Hemodynamic Effects of a Calcium Channel Promoter, BAY y 5959, are Preserved after Chronic Administration in Ischemic Heart Failure in Conscious Dogs 1

ABSTRACT BAY y 5959 is a dihydropyridine derivative that binds to L-type calcium channels in a voltage-dependent manner and promotes calcium entry into the cell during the plateau of the action potential by influencing mean open time. Because myofilament responsiveness to calcium is preserved in congestive heart failure (CHF), the inotropic responsiveness to this compound should be preserved in CHF, and tolerance should not develop despite long-term treatment. To test these hypotheses, CHF was induced in 14 chronically instrumented dogs by daily (30 Ϯ 5 days) intracoronary microsphere injections. The effects of BAY y 5959 (2-h i.v. infusions of 3 g/kg/min and 10 g/kg/min) were determined before heart failure, after heart failure was established and then 2 h after the end of a 5-day continuous BAY y 5959 intra-atrial infusion. Before CHF, the positive inotropic effect of BAY y 5959 at a dose of 10 g/kg/ min [left ventricular dP/dt (LVdP/dt) increased from 2955 Ϯ 132 mmHg to 4897 Ϯ 426 mmHg, P Ͻ .05] was associated with bradycardia (HR decreased from 92 Ϯ 4 to 78 Ϯ 6 b/min, P Ͻ.05), slight increases in mean arterial pressure (it increased from 100 Ϯ 2 mmHg to 113 Ϯ 5 mmHg, P Ͻ.05) and did not alter left ventricular end-diastolic pressure. In CHF, BAY y 5959 continued to induce dose-dependent increases in left ventricular systolic pressure, LVdP/dt and mean arterial pressure, as well as causing bradycardia and a significant decrease in left ventricular end-diastolic pressure. After a 5-day infusion of BAY y 5959, base-line LVdP/dt and left ventricular end-diastolic pressure improved. The responses of LVdP/dt and mean arterial pressure to BAY y 5959 were similar to those of the control state. The sustained responses in CHF and after long-term infusion suggest that BAY y 5959 may be an effective and potent inotropic agent for treatment of CHF that does not lead to tolerance to its positive inotropic effects. The use of inotropic agents is an important form of therapy for many patients with CHF. Currently used inotropic agents generally fall into one of two classes: ␤-agonists or phosphodiesterase inhibitors. Although they are efficacious in many settings, their use is sometimes limited by afterload-reducing effects, by decreased effectiveness in heart failure, by the development of tolerance and by potential proarrhythmic effects such as sinus tachycardia and ventricular ectopy. BAY y 5959 is a dihydropyridine derivative that binds to L-type calcium channels in a voltage-dependent manner and promotes calcium entry into the cell during the plateau of the action potential by influencing mean open time Received for publication October 17, 1997. 1 This work is supported in part by a Grant-in-Aid from the American Heart Association (National Center) and a grant from Bayer Corporation, West Haven, CT. J.W. and D.B. were supported in part by an Investigatorship Award from the American Heart Association, New York City Affiliate, Inc. ABBREVIATIONS: LA, left atrium; LAP, left atrial pressure; LV, left ventricle; LVdP/dt max , peak left ventricular dP/dt; CHF, congestive heart failure; MAP, mean arterial pressure; LVEDP, left ventricular end-diastolic pressure; LVSP, left ventricular systolic pressure; LAD, left anterior descending artery; LCX, left circumflex coronary artery; BAY y 5959, (Ϫ)

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

Heart failure and preserved left ventricular function: long term clinical outcome.

BACKGROUND: Patients with heart failure (HF) have a poor prognosis. The proportion of patients with HF and preserved left ventricular function (LVF) is increasing. Long term prognosis of HF with preserved LVF may not be so benign. OBJECTIVES: To evaluate the long term clinical outcome of patients with HF and preserved LVF and predictors of outcome. METHODS: We prospectively evaluated 309 patients hospitalized with a definite clinical diagnosis of HF. Patients were followed for a mean of 6.5 years for clinical outcome. RESULTS: More than a third (36%) of the patients had preserved systolic LVF based on echocardiography. The long term survival rate in this group was poor and not significantly different from patients with reduced LVF (28% vs 23% respectively, P=0.2). The adjusted survival rate by Cox regression analysis was also not significantly different (hazard ratio 1.16, 95% confidence interval 0.87-1.55, P=0.31). The event free survival from death or heart failure re-hospitalization was also low in both groups and not significantly different between patients with preserved vs. reduced LVF (12% vs. 10% respectively, P=0.2). Predictors of mortality in patients with preserved LVF were age, functional capacity and serum urea levels. CONCLUSIONS: The long term clinical outcome of patients with heart failure and preserved LVF is poor and not significantly different from patients with reduced LVF

Treatment of Heart Failure Patients with Anxiolytics Is Associated with Adverse Outcomes, with and without Depression

Background: Few studies have evaluated the effect of pharmacologic treatment of anxiety on outcomes in heart failure (HF) patients. This study examined the impact of treatment with anxiolytics on clinical outcomes in a real-world sample of HF patients with and without depression. Methods: Patients diagnosed with HF were retrieved from a large HMO database. Patients prescribed anxiolytic medication and patients diagnosed with depression and/or prescribed anti-depressant medication were followed for cardiac-related hospitalizations and death. Results: The study cohort included 6293 HF patients. Treatment with anxiolytics was associated with decreased one-year survival compared to untreated individuals, with a greater reduction in survival seen in patients diagnosed with depression and/or treated with anti-depressants. Multi-variable analysis adjusting for age, sex, NYHA class, cardiac risk factors and laboratory parameters found that treatment with anxiolytics remained a predictor of mortality even when adjusting for depression. Depression combined with anxiolytic treatment was predictive of increased mortality, and treatment with anxiolytics alone, depression alone and anxiolytic treatment together with depression were each associated with an increased hazard ratio for a composite outcome of death and hospitalization. Conclusions: In this real-world study of HF patients, both treatment with anxiolytics and depression were associated with increased mortality, and anxiolytic therapy remained a predictor of mortality when adjusting for depression. Treatment of anxiety together with depression was associated with the highest risk of mortality. Safe and effective treatment for anxiety and depression is warranted to alleviate the detrimental impact of these disorders on quality and of life and adverse events

Echocardiography overestimates LV mass in the elderly as compared to cardiac CT.

PURPOSE:Echocardiographic studies have shown an increase in LV mass with advanced age. However, autopsy and MRI studies demonstrate that with aging, LV mass is unchanged or slightly decreased, with a decrease in LV volume and an increase in wall thickness consistent with concentric remodeling. LV structural remodeling with aging may lead to an overestimation of LV mass in older adults when using standard echocardiography measurements and calculations. This study compared CT and echocardiographic LV mass calculation in younger and older patients and parameters associated with age-related LV remodeling. METHODS:Same subject modality comparison of echocardiographic and cardiac CT LV measurement with derivation of LV mass was performed retrospectively. Echocardiographic measurements were performed by a single observer in accordance with European Association of Cardiovascular Imaging (EACI)/American Society of Echocardiography (ASE) guidelines. CT measurements were performed in end-diastole on multiplanar reformatted image planes corresponding to those typically used in echocardiography. Calculated CT measurements were based on automatic segmentation of heart chambers via edge-tracing algorithms. RESULTS:129 patients were identified. In patients age 65 and older, LV mass was significantly higher when calculated using echocardiographic measurements compared to CT. Patients 65 years of age and older were found to have increased average wall thickness measurements with echocardiography but not with CT. The discrepancy between calculated echo and CT LV mass was reduced when using the mid-septal instead of proximal wall width for the EACI convention. CONCLUSION:In the elderly, increased echo-derived LV mass may reflect remodeling rather than a true increase in LV mass

Kaplan Meier survival curves of patients with preserved versus reduced left ventricular function.

<p>The survival rate <b>[A]</b>, event-free rate of death or heart failure re-hospitalization <b>[B]</b> and event-free from all hospitalizations <b>[C]</b> of patients with preserved versus reduced LVF (N = 309). There was no significant difference in survival or clinical event-free rate between the groups.</p

Demographics and clinical characteristics of the patients with CHF.

<p>Data is presented as mean ± standard deviation or median (interquartile range) for continuous variables and counts (percentages) for categorical variables. P value by the student T test or Mann-Whitney U test for continuous variables and the Chi-Square Test for categorical variables.</p><p>CXR - Chest X ray. LA - left atrium. LV - left ventricle. EDD – end diastolic diameter. ESD – end systolic diameter. RVF – right ventricle function. PG –pressure gradient.</p

Predictors of death by Cox Regression analysis.

*<p>Log₁₀-transformed.</p

Left Ventricular Mass and Geometry and the Risk of Ischemic Stroke

BACKGROUND AND PURPOSE: Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular events, but its effect on ischemic stroke risk is established mainly in whites. The effect of LV geometry on stroke risk has not been defined. The aim of the present study was to evaluate whether LVH and LV geometry are independently associated with increased ischemic stroke risk in a multiethnic population. METHODS: A population-based case-control study was conducted on 394 patients with first ischemic stroke and 413 age-, sex-, and race-ethnicity–matched community control subjects. LV mass was measured by transthoracic echocardiography. LV geometric patterns (normal, concentric remodeling, concentric or eccentric hypertrophy) were identified. Stroke risk associated with LVH and different LV geometric patterns was assessed by conditional logistic regression analysis in the overall group and age, sex, and race-ethnic strata, with adjustment for established stroke risk factors. RESULTS: Concentric hypertrophy carried the greatest stroke risk (adjusted odds ratio [OR], 3.5; 95% confidence interval [CI], 2.0 to 6.2), followed by eccentric hypertrophy (adjusted OR, 2.4; 95% CI, 2.0 to 4.3). Concentric remodeling carried slightly increased stroke risk (adjusted OR, 1.7; 95% CI, 1.0 to 2.9). Increased LV relative wall thickness was independently associated with stroke after adjustment for LV mass (OR, 1.6; 95% CI, 1.1 to 2.3). CONCLUSIONS: LVH and abnormal LV geometry are independently associated with increased stroke risk. LVH is strongly associated with ischemic stroke in all age, sex, and race-ethnic subgroups. Increased LV relative wall thickness imparts an increased stroke risk after adjustment for LV mass and is of additional value in stroke risk prediction