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Background Liraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with diabetes mellitus type 2 (DM2) without cardiovascular disease. Methods Patients with DM2 were randomly assigned to receive liraglutide 1.8 mg/day or placebo in this double-blind trial of 26 weeks. Primary outcome measures were LV diastolic function (early (E) and late (A) transmitral peak flow rate, E/A ratio, early deceleration peak (Edec), early peak mitral annular septal tissue velocity (Ea) and estimated LV filling pressure (E/Ea), and systolic function (stroke volume, ejection fraction, cardiac output, cardiac index and peak ejection rate) assessed with CMR. Intention-to-treat analysis of between-group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported. Results 23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (− 56 mL/s (− 91 to − 21)), E/A ratio (− 0.17 (− 0.27 to − 0.06)), Edec (− 0.9 mL/s 2  * 10 −3 (− 1.3 to − 0.2)) and E/Ea (− 1.8 (− 3.0 to − 0.6)), without affecting A (3 mL/s (− 35 to 41)) and Ea (0.4 cm/s (− 0.9 to 1.4)). Liraglutide reduced stroke volume (− 9 mL (− 16 to − 2)) and ejection fraction (− 3% (− 6 to − 0.1)), but did not change cardiac output (− 0.4 L/min (− 0.9 to 0.2)), cardiac index (− 0.1 L/min/m 2 (− 0.4 to 0.1)) and peak ejection rate (− 46 mL/s (− 95 to 3)). Conclusions Liraglutide reduced early LV diastolic filling and LV filling pressure, thereby unloading the left ventricle. LV systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading slows progression of diabetic cardiomyopathy into symptomatic stages. Trial registration ClinicalTrials.gov: NCT01761318.

Background Diabetic myocardial disorder (DbMD, evidenced by abnormal echocardiography or cardiac biomarkers) is a form of stage B heart failure (SBHF) at high risk for progression to overt HF. SBHF is defined by abnormal LV morphology and function and/or abnormal cardiac biomarker concentrations. Objective To compare the evolution of four DbMD groups based on biomarkers alone, systolic and diastolic dysfunction alone, or their combination. Methods The Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) trial was a Phase 3 randomised trial of an aldose reductase inhibitor in patients with well-controlled type 2 diabetes mellitus (T2DM). The 1858 potential participants (age 67 ± 7 years; 50% women) were screened for SBHF based on abnormal echocardiography or biomarkers (N-terminal pro-B-type natriuretic peptide ≥ 40 ng/L or high sensitivity cardiac troponin T ≥ 10 ng/L [women] and ≥ 16 ng/L [men]). Exercise capacity (peak VO 2 ) was reduced in 669 with DbMD (age 68 ± 7, 50% women), and peak VO 2 was reassessed at 15 months. Results The 1463 (79%) participants with DbMD were allocated to four clusters; 907 (49%) showed isolated elevation of cardiac biomarkers , 301 (16%) with systolic dysfunction/hypertrophy , 162 (9%) with diastolic dysfunction and 93 (5%) comprised an overlap cluster (combined diastolic, systolic or LV geometric abnormalities). Reduced VO 2 (< 75% predicted) was present in 669 (46%); 72% of those with both systolic and diastolic dysfunction, 56% of those with systolic dysfunction and LVH, 53% of those with diastolic dysfunction and 38% with biomarkers alone (p < 0.0001). In 669 patients followed over 15 months, there was a similar small decrement in VO 2 in all groups. Conclusions Among individuals with T2DM and SBHF, reduced functional capacity is most prevalent in those with multiple physiological disturbances. However, there was no difference between phenogroups in the evolution of exercise intolerance. Trial Registration : ARISE-HF, NCT04083339.

We investigated the impact of trimetazidine treatment on left ventricular (LV) functions and cardiac biomarkers in diabetic patients with diastolic dysfunction as an early stage of diabetic cardiomyopathy. Sixty-three patients were randomly assigned to receive either trimetazidine or a placebo for 3 months. At baseline and after 3-months of treatment, measurements of serum levels of glycemic control parameters, lipid profile, tumor necrosis factor alpha, transforming growth factor beta 1, n-terminal pro brain natriuretic peptide and assessment of modified Medical Research Council (mMRC) dyspnea score, echocardiographic indices of LV functions and LV global longitudinal strain (GLS) were performed. After 3-months, trimetazidine group exhibited a significant reduction in left atrial volume index by 6.99% versus an increase by 0.66% in placebo group, p = 0.034. Moreover, average e’ increased by a significantly higher percentage in trimetazidine versus placebo group (8.46 ± 18.64 vs. -2.49 ± 14.52, respectively. p  = 0.015). Trimetazidine treatment resulted in a significant increase in LVGLS by 6.66% versus LVGLS reduction by 2.79% in placebo group ( p  = 0.004). Trimetazidine group had a significantly lower median mMRC dyspnea score compared to placebo (0 vs. 1, respectively, p  = 0.015) and a significantly lower low-density lipoprotein (LDL-C) (103.43 ± 28.31 vs. 125.34 ± 45.27, respectively, p  = 0.032). There was no significant difference between both groups in levels of other biomarkers. Three-months treatment with trimetazidine improved diastolic function parameters, LVGLS, dyspnea severity and LDL-C levels in diabetic patients with diastolic dysfunction.

Background Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. Methods Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. Results The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89–1.08) in the canagliflozin group and 1.07 (95% CI 0.97–1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82–1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e′) showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e′ < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66–1.04). Conclusions In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction.

PurposeTo compare the effect of liraglutide, sitagliptin and insulin glargine added to standard therapy on left ventricular function in post-ischemic type-2 diabetes mellitus patients.MethodsWe evaluated 32 type-2 diabetes mellitus Caucasians with history of post-ischemic chronic heart failure NYHA class II/III and/or left ventricular ejection fraction ≤45 %. Participants underwent laboratory determinations, electrocardiogram, echocardiogram, Minnesota Living with Heart Failure questionnaire and 6 min walking test at baseline and following 52 weeks treatment. Patients were treated with standard therapy for chronic heart failure and were randomized to receive liraglutide, sitagliptin and glargine in addition to metformin and/or sulfonylurea.ResultsLiraglutide treatment induced an improvement in left ventricular ejection fraction from 41.5 ± 2.2 to 46.3 ± 3 %; P = 0.001). On the contrary, treatment with sitagliptin and glargine induced no changes in left ventricular ejection fraction (41.8 ± 2.6 vs. 42.5 ± 2.5 % and 42 ± 1.5 vs. 42 ± 1.6 %, respectively; P = NS). Indexed end-systolic LV volume was reduced only in liraglutide-treated patients (51 ± 9 vs. 43 ± 8 ml/m2; P < 0.05). Liraglutide treatment induced also a significant increase in the anterograde stroke volume (39 ± 9 vs. 49 ± 11 ml; P < 0.05), whereas no differences were observed in the other two groups. Cardiac output and cardiac index showed a significant increase only in liraglutide-treated patients (4.4 ± 0.5 vs. 5.0 ± 0.6 L/min; P < 0.05 and 1.23 ± 0.26 vs. 1.62 ± 0.29 L/m2; P = 0.005, respectively).Liraglutide treatment was also associated with an improvement of functional capacity and an improvement of quality of life.ConclusionsThese data provide evidence that treatment with liraglutide is associated with improvement of cardiac function and functional capacity in failing post-ischemic type-2 diabetes mellitus patients.

We investigated the clinical profiles associated with serum uric acid (sUA) levels in a large cohort of patients hospitalized for worsening chronic heart failure with ejection fraction (EF) ≤40%, with specific focus on gender, race, and renal function based interactions. In 3,955 of 4,133 patients (96%) with baseline sUA data, clinical characteristics and outcomes were compared across sUA quartiles. The primary end points were all-cause mortality and a composite of cardiovascular mortality or heart failure hospitalization. Interaction analyses were performed for gender, race, and baseline renal function. Median follow-up was 9.9 months. Mean sUA was 9.1 ± 2.8 mg/dl and was higher in men than in women (9.3 ± 2.7 vs 8.7 ± 3.0 mg/dl, p <0.001) and in blacks than in whites (10.0 ± 2.7 vs 9.0 ± 2.8 mg/dl, p <0.001). Higher sUA was associated with lower systolic blood pressure and EF, higher natriuretic peptides, and more impaired renal function. After accounting for 24 baseline covariates, in patients with enrollment estimated glomerular filtration rate ≥30 ml/min/1.73 m2, sUA was strongly associated with increased all-cause mortality (hazard ratio 1.44, 95% confidence interval 1.22 to 1.69, p <0.001) and the composite end point (hazard ratio 1.44, 95% confidence interval 1.26 to 1.64, p <0.001). However, in patients with estimated glomerular filtration rate <30 ml/min/1.73 m2, sUA was not related with either end point (both p >0.4). Adjusted interaction analyses for gender, race, and admission allopurinol use were not significant. In conclusion, sUA is commonly elevated in patients hospitalized for worsening chronic heart failure and reduced EF, especially in men and blacks. The prognostic use of sUA differs by baseline renal function, suggesting different biologic and pathophysiologic significance of sUA among those with and without significant renal dysfunction. •Mean serum uric acid (sUA) during hospitalization for heart failure is high (∼9 mg/dl).•sUA is associated with lower ejection fraction, higher B-type natriuretic peptide, and impaired renal function.•sUA is independently predictive of postdischarge outcomes in estimated glomerular filtration rate ≥30 ml/min/1.73 m2.

Circulating levels of cardiac troponin I (cTnI) after ST-segment elevation myocardial infarction (STEMI) are associated with infarct size and chronic left ventricular dysfunction, but the relation to clinical end points and biochemical measures of global cardiac function remains less well defined. One thousand sixty-six patients receiving primary percutaneous coronary intervention (PCI) in the PROTECTION AMI trial were studied in a post hoc analysis. Cardiac troponin I was measured at several time points during the index hospitalization, and patients were followed up for 3 months before reassessment including N-terminal pro-B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF) measurements. The median (quartile 1-3) cTnI levels were 0.4 (0.1-0.4) μg/L at admission, 33.1 (12.8-72.1) μg/L after 16 to 24 hours, and 9.1 (3.9-17.5) μg/L after 70 to 80 hours. In adjusted models, all post-PCI single points, peak, and area under curve were found to be independently associated with clinical events, NT-proBNP >118 pmol/L, or LVEF <40% (P for all <.001). When cTnI was added to a baseline risk model for prediction of clinical events, the C statistic improved from 0.779 to 0.846 (16-24 hours) and 0.859 (70-80 hours). Quantified by integrated discrimination improvement, the addition of cTnI significantly augmented prediction ability (relative integrated discrimination improvement 44%-154%; P for all ≤.001). Consistent improvements in discrimination of NT-proBNP >118 pmol/L and LVEF <40% were observed. Cardiac troponin I measured after primary PCI for STEMI is independently associated with clinical outcomes and cardiac function through 3-month follow-up. These results suggest that cTnI levels are a useful risk stratification tool in STEMI patients.

On-line hemodiafiltration (HDF) has been associated with better inflammatory markers profile and survival than low-flux hemodialysis (HD). This study aimed at determining the effect of HDF vs HD on hs-TnT and echocardiography parameters evolution at one year follow-up. Patients were randomized from 2007 to 2013 to HD or HDF in accordance with the CONvective TRAnsport STudy protocol initially as part of the Montreal cohort and subsequently as part of a local cohort. Pre-dialysis hs-TnT were analyzed at baseline and 1-year follow-up. A total of 54 HDF patients and 59 HD patients were included. At baseline, median hs-TnT value was 49 ng/L (IQR 31-89) in the HDF group vs. 60 ng/L (36-96) in the HD group (p = 0.370). At one year follow-up, median hs-TnT remained stable in the HDF group (p = 0.707 vs. baseline), but significantly increased to 62 ng/L (40-104) in the HD group (p = 0.021 vs. baseline). The median variation (delta) in hs-TnT values was -3 ng/L (IQR -7-+8) in the HDF group vs. +8 ng/L (-5 -+25) in the HD group (p = 0.042). In the HDF group, LVEF increased from 60.0% (IQR 55.0-65.0) at baseline to 65.0% (60.0-65.5) at 1-year follow-up (p = 0.040) whereas it remained stable in the HD group (LVEF of 60.0% [IQR 55.0-65.0] at baseline and 65.0% [55.0-65.0] at 1-year follow-up [p = 0.312]). High-efficiency HDF is associated with stability in hs-TnT values, whereas low-flux HD is associated with significant increase in hs-TnT levels.

Objective To explore whether increased adipocyte-derived serum fatty acid binding protein 4 (FABP4) predisposes to cardiac remodelling and left ventricular dysfunction in human obesity. Design Cross-sectional investigation. Setting Academic clinical research centre. Patients 108 overweight and obese non-diabetic women (body-mass index 33±5 kg/m²). Interventions None. Main outcome measures Relationship between serum FABP4 and abdominal adipose tissue quantified by MRI. Relationship between serum FABP4 and left ventricular morphology and function assessed by cardiac MRI. Results FABP4 was independently associated with visceral abdominal adipose tissue (β=0.34, p<0.01) and subcutaneous abdominal adipose tissue (β=0.22, p<0.05). After stratification into serum FABP4 tertiles, left ventricular masses were 92±16 g, 86±13 g and 81±12 g in women with high, intermediate and low FABP4 concentrations (p<0.01), respectively. Longitudinal systolic function was reduced by 8% in women with intermediate and high versus low FABP4 concentrations (p<0.01), whereas ejection fraction did not differ among tertiles (p=0.5). In multivariate linear analysis FABP4 remained an independent predictor of left ventricular mass (β=0.17, p<0.05) and reduced longitudinal fractional shortening (β=0.21, p<0.05). Conclusions In overweight and obese women, FABP4 showed an independent association with parameters of left ventricular remodelling.

The performance of biomarkers for heart failure (HF) in older residents in long-term care is poorly understood and has not differentiated between left ventricular systolic dysfunction (LVSD) and HF with preserved ejection fraction (HFpEF). This is the first diagnostic accuracy study in this population to assess the differential diagnostic performance and acceptability of a range of biomarkers against a clinical diagnosis using portable echocardiography. A total of 405 residents, aged 65-100 years (mean 84.2), in 33 UK long-term care facilities were enrolled between April 2009 and June 2010. For undifferentiated HF, BNP or NT-proBNP were adequate rule-out tests but would miss one in three cases (BNP: sensitivity 67%, NPV 86%, cut-off 115 pg/ml; NT-proBNP: sensitivity 62%, NPV 87%, cut-off 760 pg/ml). Using higher test cut-offs, both biomarkers were more adequate tests of LVSD, but would still miss one in four cases (BNP: sensitivity 76%, NPV 97%, cut-off 145 pg/ml; NT-proBNP: sensitivity 73%, NPV 97%, cut-off 1000 pg/ml). At these thresholds one third of subjects would test positive and require an echocardiogram. Applying a stricter 'rule out' threshold (sensitivity 90%), only one in 10 cases would be missed, but two thirds of subjects would require further investigation. Biomarkers were less useful for HFpEF (BNP: sensitivity 63%, specificity 61%, cut-off 110 pg/ml; NT-proBNP: sensitivity 68%, specificity 56%, cut-off 477 pg/ml). Novel biomarkers (Copeptin, MR-proADM, and MR-proANP) and common signs and symptoms had little diagnostic utility. No test, individually or in combination, adequately balanced case finding and rule-out for heart failure in this population; currently, in-situ echocardiography provides the only adequate diagnostic assessment. Controlled-Trials.com ISRCTN19781227.