Empagliflozin, irrespective of blood pressure, improves outcomes in heart failure with preserved ejection fraction: the EMPEROR-Preserved trial.

AIMS: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and preserved ejection fraction. This study aims to evaluate if systolic blood pressure (SBP) moderates these effects. METHODS AND RESULTS: The association of SBP and the treatment effects of empagliflozin in EMPEROR-Preserved (empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction) was evaluated. Randomized patients (n 5988) were grouped according to SBP at baseline (110 mmHg, n 455; 110130 mmHg, n 2415; 130 mmHg, n 3118). The effect of empagliflozin on blood pressure, cardiovascular death or HF hospitalization (primary outcome), total HF hospitalizations, and rate of decline in estimated glomerular filtration rate was studied. Over a median of 26.2 months, the placebo-corrected decline was small and not significantly different across baseline SBP. On placebo, the risk of cardiovascular death or hospitalization for HF was 8.58 at 130 mmHg, 8.26 at 110130 mmHg, and 11.59 events per 100 patient-years at 110 mmHg (P 0.12 vs. 130 mmHg, P 0.08 vs. 110130 mmHg). There was no evidence for baseline SBP moderating the effect of empagliflozin on risk of HF events (primary endpoint interaction P 0.69, recurrent HF hospitalizations interaction P 0.55). When comparing empagliflozin with placebo, SBP did not meaningfully associate with adverse events such as hypotension, volume depletion, and acute renal failure. CONCLUSION: In EMPEROR-Preserved, empagliflozin was effective and safe without SBP meaningfully moderating empagliflozins treatment effects. This analysis of EMPEROR-Preserved shows that empagliflozin can be used safely and effectively without blood pressure being a meaningful moderator of the drug benefit. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov Unique identifier: NCT03057951.

Comparison of the antiplatelet effect of clopidogrel hydrogenosulfate and clopidogrel besylate in patients with stable coronary artery disease.

It is well known that patients with poor response to antiplatelet therapy are most likely to have more thrombotic events. Clopidogrel hydrogensulfate (CHS) is a thienopyridine acting as an important antiplatelet agent alone or in combination with acetylsalicylic acid to prevent cardiovascular complications. A different clopidogrel salt, clopidogrel besylate (CB), was recently approved as a generic drug for the same purpose while data about its antiplatelet effect are very scarce. Our study compared the antiplatelet effect of CHS and CB in patients with stable coronary artery disease. Patients with stable coronary artery disease (n = 101) (coronary lesions defined angiographically 30-70 %) were randomized to either CHS (n = 50) or CB (n = 51). After randomization a 600 mg loading dose of the drug was given and monitoring of antiplatelet effect was done 12-14 h later with VerifyNow assay. Antiplatelet response was measured with P2Y12 reaction units (PRU) and % inhibition P2Y12 from baseline (% inhibition P2Y12). Moreover CYP2C19*2, CYP2C19*3 and CYP3Α5 polymorphisms were studied in all patients. Clinical characteristics were similar between the two study groups. No significant difference was observed for baseline platelet reactivity between CHS and CB patients (258 ± 38 vs. 256 ± 38 respectively, p = 0.79). No difference was found for antiplatelet response between the CHS and the CB group, assessed by PRU (195 ± 74 vs. 204 ± 67 respectively, p = 0.51) and by % inhibition P2Y12 (24 ± 25 vs. 24 ± 22 % respectively, p = 0.95). Number of heterozygotes for CYP2C19*2 polymorphism was comparable and their platelet reactivity was similar between the two study groups. Our results indicate that both CB and CHS had an identical antiplatelet effect in patients with stable coronary artery disease. No difference on platelet reactivity of heterozygotes for CYP2C19*2 polymorphism was found between the two study groups.

Long-term clinical outcomes in implantable cardioverter defibrillator recipients on the island of Crete.

PURPOSE: The aim of the current study is to disseminate long-term "real-world" data on mortality and device therapies in primary and secondary prevention implantable cardioverter defibrillator (ICD) recipients on the island of Crete. METHODS: We analyzed data for all consecutive patients who received an ICD in our tertiary university hospital from 1993 until December 2013. Follow-up visits were performed every 6 months or more frequently when indicated. Survival status was recorded, and all stored episodes during interrogation were registered and classified as appropriate or inappropriate. RESULTS: In total, 854 patients received an ICD; 623 (73%) for primary and 231 (27%) for secondary prevention. Most of these patients (490) suffered from ischemic cardiomyopathy. During the mean follow-up of 12.4±7.8 years, 218 (25.5%) patients died; 19.7% in the primary prevention group (p=0.008) and 41.1% in the secondary prevention group. Overall, 248 patients (29%) received appropriate therapy; however, the percentage was significantly higher in the secondary prevention group (44.2%) than in primary prevention group (23.4%). The cumulative incidence of inappropriate therapies during the mean follow-up period was 11.6%. Lead-related complications were noted in 49 patients (5.7%), while only 13 patients (1.5%) suffered device-related infections. CONCLUSIONS: The long-term data related to clinical outcomes in ICD recipients in our center are in accordance with those of other international centers and confirm the high efficacy and safety of these devices in preventing sudden cardiac death.

Early cardiac gene transcript levels in peripheral blood mononuclear cells reflect severity in stable coronary artery disease.

INTRODUCTION: The early cardiac marker genes myocardin, GATA4 and Nkx2.5, play a role in both embryonic cardiovascular development and adult cardiovascular disease. We evaluated transcript levels of myocardin, GATA4 and Nkx2.5 in peripheral blood mononuclear cells (PBMCs) in patients with stable coronary artery disease (CAD) and we examined the relationship between these levels and the severity of the disease, estimated by the number of stenotic vessels involved. METHODS: Ninety-eight patients with stable CAD (age 66 ± 9 years) who underwent coronary angiography participated in the study; 66 healthy individuals (age 58 ± 13 years) were also included for comparison. Gene transcript levels were determined by quantitative real-time reverse transcription polymerase chain reaction. RESULTS: Patients with 3-vessel CAD had elevated transcript levels of myocardin (median difference 2.7, p=0.001, 95% confidence interval, CI: 1-5.8), GATA4 (median difference 0.3, p=0.015, 95% CI: 0.1-1.9) and Nkx2.5 (median difference 16.1, p<0.001, 95% CI: 4.5-23) compared to healthy controls. Patients with 3-vessel CAD also showed elevated transcript levels of myocardin (median difference 2.3, p=0.001, 95% CI: 0.49-5.5) and Nkx2.5 (median difference 11.8, p<0.001, 95% CI: 1.5-21.5) compared to patients with 1-vessel CAD. CONCLUSIONS: Early cardiac marker gene transcript levels are significantly higher in the PBMCs of patients with severe stable CAD than in those of healthy controls, and show alterations in their expression profile according to the disease severity status. Our results indicate for the first time that changes in the early cardiac gene expression in the peripheral blood of stable CAD patients, possibly as a result of alterations in circulating cardiovascular progenitor cells that express these genes, may reflect the level of disease severity.

Serum markers of collagen turnover predict future shocks in implantable cardioverter-defibrillator recipients with dilated cardiomyopathy on optimal treatment.

OBJECTIVES: We investigated prospectively whether serum markers of collagen turnover could be used as predictors for the occurrence of malignant ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy (NIDC) who had received an implantable cardioverter-defibrillator (ICD) for primary prevention. BACKGROUND: Extracellular matrix alterations in NIDC might provide electrical heterogeneity, thus potentially contributing to the occurrence of ventricular arrhythmia and subsequent sudden cardiac death (SCD). METHODS: Serum C-terminal propeptide of collagen type-I, C-terminal telopeptide of collagen type-I, matrix metalloproteinase (MMP)-1, and tissue inhibitor of MMP-1 were measured as markers of collagen synthesis and degradation in 70 patients with mild to moderate symptomatic heart failure due to NIDC with left ventricular ejection fraction <35%, who received an ICD for primary prevention of SCD. Patients were evaluated for any appropriate ICD delivered therapy, whether shock or antitachycardia pacing, during a 1-year follow-up period. RESULTS: Appropriate device therapies were delivered in 14 of the 70 patients during the follow-up period, with antitachycardia pacing in 2, antitachycardia pacing with shocks in 4, and shocks in 8. Pre-implantation serum concentrations of C-terminal telopeptide of collagen type-I levels were significantly higher in patients who had appropriate ICD-delivered therapy than in those who did not have any therapy (0.46 +/- 0.19 ng/ml vs. 0.19 +/- 0.07 ng/ml, p < 0.001, respectively). The same was true for baseline MMP-1 and tissue inhibitor of MMP-1 (27.7 +/- 1.6 ng/ml vs. 24.1 +/- 2.5 ng/ml, p < 0.001, and 89 +/- 14 ng/ml vs. 58 +/- 18 ng/ml, p = 0.008, respectively). CONCLUSIONS: If the maximum benefit is to be achieved from ICD therapy in NIDC patients for the primary prevention of SCD, a more precise risk stratification is required. As extracellular matrix alterations affect the arrhythmogenic substrate in NIDC, we observed that serum markers of collagen turnover could predict arrhythmic events in ICD recipients.

Effect of sinus rhythm restoration after electrical cardioversion on apelin and brain natriuretic Peptide prohormone levels in patients with persistent atrial fibrillation.

Because humoral alterations have been implicated in the generation and perpetuation of atrial fibrillation (AF), we aimed to elucidate possible abnormalities in atrial endocrine function in the setting of lone AF. Levels of plasma apelin and amino terminal fragment of the brain natriuretic peptide prohormone (NT-pro-BNP) were measured in 40 patients with persistent AF, before and 1 month after electrical cardioversion, and in 15 controls in sinus rhythm (SR). All patients were successfully cardioverted to SR, although in 9 of them AF recurred. Baseline apelin levels were lower and NT-pro-BNP levels higher in patients with AF compared to controls (380 +/- 186 vs 700 +/- 151 pg/ml, p <0.001, and 615 +/- 611 vs 50 +/- 28 pg/ml, p <0.001, respectively). Maintenance of SR resulted in an increase of apelin and a decrease of NT-pro-BNP levels during the postcardioversion follow-up period compared to baseline (497 +/- 170 vs 368 +/- 178 pg/ml, p <0.001, and 206 +/- 106 vs 398 +/- 269 pg/ml, p <0.001 respectively). Patients who developed AF recurrence by the end of the follow-up period had similar values of apelin and NT-pro-BNP on final and initial evaluations (444 +/- 142 vs 422 +/- 217 pg/ml, p = 0.62, and 1,328 +/- 714 vs 1,362 +/- 862 pg/ml, p = 0.74, respectively). Stepwise logistic regression analysis showed that left atrial diameter (b =-0.49, p = 0.05), and baseline NT-pro-BNP (b = 0.006, p = 0.022), but not apelin, were independent predictors for AF recurrence. In conclusion, this study suggests that endocrine heart function, as judged from apelin and NT-pro-BNP levels, is reversibly modified in the setting of lone AF. This could influence systemic hemodynamics and pharmacologic measures designed to treat this arrhythmia.