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1.
Direct oral anticoagulants and vitamin K antagonists are linked to differential profiles of cardiac function and lipid metabolism.
Eggebrecht, L, Prochaska, JH, Tröbs, SO, Schwuchow-Thonke, S, Göbel, S, Diestelmeier, S, Schulz, A, Arnold, N, Panova-Noeva, M, Koeck, T, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2019;(7):787-796
Abstract
BACKGROUND Experimental data indicate that direct acting oral anticoagulants (DOAC) and vitamin K antagonists (VKA) may exert differential effects on cardiovascular disease. METHODS Data from the prospective, observational, single-center MyoVasc Study were used to examine associations of DOAC as compared to VKA with subclinical markers of cardiovascular disease, cardiac function, and humoral biomarkers in heart failure (HF). RESULTS Multivariable analysis adjusted for age, sex, traditional cardiovascular risk factors, comorbidities, and medications with correction for multiple testing demonstrated that DOAC therapy was among all investigated parameters an independent significant predictor of better diastolic function (E/E': β - 0.24 [- 0.36/- 0.12]; P < 0.0001) and higher levels of ApoA1 (β + 0.11 g/L [0.036/0.18]; P = 0.0038) compared to VKA therapy. In propensity score-weighted analyses, the most pronounced differences between DOAC and VKA-based therapy were also observed for E/E' (∆ - 2.36) and ApoA1 (∆ + 0.06 g/L). Sensitivity analyses in more homogeneous subsamples of (i) individuals with AF and (ii) individuals with asymptomatic HF confirmed the consistency and robustness of these findings. In the comparison of factor IIa and Xa-directed oral anticoagulation, no differences were observed regarding cardiac function (E/E' ratio: βIIa inhibitor - 0.22 [- 0.36/- 0.08] vs. βXa inhibitor - 0.24 [- 0.37/- 0.11]) and lipid metabolism (ApoA1: βIIa inhibitor 0.10 [0.01/0.18] vs. βXa inhibitor 0.12 [0.04/0.20]) compared to VKA therapy. CONCLUSION This study provides the first evidence for differential, non-conventional associations of oral anticoagulants on cardiac function and lipid metabolism in humans. The potentially beneficial effect of DOACs in the highly vulnerable population of HF individuals needs to be further elucidated and may have implications for individually tailored anticoagulation therapy.
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2.
The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study.
Markousis-Mavrogenis, G, Tromp, J, Ouwerkerk, W, Devalaraja, M, Anker, SD, Cleland, JG, Dickstein, K, Filippatos, GS, van der Harst, P, Lang, CC, et al
European journal of heart failure. 2019;(8):965-973
Abstract
AIMS: Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)-α were largely unsuccessful. Interleukin (IL)-6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL-6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations. METHODS AND RESULTS Interleukin-6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≤ 40%] of the BIOSTAT-CHF cohort. The primary outcome was all-cause mortality and HF hospitalization during 2 years, with all-cause, cardiovascular (CV), and non-CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL-6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N-terminal pro-brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF-α/IL-1-related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL-6 levels. IL-6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11-1.21), P < 0.001], all-cause mortality [1.22 (1.16-1.29), P < 0.001] and CV as well as non-CV mortality [1.16 (1.09-1.24), P < 0.001; 1.31 (1.18-1.45), P < 0.001], but did not improve discrimination in previously published risk models. CONCLUSIONS In a large, heterogeneous cohort of HF patients, elevated IL-6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL-6 as a potential therapeutic target in specific HF subpopulations.
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3.
Effect of etelcalcetide on cardiac hypertrophy in hemodialysis patients: a randomized controlled trial (ETECAR-HD).
Dörr, K, Kammer, M, Reindl-Schwaighofer, R, Lorenz, M, Loewe, C, Marculescu, R, Erben, R, Oberbauer, R
Trials. 2019;(1):601
Abstract
BACKGROUND Fibroblast growth factor 23 (FGF23) is associated with left ventricular hypertrophy (LVH) in patients with chronic kidney disease, and calcimimetic therapy reduces plasma concentrations of FGF23. It remains unknown whether treatment with the calcimimetic etelcalcetide (ETL) reduces LVH in patients on hemodialysis. METHODS/DESIGN This single-blinded randomized trial of 12 months duration will test the effects of ETL compared with alfacalcidol on LVH and cardiac fibrosis in maintenance hemodialysis patients with secondary hyperparathyroidism. Both treatment regimens will be titrated to equally suppress secondary hyperparathyroidism while alfacalcidol treatment causes an increase and ETL a decrease in FGF23, respectively. Patients treated thrice weekly with hemodialysis for ≥ 3 months and ≤ 3 years with parathyroid hormone levels ≥ 300 pg/ml and LVH will be enrolled in the study. The primary study endpoint is change from baseline to 12 months in left ventricular mass index (LVMI; g/m2) measured by cardiac magnetic resonance imaging. Sample size calculations showed that 62 randomized patients will be necessary to detect a difference in LVMI of at least 20 g/m2 between the two groups at 12 months. Due to the strong association of volume overload and LVH, randomization will be stratified by residual kidney function, and regular body composition monitoring will be performed to control the volume status of patients. Study medication will be administered intravenously by the dialysis nurses after every hemodialysis session, thus omitting adherence issues. Secondary study endpoints are cardiac parameters measured by echocardiography, biomarker concentrations of bone metabolism (FGF23, vitamin D, parathyroid hormone, calcium, phosphate, s-Klotho), cardiac markers (pro-brain natriuretic peptide, pre- and postdialysis troponin T) and metabolites of the renin-angiotensin-aldosterone cascade (angiotensin I (Ang I), Ang II, Ang-(1-7), Ang-(1-5), Ang-(1-9), and aldosterone). DISCUSSION The causal inference and pathophysiology of LVH regression by FGF23 reduction using calcimimetic treatment has not yet been shown. This intervention study has the potential to discover a new strategy for the treatment of cardiac hypertrophy and fibrosis in patients on maintenance hemodialysis. It might be speculated that successful treatment of cardiac morphology will also reduce the risk of cardiac death in this population. TRIAL REGISTRATION European Clinical Trials Database, EudraCT number 2017-000222-35; ClinicalTrials.gov, NCT03182699 . Registered on.
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Meta-analysis of Nicorandil effectiveness on myocardial protection after percutaneous coronary intervention.
Zhao, XT, Zhang, CF, Liu, QJ
BMC cardiovascular disorders. 2019;(1):144
Abstract
BACKGROUND Using the current meta-analysis as well as systematic review, to determine the curative effect of Nicorandil in comparison of no Nicorandil after elective percutaneous coronary intervention(PCI) on patients. METHODS Published literatures were identified via a computerized literature search of CENTRAL, PubMed, Cochrane, Embase Databases of Systematic Reviews. A set of randomized trials evaluating Nicorandil in comparison of no Nicorandil administered following PCI in patients harboring coronary artery disease were included. Outcomes were revealed based on the following parameters: peak creatine kinase-MB (CK-MB) value, left ventricular ejection fraction (LVEF), peak troponin I (cTnI), and major adverse cardiovascular events (MACEs) per randomized patients. RESULTS We included a total of 14 RCTs involving 1864 subjects in the present review. According to this meta-analysis, LVEF was significantly improved in Nicorandil group; the peak CK-MB level and the incidence of adverse cardiovascular events were remarkably lower in Nicorandil group. Nicorandil and no Nicorandil administered group appeared to be equivalent with regards to cTnI. CONCLUSIONS Nicorandil is effective for patients undergoing elective PCI with coronary artery disease in terms of reducing the incidence of adverse cardiovascular events as well as improving heart function. Nicorandil may exert potential role as a valid and adjunctive therapy accompanied with PCI.
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The conundrum of patients with obesity, exercise intolerance, elevated ventricular filling pressures and a measured ejection fraction in the normal range.
Packer, M
European journal of heart failure. 2019;(2):156-162
Abstract
Patients with obesity, a reduced exercise capacity, increased cardiac filling pressures and a measured left ventricular ejection fraction in the normal range do not have a homogeneous disorder, but instead, exhibit one of three phenotypes. First, many obese people exhibit sodium retention, plasma volume expansion and cardiac enlargement, and some are likely to have heart failure that is related to hypervolaemia, even though cardiac index and circulating levels of natriuretic peptides are not meaningfully increased. Second, in some middle-aged men and women (particularly those with minimal co-morbidities), levels of natriuretic peptides increase markedly and can lower systemic vascular resistance, thus leading to high-output heart failure (HOHF) and glomerular hyperfiltration. Third, older obese people, particularly women with multiple co-morbidities, exhibit the syndrome of heart failure with a preserved ejection fraction (HFpEF). Despite degrees of plasma volume expansion similar to HOHF, these patients exhibit only modestly increased ventricular dimensions and circulating levels of natriuretic peptides (despite a high prevalence of atrial fibrillation), and glomerular function is characteristically impaired. A conceptual framework is proposed to distinguish among the three phenotypes seen in obese patients with exercise intolerance, increased ventricular filling pressures and a measured left ventricular ejection fraction in the normal range, since they may respond differently to therapeutic interventions. Efforts are needed to enhance the recognition of heart failure in obese people and to ensure that clinical trials that are designed to study patients with HFpEF actually enrol those who have the disease.
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Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation.
Kang, DH, Park, SJ, Shin, SH, Hong, GR, Lee, S, Kim, MS, Yun, SC, Song, JM, Park, SW, Kim, JJ
Circulation. 2019;(11):1354-1365
Abstract
BACKGROUND The morbidity and mortality of patients with functional mitral regurgitation (MR) remain high, but no pharmacological therapy has been proven effective. The hypothesis of this study was that sacubitril/valsartan would be superior to valsartan alone in improving functional MR via dual inhibition of the renin-angiotensin system and neprilysin. METHODS In this double-blind trial, we randomly assigned 118 patients with heart failure with chronic functional MR secondary to left ventricular (LV) dysfunction to receive either sacubitril/valsartan or valsartan, in addition to standard medical therapy for heart failure. The primary end point was the change in effective regurgitant orifice area of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, LV end-systolic volume, LV end-diastolic volume, and incomplete mitral leaflet closure area. RESULTS The decrease in effective regurgitant orifice area was significantly greater in the sacubitril/valsartan group than in the valsartan group (-0.058±0.095 versus -0.018±0.105 cm2; P=0.032) in an intention-to-treat analysis including 117 (99%) patients. Regurgitant volume was also significantly decreased in the sacubitril/valsartan group in comparison with the valsartan group (mean difference, -7.3 mL; 95% CI, -12.6 to -1.9; P=0.009). There were no significant between-group differences regarding the changes in incomplete mitral leaflet closure area and LV volumes, with the exception of LV end-diastolic volume index ( P=0.044). We noted no significant difference in the change of blood pressure between the treatment groups, and 7 patients (12%) in the sacubitril/valsartan group and 9 (16%) in the valsartan group had ≥1 serious adverse events ( P=0.54). CONCLUSIONS Among patients with secondary functional MR, sacubitril/valsartan reduced MR to a greater extent than did valsartan. Our findings suggest that an angiotensin receptor-neprilysin inhibitor might be considered for optimal medical therapy of patients with heart failure and functional MR. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT02687932.
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Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus.
Kato, ET, Silverman, MG, Mosenzon, O, Zelniker, TA, Cahn, A, Furtado, RHM, Kuder, J, Murphy, SA, Bhatt, DL, Leiter, LA, et al
Circulation. 2019;(22):2528-2536
Abstract
BACKGROUND In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. METHODS In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. RESULTS Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). CONCLUSIONS In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.
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Effect of Rosuvastatin in Preventing Chemotherapy-Induced Cardiotoxicity in Women With Breast Cancer: A Randomized, Single-Blind, Placebo-Controlled Trial.
Nabati, M, Janbabai, G, Esmailian, J, Yazdani, J
Journal of cardiovascular pharmacology and therapeutics. 2019;(3):233-241
Abstract
OBJECTIVE Chemotherapy-induced cardiotoxicity is a major and leading cause of death in breast cancer survivors. It can present decades after chemotherapy and can manifest in different ways; some chemotherapeutic agents have a powerful dose-dependent relationship with cardiotoxicity. The aim of this study was to investigate the effect of rosuvastatin on preventing chemotherapy-induced cardiotoxicity in patients with breast cancer. METHODS Our study was a randomized, single-blind, placebo-controlled trial that involved 89 women with newly diagnosed breast cancer who were scheduled to receive chemotherapy. Patients were randomly assigned to receive rosuvastatin or a placebo in a 1:1 ratio for 6 months. Echocardiography, using 2-dimensional (2D) Doppler, tissue Doppler, and speckle-tracking methods, was used to determine the absolute changes in the left ventricular systolic ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left atrial (LA) diameter, transmitral Doppler early diastolic velocity (E wave), tissue Doppler early diastolic (e') and peak systolic (s') mitral annular velocities, E/e' ratio, and global longitudinal systolic strain. RESULTS The LVEF was significantly reduced in the placebo group at the end of the study when compared with the baseline value. However, there was no significant difference in the LVEF in the intervention group (intergroup P = .012). Furthermore, compared with the intervention group at the end of the study, there was a significant increase in the 4- and 2-chamber LVESV, LA diameter, and E/e' ratio in the placebo group (intergroup P = .019, P = .024, P < .001, and P = .021, respectively) and a significant decrease in the e' and s' velocities in the placebo group (intergroup P < .001 and P < .006, respectively). CONCLUSIONS The present study showed that the prophylactic use of rosuvastatin may prevent the development of chemotherapy-induced cardiotoxicity.
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Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial.
Verma, S, Mazer, CD, Yan, AT, Mason, T, Garg, V, Teoh, H, Zuo, F, Quan, A, Farkouh, ME, Fitchett, DH, et al
Circulation. 2019;(21):1693-1702
Abstract
BACKGROUND SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease. METHODS Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m2. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide). RESULTS Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m2, LV mass indexed to body surface area 60.7 [11.9] g/m2), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m2 and 0.01 g/m2 for those assigned empagliflozin and placebo, respectively (adjusted difference -3.35 g/m2; 95% CI, -5.9 to -0.81g/m2, P=0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference -6.8mmHg, 95% CI -11.2 to -2.3mmHg, P=0.003), diastolic blood pressure (adjusted difference -3.2mmHg; 95% CI, -5.8 to -0.6mmHg, P=0.02) and elevation of hematocrit (P=0.0003). CONCLUSIONS Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT02998970.
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Use of Nitrates and Risk of Cardiovascular Events in Patients With Heart Failure With Preserved Ejection Fraction.
Tsujimoto, T, Kajio, H
Mayo Clinic proceedings. 2019;(7):1210-1220
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Abstract
OBJECTIVE To assess the association of nitrate use with cardiovascular events in patients with heart failure with preserved ejection fraction (HFpEF). PATIENTS AND METHODS Patient data were collected from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist trial, which had been conducted at 233 sites in 6 countries from August 10, 2006, through January 31, 2012. The primary outcome was the occurrence of a major adverse cardiovascular event (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) or heart failure hospitalization. The association between nitrate use and cardiovascular risk was evaluated using Cox proportional hazards analysis. In addition, we verified the results using propensity score-matched patients. RESULTS A total of 3417 patients with HFpEF were evaluated over a mean follow-up of 3.1 years, and 778 experienced a primary outcome event. The risk of primary outcome events was significantly higher in patients taking nitrates than in those not taking nitrates (hazard ratio [HR], 1.21; 95% CI, 1.01-1.46, P=.04). The risk of major adverse cardiovascular events was significantly higher in patients taking nitrates than in those not taking nitrates (HR, 1.32; 95% CI, 1.05-1.66, P=.01). Furthermore, the risk of hospitalization for heart failure was higher in patients taking nitrates (HR, 1.25; 95% CI, 0.99-1.60, P=.06), with propensity score-matched analyses revealing similar findings. In addition, a similar association was observed in various subgroups. CONCLUSION This study reported that nitrate use in patients with HFpEF was associated with a significantly increased risk of cardiovascular events.