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. METHODS: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. RESULTS: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009). CONCLUSIONS: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764)

The Number of Endothelial Progenitor Cell Colonies in the Blood Is Increased in Patients With Angiographically Significant Coronary Artery Disease

ObjectivesThe objective of this study was to determine whether the number of endothelial progenitor cells (EPCs) and circulating angiogenic cells (CACs) in peripheral blood was associated with the presence and severity of coronary artery disease (CAD) in patients undergoing coronary angiography.BackgroundPrevious studies have suggested an inverse relationship between levels of circulating EPCs/CACs and the presence of CAD or cardiovascular risk factors, whereas other studies have observed increased numbers of EPCs in the setting of acute ischemia. However, the criteria used to identify specific angiogenic cell subpopulations and methods of evaluating CAD varied in these studies. In the present study, we used rigorous criteria to identify EPCs and CACs in the blood of patients undergoing coronary angiography.MethodsThe number of EPCs and CACs were measured in the blood of 48 patients undergoing coronary angiography. Patients with acute coronary syndromes were excluded.ResultsCompared with patients without angiographically significant CAD, the number of EPCs was increased (1.11 ± 2.50 vs. 4.01 ± 3.70 colonies/well, p = 0.004) and the number of CACs trended higher (175 ± 137 vs. 250 ± 160 cells per mm2, p = 0.09) among patients with significant CAD. The highest levels of EPCs were isolated from patients subsequently selected for revascularization (5.03 ± 4.10 colonies/well).ConclusionsIn patients referred for coronary angiography, higher numbers of EPCs, and a trend toward higher numbers of CACs, were associated with the presence of significant CAD, and EPC number correlated with maximum angiographic stenosis severity. Endothelial progenitor cell levels were highest in patients with CAD selected for revascularization

Precision medicine to improve use of bleeding avoidance strategies and reduce bleeding in patients undergoing percutaneous coronary intervention: Prospective cohort study before and after implementation of personalized bleeding risks

Objective To examine whether prospective bleeding risk estimates for patients undergoing percutaneous coronary intervention could improve the use of bleeding avoidance strategies and reduce bleeding. Design Prospective cohort study comparing the use of bleeding avoidance strategies and bleeding rates before and after implementation of prospective risk stratification for peri-procedural bleeding. Setting Nine hospitals in the United States. Participants All patients undergoing percutaneous coronary intervention for indications other than primary reperfusion for ST elevation myocardial infarction. Main outcome measures Use of bleeding avoidance strategies, including bivalirudin, radial approach, and vascular closure devices, and peri-procedural bleeding rates, stratified by bleeding risk. Observed changes were adjusted for changes observed in a pool of 1135 hospitals without access to pre-procedural risk stratification. Hospital level and physician level variability in use of bleeding avoidance strategies was examined. Results In a comparison of 7408 pre-intervention procedures with 3529 post-intervention procedures, use of bleeding avoidance strategies within intervention sites increased with pre-procedural risk stratification (odds ratio 1.81, 95% confidence interval 1.44 to 2.27), particularly among higher risk patients (2.03, 1.58 to 2.61; 1.41, 1.09 to 1.83 in low risk patients, after adjustment for control sites; P for interaction=0.05). Bleeding rates within intervention sites were significantly lower after implementation of risk stratification (1.0% v 1.7%; odds ratio 0.56, 0.40 to 0.78; 0.62, 0.44 to 0.87, after adjustment); the reduction in bleeding was greatest in high risk patients. Marked variability in use of bleeding avoidance strategies was observed across sites and physicians, both before and after implementation. Conclusions Prospective provision of individualized bleeding risk estimates was associated with increased use of bleeding avoidance strategies and lower bleeding rates. Marked variability between providers highlights an important opportunity to improve the consistency, safety, and quality of care. Study registration Clinicaltrials.gov NCT01383382

Novel patient-centered approach to facilitate same-day discharge in patients undergoing elective percutaneous coronary intervention

Background Same‐day discharge ( SDD ) after elective percutaneous coronary intervention is safe, less costly, and preferred by patients, but it is usually performed in low‐risk patients, if at all. To increase the appropriate use of SDD in more complex patients, we implemented a “patient‐centered” protocol based on risk of complications at Barnes‐Jewish Hospital. Methods and Results Our objectives were as follows: (1) to evaluate time trends in SDD ; (2) to compare (a) mortality, bleeding, and acute kidney injury, (b) patient satisfaction, and (c) hospital costs by SDD versus no SDD ( NSDD ); and (3) to compare SDD eligibility by our patient‐centered approach versus Society for Cardiovascular Angiography and Interventions guidelines. Our patient‐centered approach was based on prospectively identifying personalized bleeding, mortality, and acute kidney injury risks, with a personalized safe contrast limit and mitigating those risks. We analyzed Barnes‐Jewish Hospital's National Cardiovascular Data Registry Cath PCI Registry data from July 1, 2009 to September 30, 2015 (N=1752). SDD increased rapidly from 0% to 77% ( P &lt;0.001), independent of radial access. Although SDD patients were comparable to NSDD patients, SDD was not associated with adverse outcomes (0% mortality, 0% bleeds, and 0.4% acute kidney injury). Patient satisfaction was high with SDD . Propensity score–adjusted costs were 7331 lower/ SDD patient ( P <0.001), saving an estimated 1.8 million annually. Only 16 patients (6.95%) met the eligibility for SDD by Society for Cardiovascular Angiography and Interventions guidelines, implying our patient‐centered approach markedly increased SDD eligibility. Conclusions With a patient‐centered approach, SDD rapidly increased and was safe in 75% of patients undergoing elective percutaneous coronary intervention, despite patient complexity. Patient satisfaction was high, and hospital costs were lower. Patient‐centered decision making to facilitate SDD is an important opportunity to improve the value of percutaneous coronary intervention. </jats:sec

Antimicrobial, Anti-Inflammatory, Antiparasitic, and Cytotoxic Activities of Laennecia confusa

The current paper investigated the potential benefit of the traditional Mexican medicinal plant Laennecia confusa (Cronquist) G. L. Nesom (Asteraceae). Fractions from the hexane, chloroform, methanol, and aqueous extracts were analyzed for antibacterial, antifungal, anti-inflammatory, and antiparasitic activities. The antimicrobial activity of the extracts and fractions was assessed on bacterial and fungal strains, in addition to the protozoa Leishmania donovani, using a microdilution assay. The propensity of the plant's compounds to produce adverse effects on human health was also evaluated using propidium iodine to identify damage to human macrophages. The anti-inflammatory activity of the extracts and fractions was investigated by measuring the secretion of interleukin-6. Chemical analyses demonstrated the presence of flavonoids, cyanogenic and cardiotonic glycosides, saponins, sesquiterpene lactones, and triterpenes in the chloroform extract. A number of extracts and fractions show antibacterial activity. Of particular interest is antibacterial activity against Staphylococcus aureus and its relative methicillin-resistant strain, MRSA. Hexanic and chloroformic fractions also exhibit antifungal activity and two extracts and the fraction CE 2 antiparasitic activity against Leishmania donovani. All bioactive extracts and fractions assayed were also found to be cytotoxic to macrophages. In addition, the hexane and methane extracts show anti-inflammatory activity by suppressing the secretion of interleukine-6

Association of lower fractional flow reserve values with higher risk of adverse cardiac events for lesions deferred revascularization among patients with acute coronary syndrome

BACKGROUND: The safety of deferring revascularization based on fractional flow reserve (FFR) during acute coronary syndrome (ACS) is unclear. We evaluated the association of FFR and adverse cardiac events among patients with coronary lesions deferred revascularization based on FFR in the setting of ACS versus non-ACS. METHODS AND RESULTS: The study population (674 patients; 816 lesions) was divided into ACS (n=334) and non-ACS (n=340) groups based on the diagnosis when revascularization was deferred based on FFR values >0.80 between October 2002 and July 2010. The association and interaction between FFR and clinical outcomes was evaluated using Cox proportional hazards models within each group (mean follow-up of 4.5±2.1 years). Subsequent revascularization of a deferred lesion was classified as a deferred lesion intervention (DLI), whereas the composite of DLI or myocardial infarction (MI) attributed to a deferred lesion was designated as deferred lesion failure (DLF). In the non-ACS group, lower FFR values were not associated with any increase in adverse cardiac events. In the ACS group, every 0.01 decrease in FFR was associated with a significantly higher rate of cardiovascular death, MI, or DLI (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.03 to 1.12), MI or DLI (HR, 1.09; 95% CI: 1.04 to 1.14), DLF (HR, 1.12; 95% CI, 1.06 to 1.18), MI (HR, 1.07; 95% CI, 1.00 to 1.14), and DLI (HR, 1.12; 95% CI, 1.06 to 1.18). CONCLUSION: Lower FFR values among ACS patients with coronary lesions deferred revascularization based on FFR are associated with a significantly higher rate of adverse cardiac events. This association was not observed in non-ACS patients

Les controverses sociotechniques au prisme du Parlement

Le Parlement constitue un espace privilégié pour analyser le déploiement des controverses sociotechniques : non parce qu’il aurait la faculté de les résoudre, notamment via l’OPECST, mais parce qu’il offre de multiples occasions et modalités d’expression et de traitement de ces controverses en son sein. Espace hétérogène et poreux, il participe d’une nouvelle gouvernance des risques, plus soucieuse de leur stabilisation que de leur réduction définitive.The French Parliament offers an ideal place to analyze the unfolding of sociotechnical controversies. Not that it has any capacity to actually resolve these, including its office of science and technology; but rather because it offers a plurality of opportunities for controversies to play out within its two chambers. As a heterogeneous and porous institution, it takes part in a newly formed risk governance that aims to manage rather than definitely solve risk issues

Phytoplankton Blooms at Increasing Levels of Atmospheric Carbon Dioxide: Experimental Evidence for Negative Effects on Prymnesiophytes and Positive on Small Picoeukaryotes

Anthropogenic emissions of carbon dioxide (CO2) and the ongoing accumulation in the surface ocean together with concomitantly decreasing pH and calcium carbonate saturation states have the potential to impact phytoplankton community composition and therefore biogeochemical element cycling on a global scale. Here we report on a recent mesocosm CO2 perturbation study (Raunefjorden, Norway), with a focus on organic matter and phytoplankton dynamics. Cell numbers of three phytoplankton groups were particularly affected by increasing levels of seawater CO2 throughout the entire experiment, with the cyanobacterium Synechococcus and picoeukaryotes (prasinophytes) profiting, and the coccolithophore Emiliania huxleyi (prymnesiophyte) being negatively impacted. Combining these results with other phytoplankton community CO2 experiments into a data-set of global coverage suggests that, whenever CO2 effects are found, prymnesiophyte (especially coccolithophore) abundances are negatively affected, while the opposite holds true for small picoeukaryotes belonging to the class of prasinophytes, or the division of chlorophytes in general. Future reductions in calcium carbonate-producing coccolithophores, providing ballast which accelerates the sinking of particulate organic matter, together with increases in picoeukaryotes, an important component of the microbial loop in the euphotic zone, have the potential to impact marine export production, with feedbacks to Earth’s climate system.publishedVersio

Nuisance Bleeding With Prolonged Dual Antiplatelet Therapy After Acute Myocardial Infarction and its Impact on Health Status

ObjectivesThe purpose of this study was to examine the incidence of nuisance bleeding after AMI and its impact on QOL.BackgroundProlonged dual antiplatelet therapy (DAPT) is recommended after acute myocardial infarction (AMI) to reduce ischemic events, but it is associated with increased rates of major and minor bleeding. The incidence of even lesser degrees of post-discharge “nuisance” bleeding with DAPT and its impact on quality of life (QOL) are unknown.MethodsData from the 24-center TRIUMPH (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status) study of 3,560 patients, who were interviewed at 1, 6, and 12 months after AMI, were used to investigate the incidence of nuisance bleeding (defined as Bleeding Academic Research Consortium type 1). Baseline characteristics associated with “nuisance” bleeding and its association with QOL, as measured by the EuroQol 5 Dimension visual analog scale, and subsequent re-hospitalization were examined.ResultsNuisance (Bleeding Academic Research Consortium type 1) bleeding occurred in 1,335 patients (37.5%) over the 12 months after AMI. After adjusting for baseline bleeding and mortality risk, ongoing DAPT was the strongest predictor of nuisance bleeding (rate ratio [RR]: 1.44, 95% confidence interval [CI]: 1.17 to 1.76 at 1 month; RR: 1.89, 95% CI: 1.35 to 2.65 at 6 months; and RR: 1.39, 95% CI: 1.08 to 1.79 at 12 months; p < 0.01 for all comparisons). Nuisance bleeding at 1 month was independently associated with a decrement in QOL at 1 month (−2.81 points on EuroQol 5 Dimension visual analog scale; 95% CI: 1.09 to 5.64) and nonsignificantly toward higher re-hospitalization (hazard ratio: 1.20; 95% CI: 0.95 to 1.52).ConclusionsNuisance bleeding is common in the year after AMI, associated with ongoing use of DAPT, and independently associated with worse QOL. Improved selection of patients for prolonged DAPT may help minimize the incidence and adverse consequences of nuisance bleeding