Search

To contract, to deform, and remodel, the airway smooth muscle cell relies on dynamic changes in the structure of its mechanical force-bearing cytoskeleton. These alternate between a "fluid-like" (relaxed) state characterized by weak contractile protein-protein interactions within the cytoskeletal apparatus and a "solid-like" (contractile) state promoted by strong and highly organized molecular interactions. In this review, we discuss the roles for actin, myosin, factors promoting actin polymerization and depolymerization, adhesome complexes, and cell-cell junctions in these dynamic processes. We describe the relationship between these cytoskeletal factors, extracellular matrix components of bronchial tissue, and mechanical stretch and other changes within the airway wall in the context of the physical mechanisms of cytoskeletal fluidization-resolidification. We also highlight studies that emphasize the distinct processes of cell shortening and force transmission in airway smooth muscle and previously unrecognized roles for actin in cytoskeletal dynamics. Finally, we discuss the implications of these discoveries for understanding and treating airway obstruction in asthma., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Objective: To test the feasibility and safety of genotype guidance in the selection of P2Y 12 monotherapy within 1 week of percutaneous coronary interventions (PCIs) among patients with high bleeding risk (HBR)., Patient and Methods: The study was a single-center, open-label, pilot trial. Patients (n=100) with HBR (as defined by an academic research consortium) after successful PCI received dual antiplatelet therapy with clopidogrel and aspirin. Following availability of cytochrome P450 2C19 (CYP2C19) genotype results (mean, 2.9 days), aspirin was discontinued. Normal, rapid, or ultrarapid CYP2C19 metabolizers continued clopidogrel monotherapy for 90 days whereas loss-of-function allele carriers switched to prasugrel or ticagrelor monotherapy. The primary safety endpoints were a composite of post-dismissal cardiac death/spontaneous myocardial infarction less than 30 days or stent thrombosis <90 days of discharge. The subjects also underwent post-dismissal assessment for BARC (Bleeding Academic Research Consortium) type 3 or 5 bleeding, all-cause death, any MI, and/or repeat revascularization up to 90 days., Results: There were 98 patients with complete data (median age, 76.5 years, 36% women; 49% acute coronary syndrome). Sixty-nine (70.4%) were normal, rapid, or ultrarapid metabolizers and continued clopidogrel monotherapy, and 29 (29.6%) were intermediate CYP2C19 metabolizers and received monotherapy with prasugrel (n=21) or ticagrelor (n=8). The mean duration of dual antiplatelet therapy was 5.1 days. During 90-day follow-up, no patient died, there was one possible stent thrombosis, and three patients on clopidogrel had Bleeding Academic Research Consortium type 3 bleeding events., Conclusion: Genotype-guided P2Y 12 inhibitor monotherapy within a week of PCI is feasible and likely safe in patients with HBR (CHAMP [Clopidogrel With High Bleeding Risk and Adverse Events With Monotherapy in Patients Undergoing Percutaneous Coronary Interventions]; NCT05223335)., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This review aims to provide a comprehensive overview of the current understanding of genetic markers associated with heart failure (HF) and its underlying causative diseases, such as cardiomyopathies. It highlights the relevance of genetic biomarkers in diagnosing HF, predicting prognosis, potentially identifying its preclinical stages and identifying targets to enable the implementation of individualized medicine approaches., Recent Findings: The prevalence of HF is increasing due to an aging population but with greater access to disease-modifying therapies. Advanced diagnostic tools such as cardiac magnetic resonance, nuclear imaging, and AI-enabled diagnostic testing are now being utilized to further characterize HF patients. Additionally, the importance of genetic testing in HF diagnosis and management is increasingly being recognized. Genetic biomarkers, including single nucleotide polymorphisms (SNPs) and rare genetic variants, are emerging as crucial tools for diagnosing HF substrates, determining prognosis and increasingly directing therapy. These genetic insights are key to optimizing HF management and delivering personalized treatment tailored to individual patients. HF is a complex syndrome affecting millions globally, characterized by high mortality and significant economic burden. Understanding the underlying etiologies of HF is essential for improving management and clinical outcomes. Recent advances highlight the use of multimodal assessments, including AI-enabled diagnostics and genetic testing, to better characterize and manage HF. Genetic biomarkers are particularly promising in identifying preclinical HF stages and providing personalized treatment options. The genetic contribution to HF is heterogeneous, with both monogenic and polygenic bases playing a role. These developments underscore the shift towards personalized medicine in HF management., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Severe asthma induces substantial mortality and chronic disability due to intractable airway obstruction, which may become resistant to currently available therapies including corticosteroids and β-adrenergic agonist bronchodilators. A key effector of these changes is exaggerated airway smooth muscle (ASM) cell contraction to spasmogens. No drugs in clinical use effectively prevent ASM hyperresponsiveness in asthma across all severities. We find that N-cadherin, a membrane cell-cell adhesion protein up-regulated in ASM from patients with severe asthma, is required for the development of airway obstruction induced by allergic airway inflammation in mice. Inhibition of N-cadherin by ADH-1 reduced airway hyperresponsiveness independent of allergic inflammation, prevented bronchoconstriction, and actively promoted bronchodilation of airways ex vivo. ADH-1 inhibited ASM contraction by disrupting N-cadherin-δ-catenin interactions, which decreased intracellular actin remodeling. These data provide evidence for an intercellular communication pathway mediating ASM contraction and identify N-cadherin as a potential therapeutic target for inhibiting bronchoconstriction in asthma.

Background: During exercise stress echocardiography (ESE), there are patients with normal left ventricular ejection fraction (LVEF) who paradoxically develop reduced LVEF during exercise despite absence of coronary artery disease (CAD) and a significant hypertensive response. This study sought to describe the clinical features and outcomes of this population., Methods: Among ESEs performed between 2003 and 2022, patients without CAD by angiogram within 90 days of ESE and resting LVEF ≥50% with a ≥5% LVEF decrease during ESE were included. Outcomes assessed were all-cause mortality, heart failure (HF) hospitalization, and atrial fibrillation (AF). Kaplan-Meier and Cox regression methods were used to analyze time-to-event outcomes., Results: Among 213,643 ESE, 134 patients met the eligibility criteria. The mean age of the population was 66 ± 10 years, 76% were women, and 16% had AF at baseline. Mean LVEF was 58% ± 4% at rest and 43% ± 4% at peak stress. Stress ECG met the criteria for ischemia in 14% of these patients. The 10-year estimated incidence of HF hospitalization was 17.6% (95% CI, 9.0%-26.2%). Among the subgroup without AF at baseline, the 10-year estimated incidence of developing AF was 23.4% (95% CI, 13.4%-33.4%). The 10-year estimated incidence of all-cause mortality was 12.9% (95% CI, 5.5%-20.3%), with 89% of deaths occurring due to noncardiovascular causes., Conclusion: Patients with exercise-induced reduction in LVEF in the absence of obstructive CAD have a high incidence of HF hospitalizations and AF. The underlying pathophysiology of this disease process needs to be further investigated., Competing Interests: Conflicts of Interest None., (Copyright © 2024 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

The absence of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is commonly used to distinguish takotsubo syndrome (TTS) from other myocardial diseases. However, case series have reported the presence of LGE in TTS. This study aimed to summarize the evidence on the frequency of LGE in TTS and identify potential variables that may influence the detection of LGE. Electronic databases were systematically searched for studies reporting LGE frequency in patients with TTS. The overall frequency was estimated using the inverse variance method and a random-effects model for a single proportion. Factors influencing LGE detection were analyzed. Of 490 studies screened, 21 were included (703 patients, 90% women). The estimated overall frequency of LGE was 22.4% (95% confidence interval [CI] 8.7% to 39.6%). In patients with TTS who underwent CMR within 3 days of symptom occurrence, the frequency of LGE was 40.7% (95% CI 18.8% to 64.5%), which was significantly higher than in those who performed CMR after 3 days (3.9%, p <0.010). The sensitivity threshold used in the imaging protocols had a statistically significant impact on the frequency of LGE detection (p = 0.030). A total of 10 studies performed a follow-up CMR after at least 3 months, reporting a frequency of LGE of 1.7% (95% CI 0.0% to 8.9%). In conclusion, published studies report the presence of LGE in TTS at presentation in a significant proportion of patients. However, its detection is strongly influenced by the duration between symptom onset and CMR acquisition and by the sensitivity threshold used for the imaging protocol. LGE is rarely present at follow-up., Competing Interests: Declaration of competing interest The authors have no competing interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Current evidence indicates that dual antiplatelet therapy with aspirin plus a P2Y 12 inhibitor is essential for the prevention of thrombotic events after percutaneous coronary interventions. However, dual antiplatelet therapy is associated with increased bleeding which may outweigh the benefits. This has set the foundations for customizing antiplatelet treatments to the individual patient. However, bleeding and ischemic risks are often present in the same patient, making it difficult to achieve this balance. The fact that oral P2Y 12 inhibitors (clopidogrel, prasugrel, and ticagrelor) have diverse pharmacodynamic profiles that affect clinical outcomes supports the rationale for using platelet function and genetic testing to individualize antiplatelet treatment regimens. Indeed, up to one-third of patients treated with clopidogrel, but a minority of those treated with prasugrel or ticagrelor, exhibit high residual platelet reactivity resulting in an increased thrombotic risk. On the other hand, prasugrel and ticagrelor are frequently associated with low platelet reactivity and increased bleeding risk compared with clopidogrel without providing any additional reduction in ischemic events compared with patients who adequately respond to clopidogrel. The use of platelet function and genetic testing may allow for a guided selection of oral P2Y 12 inhibitors. However, the nonuniform results of randomized controlled trials have led guidelines to provide limited recommendations on the implementation of these tests in patients undergoing percutaneous coronary intervention. In light of recent advancements in the field, this consensus document by a panel of international experts fills in the guideline gap by providing updates on the latest evidence in the field as well as recommendations for clinical practice., Competing Interests: Funding Support and Author Disclosures Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. Dr Alexopoulos has received advisory board fees or honoraria from AstraZeneca, Bayer, Chiesi, and Pfizer; and institutional research grants from CSL Behring. Dr Aradi has received lecture fees from Amgen, AstraZeneca, Bayer AG, Biotronik, Boehringer, Egis, Krka, Medtronic, Novartis, Novo Nordisk, Pfizer, Richter Gedeon, and Vascular Venture. Dr Bhatt has served on the advisory board for Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; has served on the Board of Directors for American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); has served as a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; has served on Data Monitoring Committees for Acesion Pharma, Assistance Publique–Hôpitaux de Paris, the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic, the Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, the Population Health Research Institute, Rutgers University (for the National Institutes of Health–funded MINT trial); has served as a Data Monitoring Committee chair for Boston Scientific (PEITHO trial) and Contego Medical (PERFORMANCE 2); has received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), the Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (American Heart Association lecture), Cowen and Company, the Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), JACC (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (continuing medical education steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and U.S. national co-leader, funded by Bayer), WebMD (continuing medical education steering committees), and Wiley (steering committee); has served as the Deputy Editor for Clinical Cardiology; owns a patent for Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither Dr Bhatt nor Brigham and Women's Hospital receives any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as a Site Co-Investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; has been a trustee of the American College of Cardiology; and has conducted unfunded research for FlowCo. Dr Bonello’s his institution received payment from INARI, Boston Scientific, Abbott, Biotronik, and Bristol Myers Squibb. Dr Capodanno has received payment as an individual for consulting fees or honoraria from Sanofi. Dr Cavallari has received research support from Werfen. Dr Cuisset has received consulting and lecture fees from Abbott Vascular, Boston Scientific, Edwards Lifesciences, Europa Organisation, Medtronic, Terumo, and Sanofi. Dr Ferreiro has received lecture honoraria from Eli Lilly, Daiichi-Sankyo, AstraZeneca, Pfizer, Abbott, Boehringer Ingelheim, Bristol Myers Squibb, Rovi, Terumo and Ferrer; consulting fees from AstraZeneca, Eli Lilly, Ferrer, Boston Scientific, Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Bristol Myers Squibb, and Biotronik; and research grants from AstraZeneca. Dr Franchi has received payment as an individual for consulting fees or honoraria from AstraZeneca; and institutional payments for grants from PLx Pharma and the Scott R. MacKenzie Foundation. Dr Geisler has received lecture honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Ferrer/Chiesi, Novartis, and Pfizer; consulting fees from AstraZeneca, Bristol Myers Squibb, Ferrer, Edwards Lifesciences, Haemonetics, and Pfizer; and research grants from Bayer, Bristol Myers Squibb/Pfizer, Ferrer/Chiesi, Medtronic, and Edwards Lifesciences. Dr Gibson has received grants from SCAD Alliance, Johnson & Johnson, Janssen, and CSL Behring; has received personal fees from Bayer, AstraZeneca (during the conduct of the study), Angel Medical Corporation, CSL Behring, Janssen, Johnson & Johnson, the Boston Clinical Research Institute, the Cardiovascular Research Foundation, Gilead Sciences, WebMD, UpToDate in Cardiovascular Medicine, Somahlution, Boston Scientific, the Duke Clinical Research Institute, Medtelligence, Microport, PERT Consortium, Caladrius Biosciences, CeleCor Therapeutics, Eidos Therapeutics, Microdrop, MD Magazine, the Society for Cardiovascular Angiography and Interventions, Revance Therapeutics, Pfizer, Dyad Medical, CytoSorbents, AMAG Pharmaceuticals, Bristol Myers Squibb, Amarin, PhaseBio, Bioclinica, Inari, MedImmune, PLx Pharma, Merck, Paratek, Anthos Therapeutics, PHRI, SmartMedics, EXCITE International ($0 received), Novo Nordisk, MedTrace, and the Cardiovascular Clinical Science Foundation; has received nonfinancial support from the Baim Institute; and owns equity in nference, Absolutys, and Dyad Medical. Dr Gorog has received institutional research grants from Bayer, AstraZeneca, Medtronic, and Werfen; and personal fees from Janssen, Bristol Myers Squibb, and Chiesi. Dr Gurbel has received consulting fees and/or honoraria from Bayer, Vectura/Otitopic, Janssen, Cleveland Clinic Foundation, Wolters Kluwer Pharma, Web MD Medscape, Baron and Budd, Premier Health Care Resource, Baim Institute, and Medforce; has received institutional research grants from Accriva Diagnostics, AstraZeneca, Bayer, Cronos, Janssen Pharmaceuticals Inc., Haemonetics, Hikari Dx, Idorisa, Labcorp Drug Development, Novartis, Prolocor, Recor Medical, Vectura Limited, and Zoll Medical Corporation; owns 2 patents (Detection of restenosis risk in patients issued and Assessment of cardiac health and thrombotic risk in a patient); has served as an expert witness in a lawsuit associated with Plavix. Dr Jeong has received honoraria for lectures from Daiichi-Sankyo, Sanofi, Han-mi Pharmaceuticals, and Daewoong Pharmaceuticals; and research grants or support from Samjin Pharmaceuticals, Hanmi Pharmaceuticals, Yuhan Pharmaceuticals, Biotronik Korea, and U and I Corporation. Dr Marcucci has received consulting fees or honoraria from Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Novartis, Sanofi, Viatris, and Werfen. Dr Siller-Matula has received speaker or consulting fees from AOP, Chiesi, Biosensors, Boston Scientific, P&F, Boehringer Ingelheim, and Daiichi-Sankyo not related to the submitted work. Dr Mehran has received institutional research payments from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Amgen, Arena, AstraZeneca, Atricure, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi-Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, Pi-Cardia, RenalPro, Shockwave, Vivasure, and Zoll; has received personal fees from Cine-Med Research and WebMD; owns equity (<1%) in Applied Therapeutics, Elixir Medical, Stel, and ControlRad (via her spouse); has served on the Scientific Advisory Board for the American Medical Association, the American College of Cardiology (Board of Trustees Member), the Society for Cardiovascular Angiography and Interventions (Women in Innovations Committee Member), and JAMA (Associate Editor); and has served as faculty for the Cardiovascular Research Foundation (no fee). Dr Neumann has received consulting honoraria from Novartis and Meril; speaker honoraria from Boston Scientific, Amgen, Daiichi-Sankyo, and Meril; speaker honoraria paid to his institution from Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, Boston Scientific, Siemens, and Amgen; and research grants paid to his institution from Boston Scientific and Abbott. Dr So has received consulting fees or honoraria from Abbott Vascular, AstraZeneca, Bayer, HLS Therapeutics, JAMP Pharma Corp, Medtronic, and DYFS; and received research grants from Aggredyne, Diapharma, Eli Lilly, Fujimori Kogyo, Roche Diagnostics, and Spartan Biosciences. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, Amgen, and Boehringer Ingelheim; served as a consultant for Abbott, Daiichi-Sankyo, Ablative Solutions, CorFlow, Cardiomech, Robocath, Miracor, Vectorious, Abiomed, Valfix, Apollo Therapeutics, Elucid Bio, Cardiac Success, TherOx, HeartFlow, Neovasc, Ancora, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, Oxitope, HighLife, Elixir, Remote Cardiac Enablement, and Aria; he owns equity/options in Cardiac Success, Ancora, Cagent, Applied Therapeutics, and Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Valfix, and Xenter; and his employer (Mount Sinai Hospital) has received research grants from Shockwave, Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense Webster, Vascular Dynamics, Pulnovo, and V-wave. Dr Storey has received institutional research grants/support from AstraZeneca and Cytosorbents; and personal fees from Alfasigma, AstraZeneca, Boehringer Ingelheim/Lilly, Chiesi, Cytosorbents, Daiichi-Sankyo, Idorsia, Novartis, Novo Nordisk, Pfizer, PhaseBio, and Tabuk. Dr Tantry has received honoraria from Wolters Kluwer Pharma. Dr ten Berg has received institutional research grants from ZonMw (Dutch Government) and Daiichi-Sankyo; has served on the advisory board CeleCor; and has received lecture and advisory board fees paid to his institution from AstraZeneca, Bristol Myers Squibb, and Pfizer. Dr Trenk has received honoraria for lectures from AstraZeneca, Daiichi-Sankyo, and Novartis; and consulting fees from Atriva, Daiichi-Sankyo, and Eleva. Dr Valgimigli has received personal fees from AstraZeneca, Terumo, Alvimedica/CID, Abbott Vascular, Daiichi-Sankyo, Bayer, CoreFLOW, Idorsia Pharmaceuticals Ltd, Universität Basel | Dept. Klinische Forschung, Bristol Myers Squibb SA/Janssen, Medscape, Biotronik, Novartis, and Vesalio, outside the submitted work; and grants from Terumo, outside the submitted work. Dr Waksman has served on advisory boards for Abbott Vascular, Boston Scientific, J Valve, Medtronic Inc, Philips IGT, and Pi-Cardia Ltd.; has served as a consultant for Abbott Vascular, Biotronik, Boston Scientific, CardioMed LLC, Cordis, Medtronic Inc, Philips IGT, Pi-Cardia Ltd., Swiss Interventional Systems/SIS Medical AG, Transmural Systems Inc., and Venous MedTech; has received institutional grant support from Amgen, Biotronik, Boston Scientific, Chiesi, Medtronic Inc, and Philips IGT; and is an investor in MedAlliance, Pi-Cardia Ltd., and Transmural Systems. Dr Sibbing has received speaker fees and fees for advisory board activities from Bayer, Sanofi, and Daiichi-Sankyo. 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.)

Objective: To determine the prevalence, penetrance, and disease expression of cardiomyopathy-related genetic variants in an unselected, richly phenotyped Mayo Clinic population in the setting of preemptive sequencing, with return of incidental findings following the American College of Medical Genetics and Genomics recommendations., Patients and Methods: We analyzed a quaternary medical center-based biobank cohort (n=983) for reportable variants in 15 cardiomyopathy genes. Prioritization of genetic variants was performed using an internally developed pipeline to identify potentially reportable variants. Prioritized variants were then manually curated. The correlation of likely pathogenic/pathogenic (LP/P) variants with clinical phenotypes and outcomes was established. Artificial intelligence-enabled electrocardiographic predictions of reduced left ventricular ejection fraction and hypertrophic cardiomyopathy were applied to genotype-positive (G+) participants., Results: Of the 983 patients, 11 (1%) were G+, with 11 LP/P variants found in the MYBPC3, DSG2, MYH7, DSP, and PKP2 genes. All G+ participants underwent electrocardiography, and 10 (90%) underwent echocardiography. Most patients (10 [90%]) did not have a prior diagnosis of cardiomyopathy. Definitive disease penetrance (heart failure or cardiomyopathy) was present in 4 (36%), while 3 (27%) had possible penetrance (structural heart disease identified by echocardiography). Arrhythmias and/or cardiac conduction disease was present in 4 of 11 G+ individuals (36%). Artificial intelligence-electrocardiography was positive for hypertrophic cardiomyopathy or reduced left ventricular ejection fraction in 5 of the G+ participants (45%), of whom 4 (80%) had definitive or possible disease penetrance., Conclusion: Cardiomyopathy-associated LP/P variants are present in a small subset of a quaternary medical center population, and disease penetrance in G+ individuals is high in the form of cardiac structural abnormalities and heart failure., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: With patients with congenital heart disease increasingly living into adulthood, there is a growing population of patients with adult congenital heart disease (ACHD) who have heart failure. Limited data exist on evaluating heart transplantation in this population., Methods: A retrospective review was performed of patients with ACHD who underwent heart transplantation from November 1990 to January 2023. Kaplan-Meier, cumulative incidence accounting for competing risk of death, and subgroup analyses comparing those patients with biventricular (BiV) and univentricular (UniV) physiology were performed. Data are presented as median (interquartile range [IQR]) or counts (%)., Results: A total of 77 patients with a median age of 36 years (IQR, 27-45 years) were identified, including 57 (74%) BiV and 20 (26%) UniV patients. Preoperatively, UniV patients were more likely to have cirrhosis (9 of 20 [45.0%] vs 4 of 57 [7.0%]; P < .001) and protein losing enteropathy (4 of 20 [20.0%] vs 1 of 57 [1.8%]; P = .015). Multiorgan transplantation was performed in 23 patients (30%) and more frequently in UniV patients (10 [50%] vs 13 [23%]; P = .04). Operative mortality was 6.5%, 2 of 20 (10%) among UniV patients and 2 of 57 (4%) among BiV patients (P = .276). Median clinical follow-up was 6.0 years (IQR, 1.4-13.1 years). Survival tended to be lower among UniV patients compared with BiV patients, particularly within the first year (P = .09), but it was similar for survivors beyond 1 year. At 5 years, the incidence of rejection was 28% (IQR, 17%-38%) and that of coronary allograft vasculopathy was 16% (IQR, 7%-24%)., Conclusions: Underlying liver disease and the need for heart-liver transplantation were significantly higher among UniV patients. Survival tended to be lower among UniV patients, particularly within the first year, but it was similar for survivors beyond 1 year., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

CYP2C19 loss of function (LOF) carriers undergoing percutaneous coronary intervention (PCI) have an increased risk of ischemic events when treated with clopidogrel. PCI patients in TAILOR-PCI were randomized to clopidogrel or genotype-guided (GG) therapy in which LOF carriers received ticagrelor and non-carriers clopidogrel. Direct medical costs associated with a GG approach have not been described before. TAILOR-PCI participants for whom direct medical costs were available for the duration from the date of PCI to one-year post PCI were included. Primary cost estimates were obtained from the Mayo Clinic Cost Data Warehouse. There were no differences in direct medical costs between the GG and clopidogrel groups (mean $20,682 versus $19,747, p = 0.11) however total costs were greater in the GG group (mean $21,245 versus $19,891, p = 0.02) which was primarily driven by ticagrelor costs. In conclusion the increased expense of a GG strategy post PCI as compared to clopidogrel for all is primarily driven by the cost of ticagrelor., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The clinical efficacy and safety of antiplatelet agents vary among patients. Consequently, some patients are at increased risk of recurrent ischemic events during treatment. This interindividual variability can be a result of genetic variants in enzymes that play a role in drug metabolism. The field of pharmacogenomics explores the influence of these genetic variants on an individual's drug response. Tailoring antiplatelet treatment based on genetic variants can potentially result in optimized dosing or a change in drug selection. Most evidence supports guiding therapy based on the CYP2C19 allelic variants in patients with an indication for dual antiplatelet therapy. In ticagrelor-treated or prasugrel-treated patients, a genotype-guided de-escalation strategy can reduce bleeding risk, whereas in patients treated with clopidogrel, an escalation strategy may prevent ischemic events. Although the clinical results are promising, few hospitals have implemented these strategies. New results, technological advancements, and growing experience may potentially overcome current barriers for implementation in the future., Competing Interests: Funding Support and Author Disclosures Drs Lee, Cavallari, and Angiolillo are supported by National Institutes of Health grant R01 HL149752. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr Pereira has received grants from the National Heart, Lung, and Blood Institute. Dr Lee has received grants from the National Heart, Lung, and Blood Institute; and has received support from Werfen. Dr Cavallari has received grants from the National Heart, Lung, and Blood Institute; and has received support from Werfen. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr ten Berg has received grants from the Netherlands Organization for Health Research and Development, a Dutch government institution called ZonMw, and AstraZeneca; and has received personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, Ferrer, Pfizer, and Merck, outside the submitted work. 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.)

The increasing significance of the aquaculture sector and commercially valuable species underscores the need to develop alternatives for controlling diseases such as Ichthyophthirius multifiliis-induced ichthyophthiriasis. This ciliated protozoan parasite threatens nearly all freshwater fish species, causing substantial losses in the fishery industry. Despite this, effective large-scale treatments are lacking, emphasizing the necessity of adopting preventive strategies. While the pathogenesis of ichthyophthiriasis and its immune stimulation allows for vaccination strategies, precise adjustments are crucial to ensure the production of an effective vaccine compound. Therefore, this study aimed to evaluate the impact of immunizing Astyanax lacustris with a genetic vaccine containing IAG52A from I. multifiliis and the molecular adjuvant IL-8 from A. lacustris. Transcript analysis in immunized A. lacustris indicated mRNA production in fish muscles, demonstrating an expression of this mRNA. Fish were divided into five groups, receiving different vaccine formulations, and all groups received a booster dose 14 days after the initial immunization. Samples from vaccinated fish showed increased IL-1β mRNA expression in the spleen within 6 h post the second dose and after 14 days. In the head kidney, IL-1β mRNA expression showed no significant difference at 6 and 24 h but an increase was noted in fish injected with IAG and IAG + IL-8 after 14 days. IL-8 mRNA expression in the spleen and kidney did not significantly differ from the control group. Histological analysis revealed no variation in leukocyte concentration at 6 and 24 h post-vaccination; however, after 14 days, the groups injected with IAG and IAG + IL-8 exhibited a higher leukocyte density at the application sites than the control. The obtained data suggest that the used vaccine is transcribed, indicating its potential to stimulate innate immune response parameters through mRNA cytokine expression and leukocyte migration., (© 2024 John Wiley & Sons Ltd.)

There is significant variability in the efficacy and safety of oral P2Y12 inhibitors, which are used to prevent ischemic outcomes in common diseases such as coronary and peripheral arterial disease and stroke. Clopidogrel, a prodrug, is the most used oral P2Y12 inhibitor and is activated primarily after being metabolized by a highly polymorphic hepatic cytochrome CYP2C219 enzyme. Loss-of-function genetic variants in CYP2C219 are common, can result in decreased active metabolite levels and increased on-treatment platelet aggregation, and are associated with increased ischemic events on clopidogrel therapy. Such patients can be identified by CYP2C19 genetic testing and can be treated with alternative therapy. Conversely, universal use of potent oral P2Y12 inhibitors such as ticagrelor or prasugrel, which are not dependent on CYP2C19 for activation, has been recommended but can result in increased bleeding. Recent clinical trials and meta-analyses have demonstrated that a precision medicine approach in which loss-of-function carriers are prescribed ticagrelor or prasugrel and noncarriers are prescribed clopidogrel results in reducing ischemic events without increasing bleeding risk. The evidence to date supports CYP2C19 genetic testing before oral P2Y12 inhibitors are prescribed in patients with acute coronary syndromes or percutaneous coronary intervention. Clinical implementation of such genetic testing will depend on among multiple factors: rapid availability of results or adoption of the concept of performing preemptive genetic testing, provision of easy-to-understand results with therapeutic recommendations, and seamless integration in the electronic health record.

Aims: Graft dysfunction (GD) after heart transplantation (HTx) can develop without evidence of cell- or antibody-mediated rejection. Cardiac magnetic resonance imaging (CMR) has an evolving role in detecting rejection; however, its role in biopsy-negative GD has not been described. This study examines CMR findings, evaluates outcomes based on CMR results, and seeks to identify the possibility of rejection missed through endomyocardial biopsy by using CMR in HTx recipients with biopsy-negative GD., Methods and Results: HTx recipients with GD [defined as a decrease in left ventricular ejection fraction (LVEF) by >5% and LVEF < 50%] in the absence of rejection by biopsy or allograft vasculopathy and who underwent CMR were included in the study. The primary outcome was a composite of all-cause mortality, re-transplantation, or persistent LVEF < 50%. Overall, 34 HTx recipients developed biopsy-negative GD and underwent CMR. Left ventricular late gadolinium enhancement (LGE) on CMR was observed in 16 patients with two distinct patterns: diffuse epicardial (n = 13) and patchy (n = 3) patterns. Patients with LGE developed GD later after HTx [4 (1.4-6.8) vs. 0.8 (0.3-1.2) years, P < 0.001], were more often symptomatic (88% vs. 56%, P = 0.06), and had greater haemodynamic derangement (pulmonary capillary wedge pressure: 19 ± 7 vs. 13 ± 3 mmHg, P = 0.002) as compared with those without LGE. No significant difference was observed in the primary composite outcome between patients with LGE and those without LGE (50% vs. 38% of patients with events, P = 0.515). During a median follow-up of 3.8 years, mean LVEF improved similarly in the LGE-negative (37-55%) and LGE-positive groups (32-55%) (P = 0.16)., Conclusions: Biopsy-negative GD occurs with and without LGE when assessed by CMR, indicative of possible rejection/inflammation occurring only in a subset of patients. Irrespective of LGE, LVEF improvement occurs in most GD patients, suggesting that other neurohormonal or immunomodulatory mechanisms may also contribute to GD development., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Nondilated left ventricular cardiomyopathy (NDLVC) has been recently differentiated from dilated cardiomyopathy (DCM). A comprehensive characterization of these 2 entities using cardiac magnetic resonance (CMR) and genetic testing has never been performed., Objectives: This study sought to provide a thorough characterization and assess clinical outcomes in a large multicenter cohort of patients with DCM and NDLVC., Methods: A total of 462 patients with DCM (227) or NDLVC (235) with CMR data from 4 different referral centers were retrospectively analyzed. The study endpoint was a composite of sudden cardiac death or major ventricular arrhythmias., Results: In comparison to DCM, NDLVC had a higher prevalence of pathogenic or likely pathogenic variants of arrhythmogenic genes (40% vs 23%; P < 0.001), higher left ventricular (LV) systolic function (LV ejection fraction: 51% ± 12% vs 36% ± 15%; P < 0.001) and higher prevalence of free-wall late gadolinium enhancement (LGE) (27% vs 14%; P < 0.001). Conversely, DCM showed higher prevalence of pathogenic or likely pathogenic variants of nonarrhythmogenic genes (23% vs 12%; P = 0.002) and septal LGE (45% vs 32%; P = 0.004). Over a median follow-up of 81 months (Q1-Q3: 40-132 months), the study outcome occurred in 98 (21%) patients. LGE with septal location (HR: 1.929; 95% CI: 1.033-3.601; P = 0.039) was independently associated with the risk of sudden cardiac death or major ventricular arrhythmias together with LV dilatation, older age, advanced NYHA functional class, frequent ventricular ectopic activity, and nonsustained ventricular tachycardia., Conclusions: In a multicenter cohort of patients with DCM and NDLVC, septal LGE together with LV dilatation, age, advanced disease, and frequent and repetitive ventricular arrhythmias were powerful predictors of major arrhythmic events., Competing Interests: Funding Support and Author Disclosures This work was supported by the Paul and Ruby Tsai Family Hypertrophic Cardiomyopathy Career Development Award (Dr Giudicessi); the National Institutes of Health/National Heart, Lung, and Blood Institute R01HL147064 and R01HL164634 (Drs Mestroni and Taylor). The 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.)

Competing Interests: The authors have no conflict of interest to disclose.

Background: Accurate, timely ascertainment of clinical end points, particularly hospitalizations, is crucial for clinical trials. The Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention (TAILOR-PCI) Digital Study extended the main TAILOR-PCI trial's follow-up to 2 years, using a smartphone-based research app featuring geofencing-triggered surveys and routine monthly mobile phone surveys to detect cardiovascular (CV) hospitalizations. This pilot study compared these digital tools to conventional site-coordinator ascertainment of CV hospitalizations., Objective: The objectives were to evaluate geofencing-triggered notifications and routine monthly mobile phone surveys' performance in detecting CV hospitalizations compared to telephone visits and health record reviews by study coordinators at each site., Methods: US and Canadian participants from the TAILOR-PCI Digital Follow-Up Study were invited to download the Eureka Research Platform mobile app, opting in for location tracking using geofencing, triggering a smartphone-based survey if near a hospital for ≥4 hours. Participants were sent monthly notifications for CV hospitalization surveys., Results: From 85 participants who consented to the Digital Study, downloaded the mobile app, and had not previously completed their final follow-up visit, 73 (85.8%) initially opted in and consented to geofencing. There were 9 CV hospitalizations ascertained by study coordinators among 5 patients, whereas 8 out of 9 (88.9%) were detected by routine monthly hospitalization surveys. One CV hospitalization went undetected by the survey as it occurred within two weeks of the previous event, and the survey only allowed reporting of a single hospitalization. Among these, 3 were also detected by the geofencing algorithm, but 6 out of 9 (66.7%) were missed by geofencing: 1 occurred in a participant who never consented to geofencing, while 5 hospitalizations occurred among participants who had subsequently turned off geofencing prior to their hospitalization. Geofencing-detected hospitalizations were ascertained within a median of 2 (IQR 1-3) days, monthly surveys within 11 (IQR 6.5-25) days, and site coordinator methods within 38 (IQR 9-105) days. The geofencing algorithm triggered 245 notifications among 39 participants, with 128 (52.2%) from true hospital presence and 117 (47.8%) from nonhospital health care facility visits. Additional geofencing iterative improvements to reduce hospital misidentification were made to the algorithm at months 7 and 12, elevating the rate of true alerts from 35.4% (55 true alerts/155 total alerts before month 7) to 78.7% (59 true alerts/75 total alerts in months 7-12) and ultimately to 93.3% (14 true alerts/5 total alerts in months 13-21), respectively., Conclusions: The monthly digital survey detected most CV hospitalizations, while the geofencing survey enabled earlier detection but did not offer incremental value beyond traditional tools. Digital tools could potentially reduce the burden on study coordinators in ascertaining CV hospitalizations. The advantages of timely reporting via geofencing should be weighed against the issue of false notifications, which can be mitigated through algorithmic refinements., (©Robert Avram, Julia Byrne, Derek So, Erin Iturriaga, Ryan Lennon, Vishakantha Murthy, Nancy Geller, Shaun Goodman, Charanjit Rihal, Yves Rosenberg, Kent Bailey, Michael Farkouh, Malcolm Bell, Charles Cagin, Ivan Chavez, Mohammad El-Hajjar, Wilson Ginete, Amir Lerman, Justin Levisay, Kevin Marzo, Tamim Nazif, Jean-Francois Tanguay, Mark Pletcher, Gregory M Marcus, Naveen L Pereira, Jeffrey Olgin. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 10.11.2023.)

Background: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM., Methods: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction., Results: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P =7.12×10 -7 ). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis., Conclusions: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis., Competing Interests: Disclosures R.M. Weinshilboum is a cofounder of and stockholder in OneOme, LLC. The other authors report no conflicts.

Background: Myocardial inflammation contributes to the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a clinically and genetically heterogenous disorder. Due to phenotypic overlap, some patients with genetic ACM may be evaluated for an underlying inflammatory cardiomyopathy. However, the cardiac fludeoxyglucose (FDG) positron emission tomography (PET) findings in ACM patients have not been elucidated., Methods: All genotype-positive patients in the Mayo Clinic ACM registry (n = 323) who received a cardiac FDG PET were included in this study. Pertinent data were extracted from the medical record., Results: Collectively, 12/323 (4%; 67% female) genotype-positive ACM patients received a cardiac PET FDG scan as part of their clinical evaluation (median age at scan 49 ± 13 years). Amongst these patients, pathogenic/likely pathogenic variants were detected in LMNA (n = 7), DSP (n = 3), FLNC (n = 1) and PLN (n = 1). Of note, 6/12 (50%) had abnormal myocardial FDG uptake, including diffuse (entire myocardium) uptake in 2/6 (33%), focal (1-2 segments) uptake in 2/6 (33%) and patchy (3+ segments) in 2/6 (33%). Median myocardial standardized uptake value ratio was 2.1. Interestingly, LMNA-positive patients accounted for 3 out of 6 (50%) positive studies (diffuse uptake in 2 and focal uptake in 1)., Conclusion: Abnormal myocardial FDG uptake is common in genetic ACM patients undergoing cardiac FDG PET. This study further supports the role of myocardial inflammation in ACM. Further investigation is needed to determine role of FDG PET in diagnosis and management of ACM and investigate the role of inflammation in ACM., Competing Interests: Conflict of interest Dr. Ackerman is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daichii Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. MJA and Mayo Clinic have license agreements with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. However, none of these entities were involved in this study. Other authors declare no conflicts., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: Disclosures None.

Background: Common genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown., Methods: Multi-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255). Log extracellular volume (%) was regressed on 50 candidate single nucleotide polymorphisms (previously identified to be associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and LV traits) adjusting for age, sex, diabetes, blood pressure, and principal components of ancestry. Ancestry-specific results were pooled by fixed-effect meta-analyses. Gene knockdown experiments were performed in human cardiac fibroblasts., Results: The SMARCB1 rs2186370 intronic variant (minor allele frequency: 0.18 in White and 0.50 in Black participants), previously identified as a risk variant for dilated cardiomyopathy and hypertrophic cardiomyopathy, was significantly associated with increased extracellular volume ( P= 0.0002) after adjusting for confounding clinical variables. The SMARCB1 rs2070458 locus previously associated with increased LV wall thickness and mass was similarly significantly associated with increased extracellular volume ( P= 0.0002). The direction of effect was similar in all 4 ancestry groups, but the effect was strongest in Black participants. The variants are strong expression quantitative loci in human LV tissue and associated with genotype-dependent decreased expression of SMARCB1 ( P= 7.3×10 -22 ). SMARCB1 knockdown in human cardiac fibroblasts resulted in increased TGF (transforming growth factor)-β1-mediated α-smooth muscle actin and collagen expression., Conclusions: Common genetic variation in SMARCB1 previously associated with risk for cardiomyopathies and increased LV wall thickness is associated with increased cardiac magnetic resonance imaging-based myocardial fibrosis and increased TGF-β1 mediated myocardial fibrosis in vitro. Whether these findings suggest a pathophysiologic link between myocardial fibrosis and cardiomyopathy risk remains to be proven., Competing Interests: Disclosures The authors of this work have nothing to disclose. All authors declare that the submitted work is original and has not been published and is not under consideration for publication elsewhere. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services.

Background: Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking., Methods: The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507). The end point was death or heart failure rehospitalization within 180 days. Cox models adjusted for 11 a priori predictors of rehospitalization and 5 genetic principal components were used to test the association between single-nucleotide polymorphisms and outcome. Summary statistics from the 2 populations were combined via meta-analysis with the significance threshold considered P <5×10 - 8 ., Results: Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located in FGD5 were significantly associated with the primary outcome in both ancestry groups (European Americans: hazard ratio [HR], 1.38; P =2.42×10 -6 ; African ancestry: HR, 1.51; P =4.43×10 - 3 ; HR in meta-analysis, 1.41; P =4.25×10 -8 ). FGD5 encodes a regulator of VEGF (vascular endothelial growth factor)-mediated angiogenesis, and in silico investigation revealed several previous genome-wide association study hits in this gene, among which rs748431 was associated with our outcome (HR, 1.20; meta P <0.01). Sensitivity analysis proved FGD5 common variants survival association did not appear to operate via coronary artery disease or nesiritide treatment ( P >0.05); and the signal was still significant when changing the censoring time from 180 to 30 days (HR, 1.39; P =1.59×10 -5 )., Conclusions: In this multiethnic genome-wide association study of ASCEND-HF, single-nucleotide polymorphisms in FGD5 were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whether FGD5 could be a therapeutic target., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT00475852., Competing Interests: Disclosures Dr Lanfear is a consultant for Amgen, Janssen, Ortho Diagnostics, and Duke Clinical Research Institute (Novartis) and has participated in clinical trials from Amgen, Bayer, and Janssen. Dr Francke is currently a consultant for Janssen and was previously employed by Janssen. Dr Connolly was previously employed by Janssen. Dr McNaughton has participated in clinical studies for Pfizer. Dr Tang is a consultant to Sequana Medical AG. The other authors report no conflicts.

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions., Competing Interests: Disclosures Dr Capodanno reports speaker or consulting fees from Amgen, Arena, Daiichi Sankyo, Sanofi, and Terumo; and institutional fees from Medtronic. Dr Mehran reports institutional research payments from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, Atricure, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Filterlex Medical, Humacyte, Idorsia Pharmaceuticals, Janssen, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave, Vivasure, and Zoll; personal fees from Cine-Med Research, Ionis Pharmaceuticals, Novartis, Novo Nordisk, Vectura, and WebMD; equity <1% in Applied Therapeutics, Elixir Medical, Stel, and ControlRad (spouse); and roles with the American Medical Association (Scientific Advisory Board, JAMA Cardiology Associate editor), American College of Cardiology (board of trustees member, member clinical trials research program), and Society for Cardiovascular Angiography & Interventions (Women in Innovations committee member; faculty Cardiac Research Foundation; no fee). Dr Baber discloses honoraria from Amgen, AstraZeneca, Boston Scientific, and Abbott Vascular. Dr Bhatt discloses the following relationships: advisory board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; board of directors: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; chair: inaugural chair, American Heart Association Quality Oversight Committee; consultant: Broadview Ventures and Hims; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for PORTICO [Portico Re-sheathable Transcatheter Aortic Valve System US IDE Trial], funded by St Jude Medical, now Abbott), Boston Scientific (chair, PEITHO [Pulmonary Embolism Thrombolysis Study]), Cleveland Clinic (including for ExCEED [Centera THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis], funded by Edwards), Contego Medical (chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for ENVISAGE [Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation], funded by Daiichi Sankyo; for ABILITY-DM [Randomized Comparison of Abluminus DES+ Sirolimus-Eluting Stents Versus Everolimus-Eluting Stents in Coronary Artery Disease Patients with Diabetes Mellitus], funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT [Myocardial Ischemia and Transfusion]); honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; chair, American College of Cardiology Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI [Evaluation of Dual Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With Atrial Fibrillation That Undergo a PCI With Stenting] clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome] executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for PRONOUNCE [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] operations committee, publications committee, steering committee, and US national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (continuing medical education steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor), National Cardiovascular Data Registry–ACTION Registry Steering Committee (chair), and VA CART (Cardiovascular Assessment, Reporting, and Tracking) Research and Publications Committee (chair); patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital, assigned to Lexicon; neither the author nor Brigham and Women’s Hospital receives any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties: Elsevier (editor, Braunwald’s Heart Disease); site coinvestigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee: American College of Cardiology; and unfunded research: FlowCo and Takeda. Dr Capranzano reports speaker fees from Daiichi Sankyo, Amgen, and Bayer. Dr Collet reports grants for the institution, honoraria, or research fees from BMS Pfizer, Medtronic, Boston Scientific, and AstraZeneca. Dr Cuisset reports consulting and lecture fees from Abbott Vascular, Boston Scientific, Edwards, Europa Organisation, Medtronic, Terumo, and Sanofi, and shares from CERC, a health care company. Dr L. De Luca has received consulting fees or honoraria from Amgen, Aspen, AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, Daiichi Sankyo, Eli Lilly, Menarini, Pfizer/Bristol Myers Squibb, Sanofi, Servier, and The Medicines Company, outside the present work. Dr Farb has received payment as an individual for consulting fee or honoraria from AstraZeneca, Bayer, and Sanofi and institutional payments for grants from PLx Pharma and The Scott R. MacKenzie Foundation. Dr Gibson reports grant support paid to the institution and consulting fees from Johnson & Johnson, Bristol Myers Squibb, CeleCor, Daiichi Sankyo, and Merck. Dr Hahn reports an institutional research grant from the National Evidence-based Healthcare Collaborating Agency, Ministry of Health & Welfare, Korea, and from Abbott Vascular, Biosensors, Boston Scientific, Daiichi Sankyo, Donga-ST, Hanmi Pharmaceutical, and Medtronic Inc. Dr James repots grants to the institution from Amgen, Novartis, Janssen, and AstraZeneca. Dr Lemos reports institutional research funding, unpaid advisory board membership, unpaid membership of the steering/executive/data safety and monitoring group of trials, and unpaid interventional proctorship by Abbott, Corindus, Scitech, Boston Scientific, and Flouit but has not received personal payments by pharmaceutical companies or device manufacturers; being part of Argonauts, an innovation facilitator; and partial support by a grant from The National Council for Scientific and Technological Development (CNPq), Brazil (grant 306677/2019-9). Dr Lopes reports research support from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, and Pfizer and consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. Dr Morice reports being chief executive officer and a shareholder of CERC and a minor shareholder of Electroducer. Dr O’Donoghue reports grants through the hospital from Amgen, Novartis, Janssen, Merck, and AstraZeneca, and honoraria from Amgen, Novartis, AstraZeneca, and Janssen. Dr Serruys reports consultancy fees from SMT, Philips, Novartis, Merillife, and Xeltis. Dr Smits reports institutional research grants from Abbott Vascular and SMT and speaker or consulting honoraria from Abbott Vascular, Microport, and Terumo. Dr Steg reports research grants from Amarin, Bayer, Sanofi, and Servier; he is a speaker or consultant for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers-Squibb, Janssen, Kowa, Idorsia, Lexicon, Merck, Novartis, Novo Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, and Servier; he is senior associate editor of Circulation. Dr Storey reports institutional research grants/support and personal fees from AstraZeneca, Cytosorbents, GlyCardial Diagnostics, and Thromboserin and personal fees from Alnylam, Bayer, Bristol Myers Squibb/Pfizer, Chiesi, CSL Behring, Daiichi Sankyo, Hengrui, Idorsia, Intas Pharmaceuticals, Novartis, PhaseBio, and Sanofi Aventis. Dr Valgimigli reports grants and personal fees from Terumo and personal fees from AstraZeneca, Alvimedica/CID, Abbott Vascular, Daiichi Sankyo, Bayer, CoreFLOW, Idorsia Pharmaceuticals Ltd, Universität Basel, Dept Klinische Forschung, Vifor, Bristol Myers Squib SA, Biotronik, Boston Scientific, Medscape, Medtronic, Vesalio, Novartis, Chiesi, ECRI, and PhaseBio. Dr Vranckx received personal fees from Daiichi Sankyo, Bayer AG, CSL Behring, Novartis, and Pfizer-Bristol Meyers Squibb alliance. Dr Windecker reports research, travel, or educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohme, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave; serves as an advisory board member or member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, SINOMED, Terumo, V-Wave, and Xeltis, with payments to the institution but no personal payments; and is a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without effect on his personal remuneration. Dr Yeh reports research grants or consulting fees from Abbott Vascular, Boston Scientific, and Medtronic; and consulting fees from Cathworks, Elixir Medical, Shockwave, and Zoll. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura, outside the present work; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. The other authors have nothing to disclose.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the management of aggressive hematologic malignancies. However, its role in patients with lymphoma and cardiac metastasis or cardiomyopathy remains undefined due to potentially life-threatening complications such as ventricular rupture, cardiac tamponade, and circulatory failure. We present a case series of patients with lymphoma and cardiomyopathy or cardiac metastasis managed with chimeric antigen receptor T-cell therapy. ( Level of Difficulty: Advanced. )., Competing Interests: Dr Y. Lin has received consultancy fees from Kite/Gilead, Celgene/BMS, Juno/BMS, bluebird bio, Janssen, Legend BioTech, Gamida Cells, Novartis, Iovance, Takeda, Fosun Kite, and Pfizer. Dr Herrmann has received consultancy fees from Pfizer and is supported by the National Cancer Institute (CA 233610). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Genetic-guided P2Y 12 inhibitor selection has been proposed to reduce ischemic events by identifying CYP2C19 loss-of-function (LOF) carriers at increased risk with clopidogrel treatment after percutaneous coronary intervention (PCI). A prespecified analysis of TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) evaluated the effect of genetic-guided P2Y 12 inhibitor therapy on cumulative ischemic and bleeding events., Objectives: Here, the authors detail a prespecified analysis of cumulative endpoints. The primary endpoint was cumulative incidence rate of ischemic events at 12 months. Cumulative incidence of major and minor bleeding was a secondary endpoint. Cox proportional hazards models as adapted by Wei, Lin, and Weissfeld were used to estimate the effect of this strategy on all observed events., Methods: The TAILOR-PCI trial was a prospective trial including 5,302 post-PCI patients with acute and stable coronary artery disease (CAD) who were randomized to genetic-guided P2Y 12 inhibitor or conventional clopidogrel therapy. In the genetic-guided group, LOF carriers were prescribed ticagrelor, whereas noncarriers received clopidogrel. TAILOR-PCI's primary analysis was time to first event in LOF carriers., Results: Among 5,276 patients (median age 62 years; 25% women; 82% acute CAD; 18% stable CAD), 1,849 were LOF carriers (903 genetic-guided; 946 conventional therapy). The cumulative primary endpoint was significantly reduced in the genetic-guided group compared with the conventional therapy (HR: 0.61; 95% CI: 0.41-0.89; P = 0.011) with no significant difference in cumulative incidence of major or minor bleeding (HR: 1.36; 95% CI: 0.67-2.76; P = 0.39)., Conclusions: Among CYP2C19 LOF carriers undergoing PCI, a genetic-guided strategy resulted in a statistically significant reduction in cumulative ischemic events without a significant difference in bleeding. (Tailored Antiplatelet Therapy Following PCI [TAILOR-PCI]; NCT01742117)., Competing Interests: Funding Support and Author Disclosures Funding for this research was provided by the National Institutes of Health (NIH) grants U01HL128606 to Drs Pereira and Farkouh and U01HL128626 to Dr Bailey. The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute (NHLBI) or the National Institutes of Health. Dr Farkouh has received grants from NHLBI, Amgen, Novartis, and Novo Nordisk. Mr Lennon has received grants from the National Institutes of Health (NIH)/NHLBI and receiving nonfinancial support from Spartan Biosciences. Dr So has received grants from Eli Lilly Canada, Spartan Biosciences, Roche Diagnostics, and Aggredyne Inc; and has received personal fees from AstraZeneca Canada, Bayer Canada, and Servier Canada. Dr Goodman has received research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; and has received salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, and the TIMI Study Group (Brigham Health). Dr Lerman has received personal fees from Itamar Medical, Phillips/Volcano, Shahal, and Wei Jian RC Inc. Dr Tanguay has received personal fees from Mayo Clinic, AstraZeneca, Bayer, Daiichi Sankyo, Servier, Novartis, and BMS-Pfizer Alliance. Dr Welsh has received grants and/or personal fees from AstraZeneca, Pfizer, Bayer, Canadian Cardiac Society, Mayo Clinic, Boehringer Ingelheim, and Novartis. Dr Bailey has received grants from NIH. Dr Pereira has received grants from the NHLBI. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Despite its clinical implications in screening and therapy, genetic testing in dilated cardiomyopathy (DCM) is underused. This study evaluated implementing a practice intervention in a heart failure clinic to automate and streamline the process of genetic testing., Methods: Eligible patients with DCM were compared for frequency of pretest genetic education and testing during pre- and postintervention periods. The intervention comprised automated prescheduling of a cardiovascular genomics e-consult that served as a placeholder for downstream, pretest education, testing, and post-test review of genetic results., Results: Patients with DCM were more likely to undergo pretest genetic education after intervention than before intervention (33.5% vs 14.8%, P < .0001). Similarly, patients with DCM were more likely to undergo genetic testing after intervention than before intervention (27.3% vs 13.0%, P = .0006). The number of patients who were diagnosed to have likely pathogenic or pathogenic genetic variants were 2 of 21 (9.5%) and 6 of 53 (11.1%) before and after intervention, respectively, and variants were present in the following genes: FLNC, TTN, DES, LMNA, PLN, and TNNT2., Conclusion: An intervention strategy in a heart failure clinic to increase the rates of pretest genetic education and testing in eligible patients with DCM was feasible and efficacious and may have important implications for the management of DCM., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Loss-of-function CYP2C19 variants are associated with increased cumulative ischemic outcomes warranting CYP2C19 genotyping prior to clopidogrel administration. TAILOR-PCI was an international, multicenter (40 sites), prospective, randomized trial comparing rapid point of care (POC) genotype-guided vs. conventional anti-platelet therapy. The performance of buccal-based rapid CYP2C19 genotyping performed by non-laboratory-trained staff in TAILOR-PCI was assessed. Pre-trial training and evaluation involved rapid genotyping of 373 oral samples, with 99.5% (371/373) concordance with Sanger sequencing. During TAILOR-PCI, 5302 patients undergoing PCI were randomized to POC rapid CYP2C19 *2, *3, and *17 genotyping versus no genotyping. At 12 months post-PCI, TaqMan genotyping determined 99.1% (2,364/2,385) concordance with the POC results, with 90.7-98.8% sensitivity and 99.2-99.6% specificity. In conclusion, non-laboratory personnel can be successfully trained for on-site instrument operation and POC rapid genotyping with analytical accuracy and precision across multiple international centers, thereby supporting POC genotyping in patient-care settings, such as the cardiac catheterization laboratory.Clinical Trial Registration: https://www.clinicalTrials.gov (Identifier: NCT01742117)., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose of Review: Artificial intelligence (AI) techniques have the potential to remarkably change the practice of cardiology in order to improve and optimize outcomes in heart failure and specifically cardiomyopathies, offering us novel tools to interpret data and make clinical decisions. The aim of this review is to describe the contemporary state of AI and digital health applied to cardiomyopathies as well as to define a potential pivotal role of its application by physicians in clinical practice., Recent Findings: Many studies have been undertaken in recent years on cardiomyopathy screening especially using AI-enhanced electrocardiography (ECG). Even with mild left ventricular (LV) dysfunction, AI-ECG screening for amyloidosis, hypertrophic cardiomyopathy, or dilated cardiomyopathy is now feasible. Introduction of AI-ECG in routine clinical care has resulted in higher detection of LV systolic dysfunction; however, clinical research on a broader scale with diverse populations is necessary and ongoing. In the area of cardiac-imaging, AI automatically assesses the thickness and characteristics of myocardium to differentiate cardiomyopathies, but research on its prognostic capability has yet to be conducted. AI is also being applied to cardiomyopathy genomics, especially to predict pathogenicity of variants and identify whether these variants are clinically actionable. While the implementation of AI in the diagnosis and treatment of cardiomyopathies is still in its infancy, an ever-growing clinical research strategy will ascertain the clinical utility of these AI tools to help improve diagnosis of and outcomes in cardiomyopathies. We also need to standardize the tools used to monitor the performance of AI-based systems which can then be used to expedite decision-making and rectify any hidden biases. Given its potential important role in clinical practice, healthcare providers need to familiarize themselves with the promise and limitations of this technology., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The International Society for Heart and Lung Transplant consensus panel notes that too little data exist regarding the role of non-HLA in allograft rejection. We developed a novel shotgun immunoproteomic approach to determine the identities and potential roles non-HLA play in antibody-mediated rejection (AMR) in heart transplant recipients., Methods: Serum was collected longitudinally from heart transplant recipients experiencing AMR in the absence of donor-specific anti-HLA antibodies (n = 6) and matched no rejection controls (n = 7). Antidonor heart affinity chromatography columns were formed by recipient immunoglobulin G immobilization at transplantation, acute rejection, and chronic postrejection time points. Affinity chromatography columns were used to capture antigens from individual patient's donor heart biopsies collected at transplantation. Captured proteins were subjected to quantitative proteomic analysis and the longitudinal response was calculated., Results: Overlap in antigen-specific response between AMR and non-AMR patients was only 8.3%. In AMR patients, a total of 155 non-HLAs were identified, with responses toward 43 high prevalence antigens found in ≥50% of patients. Immunofluorescence staining for representative high prevalence antigens demonstrated that their abundance increased at acute rejection, correlating with their respective non-HLA antibody response. Physiological changes in cardiomyocyte and endothelial cell function, following in vitro culture with patient immunoglobulin G, correlated with response toward several high prevalence antigens., Conclusions: This work demonstrates a novel high-throughput strategy to identify clinically relevant non-HLA from donor endomyocardial biopsy. Such a technique has the potential to improve understanding of longitudinal timing of antigen-specific responses and their cause and effect relationship in graft rejection., Competing Interests: Mayo Clinic and T.J.N. have financial rights to ReGen Theranostics through licensing agreements. The remaining authors have no relevant conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype-guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss-of-function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex-specific analysis of genotyping and associated cardiovascular outcomes from this study. Methods and Results Associations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional-hazards models. Among 5276 randomized patients, loss-of-function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P =0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P =0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value ( P int =0.59) or BARC bleeding ( P int =0.47) nor for sex and genotype (MACE P int =0.15, and BARC bleeding P int =0.60). Conclusions CYP2C19 loss-of-function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype-guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01742117.

Aims: Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS., Methods and Results: We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65-0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96-1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments., Conclusion: In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS., Study Registration Number: This study is registered in PROSPERO (CRD42021258603)., Key Question: A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored., Key Finding: In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality., Take Home Message: A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Rare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA)., Objectives: To identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR., Methods: MESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes ( n = 82). Coding variants with a frequency of <0.1% in gnomAD and 1,000 Genomes Project databases and damaging/deleterious effects based on in-silico scoring tools were assessed by ClinVar database and ACMG curation guidelines for evidence of pathogenicity. Cases were participants with high myocardial fibrosis defined as highest quartile of extracellular volume (ECV) or native T1 time in T1-mapping CMR and controls were the remainder of participants., Results: A total of 1,135 MESA participants had available genetic data and phenotypic measures and were free of clinical CVD at the time of CMR. We identified 6,349 rare variants in CM-associated genes in the overall MESA population, of which six pathogenic/likely pathogenic (P/LP) variants were present in the phenotyped subpopulation. The genes harboring P/LP variants in the case group were MYH7, CRYAB , and SCN5A . The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], p = 0.03). We identified two MYBPC3 Variants of Unknown Significance (VUS)s with borderline pathogenicity in the case group. The left ventricle (LV) volume, mass, ejection fraction (EF), and longitudinal and circumferential strain in participants with the variants were not different compared to the overall cohort., Conclusions: We observed a higher prevalence of rare potentially pathogenic CM associated genetic variants in participants with significant myocardial fibrosis quantified in CMR as compared to controls without significant fibrosis. No cardiac structural or functional differences were found between participants with or without P/LP variants., 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. The handling editor declared a past co-authorship with one of the authors with the authors WP, KT, SR, JR, and JL., (Copyright © 2022 Shabani, Dutta, Ambale-Venkatesh, Post, Taylor, Rich, Wu, Pereira, Shah, Chatterjee, Rotter, Arking and Lima.)

Background In TAILOR-PCI, genotype-guided selection of P2Y 12 inhibitors after percutaneous coronary intervention did not significantly reduce the risk of ischemic events at 12 months. The Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping (ABCD-GENE) score identifies patients with high platelet reactivity on clopidogrel at increased risk of ischemic events. The aim of this study was to investigate the value of the ABCD-GENE score for tailoring P2Y 12 inhibitor selection after percutaneous coronary intervention. Methods and Results In a post hoc analysis of the TAILOR-PCI, outcomes were analyzed by ABCD-GENE score and allocation to genotype-guided or conventional P2Y 12 inhibitor selection. Primary (death, myocardial infarction, or stroke) and secondary (cardiovascular death, myocardial infarction, stroke, stent thrombosis, or severe recurrent ischemia) outcomes were assessed. Among 3883 patients discharged on clopidogrel in the genotype-guided and conventional therapy groups, 15.8% and 84.2% had high (≥10 points) or low (<10) ABCD-GENE scores, respectively. At 12 months, both the primary (5.2% versus 2.6%, P <0.001) and secondary outcomes (7.7% versus 4.6%, P =0.001) were significantly increased in patients with high ABCD-GENE score. Among 4714 patients allocated to genotype-guided or conventional therapy, the former did not significantly reduce the 12-month risk of the primary and secondary outcomes in both the high and low ABCD-GENE score groups (p interaction =0.48 and 0.27, respectively). Conclusions Among patients with percutaneous coronary intervention on clopidogrel, the ABCD-GENE score was helpful in identifying those at higher risk. The ABCD-GENE score may potentially enhance the precision of tailored selection of P2Y 12 inhibitors, which needs to be confirmed in prospective investigations. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01742117.

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein-Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8-26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04-0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03-0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.

Background: Among patients receiving percutaneous coronary intervention (PCI), the role of a genotype-guided approach for antiplatelet therapy compared with usual care is unclear. We conducted a Bayesian analysis of the entire TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) randomized clinical trial population to evaluate the effect of the genotype-guided antiplatelet therapy post-PCI compared with the usual care on the risk of major adverse cardiovascular events (MACE)., Methods: The primary outcome for our study was the composite of MACE (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included cardiovascular death, stroke, myocardial infarction, stent thrombosis, and major/minor bleeding. Bayesian modeling was used to estimate the probability of clinical benefit of genotype-guided therapy using (1) noninformative priors (ie, analyzing the TAILOR-PCI trial) and (2) informative priors derived from the ADAPT, POPular Genetics, IAC-PCI, and PHARMCLO trials (ie, analyzing TAILOR-PCI trial in the context of prior evidence). Risk ratio (RR: ratio of cumulative outcome incidence between genotype-guided and conventional therapy group) and 95% credible interval (CrI) were estimated for the study outcomes, and probability estimates for RR <1 were computed., Results: Using noninformative priors, in TAILOR-PCI the RR for MACE was 0.78 (95% CrI, 0.55-1.07) in genotype-guided therapy after PCI, and the probability of RR <1 was 94%. Using noninformative priors, the probability of RR <1 for cardiovascular death (RR, 0.95 [95% CrI, 0.52-1.74]), stroke (RR, 0.68 [95% CrI, 0.44-1.06]), myocardial infarction (RR, 0.84 [95% CrI, 0.37-1.89]), stent thrombosis (RR, 0.75 [95% CrI, 0.37-1.45]), and major or minor bleeding (RR, 1.22 [95% CrI, 0.84-1.77]) were 57%, 96%, 67%, 81%, and 15%, respectively. Using informative priors, the posterior probability of RR <1 for MACE, from genotype-guided therapy, was 99% (RR, 0.69 [95% CrI, 0.57-0.84]). Using informative priors, the posterior probability of RR <1 for cardiovascular death (RR, 0.86 [95% CrI, 0.61-1.19]), stroke (RR, 0.69 [95% CrI, 0.48-0.99]), myocardial infarction (RR:0.56 [95% CrI, 0.40-0.78]), stent thrombosis (RR, 0.59 [95% CrI, 0.38-0.94]), and major or minor bleeding (RR, 0.84 [95% CrI, 0.70-0.99]) were 81%, 99%, 99%, 99%, and 99%, respectively., Conclusions: Bayesian analysis of the TAILOR-PCI trial provides clinically meaningful data on the posterior probability of reducing MACE using genotype-guided P2Y 12 inhibitor therapy after PCI.

Genetics has played an important role in the understanding of different cardiomyopathies, and the field of heart failure (HF) genetics is progressing rapidly. Much research has also focused on distinguishing markers of risk in patients with cardiomyopathy using genetic testing. While these efforts currently remain incomplete, new genomic technologies and analytical strategies provide promising opportunities to further explore the genetic architecture of cardiomyopathies, afford insight into the early manifestations of cardiomyopathy, and help define the molecular pathophysiological basis for cardiac remodeling. Cardiovascular physicians should be fully aware of the utility and potential pitfalls of incorporating genetic test results into pre-emptive treatment strategies for patients in the preliminary stages of HF. Future work will need to be directed towards elucidating the biological mechanisms of both rare and common gene variants and environmental determinants of plasticity in the genotype-phenotype relationship. This future research should aim to further our ability to identify, diagnose, and treat disorders that cause HF and sudden cardiac death in young patients, as well as prioritize improving our ability to stratify the risk for these patients prior to the onset of the more severe consequences of their disease., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2021. The Korean Society of Cardiology.)

Undiagnosed dilated cardiomyopathy (DC) can be asymptomatic or present as sudden cardiac death, therefore pre-emptively identifying and treating patients may be beneficial. Screening for DC with echocardiography is expensive and labor intensive and standard electrocardiography (ECG) is insensitive and non-specific. The performance and applicability of artificial intelligence-enabled electrocardiography (AI-ECG) for detection of DC is unknown. Diagnostic performance of an AI algorithm in determining reduced left ventricular ejection fraction (LVEF) was evaluated in a cohort that comprised of DC and normal LVEF control patients. DC patients and controls with 12-lead ECGs and a reference LVEF measured by echocardiography performed within 30 and 180 days of the ECG respectively were enrolled. The model was tested for its sensitivity, specificity, negative predictive (NPV) and positive predictive values (PPV) based on the prevalence of DC at 1% and 5%. The cohort consisted of 421 DC cases (60% males, 57±15 years, LVEF 28±11%) and 16,025 controls (49% males, age 69 ±16 years, LVEF 62±5%). For detection of LVEF≤45%, the area under the curve (AUC) was 0.955 with a sensitivity of 98.8% and specificity 44.8%. The NPV and PPV were 100% and 1.8% at a DC prevalence of 1% and 99.9% and 8.6% at a prevalence of 5%, respectively. In conclusion AI-ECG demonstrated high sensitivity and negative predictive value for detection of DC and could be used as a simple and cost-effective screening tool with implications for screening first degree relatives of DC patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Small patella syndrome presents with small or absent patellae and may result in pulmonary arterial hypertension, typically in children. A pathogenic canonical splice site variant, c.1021+1G>A in the T-box transcription factor 4 ( TBX4 ) gene, currently not included in commercial gene panel, was detected in an adult with pulmonary arterial hypertension and absent patellae. (Level of Difficulty: Advanced.) ., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Background and Objectives: We aimed to determine the genetic and clinical phenotypes of patients with desmin-related myopathy and long-term outcomes after cardiac transplantation., Methods: We performed a retrospective review of cardiac and neurologic manifestations of patients with genetically confirmed desmin-related myopathy (January 1, 1999-January 1, 2020)., Results: Twenty-five patients in 20 different families were recognized. Median age at onset of symptoms was 20 (range 4-50) years; median follow-up time was 36 (range 1-156) months. Twelve patients initially presented with skeletal muscle involvement, and 13 presented with cardiac disease. Sixteen patients had both cardiac and skeletal muscle involvement. Clinically muscle weakness distribution was distal (n = 11), proximal (n = 4), or both (n = 7) in 22 patients. Skeletal muscle biopsy from patients with missense and splice site variants (n = 12) showed abnormal fibers containing amorphous material in Gomori trichrome-stained sections. Patients with cardiac involvement had atrioventricular conduction abnormalities or cardiomyopathy. The most common ECG abnormality was complete atrioventricular block in 11 patients, all of whom required a permanent pacemaker at a median age of 25 (range 16-48) years. Sudden cardiac death resulting in implantable cardioverter-defibrillator (ICD) shocks or resuscitation was reported in 3 patients; a total of 5 patients had ICDs. Orthotopic cardiac transplantation was performed in 3 patients at 20, 35, and 39 years of age., Discussion: Pathogenic variants in desmin can lead to varied neurologic and cardiac phenotypes beginning at a young age. Two-thirds of the patients have both neurologic and cardiac symptoms, usually starting in the third decade. Heart transplantation was tolerated with improved cardiac function and quality of life., (© 2021 American Academy of Neurology.)

Purpose: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies., Methods: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations., Results: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases., Conclusion: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

Background: Enhanced platelet reactivity may play a role in cardiac allograft vasculopathy (CAV) progression. The use of antiplatelet agents after heart transplantation (HT) has been inconsistent and although aspirin (ASA) is often a part of the medication regimen after HT, limited evidence is available on its benefit., Methods and Results: CAV progression was assessed by measuring the difference in plaque volume and plaque index between the last follow-up and the baseline coronary intravascular ultrasound examination. Overall, 529 HT recipients were retrospectively analyzed (337 had ≥2 intravascular ultrasound studies). The progression in plaque volume (P = .007) and plaque index (P = .002) was significantly attenuated among patients treated with early ASA (within the first year after HT). Over a 6.7-year follow-up, all-cause mortality was lower with early ASA compared with late or no ASA use (P < .001). No cardiac deaths were observed in the early ASA group, and the risk of CAV-related graft dysfunction was significantly lower in this group (P = .03). However, the composite of all CAV-related events (cardiac death, CAV-related graft dysfunction, or coronary angioplasty) was not significantly different between the groups (P = .16)., Conclusions: Early ASA use after HT may delay CAV progression and decrease mortality and CAV-related graft dysfunction, but does not seem to affect overall CAV-associated events., (Copyright © 2021 Elsevier Inc. All rights reserved.)