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Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Signaling pathways that link genetic sequence variants to clinically overt HCM and progression to severe forms of HCM remain unknown., Objectives: The purpose of this study was to identify signaling pathways that are differentially regulated in HCM, using proteomic profiling of human myocardium, confirmed with transcriptomic profiling., Methods: In this multicenter case-control study, myocardial samples were obtained from cases with HCM and control subjects with nonfailing hearts. Proteomic profiling of 7,289 proteins from myocardial samples was performed using the SomaScan assay (SomaLogic). Pathway analysis of differentially expressed proteins was performed, using a false discovery rate <0.05. Pathway analysis of proteins whose concentrations correlated with clinical indicators of severe HCM (eg, reduced left ventricular ejection fraction, atrial fibrillation, and ventricular tachyarrhythmias) was also executed. Confirmatory analysis of differentially expressed genes was performed using myocardial transcriptomic profiling., Results: The study included 99 HCM cases and 15 control subjects. Pathway analysis of differentially expressed proteins revealed dysregulation of the Ras-mitogen-activated protein kinase, ubiquitin-mediated proteolysis, angiogenesis-related (eg, hypoxia-inducible factor-1, vascular endothelial growth factor), and Hippo pathways. Pathways known to be dysregulated in HCM, including metabolic, inflammatory, and extracellular matrix pathways, were also dysregulated. Pathway analysis of proteins associated with clinical indicators of severe HCM and of differentially expressed genes supported these findings., Conclusions: The present study represents the most comprehensive (>7,000 proteins) and largest-scale (n = 99 HCM cases) proteomic profiling of human HCM myocardium to date. Proteomic profiling and confirmatory transcriptomic profiling elucidate dysregulation of both newly recognized (eg, Ras-mitogen-activated protein kinase) and known pathways associated with pathogenesis and progression to severe forms of HCM., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health (R01 HL157216 and R01 HL168382 to Dr Shimada, UL1 TR001873 to Dr Reilly, K24 HL107643 to Dr Reilly, K24 AG036778 to Dr Maurer, R01 HL170132 to Dr Topkara, R01 HL131872 to Dr Ferrari, and T32 HL007854 to Dr Lumish), the American Heart Association (2 National Clinical and Population Research Awards, 1 Career Development Award, and 1 Transformational Project Award to Dr Shimada), Korea Institute of Oriental Medicine (W22005 to Dr Shimada), Feldstein Medical Foundation (to Dr Shimada), Columbia University Irving Medical Center Precision Medicine Pilot Award (to Dr Shimada), and Columbia University Irving Medical Center Marjorie and Lewis Katz Cardiovascular Research Prize (to Dr Shimada). The funding organizations did not have any role in the study design, collection, analysis, or interpretation of data, in writing of the manuscript, or in the decision to submit the paper for publication. The researchers were independent from the funding organizations. Dr Maurer has received consulting income from Akcea, Alnylam, Eidos Therapeutics, Pfizer, Prothena, Novo Nordisk, and Intellia. Dr Shimada has received research funding from Bristol Myers Squibb; and has received consulting income from Bristol Myers Squibb and Moderna Japan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Distinguishing hypertrophic cardiomyopathy (HCM) from other cardiomyopathies with left ventricular hypertrophy (LVH), such as hypertensive LVH, transthyretin amyloid cardiomyopathy (ATTR-CM), and aortic stenosis (AS), is sometimes challenging. Using plasma proteomics profiling, we aimed to identify circulating biomarkers and dysregulated signaling pathways specific to HCM. Methods: In this multicenter case-control study, plasma proteomics profiling was performed in cases with HCM and controls with hypertensive LVH, ATTR-CM, and AS. Two-thirds of patients enrolled earlier in each disease group were defined as the training set, and the remaining one-third as the test set. Protein concentrations in HCM were compared with those in hypertensive LVH (comparison 1), ATTR-CM (comparison 2), and AS (comparison 3). Candidate proteins that meet the following 2 criteria were selected: (1) Higher abundance in HCM throughout all 3 comparisons or lower abundance in HCM throughout all 3 comparisons with univariable P<0.05 and |log 2 (fold change)| >0.5 in both the training and test sets and (2) Independently associated with HCM with multivariable P<0.05 after adjusting for clinical parameters significantly different between HCM and controls. Using the selected candidate proteins, a logistic regression model to distinguish HCM from controls was developed in the training set and applied to the test set. Finally, pathway analysis was performed in each comparison using proteins with different abundance. Results: Overall, 4,979 proteins in 1,415 patients (HCM, n=879; hypertensive LVH, n=331; ATTR-CM, n=169; AS, n=36) were analyzed. Of those, 5 proteins were selected as candidate proteins. The logistic regression model with these 5 proteins had an area under the receiver-operating-characteristic curve of 0.86 (95% CI 0.82-0.89) in the test set. The MAPK and HIF-1 pathways were dysregulated in HCM throughout the 3 comparisons. Conclusions: This study identified circulating biomarkers that distinguish HCM from other cardiomyopathies with LVH independently from confounders and revealed signaling pathways associated with HCM.

Aims: Atrial fibrillation (AF) is the most common sustained arrhythmia among patients with hypertrophic cardiomyopathy (HCM), increasing symptom burden and stroke risk. We aimed to construct a plasma proteomics-based model to predict new-onset AF in patients with HCM and determine dysregulated signalling pathways., Methods and Results: In this prospective, multi-centre cohort study, we conducted plasma proteomics profiling of 4986 proteins at enrolment. We developed a proteomics-based machine learning model to predict new-onset AF using samples from one institution (training set) and tested its predictive ability using independent samples from another institution (test set). We performed a survival analysis to compare the risk of new-onset AF among high- and low-risk groups in the test set. We performed pathway analysis of proteins significantly (univariable P < 0.05) associated with new-onset AF using a false discovery rate (FDR) threshold of 0.001. The study included 284 patients with HCM (training set: 193, test set: 91). Thirty-seven (13%) patients developed AF during median follow-up of 3.2 years [25-75 percentile: 1.8-5.2]. Using the proteomics-based prediction model developed in the training set, the area under the receiver operating characteristic curve was 0.89 (95% confidence interval 0.78-0.99) in the test set. In the test set, patients categorized as high risk had a higher rate of developing new-onset AF (log-rank P = 0.002). The Ras-MAPK pathway was dysregulated in patients who developed incident AF during follow-up (FDR < 1.0 × 10-6)., Conclusion: This is the first study to demonstrate the ability of plasma proteomics to predict new-onset AF in HCM and identify dysregulated signalling pathways., Competing Interests: Conflict of interest: Y.J.S. has received research funding from Bristol Myers Squibb and consulting income from Bristol Myers Squibb and Moderna Japan. M.S.M. has received consulting income from Akcea, Alnylam, Eidos Therapeutics, Pfizer, Prothena, Novo Nordisk, and Intellia. All remaining authors have declared no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Hypertrophic cardiomyopathy (HCM) can cause myocardial fibrosis, which can be a substrate for fatal ventricular arrhythmias and subsequent sudden cardiac death. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) represents myocardial fibrosis and is associated with sudden cardiac death in patients with HCM, CMR is resource-intensive, can carry an economic burden, and is sometimes contraindicated. In this study for patients with HCM, we aimed to distinguish between patients with positive and negative LGE on CMR using deep learning of echocardiographic images., Methods: In the cross-sectional study of patients with HCM, we enrolled patients who underwent both echocardiography and CMR. The outcome was positive LGE on CMR. Among the 323 samples, we randomly selected 273 samples (training set) and employed deep convolutional neural network (DCNN) of echocardiographic 5-chamber view to discriminate positive LGE on CMR. We also developed a reference model using clinical parameters with significant differences between patients with positive and negative LGE. In the remaining 50 samples (test set), we compared the area under the receiver-operating-characteristic curve (AUC) between a combined model using the reference model plus the DCNN-derived probability and the reference model., Results: Among the 323 CMR studies, positive LGE was detected in 160 (50%). The reference model was constructed using the following 7 clinical parameters: family history of HCM, maximum left ventricular (LV) wall thickness, LV end-diastolic diameter, LV end-systolic volume, LV ejection fraction < 50%, left atrial diameter, and LV outflow tract pressure gradient at rest. The discriminant model combining the reference model with DCNN-derived probability significantly outperformed the reference model in the test set (AUC 0.86 [95% confidence interval 0.76-0.96] vs. 0.72 [0.57-0.86], P = 0.04). The sensitivity, specificity, positive predictive value, and negative predictive value of the combined model were 0.84, 0.76, 0.78, and 0.83, respectively., Conclusion: Compared to the reference model solely based on clinical parameters, our new model integrating the reference model and deep learning-based analysis of echocardiographic images demonstrated superiority in distinguishing LGE on CMR in patients with HCM. The novel deep learning-based method can be used as an assistive technology to facilitate the decision-making process of performing CMR with gadolinium enhancement., (© 2024. The Author(s).)

For many years, treatment of hypertrophic cardiomyopathy (HCM) has focused on non-disease-specific therapies. Cardiac myosin modulators (ie, mavacamten and aficamten) reduce the pathologic actin-myosin interactions that are characteristic of HCM, leading to improved cardiac energetics and reduction in hypercontractility. Several recently published randomized clinical trials have demonstrated that mavacamten improves exercise capacity, left ventricular outflow tract obstruction and symptoms in patients with obstructive HCM and may delay the need for septal-reduction therapy. Long-term data in real-world populations will be needed to fully assess the safety and efficacy of mavacamten. Importantly, HCM is a complex and heterogeneous disease, and not all patients will respond to mavacamten; therefore, careful patient selection and shared decision making will be necessary in guiding the use of mavacamten in obstructive HCM., Competing Interests: Disclosures YJS has received research funding from Bristol Myers Squibb and consulting income from Bristol Myers Squibb and Moderna Japan. MSM has received consulting income from Akcea, Alnylam, Eidos Therapeutics, Pfizer, Prothena, Novo Nordisk, and Intellia., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Backgrounds and Aims: Hypertrophic cardiomyopathy (HCM) causes cardiac death through both sudden cardiac death (SCD) and death due to heart failure (HF). Although adipokines lead to adverse cardiac remodeling in HCM, the prognostic value of plasma adipokines in HCM remains unknown. We aimed to predict cardiac death in patients with HCM using plasma adipokines., Methods and Results: We performed a multicenter prospective cohort study of patients with HCM. The outcome was cardiac death including heart transplant, death due to HF, and SCD. With data from 1 institution (training set), a prediction model was developed using random forest classification algorithm based on 10 plasma adipokines. The performance of the prediction model adjusted for 8 clinical parameters was examined in samples from another institution (test set). Time-to-event analysis was performed in the test set to compare the rate of outcome events between the low-risk and high-risk groups determined by the prediction model. In total, 389 (267 in the training set; 122 in the test set) patients with HCM were included. During the median follow-up of 2.7 years, 21 patients experienced the outcome event. The area under the covariates-adjusted receiver-operating characteristics curve was 0.89 (95 % confidence interval [CI] 0.71-0.99) in the test set. revealed the high-risk group had a significantly higher risk of cardiac death (hazard ratio 17.8, 95 % CI 2.1-148.3, P = 0.008)., Conclusion: The present multicenter prospective study demonstrated that a panel of plasma adipokines predicts cardiac death in patients with HCM., Competing Interests: Declaration of competing interest This work was supported by the National Institutes of Health [R01 HL157216 and R01 HL168382 to Y.J.S., UL1 TR001873 to M.P.R., K24 HL107643 to M.P.R., and K24 AG036778 to M.S.M.], the American Heart Association [2 National Clinical and Population Research Awards and Career Development Award to Y.J.S.], Korea Institute of Oriental Medicine [W22005 to Y.J.S.], Feldstein Medical Foundation to Y.J.S., Columbia University Irving Medical Center Irving Institute for Clinical & Translational Research Precision Medicine Pilot Award to Y.J.S., and Columbia University Irving Medical Center Marjorie and Lewis Katz Cardiovascular Research Prize to Y.J.S. Y.J.S. has also received funding from Bristol-Myers Squibb, and consulting income from Bristol-Myers Squibb and Moderna Japan. M.S.M. has also received consulting income from Akcea, Alnylam, Eidos Therapeutics, Pfizer, Prothena, Novo Nordisk, and Intellia. The funding organizations did not have any role in the study design, collection, analysis, or interpretation of data, in writing of the manuscript, or in the decision to submit the article for publication. The researchers were independent from the funding organizations., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. A subset of patients experience major adverse cardiovascular events (MACEs), including arrhythmias, strokes and heart failure. However, the molecular mechanisms underlying MACEs in HCM are still not well understood. Therefore, we conducted a multicenter case-control study of patients with HCM, comparing those with and without prior histories of MACEs to identify dysregulated signaling pathways through plasma proteomics profiling., Methods: We performed plasma proteomics profiling of 4986 proteins. We developed a proteomics-based discrimination model in patients enrolled at 1 institution (training set) and externally validated the model in patients enrolled at another institution (test set). We performed pathway analysis of proteins dysregulated in patients with prior MACEs., Results: A total of 402 patients were included, with 278 in the training set and 124 in the test set. In this cohort, 257 (64%) patients had prior MACEs (172 in the training set and 85 in the test set). Using the proteomics-based model from the training set, the area under the receiver operating characteristic curve was 0.82 (95% confidence interval, 0.75-0.90) in the test set. Patients with prior MACEs demonstrated dysregulation in pathways known to be associated with MACEs (eg, TGF-β) and novel pathways (eg, Ras-MAPK and associated pathways)., Conclusions: In this multicenter study of 402 patients with HCM, we identified both known and novel pathways dysregulated in a subset of patients with more advanced disease., Competing Interests: Disclosures None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Alcohol septal ablation (ASA) and septal myectomy (SM) are 2 options for septal reduction therapy (SRT) to treat medication-resistant symptomatic obstructive hypertrophic cardiomyopathy (HCM). Because differences in mortality rates after these different SRT methods have not been extensively investigated in real-world settings, in this study compared the 1-year mortality rates after ASA and SM using population-based database. Methods and Results: Utilizing New York Statewide Planning and Research Cooperative System (SPARCS) data from 2005 to 2016, we performed a comparative effectiveness study of ASA vs. SM in patients with HCM. The outcome was all-cause death up to 360 days after SRT. We constructed a multivariable logistic regression model and performed sensitivity analysis with propensity score (PS)-matching and inverse probability of treatment weighting (IPTW) methods. We identified 755 patients with HCM who underwent SRT: 348 with ASA and 407 with SM. The multivariable analysis showed that all-cause deaths were significantly fewer in the ASA group at 360 days after SRT (adjusted odds ratio=0.34; 95% confidence interval [CI] 0.13-0.84; P=0.02). The PS-matching and IPTW methods also supported a lower mortality rate in the ASA group at 360 days post-SRT. Conclusions: In this population-based study of patients with HCM who underwent SRT in a real-world setting, the 1-year all-cause mortality rate was significantly lower in patients who underwent ASA compared with SM., Competing Interests: None declared., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background: Systolic anterior motion (SAM) of the mitral valve can result in mitral regurgitation (MR) and adverse outcomes in patients with obstructive hypertrophic cardiomyopathy (HCM). However, the mechanism and characteristics of MR severity mediated by SAM are unresolved. This study aimed to elucidate the anatomic and hemodynamic associations of MR and the impact of septal myectomy on changes in MR severity in patients with HCM., Methods: We retrospectively reviewed patients who underwent septal myectomy with SAM and interpretable imaging between 2017-2022. Significant MR was defined as moderate or more MR. The mitral valve, papillary muscle, and left ventricular geometry were quantitatively evaluated via echocardiography and cardiac computed tomography., Results: Out of 34 patients, two groups were identified: those with preoperative significant MR (n=16) and those without significant MR (n=18). Patients with significant preoperative MR exhibited worse heart failure symptoms at baseline than those without. Following myectomy, these patients showed higher residual left ventricular outflow tract (LVOT) gradients at rest and with provocative measures than those without preoperative MR. Multivariate regression analysis revealed a significant association between the tenting area and MR severity. Additionally, the chordal cutting procedure alleviated the tenting area [2.1 (1.8-2.6) vs. 1.4 (1.2-1.6) cm 2 ] compared to those without it., Conclusions: Our preliminary data suggested that chordal cutting with septal myectomy was associated with an improvement in the tenting area, contributing to MR severity. This procedure may serve as an effective therapy for patients with SAM and significant MR., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1206/coif). H.T. serves as an unpaid editorial board member of Journal of Thoracic Disease from October 2022 to January 2025. R.T.H. reports receiving speaker fees from Abbott Structural, Baylis Medical, Edwards Lifesciences, and Philips Healthcare. Additionally, she has institutional consulting contracts for which she receives no direct compensation with Abbott Structural, Boston Scientific, Edwards Lifesciences, Medtronic, and Novartis. R.T.H. also has stock options with Navigate and is Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored trials, for which she receives no direct industry compensation. The other authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Objective: Heart 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., Methods: In 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., Results: Using 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., Conclusions: The 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., Competing Interests: Competing interests: Research grant and consultation fee from Bristol Meyers Squibb to YJS., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypertrophic cardiomyopathy (HCM) is most commonly associated with obstructive symptoms and sudden cardiac death; however, predominantly nonobstructive advanced heart failure in HCM, marked by medically refractory disease with severe functional impairment, occurs in 5% to 7% of patients with HCM. The diagnosis relies on the integration of imaging (echocardiography/cardiac magnetic resonance), hemodynamic data, and cardiopulmonary exercise testing to identify the patients who will benefit from advanced heart failure therapies. Most advanced heart failure therapies focus on systolic dysfunction and are not always applicable to this patient population. Left ventricular assist devices may be an option in a highly selected population with left ventricular dilation. Heart transplantation is often the best option for patients with advanced heart failure in HCM with excellent post-transplantation survival., Competing Interests: Funding Support and Author Disclosures Dr Shimada was supported by the National Institutes of Health (R01 HL157216). Dr Maurer was supported by funding from the National Institutes of Health (HL139671-01, AG R21AG058348, and AG K24AG036778). Dr Clerkin was supported by the National Institutes of Health (K23 HL148528). Dr Shimada has received research support from the American Heart Association National Clinical and Population Research Awards, an American Heart Association Career Development Award, the Korea Institute of Oriental Medicine, a Columbia University Irving Medical Center Irving Institute for Clinical and Translational Research Precision Medicine Pilot Award, and Bristol Myers Squibb; and consulting income from Bristol Myers Squibb; and his institution has also received funding for clinical trials for Bristol Myers Squibb. Dr Maurer has received consulting income from Akcea, Alnylam, Eidos Therapeutics, Pfizer, Prothena, Novo Nordisk, and Intellia; and his institution has also received funding for clinical trials for Alnylam, Eidos Therapeutics, Pfizer, and Prothena. Dr Sayer has received consulting fees from Abbott. Dr Uriel has received grants from Abbott, Abiomed, and Fire 1; and served on the medical advisory board for Livemetric, Leviticus, and Revamp outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Prior studies have suggested causal relationships between obesity and acute cardiovascular events. It has been also known that the risk of acute cardiovascular events is reduced by bariatric surgery. However, little is known about whether bariatric surgery lowers the risk of acute cardiovascular events in patients with obesity and hypertrophic cardiomyopathy (HCM). In this context, we aimed to investigate whether bariatric surgery is associated with a reduced risk of cardiovascular-related acute care use in patients with HCM., Methods and Results: In this population-based study, the bariatric surgery group consisted of patients with HCM who underwent bariatric surgery from January 2004 to December 2014. The control group included those who have obesity and HCM and received non-bariatric elective intra-abdominal surgery during the same period. The outcome was cardiovascular-related acute care use (i.e. emergency department (ED) visits or unplanned hospitalizations for cardiovascular disease) during a 1-year post-surgery period. We used the SPARCS database, a population-based ED and inpatient database in New York State. We constructed logistic regression models with generalized estimating equations to compare the risk of the outcome events during sequential 6-month post-surgery periods. We adjusted for age, sex, number of ED visits and hospitalizations for cardiovascular disease within 2 years before the index surgery, and the Elixhauser co-morbidity measures. We also performed propensity score (PS)-matching and inverse probability treatment weighting analyses using these variables. The analytic cohort consisted of 207 adults with obesity and HCM, including 147 patients who underwent bariatric surgery and 60 in the control group. The risk was not significantly different in the 1-6 months post-surgery period. By contrast, in the 7-12 months post-surgery period, the risk of cardiovascular-related acute care use was significantly lower in the bariatric surgery group (adjusted odds ratio 0.23; 95% CI 0.068-0.71; P = 0.01) compared with the control group. In the PS-matched cohort, there were no significant differences in the baseline characteristics. The PS-matched analysis demonstrated lower risk of the outcome event in the bariatric surgery group in the 7-12 months post-surgery period. The inverse probability treatment weighting analysis replicated the findings., Conclusions: Bariatric surgery was associated with a lower risk of cardiovascular-related acute care use in the 7-12 months post-surgery period in this population-based study., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes coding for proteins essential for myocardial contraction. However, it remains unclear through which signaling pathways these gene mutations mediate HCM pathogenesis. Growing evidence indicates that microRNAs (miRNAs) play an important role in the regulation of gene expression. We hypothesized that transcriptomics profiling of plasma miRNAs would reveal circulating biomarkers and dysregulated signaling pathways in HCM., Methods: We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma transcriptomics profiling of miRNAs using RNA sequencing. We developed a transcriptomics-based discrimination model using samples retrieved during the first two-thirds of the study period at one institution (training set). We prospectively tested its discriminative ability in samples collected thereafter from the same institution (prospective test set). We also externally validated the model by applying it to samples collected from the other institutions (external test set). We executed pathway analysis of dysregulated miRNAs with univariable P <0.05., Results: This study included 555 patients (392 cases and 163 controls). One thousand one hundred forty-one miRNAs passed our quality control filters. The area under the receiver operating characteristic curve of the transcriptomics-based model derived from the training set was 0.86 (95% CI, 0.79-0.93) in the prospective test set and 0.94 (95% CI, 0.90-0.97) in the external test set. Pathway analysis revealed dysregulation of the Ras-MAPK (mitogen-activated protein kinase) pathway and pathways related to inflammation in HCM., Conclusions: This study utilized comprehensive transcriptomics profiling with RNA sequencing in HCM, revealing circulating miRNA biomarkers and dysregulated pathways., Competing Interests: Disclosures None.

Objectives: To elucidate the optimal septal reduction therapy for obstructive hypertrophic cardiomyopathy, we conducted a meta-analysis comparing alcohol septal ablation (ASA) and septal myectomy., Methods: MEDLINE, EMBASE and Cochrane CENTRAL were searched to identify studies investigating the outcomes of ASA and septal myectomy in patients with obstructive hypertrophic cardiomyopathy in January 2023. The primary outcome of interest was all-cause mortality in studies with ≥1 year of follow-up. The secondary outcomes of interest comprised left ventricular outflow tract (LVOT) pressure gradient reduction and reoperations of LVOT. A subgroup analysis of all-cause mortality including studies with follow-up ≥5 years was performed., Results: 27 observational studies were included (15 968 patients). Analysis demonstrated similar all-cause mortality [hazard ratio (HR) (95% confidence interval) (CI) 1.24 (0.88-1.76); P = 0.21; I2 = 56%]. In contrast, ASA was associated with less reduction of LVOT pressure gradient and a reoperation rate [weighted mean difference (95% CI) 11.04 mmHg (5.60-16.48); P < 0.01; I2 = 64%, HR (95% CI) 9.14 (6.55-12.75); P < 0.001; I2 = 0%, respectively]. The subgroup analysis with follow-up ≥5 years revealed higher long-term mortality with ASA [HR (95% CI) 1.50 (1.04-2.15); P = 0.03; I2 = 52%]., Conclusions: Although both septal reduction therapies were associated with similar all-cause mortality, ASA was associated with a higher rate of reoperation and less reduction of LVOT pressure gradient. Furthermore, all-cause mortality with follow-up ≥5 years showed favourable outcomes with septal myectomy, although the result is only hypothesis-generating given a subgroup analysis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Hypertrophic cardiomyopathy often causes major adverse cardiovascular events (MACE), for example, arrhythmias, stroke, heart failure, and sudden cardiac death. Currently, there are no models available to predict MACE. Furthermore, it remains unclear which signaling pathways mediate MACE. Therefore, we aimed to prospectively determine protein biomarkers that predict MACE in hypertrophic cardiomyopathy and to identify signaling pathways differentially regulated in patients who subsequently develop MACE., Methods: In this multi-centre prospective cohort study of patients with hypertrophic cardiomyopathy, we conducted plasma proteomics profiling of 4979 proteins upon enrollment. We developed a proteomics-based model to predict MACE using data from one institution (training set). We tested the predictive ability in independent samples from the other institution (test set) and performed time-to-event analysis. Additionally, we executed pathway analysis of predictive proteins using a false discovery rate threshold of <0.001., Results: The study included 245 patients (n=174 in the training set and n=71 in the test set). Using the proteomics-based model to predict MACE derived from the training set, the area under the receiver-operating-characteristic curve was 0.81 (95% CI, 0.68-0.93) in the test set. In the test set, the high-risk group determined by the proteomics-based predictive model had a significantly higher rate of developing MACE (hazard ratio, 13.6 [95% CI, 1.7-107]; P =0.01). The Ras -MAPK (mitogen-activated protein kinase) pathway was upregulated in patients who subsequently developed MACE (false discovery rate<1.0×10 -7 ). Pathways involved in inflammation and fibrosis-for example, the TGF (transforming growth factor)-β pathway-were also upregulated., Conclusions: This study serves as the first to demonstrate the ability of proteomics profiling to predict MACE in hypertrophic cardiomyopathy, exhibiting both novel (eg, Ras -MAPK) and known (eg, TGF-β) pathways differentially regulated in patients who subsequently experience MACE.

Objective: Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease, likely encompassing several subtypes of disease with distinct biological mechanisms (ie, molecular subtypes). Current models based solely on clinical data have yielded limited accuracy in predicting the risk of major adverse cardiovascular events (MACE). Our aim in this study was to derive molecular subtypes in our multicentre prospective cohort of patients with HCM using proteomics profiling and to examine their longitudinal associations with MACE., Methods: We applied unsupervised machine learning methods to plasma proteomics profiling data of 1681 proteins from 258 patients with HCM who were prospectively followed for a median of 2.8 years. The primary outcome was MACE, defined as a composite of arrhythmia, heart failure, stroke and sudden cardiac death., Results: We identified four molecular subtypes of HCM. Time-to-event analysis revealed significant differences in MACE-free survival among the four molecular subtypes (p logrank =0.007). Compared with the reference group with the lowest risk of MACE (molecular subtype A), patients in molecular subtype D had a higher risk of subsequently developing MACE, with an HR of 3.41 (95% CI 1.54 to 7.55, p=0.003). Pathway analysis of proteins differentially regulated in molecular subtype D demonstrated an upregulation of the Ras/mitogen-activated protein kinase and associated pathways, as well as pathways related to inflammation and fibrosis (eg, transforming growth factor-β pathway)., Conclusions: Our prospective plasma proteomics study not only exhibited the presence of HCM molecular subtypes but also identified pathobiological mechanisms associated with a distinct high-risk subtype of HCM., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypertrophic cardiomyopathy (HCM) is a complex but relatively common genetic disease that usually arises from pathogenic variants that disrupt sarcomere function and lead to variable structural, hypertrophic, and fibrotic remodeling of the heart which result in substantial adverse clinical outcomes including arrhythmias, heart failure, and sudden cardiac death. HCM has had few effective treatments with the potential to ameliorate disease progression until the recent advent of inhibitory myosin modulators like mavacamten. Preclinical investigations and clinical trials utilizing this treatment targeted to this specific pathophysiological mechanism of sarcomere hypercontractility in HCM have confirmed that myosin modulators can alter disease expression and attenuate hypertrophic remodeling. Here, we summarize the state of hypertrophic remodeling and consider the arguments for and against salutary HCM disease modification using targeted myosin modulators. Further, we consider critical unanswered questions for future investigative and therapeutic avenues in HCM disease modification. We are at the precipice of a new era in understanding and treating HCM, with the potential to target agents toward modifying disease expression and natural history of this most common inherited disease of the heart., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sewanan and Shimada.)

Objectives: The purpose of this study is to determine whether or not left ventricular remodeling can be induced after septal myectomy in patients with obstructive hypertrophic cardiomyopathy, and if so, how it occurs, using gated cardiac computed tomography., Methods: Fifty patients with hypertrophic obstructive cardiomyopathy who underwent septal myectomy along the septal band between March 2016 and July 2020 were retrospectively reviewed. Recent consecutive 19 patients underwent postoperative cardiac computed tomography. In these patients, volumes of the septal band and thickness of 17 left ventricular myocardial segments were measured to determine the changes after surgery., Results: The resection volume predicted by preoperative computed tomography and the actual resection volume were 6.7 ± 3.3 mL and 6.4 ± 2.7 mL. In-hospital mortality was 0%. Moderate or greater mitral valve regurgitation and systolic anterior motion decreased from 56% to 6% and 86% to 6%, respectively. Median preoperative ventricular septal thickness and left ventricular outflow tract pressure gradient at rest decreased from 20.0 mm (interquartile range, 17.0-24.0 mm) and 74.0 mm Hg (interquartile range, 42.5-92.5 mm Hg) to 14.0 mm (interquartile range, 11.5-16.0 mm) and 15.5 mm Hg (interquartile range, 12.1-21.5 mm Hg), respectively. Postoperative computed tomography confirmed a reduction in septal band volume of 5.7 ± 2.8 mL. Total left ventricular myocardial volume was reduced by 12.9 ± 8.8 mL, which exceeded the volume reduction of the resected septal band. All segments except the basal inferior and basal inferolateral regions showed a significant decrease in wall thickness by a median of 6.4%., Conclusions: Properly performed septal myectomy may induce remodeling of the entire left ventricle, not just the resected area., (© 2022 The Author(s).)

Introduction: In hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) represents myocardial fibrosis and is associated with sudden cardiac death. However, CMR requires particular expertise and is expensive and time-consuming. Therefore, it is important to specify patients with a high pre-test probability of having LGE as the utility of CMR is higher in such cases. The objective was to determine whether plasma proteomics profiling can distinguish patients with and without LGE on CMR in the HCM population., Materials and Methods: We performed a multicenter case-control (LGE vs. no LGE) study of 147 patients with HCM. We performed plasma proteomics profiling of 4,979 proteins. Using the 17 most discriminant proteins, we performed logistic regression analysis with elastic net regularization to develop a discrimination model with data from one institution (the training set; n = 111) and tested the discriminative ability in independent samples from the other institution (the test set; n = 36). We calculated the area under the receiver-operating-characteristic curve (AUC), sensitivity, and specificity., Results: Overall, 82 of the 147 patients (56%) had LGE on CMR. The AUC of the 17-protein model was 0.83 (95% confidence interval [CI], 0.75-0.90) in the training set and 0.71 in the independent test set for validation (95% CI, 0.54-0.88). The sensitivity of the training model was 0.72 (95% CI, 0.61-0.83) and the specificity was 0.78 (95% CI, 0.66-0.90). The sensitivity was 0.71 (95% CI, 0.49-0.92) and the specificity was 0.74 (95% CI, 0.54-0.93) in the test set. Based on the discrimination model derived from the training set, patients in the test set who had high probability of having LGE had a significantly higher odds of having LGE compared to those who had low probability (odds ratio 29.6; 95% CI, 1.6-948.5; p = 0.03)., Conclusions: In this multi-center case-control study of patients with HCM, comprehensive proteomics profiling of 4,979 proteins demonstrated a high discriminative ability to distinguish patients with and without LGE. By identifying patients with a high pretest probability of having LGE, the present study serves as the first step to establishing a panel of circulating protein biomarkers to better inform clinical decisions regarding CMR utilization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lander, Zhao, Hasegawa, Maurer, Tower-Rader, Fifer, Reilly and Shimada.)

Background: The COVID-19 pandemic has necessitated the rapid and widespread adoption of novel mechanisms of service delivery, including the use of telemedicine. The aim of this study was to examine the impact of COVID-19 on cardiogenetics practices., Methods: We retrospectively analyzed the clinical characteristics of patients who were seen for cardiogenetics visits pre-pandemic (1 April-23 December 2019) and during the pandemic (1 April-23 December 2020) at Columbia University Irving Medical Center., Results: Six percent (n = 6) of visits in 2019 were remote telemedicine encounters, whereas 80% (n = 106) of visits in 2020 were telemedicine encounters. In 2019, only 18% (n = 19) of the patients seen for genetic counseling were family members of probands; this percentage increased to 34% in 2020 (n = 45; p = .01). In 2020, the geographic reach of genetic counseling also extended far beyond New York State, reaching a total of 11 states as well as one patient in Puerto Rico. Genetic testing results were similar in 2019 and 2020., Conclusion: Despite the health-care delivery barriers created by the COVID-19 pandemic, the use of telemedicine allowed us to expand the reach of cardiovascular genetic counseling and testing., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Septal reduction therapy (SRT) -i.e. septal myectomy and alcohol septal ablation-has been performed to treat medically refractory hypertrophic cardiomyopathy (HCM) for decades. However, it is largely unknown whether SRT prevents HCM-related cardiovascular events or death. The objective was to examine the effects of SRT on acute cardiovascular events and all-cause mortality in HCM. We performed a propensity score (PS) -matched study using databases that capture all hospitalizations and outpatient visits in New York state. We identified patients with HCM who underwent SRT between 2007 and 2014 (i.e. the SRT group) and those who had never had SRT but had at least one hospitalization for HCM during the same period (i.e. the control group). We performed PS matching at a 1:1 ratio. The primary outcome was a composite of acute cardiovascular events and all-cause mortality during 0-180 days and 181-360 days. The secondary outcome was 180- and 360-day all-cause mortality. We included 846 patients with HCM (423 PS-matched pairs). Patients who underwent SRT had a lower risk of the primary outcome event (0-180 days: odds ratio [OR], 0.54; 95% confidence intervals (CI), 0.37-0.80; P = 0.002 and 181-360 days: OR, 0.33; 95% CI, 0.22-0.51; P < 0.0001). Furthermore, the risk of all-cause mortality was lower at 180 days (OR, 0.37; 95% CI, 0.22-0.63; P = 0.0003) and 360 days post-SRT (OR, 0.32; 95% CI, 0.20-0.51; P < 0.0001). In conclusion, our PS-matched study using population-based datasets demonstrated that SRT was associated with a reduced risk of a composite of acute cardiovascular events and all-cause mortality in HCM during the first post-SRT year.

Genetic testing provides valuable insights into family screening strategies, diagnosis, and prognosis in patients with hypertrophic cardiomyopathy (HCM). On the other hand, genetic testing carries socio-economical and psychological burdens. It is therefore important to identify patients with HCM who are more likely to have positive genotype. However, conventional prediction models based on clinical and echocardiographic parameters offer only modest accuracy and are subject to intra- and inter-observer variability. We therefore hypothesized that deep convolutional neural network (DCNN, a type of deep learning) analysis of echocardiographic images improves the predictive accuracy of positive genotype in patients with HCM. In each case, we obtained parasternal short- and long-axis as well as apical 2-, 3-, 4-, and 5-chamber views. We employed DCNN algorithm to predict positive genotype based on the input echocardiographic images. We performed 5-fold cross-validations. We used 2 reference models-the Mayo HCM Genotype Predictor score (Mayo score) and the Toronto HCM Genotype score (Toronto score). We compared the area under the receiver-operating-characteristic curve (AUC) between a combined model using the reference model plus DCNN-derived probability and the reference model. We calculated the p -value by performing 1,000 bootstrapping. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In addition, we examined the net reclassification improvement. We included 99 adults with HCM who underwent genetic testing. Overall, 45 patients (45%) had positive genotype. The new model combining Mayo score and DCNN-derived probability significantly outperformed Mayo score (AUC 0.86 [95% CI 0.79-0.93] vs. 0.72 [0.61-0.82]; p < 0.001). Similarly, the new model combining Toronto score and DCNN-derived probability exhibited a higher AUC compared to Toronto score alone (AUC 0.84 [0.76-0.92] vs. 0.75 [0.65-0.85]; p = 0.03). An improvement in the sensitivity, specificity, PPV, and NPV was also achieved, along with significant net reclassification improvement. In conclusion, compared to the conventional models, our new model combining the conventional and DCNN-derived models demonstrated superior accuracy to predict positive genotype in patients with HCM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Morita, Kusunose, Haga, Sata, Hasegawa, Raita, Reilly, Fifer, Maurer and Shimada.)

Endotyping is an emerging concept in which diseases are classified into distinct subtypes based on underlying molecular mechanisms. Heart failure (HF) is a complex clinical syndrome that encompasses multiple endotypes with differential risks of adverse events, and varying responses to treatment. Identifying these distinct endotypes requires molecular-level investigation involving multi-"omics" approaches, including genomics, transcriptomics, proteomics, and metabolomics. The derivation of these HF endotypes has important implications in promoting individualized treatment and facilitating more targeted selection of patients for clinical trials, as well as in potentially revealing new pathways of disease that may serve as therapeutic targets. One challenge in the integrated analysis of high-throughput omics and detailed clinical data is that it requires the ability to handle "big data", a task for which machine learning is well suited. In particular, unsupervised machine learning has the ability to uncover novel endotypes of disease in an unbiased approach. In this review, we will discuss recent efforts to identify HF endotypes and cover approaches involving proteomics, transcriptomics, and genomics, with a focus on machine-learning methods.

Background: Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes coding for proteins essential in normal myocardial contraction. However, it remains unclear through which molecular pathways gene mutations mediate the development of HCM. The objectives were to determine plasma protein biomarkers of HCM and to reveal molecular pathways differentially regulated in HCM., Methods: We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma proteomics profiling of 1681 proteins. We performed a sparse partial least squares discriminant analysis to develop a proteomics-based discrimination model with data from 1 institution (ie, the training set). We tested the discriminative ability in independent samples from the other institution (ie, the test set). As an exploratory analysis, we executed pathway analysis of significantly dysregulated proteins. Pathways with false discovery rate <0.05 were declared positive., Results: The study included 266 cases and 167 controls (n=308 in the training set; n=125 in the test set). Using the proteomics-based model derived from the training set, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83-0.94) in the test set. Pathway analysis revealed that the Ras-MAPK (mitogen-activated protein kinase) pathway, along with its upstream and downstream pathways, was upregulated in HCM. Pathways involved in inflammation and fibrosis-for example, the TGF (transforming growth factor)-β pathway-were also upregulated., Conclusions: This study serves as the largest-scale investigation with the most comprehensive proteomics profiling in HCM, revealing circulating biomarkers and exhibiting both novel (eg, Ras-MAPK) and known (eg, TGF-β) pathways differentially regulated in HCM.

Background: Genetic testing can determine family screening strategies and has prognostic and diagnostic value in hypertrophic cardiomyopathy (HCM). However, it can also pose a significant psychosocial burden. Conventional scoring systems offer modest ability to predict genotype positivity. The aim of our study was to develop a novel prediction model for genotype positivity in patients with HCM by applying machine learning (ML) algorithms., Methods: We constructed 3 ML models using readily available clinical and cardiac imaging data of 102 patients from Columbia University with HCM who had undergone genetic testing (the training set). We validated model performance on 76 patients with HCM from Massachusetts General Hospital (the test set). Within the test set, we compared the area under the receiver operating characteristic curves (AUROCs) for the ML models against the AUROCs generated by the Toronto HCM Genotype Score (the Toronto score) and Mayo HCM Genotype Predictor (the Mayo score) using the Delong test and net reclassification improvement., Results: Overall, 63 of the 178 patients (35%) were genotype positive. The random forest ML model developed in the training set demonstrated an AUROC of 0.92 (95% CI, 0.85-0.99) in predicting genotype positivity in the test set, significantly outperforming the Toronto score (AUROC, 0.77 [95% CI, 0.65-0.90], P =0.004, net reclassification improvement: P <0.001) and the Mayo score (AUROC, 0.79 [95% CI, 0.67-0.92], P =0.01, net reclassification improvement: P =0.001). The gradient boosted decision tree ML model also achieved significant net reclassification improvement over the Toronto score ( P <0.001) and the Mayo score ( P =0.03), with an AUROC of 0.87 (95% CI, 0.75-0.99). Compared with the Toronto and Mayo scores, all 3 ML models had higher sensitivity, positive predictive value, and negative predictive value., Conclusions: Our ML models demonstrated a superior ability to predict genotype positivity in patients with HCM compared with conventional scoring systems in an external validation test set.

It is unclear how hypertrophic cardiomyopathy (HCM) affects cardiac metabolic pathways at rest and with exercise. This case-control study compared 15 cases with HCM to 2 control groups without HCM. Metabolomic profiling of 210 metabolites was carried out at rest and at peak exercise. The 50 most discriminant metabolites differentially regulated during exercise were selected using partial least squares discriminant analysis. Pathway enrichment analysis was also performed. At rest, no significant difference was observed in metabolomic profiling of HCM cases as compared to controls. By contrast, there were significant differences in metabolomic profiling in response to exercise (p < 0.05) in the following metabolic pathways: the aminoacyl-tRNA biosynthesis pathway; the nitrogen metabolism pathway; the glycine, serine, and threonine metabolism pathway; and the arginine and proline metabolism pathway. The present study demonstrates differential regulation of several metabolic pathways in patients with HCM in the setting of exercise stress.

Background: Only a subset of patients with hypertrophic cardiomyopathy (HCM) develop adverse cardiac events - e.g., end-stage heart failure, cardiovascular death. Current risk stratification methods are imperfect, limiting identification of high-risk patients with HCM. Our aim was to improve the prediction of adverse cardiac events in patients with HCM using machine learning methods., Methods: We applied modern machine learning methods to a prospective cohort of adults with HCM. The outcome was a composite of death due to heart failure, heart transplant, and sudden death. As the reference model, we constructed logistic regression model using known predictors. We determined 20 predictive characteristics based on random forest classification and a priori knowledge, and developed 4 machine learning models. Results Of 183 patients in the cohort, the mean age was 53 (SD = 17) years and 45% were female. During the median follow-up of 2.2 years (interquartile range, 0.6-3.8), 33 subjects (18%) developed an outcome event, the majority of which (85%) was heart transplant. The predictive accuracy of the reference model was 73% (sensitivity 76%, specificity 72%) while that of the machine learning model was 85% (e.g., sensitivity 88%, specificity 84% with elastic net regression). All 4 machine learning models significantly outperformed the reference model - e.g., area under the receiver-operating-characteristic curve 0.79 with the reference model vs. 0.93 with elastic net regression (p < 0.001)., Conclusions: Compared with conventional risk stratification, the machine learning models demonstrated a superior ability to predict adverse cardiac events. These modern machine learning methods may enhance identification of high-risk HCM subpopulations., Competing Interests: Declaration of competing interest No author has a relationship with industry to disclose., (Copyright © 2020. Published by Elsevier B.V.)

Objective: In 2011, a multidisciplinary hypertrophic cardiomyopathy (HCM) program with a dedicated myectomy surgeon was implemented at our institution. We hypothesized that a dedicated approach allows better identification and management of mitral regurgitation (MR) during septal myectomy (SM) for obstructive HCM with significant mitral regurgitation., Methods: Between 2006 and 2018, 181 patients had SM at our institution. This study consists of 53 patients with preoperative moderate or greater MR associated with systolic anterior motion who underwent isolated SM with or without mitral intervention. Patients were divided into those who underwent SM by a dedicated myectomy surgeon (group D, n = 31) or by a non-dedicated surgeon (group ND, n = 22). Primary outcome of interest was rate of mitral valve replacement (MVR) at SM. Secondary outcomes include in-hospital mortality, need for permanent pacemaker, mitral valve reoperation, and residual MR and left ventricular outflow tract gradient on postoperative echocardiography., Results: 12 patients (55%) had a concomitant MVR during septal myectomy in group ND compared to 2 patients (6%) in group D (p < 0.01). Among patients who did not undergo MVR, patients in group D less commonly had residual MR than patients in ND after SM (p < 0.01). Group D had 100% survival with NYHA class I in 94% patients at follow-up visit (p = 0.01). Reoperation for MVR was required in four patients in group ND vs. none in group D (p < 0.01)., Conclusions: A dedicated surgeon is able to spare the mitral valve in patients undergoing SM. This study emphasizes the importance of surgical expertise in this cohort.

Objectives: We aimed to investigate the efficacy and safety of different antithrombotic strategies in patients undergoing transcatheter aortic valve implantation (TAVI) using network meta-analyses., Background: Meta-analyses comparing single antiplatelet therapy (SAPT) vs. dual antiplatelet therapy (DAPT), ± oral anticoagulant (OAC) was conducted to determine the appropriate post TAVI antithrombotic regimen. However, there was limited direct comparisons across the different therapeutic strategies., Methods: MEDLINE and EMBASE were searched through December 2018 to investigate the efficacy and safety of different antithrombotic strategies (SAPT, DAPT, OAC, OAC + SAPT, and OAC + DAPT) in patients undergoing TAVI. The main outcome were all-cause mortality, major or life-threatening bleeding events, and stroke., Results: Our search identified 3 randomized controlled trials and 10 nonrandomized studies, a total of 20,548 patients who underwent TAVI. All OACs were vitamin K antagonists. There was no significant difference on mortality except that OAC + DAPT had significantly higher rates of mortality compared with others (p < .05, I 2 = 0%). SAPT had significantly lower rates of bleeding compared with DAPT, OAC+SAPT, and OAC+DAPT (hazard ratio [HR]: 0.59 [0.46-0.77], p < .001, HR: 0.58 [0.34-0.99], p = .045, HR: 0.41 [0.18-0.93], p = .033, respectively, I 2 = 0%). There was no significant difference on stroke among all antithrombotic strategies., Conclusion: Patients who underwent TAVI had similar all-cause mortality rates among different antithrombotic strategies except OAC+DAPT. Patients on SAPT had significantly lower bleeding risk than those on DAPT, OAC + SAPT, and OAC + DAPT. Our results suggest SAPT is the preferred regimen when there is no indication for DAPT or OAC. When DAPT or OAC is indicated, DAPT + OAC should be avoided., (© 2019 Wiley Periodicals, Inc.)

Amputation has been known to be a rare adverse event of sodium glucose co-transporter-2 (SGLT2) inhibitors. It remains unclear whether the SGLT2 inhibitor as a class or specific categories of the SGLT2 inhibitors are linked with an increased risk of amputation. The objective of this meta-analysis was to investigate the association between the amputation risk and the use of SGLT2 inhibitors. The main outcome measure was the risk of amputation. Multiple databases were searched up to February 2020 and data extraction was performed. Inclusion criteria were randomized controlled trials (RCTs) which reported risk of amputation with SGLT2 inhibitors over non-SGLT2 inhibitors or placebo. The risk of bias was assessed by Cochrane bias tool. The initial search yielded 1,873 citations and a total of five RCTs were included in the meta-analysis. The five included studies evaluated a total of 39,067 patients with diabetes mellitus, including 21,395 patients on SGLT2 inhibitors. The incidence rate of amputation ranged from 0.36 to 3.18% in the SGLT2 inhibitor group and from 0% to 2.87% in the control group. Follow up duration ranged from 24 weeks to 4.2 years. Use of SGLT2 inhibitors was not associated with significant increase in the risk of amputation as compared with controls (OR: 1.31, 95% CI: 0.92-1.87, I 2  = 75%). Subgroup analysis showed that neither canagliflozin, empagliflozin, nor dapagliflozin was associated with increased risk of amputation. In conclusion, our meta-analysis showed that neither canagliflozin nor other SGLT2 inhibitors increase the risk of amputation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Patients on long-term dialysis are at increased risk of bleeding. Although oral anticoagulants (OACs) are recommended for atrial fibrillation (AF) to reduce the risk of stroke, randomized trials have excluded these populations. As such, the net clinical benefit of OACs among patients on dialysis is unknown., Objectives: This study aimed to investigate the efficacy and safety of OACs in patients with AF on long-term dialysis., Methods: MEDLINE and EMBASE were searched through June 10, 2019, for studies that investigated the efficacy and safety of different OAC strategies in patients with AF on long-term dialysis. The efficacy outcomes were ischemic stroke and/or systemic thromboembolism, all-cause mortality, and the safety outcome was major bleeding., Results: This study identified 16 eligible observational studies (N = 71,877) regarding patients on long-term dialysis who had AF. Only 2 of 16 studies investigated direct OACs. Outcomes for dabigatran and rivaroxaban were limited to major bleeding events. Compared with no anticoagulants, apixaban and warfarin were not associated with a significant decrease in stroke and/or systemic thromboembolism (apixaban 5 mg, hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.30 to 1.17; apixaban 2.5 mg, HR: 1.00; 95% CI: 0.52 to 1.93; warfarin, HR: 0.91; 95% CI: 0.72 to 1.16). Apixaban 5 mg was associated with a significantly lower risk of mortality (vs. warfarin, HR: 0.65; 95% CI: 0.45 to 0.93; vs. apixaban 2.5 mg, HR: 0.62; 95% CI: 0.42 to 0.90; vs. no anticoagulant, HR: 0.61; 95% CI: 0.41 to 0.90). Warfarin was associated with a significantly higher risk of major bleeding than apixaban 5 min/2.5 mg and no anticoagulant (vs. apixaban 5 mg, HR: 1.41; 95% CI: 1.07 to 1.88; vs. apixaban 2.5 mg, HR: 1.40; 95% CI: 1.07 to 1.82; vs. no anticoagulant, HR: 1.31; 95% CI: 1.15 to 1.50). Dabigatran and rivaroxaban were also associated with significantly higher risk of major bleeding than apixaban and no anticoagulant., Conclusions: This meta-analysis showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. Warfarin, dabigatran, and rivaroxaban were associated with significantly higher bleeding risk compared with apixaban and no anticoagulant. The benefit-to-risk ratio of OACs in patients with AF on long-term dialysis warrants validation in randomized clinical trials., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with asthma have a high incidence of acute myocardial infarction and ischemic stroke., Objective: To investigate the acute effect of asthma exacerbation on these cardiovascular events., Methods: Using population-based inpatient data of 3 geographically diverse US states (Florida, Nebraska, and New York) during the period 2011 to 2014, we conducted a self-controlled case series study of adults (aged ≥40 years) hospitalized with asthma exacerbation. The primary outcome was a composite of acute myocardial infarction and ischemic stroke. We used conditional Poisson regression to compare each patient's incidence rate of the outcome during 3 sequential risk periods (1-7, 8-14, and 15-28 days after asthma exacerbation) with that of the reference period (ie, summed period before and after the 3 risk periods)., Results: We identified 4607 adults hospitalized for asthma exacerbation who had a first episode of acute myocardial infarction or ischemic stroke. During the reference period, the incidence rate of acute myocardial infarction or ischemic stroke was 25.0/100 person-years. Compared with the reference period, the incidence rate significantly increased during the first risk period (129.1/100 person-years), with a corresponding adjusted incidence rate ratio of 5.04 (95% CI, 4.29-5.88; P < .001). In the 2 subsequent risk periods, the incidence rate declined but remained high-50.1/100 person-years (adjusted incidence rate ratio, 1.96; 95% CI, 1.51-2.48; P < .001) and 38.0/100 person-years (adjusted incidence rate ratio, 1.48; 95% CI, 1.20-1.81; P < .001), respectively. The findings were similar when the 2 outcomes were examined separately., Conclusions: In this population-based study of adults with asthma, the risk of acute myocardial infarction and ischemic stroke increased significantly after asthma exacerbation., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

High-throughput proteomics profiling has never been applied to discover biomarkers in patients with hypertrophic cardiomyopathy (HCM). The objective was to identify plasma protein biomarkers that can distinguish HCM from controls. We performed a case-control study of patients with HCM (n = 15) and controls (n = 22). We carried out plasma proteomics profiling of 1129 proteins using the SOMAscan assay. We used the sparse partial least squares discriminant analysis to identify 50 most discriminant proteins. We also determined the area under the curve (AUC) of the receiver operating characteristic curve using the Monte Carlo cross validation with balanced subsampling. The average AUC was 0.94 (95% confidence interval, 0.82-1.00) and the discriminative accuracy was 89%. In HCM, 13 out of the 50 proteins correlated with troponin I and 12 with New York Heart Association class. Proteomics profiling can be used to elucidate protein biomarkers that distinguish HCM from controls.

Alcohol septal ablation (ASA) and ventricular septal myectomy (VSM) are 2 options of ventricular septal reduction therapy (VSRT) for obstructive hypertrophic cardiomyopathy (HC). We hypothesized that patients with HC who underwent ASA have a higher risk of acute care use (i.e., emergency department [ED] visit or unplanned hospitalization) for cardiovascular disease (CVD) than VSM. We performed a comparative effectiveness study of ASA versus VSM (reference group) among patients with HC who underwent VSRT, using population-based ED and inpatient databases in 3 states, 2005 to 2014. The outcome was acute care use for CVD during a 2-year post-VSRT period. We constructed univariable and multivariable logistic regression models to compare the risk during sequential 6-month periods. We also performed sensitivity analysis with propensity score-matching at 1:1 ratio. We identified 850 patients with HC who underwent VSRT, including 393 with ASA and 457 with VSM. During 13 to 18 months after VSRT, there was a nonsignificantly higher risk with ASA than VSM (adjusted odds ratio [OR] 1.73; 95% confidence interval [CI] 0.83 to 3.60; p = 0.14). Patients who had ASA had a significantly higher risk in the 19 to 24 months post-VSRT period (adjusted OR 2.12; 95% CI 1.06 to 4.23; p = 0.03). Similarly, the propensity score-matched analysis demonstrated a higher risk with ASA than VSM during 13 to 18 months (OR 2.97; 95% CI 1.04 to 8.46; p = 0.04) and 19 to 24 months (OR 7.06; 95% CI 2.04 to 24.36; p = 0.002) after VSRT. In conclusion, among 850 patients with HC who underwent VSRT, the risk of acute care use for CVD was higher after ASA than VSM during the second post-VSRT year., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Although septal myectomy (SM) is the preferred treatment for medication-refractory obstructive hypertrophic cardiomyopathy, the procedure remains subjective. We have developed a virtual myectomy (VM) technique using 3-dimensional reconstruction of gated cardiac computed tomography (CT) to assist intraoperative objective assessment of the adequacy of the resection., Methods: We retrospectively reviewed patients 15 patients who underwent a SM guided by preoperative VM at our program between March 2016 and July 2017. Gated cardiac CT was performed to allow delineation of the left ventricular (LV) myocardium at end-diastole to replicate the cardioplegic myocardial arrest (90%-95% RR interval). SM was performed to attain resection volume predicted by VM. Retrospective, blinded VM also was performed with fixed parameters to determine relationship between ideal (VM1) and conservative (VM2) VM and actual resection., Results: Mean patient age was 52.1 ± 10.6 years, 27% were male, and 80% had New York Heart Association class 3 or 4. Preoperative mean peak LV outflow tract gradient was 79 mm Hg (range 47-82). In-hospital mortality was 0%. Mean postoperative LV outflow tract gradient was 13 mm Hg (11-19). Gated cardiac CT was performed with mean phase 94% (86%-98%). Mean total LV myocardial volume was 226 cm 3 (146-365) and volume of the asymmetric portion of the LV was 19 cm 3 (5.2-48.8). Actual surgical resection volume was 6.2 ± 1.7 cm 3 . Retrospective VM1 and VM2 performed postoperatively blinded to surgical results were 12.8 cm 3 (4.8-29.23) and 6.7 cm 3 (3.5-13.2), showing a modest correlation (R 1  = 0.44, R 2  = 0.56) with actual myectomy., Conclusions: Three-dimensional CT and VM can be a viable addition to preoperative assessment of patients with obstructive hypertrophic cardiomyopathy., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Patients with obesity often have multiple cardiovascular comorbidities as obesity is an established risk factor for various cardiovascular diseases (CVDs)-e. g., heart failure (HF), coronary artery disease (CAD), hypertension, dysrhythmia, and venous thromboembolism. In the United States, obesity is the nationwide public health issue of the day with the prevalence exceeding 30%. It has become a substantial health and financial burden to the society and national healthcare system; the direct cost accounted for 150 billion US dollars in 2014. Lifestyle interventions have been shown to be successful in the short term, however their long-term results are still equivocal likely due to modest weight reduction and high recurrence rates. For instance, the mean weight reduction in a randomized controlled trial of patients with type 2 diabetes mellitus (DM) and either overweight or obesity was 6.0% in the intensive lifestyle modification arm and 3.5% in the control arm. On the contrary, bariatric surgery is known to be the most effective in achieving substantial and long-term weight loss and can prevent the development of CVD risk factors such as DM, hypertension, and dyslipidemia. Bariatric surgery induces prompt weight loss within a few months which lasts for at least 12-18 months, with mean weight loss of ~35% (~70% loss of excess weight), lowering the risk of all-cause mortality, myocardial infarction, and stroke. Furthermore, recent studies demonstrated that bariatric surgery contributed to the reduction of acute care use for HF, CAD, and hypertension. On the other hand, it was reported that bariatric surgery may worsen the control of certain types of CVD (e.g., dysrhythmia), especially in the early postoperative period. Additionally, the notion that being overweight or obese could contribute to higher survival rate in certain populations (e.g., patients with HF)-also known as "obesity paradox"-has been repetitively documented in the past, while most recent investigations suggested that the observed paradox may be attributable to confounding factors including pre-existing comorbidities. Considering the aforementioned advances in the field, this paper reviews a series of recent studies with regard to the short-term and long-term effects of bariatric surgery on various types of CVDs.

Background: Myocardial contraction fraction (MCF), the ratio of left ventricular stroke volume to myocardial volume, is a novel parameter that can distinguish between pathologic and physiologic hypertrophy. However, its prognostic value in hypertrophic cardiomyopathy (HCM) has never been examined. The objective was to determine if MCF is associated with functional capacity and predicts adverse cardiovascular outcomes in patients with HCM and normal left ventricular ejection fraction (LVEF)., Methods and Results: We conducted a prospective cohort study of 137 patients with HCM and LVEF ≥55%. Patients were followed for 2.7 ± 2.5 years. We examined association of MCF with New York Heart Association (NYHA) functional class and a composite outcome of embolic stroke, heart transplantation, and cardiac death. We performed time-to-event analysis with the use of Cox proportional hazards modeling and stepwise elimination. The average age was 52 ± 18 years. The average MCF was 26 ± 11%. MCF was inversely correlated with NYHA functional class (P = .001). A total of 20 subjects experienced an outcome event with an event rate of 5.6% per patient-year. MCF independently predicted the outcome (adjusted hazard ratio 0.50 per 10% increase, 95% confidence interval 0.28-0.90, adjusted P = .02)., Conclusions: In patients with HCM and normal LVEF, MCF is associated with functional capacity and independently predicts adverse cardiovascular outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Aims: Gastric bypass is known to have larger effects on weight and metabolism than gastric banding. However, scarce data exist as to whether the differences are translated into differential risks of cardiovascular disease (CVD)-related morbidities. The objective was to examine whether adults with obesity and CVD who underwent gastric bypass have a lower rate of acute care use (emergency department [ED] visit or unplanned hospitalization) for CVD than those with gastric banding., Methods and Results: We performed a comparative effectiveness study of gastric bypass versus banding among adults with obesity and CVD who underwent either surgery, using population-based [ED] and inpatient samples in California, Florida, and Nebraska from 2005 through 2011. The primary outcome was acute care use for CVD during a two-year postoperative period. We constructed negative binomial regression models to compare the event rate during sequential 6-month periods, using gastric banding group as the reference. We identified 11,229 adults with obesity and CVD who underwent gastric bypass and 3896 adults who had gastric banding. Patients with gastric bypass had significantly lower rate of the outcome compared to those with banding in the 7-12 months postoperative period (adjusted rate ratio [aRR] 0.77; 95% confidence interval [CI], 0.61-0.98; P = 0.03). The significant reduction in the rate persisted during 13-18 months (aRR 0.71; 95% CI, 0.57-0.90; P = 0.005) and 19-24 months (aRR 0.66; 95% CI, 0.52-0.82; P < 0.001) after bariatric surgery., Conclusion: In this population-based comparative effectiveness study of adults with obesity and CVD, the rate of acute care use for CVD was lower after gastric bypass compared to gastric banding., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Studies have suggested relationships between obesity and cardiovascular disease (CVD) morbidity. However, little is known about whether substantial weight reduction affects the risk of CVD-related acute care use in obese patients with CVD. The objective of this study was to determine whether bariatric surgery is associated with decreased risk of CVD-related acute care use., Methods and Results: We performed a self-controlled case series study of obese adults with CVD who underwent bariatric surgery, using population-based emergency department (ED), and inpatient samples in California, Florida, and Nebraska from 2005 to 2011. The primary outcome was ED visit or unplanned hospitalization for CVD. We used conditional logistic regression to compare the risk during sequential 12-month periods, using pre-surgery months 13-24 as the reference period. We identified 11 106 obese adults with CVD who underwent bariatric surgery. During the reference period, 20.6% [95% confidence interval (CI), 19.8-21.3%] of patients had an ED visit or unplanned hospitalization for CVD. The risk did not significantly change in the subsequent 12-month pre-surgery period [adjusted odds ratio (aOR) 0.98; 95% CI, 0.93-1.04; P = 0.42]. By contrast, in the first 12-month period after bariatric surgery, the risk significantly decreased (aOR 0.91; 95% CI, 0.86-0.96; P = 0.002). The risk remained reduced in the subsequent 13-24 months post-bariatric surgery (aOR 0.84; 95% CI, 0.79-0.89; P < 0.001). There was no reduction in the risk in separate obese populations that underwent non-bariatric surgery (i.e. cholecystectomy, hysterectomy). By CVD category, the risk of acute care use for coronary artery disease (CAD), heart failure (HF), and hypertension decreased after bariatric surgery, whereas that of dysrhythmia and venous thromboembolism transiently increased (Bonferroni corrected P < 0.05 for all comparisons)., Conclusion: Bariatric surgery is associated with a lower risk of overall CVD-related ED visit or unplanned hospitalization. The decline was mainly driven by reduced risk of acute care use for CAD, HF, and hypertension after bariatric surgery., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)