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Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).

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. VALOR-HCM is designed as a multicenter (approximately 20 centers in United States) phase 3, double-blind, placebo-controlled, randomized study. The study population consists of approximately 100 patients (≥18 years old) with symptomatic oHCM who meet 2011 American College of Cardiology/American Heart Association and/or 2014 European Society of Cardiology HCM-guideline criteria and are eligible and willing to undergo septal reduction therapy (SRT). The study duration will be up to 138 weeks, including an initial 2-week screening period, followed by16 weeks of placebo-controlled treatment, 16 weeks of active blinded treatment, 96 weeks of long-term extension, and an 8-week posttreatment follow-up visit. The primary endpoint will be a composite of the decision to proceed with SRT prior to or at Week 16 or remain guideline eligible for SRT at Week 16. Secondary efficacy endpoints will include change (from baseline to Week 16 in the mavacamten group vs placebo) in postexercise LVOT gradient, New York Heart Association class, Kansas City Cardiomyopathy Questionnaire clinical summary score, NT-proBNP, and cardiac troponin. Exploratory endpoints aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. In severely symptomatic drug-refractory oHCM patients meeting guideline criteria of eligibility for SRT, VALOR-HCM will primarily study if a 16-week course of mavacamten reduces or obviates the need for SRT using clinically driven endpoints.

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. Here, we integrate the results of clinical observations with mavacamten, an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere, to develop an integrated pathophysiological pathway model of HCM, confirming the key role of excess sarcomeric activity. This model may serve as a foundation to understand the role of HCM pathophysiological pathways in the clinical presentation of the disease, and how a targeted therapeutic intervention capable of normalizing sarcomeric activity and repopulating low-energy utilization states may reduce the impact of these pathways in HCM and potentially related disease states.

Endothelial microparticles (EMPs) belong to a family of extracellular vesicles that are dynamic, mobile, biological effectors capable of mediating vascular physiology and function. The release of EMPs can impart autocrine and paracrine effects on target cells through surface interaction, cellular fusion, and, possibly, the delivery of intra-vesicular cargo. A greater understanding of the formation, composition, and function of EMPs will broaden our understanding of endothelial communication and may expose new pathways amenable for therapeutic manipulation.

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. Results We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. Conclusions The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.

CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39 -deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro . This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39 -deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.

Recent advances in stem cell biology have given rise the new field of cardiac regenerative medicine. Specifically, the development of cardiac stem cell science now offers the promise of novel cardiovascular therapies based on a dynamic body of basic and translational research. Importantly, the potential wide-spread clinical application of this technology will require that therapies be optimized for individuals with potential impairments in cardiac stem cell function. To this end, the previous experience of hematopoietic stem cell therapies can provide important guidance in the development and maturation of the young cardiac stem cell field. Parallel to the impact that exogenous growth factors have made in the field of hematopoietic therapies, the discovery and potential application of the factor(s) that govern cardiac regeneration may speed the progression of cardiac stem cell technology into an assessable and potent clinical therapy.

Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).

Vascular function in the aging heart is impaired and may underlie the increased morbidity and mortality associated with ischemic heart disease in older individuals. This vascular dysfunction is due, in part, to impairment of platelet derived growth factor (PDGF)-mediated pathways in senescent cardiac microvascular endothelial cells. Restoration of these pathways by intramyocardial injection of growth factor transiently rescues senescent cardiac angiogenesis. Longer-term reconstitution can be achieved experimentally by transplantation of young bone marrow-derived stem cells to promote senescent cardiac angiogenic function in the murine host. Moreover, enhancement of PDGF pathways is cardioprotective, markedly reducing the extent of myocardial injury following coronary occlusion. The clinical translation of these findings for treatment of ischemic heart diseases must overcome the limitation of the proatherosclerotic actions of PDGF, as well as the generation of autologous stem/precursor cell approaches, for the aging cardiovascular system. Strategies targeting growth factor and/or stem-cell homing to gene products downstream of PDGF in the cardiac microvasculature may provide positive feedback loops to enhance cardiac angiogenesis and protection from myocardial infarction and may offer a foundation for developing novel therapies for the prevention and treatment of cardiovascular disease associated with aging.