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).

Effect of beta-blocker therapy on the response to mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy.

Aims: In the EXPLORER-HCM trial, mavacamten improved exercise capacity and symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten effects on the primary endpoint, a composite of peak oxygen consumption (VO ) and New York Heart Association (NYHA) class, were greater in patients not receiving background beta-blockers than in those receiving beta-blockers. We sought to determine if the effect of background treatment was consistent across other clinically meaningful parameters.

Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy.

Background: Septal reduction therapy (SRT), surgical myectomy or alcohol ablation, is recommended for obstructive hypertrophic cardiomyopathy (oHCM) patients with intractable symptoms despite maximal medical therapy, but is associated with morbidity and mortality.

Objectives: This study sought to determine whether the oral myosin inhibitor mavacamten enables patients to improve sufficiently to no longer meet guideline criteria or choose to not undergo SRT.

Methods: Patients with left ventricular (LV) outflow tract (LVOT) gradient ≥50 mm Hg at rest/provocation who met guideline criteria for SRT were randomized, double blind, to mavacamten, 5 mg daily, or placebo, titrated up to 15 mg based on LVOT gradient and LV ejection fraction.

The Impact of Mavacamten on the Pathophysiology of Hypertrophic Cardiomyopathy: A Narrative Review.

Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways.

Assessment of Disease Status and Treatment Response With Artificial Intelligence-Enhanced Electrocardiography in Obstructive Hypertrophic Cardiomyopathy.

AI analysis of HCM ECGs correlates with longitudinal hemodynamic, cardiac structural and laboratory markers in obstructive HCM patients.

Clinical and economic burden of obstructive hypertrophic cardiomyopathy in the United States.

Aims: Obstructive hypertrophic cardiomyopathy (oHCM) is a disease of the cardiomyocyte in which dynamic left ventricular outflow track obstruction may lead to heart failure, valvular disease, and sudden death. Little is known about healthcare resource utilization (HRU) and costs associated with oHCM. This study investigated the clinical and economic burden of oHCM in patients with or without symptoms associated with oHCM.

Study design and rationale of VALOR-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy who are eligible for septal reduction therapy.

Background: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder which frequently leads to symptoms such as dyspnea and exercise intolerance, often due to severe dynamic left ventricular outflow tract obstruction (LVOTO). Current guideline-recommended pharmacotherapies have variable therapeutic responses to relieve LVOTO. In recent phases 2 and 3, clinical trials for symptomatic obstructive HCM (oHCM), mavacamten, a small molecule inhibitor of β-cardiac myosin has been shown to improve symptoms, exercise capacity, health status, reduce LVOTO, along with having a beneficial impact on cardiac structure and function.

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.

Background: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.

Time-Dependent Cardiovascular Treatment Benefit Model for Lipid-Lowering Therapies.

Background With the availability of new lipid-lowering therapy options, there is a need to compare the expected clinical benefit of different treatment strategies in different patient populations and over various time frames. We aimed to develop a time-dependent model from published randomized controlled trials summarizing the relationship between low-density lipoprotein cholesterol lowering and cardiovascular risk reduction and to apply the model to investigate the effect of treatment scenarios over time. Methods and Results A cardiovascular treatment benefit model was specified with parameters as time since treatment initiation, magnitude of low-density lipoprotein cholesterol reduction, and additional patient characteristics.

Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial.

Aims: Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.

Methods And Results: We studied the effects of danicamtiv on LV and LA function in non-clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double-blind, single- and multiple-dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50-100 mg twice daily for 7 days).

Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy.

Background: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM.

Objectives: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM.

Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome.

Background: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).

Objectives: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).

Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery.

Background: Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death.

Objectives: This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab).

Methods: Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks.

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial.

Aims: The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin-kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.

Effect of Alirocumab on Mortality After Acute Coronary Syndromes.

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome.

Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy.

Alirocumab in Patients With Polyvascular Disease and Recent Acute Coronary Syndrome: ODYSSEY OUTCOMES Trial.

Background: Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by proprotein convertase subtilisin-kexin type 9 inhibition in such patients is undetermined.

Objectives: This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy.

Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial.

Background: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.

Objectives: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.

Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.

Background: Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy.

Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.

Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference.

Purpose: The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease.

Methods: The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe.

Long-term treatment adherence to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in 6 ODYSSEY Phase III clinical studies with treatment duration of 1 to 2 years.

Background: Nonadherence to cardiovascular medications, including daily, oral statin therapy, negatively impacts outcomes in patients requiring low-density lipoprotein cholesterol (LDL-C)-lowering therapy. The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab also reduces LDL-C, but has a different mode of administration (subcutaneous injection).

Objective: The objective of the study was to assess long-term adherence to alirocumab 75 or 150 mg, given every 2 weeks, in phase III trials of patients with sub-optimally controlled hypercholesterolemia.

Relationship of microparticles to progenitor cells as a measure of vascular health in a diabetic population.

Objective: Quantitative measures are needed to identify diabetic patients at higher risk for CV events. Cell-derived microparticles (MPs) are submicron membrane vesicles released from activated cells that are indicative of cell damage. Progenitor cells (PCs) including proangiogenic cells (PACs), often termed endothelial progenitor cells (EPCs), are mediators of reparative capacity.

Stem cell review series: regulating highly potent stem cells in aging: environmental influences on plasticity.

Significant advances in the past decade have revealed that a large number of highly plastic stem cells are maintained in humans through adulthood and are present even in older adults. These findings are notable in light of the reduced capacity for repair and regeneration in older tissues. The apparent dichotomy can be reconciled through an appreciation of the age-associated changes in the microenvironmental pathways that govern adult stem cell plasticity and differentiation patterns.

Stem cells for cardiovascular repair - the challenges of the aging heart.

The discovery of extracardiac progenitor cells and resident cardiac stem cells in recent years has led to a great deal of interest in the development of therapeutic strategies that target these endogenous cell sources for promotion of cardiovascular repair mechanisms in the diseased heart. Cardiovascular risk increases with age and among many factors, the age-associated decline in cardiac and vascular regenerative capacity may contribute to the progressive deterioration of cardiovascular health. Thus, understanding the mechanisms which underlie the dysregulation of cardiac stem and progenitor cells may lead to the identification of novel targets and approaches to reverse this decline.

Targets for regulating angiogenesis in the ageing endothelium.

Vascular dysfunction underlies the pathophysiology of a wide range of diseases, including atherosclerosis, diabetes and arthritis. Angiogenic function is progressively impaired with increasing age and, therefore, has been linked to the increased risk of many of these diseases among older people. Elucidating the cellular and molecular angiogenic pathways that become dysregulated with age will lead to the identification of novel targets for the restoration of vascular repair mechanisms in the older population.