Cardiac Troponin and Treatment Effects of Omecamtiv Mecarbil: Results From the GALACTIC-HF Study.

BACKGROUND: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329). METHODS: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil. RESULTS: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2). CONCLUSIONS: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI.

Gender differences in risk factor management and pharmacological treatment among CHD patients: Belgian results of the EUROASPIRE IV and EUROASPIRE V surveys.

AIMS: The aim of this study was to provide an up-to-date overview of gender differences or similarities in risk factor control and medical management in the Belgian CHD population. METHODS: All analyses are based on the ESC EORP EUROASPIRE IV and EUROASPIRE V (European Survey Of Cardiovascular Disease Prevention And Diabetes) surveys. Patients between 18 and 80 years old, hospitalised for a first or recurrent coronary event, were included in the survey. RESULTS: Data were available for 10,519 patients, of which 23.9% were women. Women had a worse risk factor profile compared to men. Women were more physical inactive (OR = 1.31, 95% CI = 1.19-1.44), had a higher prevalence of obesity (OR = 1.37, 95% CI = 1.25-1.50) and had a worse LDL-C control (OR = 1.52, 95% CI = 1.36-1.70). Moreover, women were less likely to use ACE-I/ARBs (OR = 0.84, 95% CI = 0.76-0.94) and statins (OR = 0.79, 95% CI = 0.70-0.90). In addition, little gender differences were found in patients' risk factor awareness, except on cholesterol awareness. Women were more aware about their total cholesterol levels (OR = 1.37, 95% CI = 1.21-1.56). CONCLUSION: Despite little to no gender differences in the management of CHD patients, women still have a worse risk factor profile, both in Belgian and in other European high-income countries.

Efficacy of omecamtiv mecarbil in heart failure with reduced ejection fraction according to N-terminal pro-B-type natriuretic peptide level: insights from the GALACTIC-HF trial.

AIM: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT-proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC-HF). METHODS AND RESULTS: The primary outcome was the composite of a worsening heart failure event (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death. We prespecified analysis of the effect of treatment according to baseline NT-proBNP (≤ median, > median), excluding individuals with atrial fibrillation/flutter (AF/AFL). Of the 8232 patients analysed, 8206 had an available baseline NT-proBNP measurement. Among the 5971 patients not in AF/AFL, the median (Q1-Q3) NT-proBNP level was 1675 (812-3579) pg/ml. Hazard ratios (HR) for the effect of omecamtiv mecarbil, compared with placebo, for the primary endpoint in patients without AF/AFL were: ≤ median 0.94 (95% confidence interval [CI] 0.80-1.09), > median 0.81 (0.73-0.90) (p-interaction = 0.095); for the overall population (including patients with AF/AFL) the HRs were ≤ median 1.01 (0.90-1.15) and > median 0.88 (0.80-0.96) (p-interaction = 0.035). There was an interaction between treatment and NT-proBNP, examined as a continuous variable, with greater effect of omecamtiv mecarbil on the primary outcome in patients with a higher baseline NT-proBNP (p-interaction = 0.086). CONCLUSIONS: In GALACTIC-HF, the benefit of omecamtiv mecarbil appeared to be larger in patients with higher baseline NT-proBNP levels, especially in patients without AF/AFL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02929329; EudraCT number, 2016-002299-28.

Acetazolamide in Decompensated Heart Failure with Volume Overload trial (ADVOR): baseline characteristics.

AIMS: To describe the baseline characteristics of participants in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial and compare these with other contemporary diuretic trials in acute heart failure (AHF). METHODS AND RESULTS: ADVOR recruited 519 patients with AHF, clinically evident volume overload, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) and maintenance loop diuretic therapy prior to admission. All participants received standardized loop diuretics and were randomized towards once daily intravenous acetazolamide (500 mg) versus placebo, stratified according to study centre and left ventricular ejection fraction (LVEF) (≤40% vs. >40%). The primary endpoint was successful decongestion assessed by a dedicated score indicating no more than trace oedema and no other signs of congestion after three consecutive days of treatment without need for escalating treatment. Mean age was 78 years, 63% were men, mean LVEF was 43%, and median NT-proBNP 6173 pg/ml. The median clinical congestion score was 4 with an EuroQol-5 dimensions health utility index of 0.6. Patients with LVEF ≤40% were more often male, had more ischaemic heart disease, higher levels of NT-proBNP and less atrial fibrillation. Compared with diuretic trials in AHF, patients enrolled in ADVOR were considerably older with higher NT-proBNP levels, reflecting the real-world clinical situation. CONCLUSION: ADVOR is the largest randomized diuretic trial in AHF, investigating acetazolamide to improve decongestion on top of standardized loop diuretics. The elderly enrolled population with poor quality of life provides a good representation of the real-world AHF population. The pragmatic design will provide novel insights in the diuretic treatment of patients with AHF.

Feasibility and cost of FH cascade screening in Belgium (BEL-CASCADE) including a novel rapid rule-out strategy.

BACKGROUND: Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. METHODOLOGY: Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. RESULTS: In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. CONCLUSION: In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families.

Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC-HF baseline characteristics and comparison with contemporary clinical trials.

AIMS: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials. METHODS AND RESULTS: Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594). CONCLUSIONS: GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation.

Lifestyle behaviour and risk factor control in coronary patients: Belgian results from the cross-sectional EUROASPIRE surveys.

OBJECTIVE: The aim of this study was to assess lifestyle behaviour as well as risk factor management across Belgian coronary patients who participated in the cross-sectional European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE) surveys. METHODS: Analyses are based on a series of coronary patients by combining data from the Belgian participants in the EUROASPIRE III (328 patients; in 2006-2007) and EUROASPIRE IV (343 patients; in 2012-2013) surveys. Four hospitals located in the Ghent area participated in the surveys. Patients included in the analyses were ≥18 years old and had been hospitalised for a coronary event. Information on cardiovascular risk factors, lifestyle behaviour and medical treatment were obtained. RESULTS: Overall, the proportion of smokers was 11% with 40% persistent smokers. Adequate physical activity levels were reported by 17%, 28% of patients were obese, 47% was central obese and known diabetes was prevalent in 21% of patients. Hypertension was observed in 46% of patients and 20% had a total cholesterol ≥5 mmol/L. About 80% had participated in a cardiac rehabilitation programme and the majority of patients were treated with blood pressure (92%) or lipid-lowering drugs (92%). Anxiety and depressive symptoms were reported by 30% and 24%, respectively. Differences between EUROASPIRE III and IV were limited. CONCLUSIONS: Compared to the overall EUROASPIRE results in Europe, Belgian CHD patients seem to do slightly better. However, tackling obesity, physical inactivity, hypertension and psychosocial distress remains an important challenge in the management of coronary patients.

Atrial Myxoma With Feeding Vessels From Both the Right and Left Coronary Arteries: A Rare Finding During Coronary Angiography.

A 73-year-old woman presented with exertional chest pain and mild dyspnea for several months. In this case, preoperative coronary angiography showed neovascularization originating from the right coronary artery (RCA) and left circumflex (LCX). Vascular supply in left atrial myxomas usually originates from the LCX and sometimes from the RCA, but vascular supply from both the right and left coronary arteries is rarely seen.

Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial.

BACKGROUND: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil. METHODS: In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512. FINDINGS: From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18-32, p<0·0001), stroke volume 3·6 mL (0·5-6·7, p=0·0217), left ventricular end-systolic diameter -1·8 mm (-2·9 to -0·6, p=0·0027), left ventricular end-diastolic diameter -1·3 mm, (-2·3 to 0·3, p=0·0128), heart rate -3·0 beats per min (-5·1 to -0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma -970 pg/mL (-1672 to -268, p=0·0069). The frequency of adverse clinical events did not differ between groups. INTERPRETATION: Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter. FUNDING: Amgen.

Assessment of variables affecting late left ventricular flow propagation velocity.

UNLABELLED: Early colour M-mode flow propagation velocity (Vpe) in the left ventricle is a well-known non-invasive index for assessing left ventricular relaxation. However, the utility and determinants of late colour M-mode flow propagation (Vpa) have received little attention to date. Vpa as a representation of the left ventricular vortex travelling velocity during late filling could have a distinct role in differentiating potential subgroups in diastolic failure. The aim of the present study was to establish the normal values of late flow propagation in a healthy population of various ages (18-79 years), and to examine the general and echocardiographic variables that affect Vpa. METHODS: We studied 75 apparently healthy subjects (age range, 18-79 years; 38 women, 37 men) as part of an outpatient clinic check-up screening. General parameters were recorded, including age, gender, height, weight, blood pressure, and heart rate. In addition, conventional grey-scale M-mode, 2D, as well as colour M-mode, 2D, and pulsed wave (tissue) Doppler echocardiographic parameters were obtained in a single centre and using a single operator setting. Backward linear regression analysis (dependent variable: Vpa) was performed to find the optimal model, taking into account multicollinearity and maximum coefficient of determination (R2). Due to the heteroscedasticity of the collected data, a logarithmic transformation was used. In addition, separate linear backward regression analysis was performed for the male and female subgroups. RESULTS: Vpa values were 26-179 cm/s. The optimal regression model after elimination included the following variables: age (beta = 0.684, P < 0.001), height (beta = 0.521, P < 0.001), gender (beta = 0.343, P < 0.05), left ventricular Vpe (beta = 0.299, P < 0.01), left ventricular posterior systolic (M-mode) wall thickness (beta = 0.288, P < 0.01), interventricular septum thickness diastole (beta = 0.346, P < 0.005), transmitral Doppler E-wave deceleration time apical 4-chamber (beta = -0.297, P < 0.05), and tissue Doppler peak E-wave mitral annulus (beta = 0.459, P < 0.005). The total coefficient of determination (R2) for this model was 0.540 (P < 0.001); 0.673 (P < 0.001) for men and 0.645 (P < 0.001) for women. CONCLUSION: Vpa, representing left ventricular vortex travelling velocity during late filling, shows a large range of values in normal healthy subjects. It is mainly depending on age, gender and left ventricular mass. Moreover, substantially different determinants are found between men and women. Further study is required to explore these findings.

Cytomegalovirus myocarditis in an immunocompetent patient.

Viral infections can lead to myocardial inflammation, resulting in acute myocarditis. Acute myocarditis is mostly self-limiting, but it can lead to severe dilated cardiomyopathy and rarely to acute cardiac tamponade. We report a rare case of myocarditis in a young immunocompentent male patient due to a recent cytomegalovirus (CMV) infection. The clinical presentation was an influenza-like syndrome, classical for a CMV infection, in combination with mild chest pain. Further exploration showed inflammation-compatible perimyocardial images on magnetic resonance imaging (MRI). Following the symptomatic perimyocardial inflammation, the patient developed an acute asymptomatic self-limiting CMV hepatitis, a rare combination. Moreover, there was a remarkable evolution of both clinical signs with first increasing cardiac enzymes due to myocarditis and later on development of acute hepatitis. In this case report, we present the typical MRI images of myocarditis and discuss the CMV cardiac effects as well as the combination of CMV myocarditis and hepatitis.

Beta-blockers: focus on mechanism of action. Which beta-blocker, when and why?

Beta-blockers are a heterogeneous group of antihypertensive agents. What they have in common is competitive antagonistic action on beta-adrenoreceptors (B1, B2 and B3). They differ in their receptor selectivity, intrinsic sympathomimetic activity (ISA), vasodilating properties and metabolism. Antihypertensive mechanisms and effect differ according to receptor-specificity and ISA, where differences in duration of action also have to be considered. An unfavourable metabolic profile of beta-blockers was reported based on studies describing the metabolic side effects of weakly-selective or non-selective agents. Newer generation beta-blockers appear to have a metabolic neutral profile. In systolic heart failure, three agents proved to improve survival up to 30%, mainly because of B1-blocking and/or vasodilating properties. The position of beta-blockers in treating diastolic heart failure remains uncertain. Beta-blocker therapy in coronary artery disease also leads to uncontested survival benefit, the cardioprotective mechanism largely due to rate reduction. This paper aims to describe the basis of heterogeneity of the available agents and to translate this into their applicability in different cardiovascular diseases, with focus on the underlying physiopathological mechanisms.

Assessment of the tilting properties of the human mitral valve during three main phases of the heart cycle: an echocardiographic study.

RATIONALE AND OBJECTIVES: In experimental models of the left heart, the mitral valve (MV) is commonly implanted perpendicular to a central axis of the apex/MV. To adapt this to a more correct anatomical model, as well as for further studies of the left ventricle, we created a database of implantation angles of the MV and annulus during three main phases of the heart cycle, based on standard cardiac ultrasound measurements. MATERIALS AND METHODS: Twenty-eight patients were studied with the standard cardiac ultrasound equipment. From the apical echo window, an anteroposterior (AP) plane and a perpendicular commisure-commisure (CC) plane were generated during three critical moments in the heart cycle: systole (S); diastole early filling (E); and diastole late filling (A). In both planes, the angles between the annular plane and each mitral leaflet, as well as the angle between a theoretical longitudinal axis through the apex and center of the MV orifice and the mitral annulus plane, were measured with a custom-made application of Matlab R14. RESULTS: We observed an inclination of the angle mitral annulus/central left ventricle axis, with its lowest point in the direction of the aortic valve (AP plane) of 85 degrees+/-7 degrees in systole (S), 88 degrees+/-8 degrees in early diastole (E), and 88 degrees+/-7 degrees in late diastole (A). In the CC plane, we observed an almost horizontal implantation of 91 degrees+/-5 degrees in systole (S), 91 degrees+/-8 degrees in early diastole (E), and 91 degrees+/-7 degrees in late diastole (A).