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Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients-a description of the DAPACARD study.
Åkerblom, A, Oldgren, J, Latva-Rasku, A, Johansson, L, Lisovskaja, V, Karlsson, C, Oscarsson, J, Nuutila, P
Upsala journal of medical sciences. 2019;(1):59-64
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Abstract
BACKGROUND Diabetes increases the risk for cardiovascular (CV) events. It has recently been shown that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to a reduction in CV outcomes in patients with type 2 diabetes mellitus (T2DM), including mortality and heart failure hospitalization. The exact mechanisms of how SGLT2 inhibitors lead to this CV risk reduction remain incompletely understood. The study of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients (DAPACARD) (NCT03387683) explores the possible effects of dapagliflozin, an SGLT2 inhibitor, on cardiac work, metabolism, and biomarker levels. METHODS DAPACARD is an international, randomized, double-blind trial that aims to examine the effects of dapagliflozin versus matching placebo in 52 patients with T2DM that are on stable metformin therapy prior to and during the 6 weeks of treatment. The primary efficacy endpoint is change in global longitudinal strain of the left ventricle (GLSLV) measured with magnetic resonance imaging (MRI) between baseline (pre-treatment) and end of study (on-treatment). The secondary endpoint is the corresponding change in myocardial efficiency measured as external left ventricular work divided by total left ventricular work, which is estimated using [11C]-acetate clearance using positron emission tomography (PET). CONCLUSION The DAPACARD study is an extensive investigation of cardiac function and metabolism, by advanced imaging with PET and MRI, as well as biomarkers, performed in order to further explore how the SGLT2 inhibitor dapagliflozin could influence cardiovascular outcomes in patients with T2DM.
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Acute elevation of triglycerides increases left ventricular contractility and alters ventricular-vascular interaction.
Holland, DJ, Erne, D, Kostner, K, Leano, R, Haluska, BA, Marwick, TH, Sharman, JE
American journal of physiology. Heart and circulatory physiology. 2011;(1):H123-8
Abstract
Acute elevation of circulating lipids, such as the postprandial state, contributes to increased cardiovascular risk. However, the effect of acutely elevated triglycerides on arterial and left ventricular function is not completely understood. We aimed to assess whether an acute increase in triglycerides affects ventricular-vascular interaction. Fifteen healthy men (age, 49 ± 8 yr) underwent blinded, randomized infusion of saline and intravenous fat emulsion to acutely raise plasma triglycerides. All subjects underwent both randomization trials, in random order on two separate days. Ventricular-vascular interaction measures were recorded by tonometry (central blood pressure) and echocardiography (left ventricular volumes, strain, and strain rate) at baseline and after 1 h infusion. Net ventricular-vascular interaction was defined by the effective arterial elastance (E(A))-to-left ventricular end-systolic elastance (E(LV)) ratio (E(A)/E(LV)). When compared with saline, the infusion of intravenous fat emulsion increased triglycerides and free fatty acids (ΔP < 0.001 for both) and improved left ventricular contractility (ΔE(LV), end-systolic volume and strain rate; P < 0.05 for all). However, arterial function was unchanged (ΔE(A), brachial and central blood pressure; P > 0.05 for all). Overall, E(A)/E(LV) was decreased by an infusion of intravenous fat emulsion (P = 0.004) but not saline (P > 0.05, P = 0.001 for Δ between trials). We conclude that intravenous fat emulsion and acute elevation of blood lipids (including triglycerides and free fatty acids) alter ventricular-vascular interaction by increasing left ventricular contractility without affecting arterial load. These findings may have implications for cardiovascular responses to parenteral nutrition.
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Atorvastatin improves endothelial function and cardiac performance in patients with dilated cardiomyopathy: the role of inflammation.
Liu, M, Wang, F, Wang, Y, Jin, R
Cardiovascular drugs and therapy. 2009;(5):369-76
Abstract
AIM: Statins have been demonstrated to significantly affect the prognosis and outcome of patients with cardiac diseases. Several studies have suggested pleiotropic effects of the statins in these patients. The present study was designed to examine the effects of atorvastatin on inflammation, endothelial function, cardiac performance and exercise tolerance in patients with idiopathic dilated cardiomyopathy (IDCM). METHODS Sixty-four patients with IDCM were divided randomly into an atorvastatin treatment group (atorvastatin 10 mg/d orally) and a placebo control group. Before and 12 weeks after the treatment, circulating soluble intercellular adhesion molecule-1 (sICAM-1), Von Willebrand factor (vWF) and C-reactive protein (CRP) levels were detected using enzyme-linked immunosorbent assay (ELISA); Flow-mediated dilatation (FMD) of the brachial artery was measured, and left ventricular ejection fraction (LVEF) and the 6-min walk test (6MWT) evaluated. RESULTS After atorvastatin treatment, LVEF increased from 34.5 +/- 5.7% to 41.4 +/- 4.5% (P < 0.05), and from 32.8 +/- 4.0% to 36.9 +/- 5.2% (P < 0.05) in the placebo group. Also, the distances covered in the 6MWT increased from 358 +/- 61 m to 431 +/- 66 m in the atorvastatin group, and from 351 +/- 70 m to 382 +/- 74 m in the placebo group (both p < 0.05 vs. baseline). The increases in LVEF and 6MWT distances were significantly greater in the atorvastatin than in the placebo group. sICAM-1, CRP and vWF levels decreased and FMD increased significantly in the atorvastatin group, but not in the control group. Correlation analysis showed that the baseline sICAM-1 level was positively correlated with plasma CRP and vWF levels (r = 0.554 and 0.628, respectively); FMD was inversely correlated with serum sICAM-1 and plasma vWF levels (r = -0.579 and -0.590, respectively) and positively correlated with LVEF and distance attained in 6MWT (r = 0.536 and 0.522, respectively). CONCLUSIONS Twelve weeks of treatment with atorvastatin significantly decreased serum sICAM-1, CRP and vWF levels, and improved the FMD, LVEF and 6MWT outcomes. Inhibition of inflammation, alleviating endothelium damage and endothelial dysfunction might comprise part of the underlying mechanisms leading to the improvement of LV function and exercise tolerance in patients with IDCM.
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[Effect of Chinese herbal medicine for benefiting qi and nourishing yin to promote blood circulation on ventricular wall motion of AMI patients after revascularization].
Li, YQ, Jin, M, Qiu, SL
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2009;(4):300-4
Abstract
OBJECTIVE To investigate the effect of Chinese herbal medicine for benefiting qi and nourishing yin to promote the blood circulation (abbr. as CHM) in promoting ventricular wall motion and myocardial contraction in acute myocardial infarction (AMI) patients after revascularization. METHODS Subjects were 80 AMI patients after revascularization, of those, the 40 patients in the TCM group were treated with Xinyue Capsule and compound Tanshinon Tablet upon the basic conventional Western medical treatment and the other 40 in the control group were given conventional Western medicine alone, the course for them all was 3 months. Cardiac function indexes, including left ventricular ejection fraction (LVEF), wall motion indices, normal myocardial percentage (NMP), longitudinal systolic peak strain (LSPS) and rate (LSPSR), were observed by Doppler ultrasound under dobutamine stress at the 14 days after revascularization and the end of 3-month treatment. RESULTS Except the 5 cases (3 in the TCM group and 2 in the control group) dropped out in the observation period, the trial was completed in 75 patients totally. LVEF, NMP, minus LSPS of left ventricular anterior apex and inferior basement, minus LSPSR of anterior apex, middle, basement, and minus LSPSR of inferior middle, basement were more significantly increased in Chinese medicinal treatment group than those in the control group at 14-day after revascularization (P < 0.01). The treatment group, minus LSPS and minus LSPSR of the left ventricular anterior apex and the inferior basement were at markedly higher levels compared with the controls at 3-month after revascularization (P < 0.05). Minus LSPSR of the left ventricular anterior apex and the inferior basement in the treatment group at 3-month was higher than that at 14-day after revascularization (P < 0.05). CONCLUSION CHM combining with conventional Western medicine treatment could improve the left ventricular contractive function and wall motion in AMI patients after revascularization.
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Effects of beta-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome.
Palazzuoli, A, Silverberg, DS, Iovine, F, Calabrò, A, Campagna, MS, Gallotta, M, Nuti, R
American heart journal. 2007;(4):645.e9-15
Abstract
BACKGROUND Although anemia is frequently found in congestive heart failure (CHF), little is known about the effect of its correction with erythropoietin (EPO) on cardiac structure and function. OBJECTIVES The present study examines in patients with advanced CHF, chronic renal insufficiency, and anemia the effects of beta-EPO on left ventricular (LV) systolic diameter and volume (LVSD and LVSV), LV diastolic diameter and volume (LVDD and LVDV), LV mass, LV ejection fraction (LVEF), pulmonary artery pressure (PAP), and B-type natriuretic peptide (BNP) levels. METHODS Fifty-one consecutive subjects affected with advanced CHF and anemia were studied. We performed a randomized double-blind controlled study of correction of anemia with subcutaneous EPO for 4 months (group A, 26 patients) using saline as the placebo in the control group (group B, 25 patients). We then maintained the EPO treatment in the treated group for another 8 months. Both groups received oral iron throughout the total 12-month period. Echocardiographic evaluation, BNP levels, and hematological parameters are reported at 4 and 12 months. RESULTS The patients in group A during the double-blind phase (4 months) demonstrated an increase in LVEF and mild reduction in LVSD and LVSV with respect to baseline and to group B with no differences in PAP, LVDD, and LVDV. Over the 12-month period, the hemoglobin increased from 10.40.6 to 12.4 +/- 0.8 g/dL (P < .01) in group A but did not change in group B. Compared with group B, group A had lower LVDD, LVSD, LVDV, LVSV, LV mass, PAP, and BNP and higher LVEF. The serum creatinine and creatinine clearance remained unchanged in the 2 groups. CONCLUSIONS In anemic patients with CHF, correction of anemia with EPO and oral iron over 1 year lead to an improvement in LV systolic function, LV remodeling, BNP levels, and PAP compared with a control group in which only oral iron was used.
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Dietary sodium intake modulates myocardial relaxation responsiveness to angiotensin II.
Williams, JS, Solomon, SD, Crivaro, M, Conlin, PR
Translational research : the journal of laboratory and clinical medicine. 2006;(2):49-54
Abstract
Dietary sodium alters renovascular responsiveness to angiotensin II (Ang II) in normal subjects. Evidence supports a connection among dietary sodium, the rennin-angiotensin system, and myocardial function. The authors hypothesized that a similar relationship would exist in the heart, and that the pattern of responses would be qualitatively similar to the renal vasculature. Thirteen healthy volunteers (aged 38.6 +/- 4 years) entered a 2 week crossover design study (week 1, high sodium diet [HS] > 200 mmol Na/day; week 2, low sodium diet [LS], < 10 mmol Na/day) to investigate the influence of dietary sodium and Ang II on myocardial relaxation and renal blood flow (RBF). At the end of each study week, the authors assessed diastolic function (myocardial relaxation velocities [E'] using tissue Doppler imaging) and RBF (para-aminohippurate clearance) at baseline and after infusion of Ang II (3 ng/kg/min x 45 min). On HS diet, E' and RBF were higher than on LS diet (E' 14.0 +/- 1.2 vs 12.6 +/- 1.0 cm/s, P = 0.02; RBF 596 +/- 24 vs 563 +/- 26 mL/min, P = 0.02). Dietary sodium significantly modulated E' and RBF responsiveness to Ang II infusion in like manner. HS was associated with increased responsiveness compared with a blunted LS response (HS DeltaE' -1.4 +/- 0.4 cm/s vs LS DeltaE' -0.1 +/- 0.3 cm/s, P = 0.02; HS DeltaRBF -135.2 +/- 13.2 vs LS DeltaRBF -62.5 +/- 10.1 mL/min, P < 0.01). The authors describe for the first time that dietary sodium modulates myocardial relaxation and responsiveness to Ang II. It is important to consider dietary sodium intake when assessing diastolic function. Ang II may play a role in the interaction between dietary sodium and myocardial relaxation. Future research will investigate whether abnormalities in these mechanisms play a role in disorders of diastolic function.
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Effects of canrenoate plus angiotensin-converting enzyme inhibitors versus angiotensin-converting enzyme inhibitors alone on systolic and diastolic function in patients with acute anterior myocardial infarction.
Di Pasquale, P, Cannizzaro, S, Scalzo, S, Parrinello, G, Fasullo, S, Giambanco, F, Fatta, A, Paterna, S
American heart journal. 2005;(5):919
Abstract
BACKGROUND Aldosterone (ALDO) exerts profibrotic effects, acting via the mineralocorticoid receptors in cardiovascular tissues. Aldosterone antagonism in combination with angiotensin-converting enzyme inhibition may better protect against the untoward effects of ALDO than angiotensin-converting enzyme inhibition alone. METHODS In a double-blind randomized study, the tolerability and efficacy of canrenoate (25 mg/d) plus captopril versus captopril alone were evaluated in 510 patients with an acute anterior myocardial infarction (MI), a serum creatinine concentration < 2.0 mg/dL, and a serum potassium level < 5.0 mmol/L. Three hundred forty-one patients received captopril and 25-mg canrenoate (group A). Group B (346 patients) received captopril and placebo. At baseline and at 10, 90, and 180 days after admission, Doppler echocardiography was performed. RESULTS Clinical and demographic aspects were similar in both groups. In addition, baseline cardiac enzyme levels, left ventricular function, and incidence of surgical interventions and angioplasty were comparable. Overall, creatinine, blood urea, and serum potassium levels did not show significant differences between groups. However, in 18 patients in group A, increases in serum potassium levels to > 5.5 mEq/L and creatinine levels to > 2.0 mg/L after 10 days of treatment were observed. At 180 days, the mitral E-wave-A-wave ratio was higher (P = .0001) and left ventricular end-systolic volume was smaller (P = .0001) in patients treated with canrenoate than in those receiving placebo. No further side effects were observed during the study period. CONCLUSIONS Our data suggest that the combination of captopril plus canrenoate is well tolerated after an acute MI and has beneficial effect on systolic and diastolic parameters and may decrease post-MI remodeling.
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Carvedilol improves myocardial contractility compared with metoprolol in patients with chronic hibernating myocardium after revascularization.
Schwarz, ER, Gupta, R, Diep, TP, Nowak, B, Kostin, S, Grohmann, B, Uretsky, BF, Schaper, J
Journal of cardiovascular pharmacology and therapeutics. 2005;(3):181-90
Abstract
BACKGROUND We tested the hypothesis of whether carvedilol delays morphologic degeneration and improves functional outcome compared with metoprolol tartrate in patients with hibernating myocardium undergoing surgical revascularization. We have previously shown that patients with chronic hibernating myocardium undergo progressive cellular degeneration and fibrosis. METHODS Twenty patients with multivessel coronary artery disease revascularization and hibernating myocardium as assessed by technetium-99m perfusion scintigraphy and fluorine-18-fluorodeoxyglucose positron emission tomography were randomized to receive either carvedilol or metoprolol tartrate for at least 2 months before surgery, and this was continued for 7 months postoperatively. Left ventricular ejection fraction and regional wall motion abnormalities were assessed by left ventriculography at baseline and 7 months postoperatively. Intraoperative transmural needle biopsy samples were obtained for microscopic analysis. RESULTS Postoperatively, the ejection fraction increased from 31% +/- 5% to 44% +/- 4% (P < .005) in the carvedilol group (n = 10), and from 30% +/- 6% to 40% +/- 6% in the metoprolol tartrate group (P < .05 vs preoperatively and vs carvedilol). Wall motion abnormalities in the carvedilol group improved from -2.1 +/- 0.4 to -0.6 +/- 0.5 (P < .05) and from -2.3 +/- 0.5 to -1.6 +/- 0.6 in the metoprolol tartrate group (P < .05 vs preoperatively and vs carvedilol). Microscopic analysis after 72 +/- 18 days of either treatment showed mild cardiomyocyte degeneration and moderate-to-severe fibrosis (28% +/- 7%) in the carvedilol group compared with moderate cardiomyocyte degeneration and moderate-to-severe fibrosis (33% +/- 6%) in the metoprolol tartrate group. Apoptosis, as assessed by the terminal deoxynucleotidyl transferase nick end labeling method, was observed in only 1 patient in each group. CONCLUSIONS Carvedilol treatment of hibernating myocardium results in improved functional recovery after revascularization compared with metoprolol tartrate, and this might partially be related to reduced cardiomyocyte degeneration.
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Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue.
Rosenfeldt, F, Marasco, S, Lyon, W, Wowk, M, Sheeran, F, Bailey, M, Esmore, D, Davis, B, Pick, A, Rabinov, M, et al
The Journal of thoracic and cardiovascular surgery. 2005;(1):25-32
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Abstract
OBJECTIVES Previous clinical trials suggest that coenzyme Q(10) might afford myocardial protection during cardiac surgery. We sought to measure the effect of coenzyme Q(10) therapy on coenzyme Q(10) levels in serum, atrial trabeculae, and mitochondria; to assess the effect of coenzyme Q(10) on mitochondrial function; to test the effect of coenzyme Q(10) in protecting cardiac myocardium against a standard hypoxia-reoxygentation stress in vitro; and to determine whether coenzyme Q(10) therapy improves recovery of the heart after cardiac surgery. METHODS Patients undergoing elective cardiac surgery were randomized to receive oral coenzyme Q(10) (300 mg/d) or placebo for 2 weeks preoperatively. Pectinate trabeculae from right atrial appendages were excised, and mitochondria were isolated and studied. Trabeculae were subjected to 30 minutes of hypoxia, and contractile recovery was measured. Postoperative cardiac function and troponin I release were assessed. RESULTS Patients receiving coenzyme Q(10) (n = 62) had increased coenzyme Q(10) levels in serum (P = .001), atrial trabeculae (P = .0001), and isolated mitochondria (P = .0002) compared with levels seen in patients receiving placebo (n = 59). Mitochondrial respiration (adenosine diphosphate/oxygen ratio) was more efficient (P = .012), and mitochondrial malondialdehyde content was lower (P = .002) with coenzyme Q(10) than with placebo. After 30 minutes of hypoxia in vitro, pectinate trabeculae isolated from patients receiving coenzyme Q(10) exhibited a greater recovery of developed force compared with those in patients receiving placebo (46.3% +/- 4.3% vs 64.0% +/- 2.9%, P = .001). There was no between-treatment difference in preoperative or postoperative hemodynamics or in release of troponin I. CONCLUSIONS Preoperative oral coenzyme Q(10) therapy in patients undergoing cardiac surgery increases myocardial and cardiac mitochondrial coenzyme Q(10) levels, improves mitochondrial efficiency, and increases myocardial tolerance to in vitro hypoxia-reoxygenation stress.
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Coenzyme Q10 improves contractility of dysfunctional myocardium in chronic heart failure.
Belardinelli, R, Muçaj, A, Lacalaprice, F, Solenghi, M, Principi, F, Tiano, L, Littarru, GP
BioFactors (Oxford, England). 2005;(1-4):137-45
Abstract
BACKGROUND There is evidence that plasma CoQ(10) levels decrease in patients with advanced chronic heart failure (CHF). OBJECTIVE To investigate whether oral CoQ(10) supplementation could improve cardiocirculatory efficiency in patients with CHF. METHODS We studied 21 patients in NYHA class II and III (18M, 3W, mean age 59 +/- 9 years) with stable CHF secondary to ischemic heart disease (ejection fraction 37 +/- 7%), using a double-blind, placebo-controlled cross-over design. Patients were assigned to oral CoQ(10) (100 mg tid) and to placebo for 4 weeks, respectively. RESULTS CoQ(10) supplementation resulted in a threefold increase in plasma CoQ(10) level (P < 0.0001 vs placebo). Systolic wall thickening score index (SWTI) was improved both at rest and peak dobutamine stress echo after CoQ(10) supplementation (+12.1 and 15.6%, respectively, P < 0.05 vs placebo). Left ventricular ejection fraction improved significantly also at peak dobutamine (15% from study entry P < 0.0001) in relation to a decrease in LV end-systolic volume index (from 57 +/- 7 mL/m(2) to 45 mL/m(2), P < 0.001). Improvement in the contractile response was more evident among initially akinetic (+33%) and hypokinetic (+25%) segments than dyskinetic ones (+6%). Improvement in SWTI was correlated with changes in plasma CoQ(10) levels (r = -0.52, P < 0.005). Peak VO(2) was also improved after CoQ(10) as compared with placebo (+13%, <0.005). No side effects were reported with CoQ(10). CONCLUSIONS Oral CoQ(10) improves LV contractility in CHF without any side effects. This improvement is associated with an enhanced functional capacity.