKGROUND: Patients with refractory, symptomatic left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy have few therapeutic options. Right ventricular pacing is associated with modest hemodynamic and symptomatic improvement, and LV pacing pilot data suggest therapeutic potential. We hypothesized that site-specific pacing would reduce LVMCO gradients and improve symptoms. METHODS: Patients with symptomatic-drug-refractory LVMCO were recruited for a randomized, blinded trial of personalized prescription of pacing (PPoP). Multiple LV and apical right ventricular pacing sites were assessed during an invasive hemodynamic study of multisite pacing. Patient-specific pacing-site and atrioventricular delays, defining PPoP, were selected on the basis of LVMCO gradient reduction and acceptable pacing parameters. Patients were randomized to 6 months of active PPoP or backup pacing in a crossover design. The primary outcome examined invasive gradient change with best-site pacing. Secondary outcomes assessed quality of life and exercise following randomization to PPoP. RESULTS: A total of 17 patients were recruited; 16 of whom met primary end points. Baseline New York Heart Association was 3±0.6, despite optimal medical therapy. Hemodynamic effects were assessed during pacing at the right ventricular apex and at a mean of 8 LV sites. The gradients in all 16 patients fell with pacing, with maximum gradient reduction achieved via LV pacing in 14 (88%) patients and right ventricular apex in 2. The mean baseline gradient of 80±29 mm Hg fell to 31±21 mm Hg with best-site pacing, a 60% reduction (P<0.0001). One cardiac vein perforation occurred in 1 case, and 15 subjects entered crossover; 2 withdrawals occurred during crossover. Of the 13 completing crossover, 9 (69%) chose active pacing in PPoP configuration as preferred setting. PPoP was associated with improved 6-minute walking test performance (328.5±99.9 versus 285.8±105.5 m; P=0.018); other outcome measures also indicated benefit with PPoP. CONCLUSIONS: In a randomized placebo-controlled trial, PPoP reduces obstruction and improves exercise performance in severely symptomatic patients with LVMCO. REGISTRATION: URL: https://clinicaltrials.gov/study; Unique Identifier: NCT03450252.

High prevalence of ALPK3 premature terminating variants in Korean hypertrophic cardiomyopathy patients.

Background: The alpha-protein kinase 3 (ALPK3) gene (OMIM: 617608) is associated with autosomal recessive familial hypertrophic cardiomyopathy-27 (CMH27, OMIM: 618052). Recently, several studies have shown that monoallelic premature terminating variants (PTVs) in ALPK3 are associated with adult-onset autosomal dominant hypertrophic cardiomyopathy (HCMP). However, these studies were performed on patient cohorts mainly from European Caucasian backgrounds. Methods: To determine if this finding is replicated in the Korean HCMP cohort, we evaluated 2,366 Korean patients with non-syndromic HCMP using exome sequencing and compared the cohort dataset with three independent population databases. Results: We observed that monoallelic PTVs in ALPK3 were also significantly enriched in Korean patients with HCMP with an odds ratio score of 10-21. Conclusions: We suggest that ALPK3 PTV carriers be considered a risk group for developing HCMP and be monitored for cardiomyopathies.