Management of Type 2 Diabetes in Stage C Heart Failure with Reduced Ejection Fraction

Type 2 diabetes is an increasingly common comorbidity of stage C heart failure with reduced ejection fraction (HFrEF). The two diseases are risk factors for each other and can bidirectionally independently worsen outcomes. The regulatory requirement of cardiovascular outcomes trials for antidiabetic agents has led to an emergence of novel therapies with robust benefits in heart failure, and clinicians must now ensure they are familiar with the management of patients with concurrent diabetes and stage C HFrEF. This review summarises the current evidence for the management of type 2 diabetes in stage C HFrEF, recapitulating data from landmark heart failure trials regarding the use of guideline-directed medical therapy for heart failure in patients with diabetes. It also provides a preview of upcoming clinical trials in these populations

The Interaction of Neuraminidase and Hemagglutinin Mutations in Influenza Virus in Resistance to 4-Guanidino-Neu5Ac2en

AbstractWe have previously described a 4-guanidino-Neu5Ac2en (zanamivir)-resistant neuraminidase (NA) variant G70C4-G, with an active site mutation Glu 119 to Gly. This variant has been found to also harbor a hemagglutinin (HA) mutation in the receptor binding site, Ser 186 to Phe. Examination of early passages of the G70C4-G virus revealed that this HA mutation had arisen by the first passage. From a subsequent passage two transient variants were isolated which had each acquired a different second HA mutation, Ser 165 to Asn and Lys 222 to Thr. Both were highly drug resistant and drug dependent and their ability to adsorb to and penetrate cells was decreased. Comparison of drug sensitivities between the variant, with the additional HA mutation at Ser 165, and viruses with either mutation alone revealed that these two HA mutations acted synergistically to increase resistance. To determine the contribution to resistance of each of the NA and HA mutations in G70C4-G, the NA mutation was separated from the HA mutation by reassorting. The NA mutation and the HA mutation each conferred low-level resistance to zanamivir, while the two mutations interacted synergistically in the double mutant to give higher resistancein vitro.Infectivity was not adversely affected in the double mutant and while there was a small decrease in sensitivity to zanamivir in the mouse model, there was no detectable resistance to zanamivir in the ferret model

Frequency of Arrhythmias and Postural Orthostatic Tachycardia Syndrome in Patients With Marfan Syndrome: A Nationwide Inpatient Study.

Background Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder affecting multiple systems, particularly the cardiovascular system. The leading causes of death in MFS are aortopathies and valvular disease. We wanted to identify the frequency of arrhythmia and postural orthostatic tachycardia syndrome, length of hospital stay, health care-associated costs (HAC), and in-hospital mortality in patients with MFS. Methods and Results The National Inpatient Sample database from 2005 to 2014 was queried using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for MFS and arrhythmias. Patients were classified into subgroups: supraventricular tachycardia, ventricular tachycardia (VT), atrial fibrillation, atrial flutter, and without any type of arrhythmia. Data about length of stay, HAC, and in-hospital mortality were also abstracted from National Inpatient Sample database. Adjusted HAC was calculated as multiplying HAC and cost-to-charge ratio; 12 079 MFS hospitalizations were identified; 1893 patients (15.7%) had an arrhythmia; and 4.9% of the patients had postural orthostatic tachycardia syndrome. Median values of length of stay and adjusted HAC in VT group were the highest among the groups (VT: 6 days, $18 975.8; supraventricular tachycardia: 4 days,$11 906.6; atrial flutter: 4 days, $11 274.5; atrial fibrillation: 5 days,$10431.4; without any type of arrhythmia: 4 days, $8336.6; both P=0.0001). VT group had highest in-patient mortality (VT: 5.3%, atrial fibrillation: 4.1%, without any type of arrhythmia: 2.1%, atrial flutter: 1.7%, supraventricular tachycardia: 0%; P<0.0001) even after adjustment for potential confounders (without any type of arrhythmia versus VT; odds ratio [95% CI]: 3.18 [1.62-6.24], P=0.001). Conclusions Arrhythmias and postural orthostatic tachycardia syndrome in MFS were high and associated with increased length of stay, HAC, and in-hospital mortality especially in patients with VT

State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family members has revealed incomplete penetrance and variable expressivity in ACM, suggesting a complex genotype-phenotype relationship. This review details the genetic basis of ACM with specific genotype-phenotype associations, providing the reader with a nuanced perspective of this condition; whilst also proposing a future roadmap to delivering precision medicine-based management in ACM

Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption: A Secondary Analysis of the EXPLORER-HCM Randomized Trial

IMPORTANCE: Mavacamten, a cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in the EXPLORER-HCM study. However, the full extent of mavacamten's effects on exercise performance remains unclear. OBJECTIVE: To investigate the effect of mavacamten on exercise physiology using cardiopulmonary exercise testing (CPET). DESIGN, SETTING, AND PARTICIPANTS: Exploratory analyses of the data from the EXPLORER-HCM study, a randomized, double-blind, placebo-controlled, phase 3 trial that was conducted in 68 cardiovascular centers in 13 countries. In total, 251 patients with symptomatic obstructive HCM were enrolled. INTERVENTIONS: Patients were randomly assigned in a 1:1 ratio to mavacamten or placebo. MAIN OUTCOMES AND MEASURES: The following prespecified exploratory cardiovascular and performance parameters were assessed with a standardized treadmill or bicycle ergometer test protocol at baseline and week 30: carbon dioxide output (VCO2), minute ventilation (VE), peak VE/VCO2 ratio, ventilatory efficiency (VE/VCO2 slope), peak respiratory exchange ratio (RER), peak circulatory power, ventilatory power, ventilatory threshold, peak metabolic equivalents (METs), peak exercise time, partial pressure of end-tidal carbon dioxide (PETCO2), and VO2/workload slope. RESULTS: Two hundred fifty-one patients were enrolled. The mean (SD) age was 58.5 (11.9) years and 59% of patients were male. There were significant improvements with mavacamten vs placebo in the following peak-exercise CPET parameters: peak VE/VCO2 ratio (least squares [LS] mean difference, -2.2; 95% CI, -3.05 to -1.26; P < .001), peak METs (LS mean difference, 0.4; 95% CI, 0.17-0.60; P < .001), peak circulatory power (LS mean difference, 372.9 mL/kg/min × mm Hg; 95% CI, 153.12-592.61; P = .001), and peak PETCO2 (LS mean difference, 2.0 mm Hg; 95% CI, 1.12-2.79; P < .001). Mavacamten also improved peak exercise time compared with placebo (LS mean difference, 0.7 minutes; 95% CI, 0.13-1.24; P = .02). There was a significant improvement in nonpeak-exercise CPET parameters, such as VE/VCO2 slope (LS mean difference, -2.6; 95% CI, -3.58 to -1.52; P < .001) and ventilatory power (LS mean difference, 0.6 mm Hg; 95% CI, 0.29-0.90; P < .001) favoring mavacamten vs placebo. CONCLUSIONS AND RELEVANCE: Mavacamten improved a range of CPET parameters beyond pVO2, indicating consistent and broad benefits on maximal exercise capacity. Although improvements in peak-exercise CPET parameters are clinically meaningful, the favorable effects of mavacamten on submaximal exertional tolerance provide further insights into the beneficial impact of mavacamten in patients with obstructive HCM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03470545

Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From the MAVA-LTE Study, EXPLORER-LTE Cohort.

This study was funded by Bristol Myers Squibb, Princeton, New Jersey, USA. Bristol Myers Squibb’s policy on data sharing is available online at https://www.bms.com/researchers-and-partners/clinicaltrials-and-research/disclosure-commitment.html. Dr Rader has received consulting fees from Medtronic, Bristol Myers Squibb, and ReCor Medical. Dr Ore˛ziak has received personal fees from Bristol Myers Squibb. Dr Saberi has received personal fees from Bristol Myers Squibb. Dr Fermin has received consulting fees from Alnylam, Eidos Therapeutics, Bristol Myers Squibb, and Pfizer. Dr Wheeler has received personal fees and research support from Bristol Myers Squibb. Dr Garcia-Pavia has received consulting and speaking fees from Bristol Myers Squibb, Rocket Pharmaceuticals, and Cytokinetics and speaking fees from Bristol Myers Squibb and Cytokinetics. Dr Zwas has received personal fees from Bristol Myers Squibb. Dr Masri has received grants from Akcea, Pfizer, and Ultromics and consulting fees from Alnylam, Cytokinetics, Eidos Therapeutics, Ionis, and Pfizer. Dr Owens has received consulting fees from Bristol Myers Squibb, Cytokinetics, and Pfizer. Dr Hegde serves on the faculty of the Cardiovascular Imaging Core Laboratory at Brigham and Women’s Hospital, and her institution has received payments for her consulting work from Bristol Myers Squibb. Dr Seidler has received consulting fees or honoraria for lectures from Bristol Myers Squibb and Cytokinetics. Dr Balaratnam and Dr Sehnert are employees of Bristol Myers Squibb and own stock of Bristol Myers Squibb. Shawna Fox is an employee of IQVIA, a partner providing statistics services to Bristol Myers Squibb. Dr Olivotto has received grants from Amicus, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Genzyme, and Menarini International and consulting fees from Amicus, Cytokinetics, Genzyme, MS Pharma, Rocket Pharmaceuticals, and Tenaya Therapeutics.BACKGROUND Data assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed. OBJECTIVES The authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655). METHODS After mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms. RESULTS Between April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: -35.6 ± 32.6 mm Hg; Valsalva: -45.3 ± 35.9 mm Hg), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (median: -480 ng/L; Q1-Q3: -1,104 to -179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events. CONCLUSIONS Mavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up.S

Exercise Capacity in Patients With Obstructive Hypertrophic Cardiomyopathy:SEQUOIA-HCM Baseline Characteristics and Study Design

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818).</p

Impact of SARS-Cov-2 infection in patients with hypertrophic cardiomyopathy : results of an international multicentre registry

To describe the natural history of SARS-CoV-2 infection in patients with hypertrophic cardiomyopathy (HCM) compared with a control group and to identify predictors of adverse events. Three hundred and five patients [age 56.6 ± 16.9 years old, 191 (62.6%) male patients] with HCM and SARS-Cov-2 infection were enrolled. The control group consisted of 91 131 infected individuals. Endpoints were (i) SARS-CoV-2 related mortality and (ii) severe clinical course [death or intensive care unit (ICU) admission]. New onset of atrial fibrillation, ventricular arrhythmias, shock, stroke, and cardiac arrest were also recorded. Sixty-nine (22.9%) HCM patients were hospitalized for non-ICU level care, and 21 (7.0%) required ICU care. Seventeen (5.6%) died: eight (2.6%) of respiratory failure, four (1.3%) of heart failure, two (0.7%) suddenly, and three (1.0%) due to other SARS-CoV-2-related complications. Covariates associated with mortality in the multivariable were age {odds ratio (OR) per 10 year increase 2.25 [95% confidence interval (CI): 1.12-4.51], P = 0.0229}, baseline New York Heart Association class [OR per one-unit increase 4.01 (95%CI: 1.75-9.20), P = 0.0011], presence of left ventricular outflow tract obstruction [OR 5.59 (95%CI: 1.16-26.92), P = 0.0317], and left ventricular systolic impairment [OR 7.72 (95%CI: 1.20-49.79), P = 0.0316]. Controlling for age and sex and comparing HCM patients with a community-based SARS-CoV-2 cohort, the presence of HCM was associated with a borderline significant increased risk of mortality OR 1.70 (95%CI: 0.98-2.91, P = 0.0600). Over one-fourth of HCM patients infected with SARS-Cov-2 required hospitalization, including 6% in an ICU setting. Age and cardiac features related to HCM, including baseline functional class, left ventricular outflow tract obstruction, and systolic impairment, conveyed increased risk of mortality

City of Hitchcock Comprehensive Plan 2020-2040

Hitchcock is a small town located in Galveston County (Figure 1.1), nestled up on the Texas Gulf Coast. It lies about 40 miles south-east of Houston. The boundaries of the city encloses an area of land of 60.46 sq. miles, an area of water of 31.64 sq. miles at an elevation just 16 feet above sea level. Hitchcock has more undeveloped land (~90% of total area) than the county combined. Its strategic location gives it a driving force of opportunities in the Houston-Galveston Region.The guiding principles for this planning process were Hitchcock’s vision statement and its corresponding goals, which were crafted by the task force. The goals focus on factors of growth and development including public participation, development considerations, transportation, community facilities, economic development, parks, and housing and social vulnerabilityTexas Target Communitie

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.This work was supported in part by grants from the Instituto de Salud Carlos III (ISCIII) (PI15/01551, PI17/01941 and CB16/11/00432 to P.G-P. and L.A-P.), the Spanish Ministry of Economy and Competitiveness (SAF2015-71863-REDT to P.G-P.), the John S. LaDue Memorial Fellowship at Harvard Medical School (Y.K.), Wellcome Trust (107469/Z/15/Z to J.S.W.), Medical Research Council (intramural awards to S.A.C. and J.S.W; MR/M003191/1 to U.T), National Institute for Health Research Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College London (P.J.B., S.A.C., J.S.W.), National Institute for Health Research Biomedical Research Centre at Imperial College London Healthcare National Health Service Trust and Imperial College London (D.O.R., S.A.C., S.P., J.S.W.), Sir Henry Wellcome Postdoctoral Fellowship (C.N.T.), Rosetrees and Stoneygate Imperial College Research Fellowship (N.W.), Fondation Leducq (S.A.C., C.E.S., J.G.S.), Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health (UK; HICF-R6-373; S.A.C., P.J.B., J.S. W.), the British Heart Foundation (NH/17/1/32725 to D.O.R.; SP/10/10/28431 to S.A.C), Alex’s Lemonade Stand Foundation (K.G.), National Institutes of Health (R.A.: U01CA097452, R01CA133881, and U01CA097452; Z.A.: R01 HL126797; B.K.: R01 HL118018 and K23-HL095661; J.G.S. and C.E.S.: 5R01HL080494, R01HL084553), and the Howard Hughes Medical Institute (C.E.S.). The Universitario Puerta de Hierro and Virgen de la Arrixaca Hospitals are members of the European Reference Network on Rare and Complex Diseases of the Heart (Guard-Heart; http://guard-heart.ern-net.eu). This publication includes independent research commissioned by the Health Innovation Challenge Fund (HICF), a parallel funding partnership between the Department of Health and Wellcome Trust. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Ministry of Economy, Industry and Competitiveness and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Grants from ISCIII and the Spanish Ministry of Economy and Competitiveness are supported by the Plan Estatal de I+D+I 2013-2016 – European Regional Development Fund (FEDER) “A way of making Europe”.S