Background: Left ventricular hypertrophy (LVH) is highly prevalent in patients with coronary artery disease (CAD) and is an independent predictor of cardiovascular mortality. Metformin has been shown to regress LV mass (LVM) in animal models of LVH. We hypothesize that metformin may regress LVH in nondiabetic and normotensive CAD patients with prediabetes and/or insulin resistance. Methods: In this randomized double-blind placebo controlled trial, 68 patients with prediabetes (HbA1c ?39 mmol/mol and less than 48 mmol/mol) and/or insulin resistance (fasting insulin resistance index ? 2.7) were assigned to receive either metformin (2g daily dose) or placebo for 12 months. An intention-to-treat (ITT) and per-protocol analysis was designed to determine the effect of metformin on the following study endpoints: Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging; other endpoints were changes in LVM, changes in body weight, office blood pressure (BP) and biomarkers. Results: In the ITT analysis (n=61), metformin treatment significantly reduced: LVMI (metformin -2.7 ± 2.3 g/m1.7 vs. placebo -1.4 ± 2.7 g/m1.7; P=0.05), body weight (lowered by 3.6 kgs, p=0.002), office systolic BP (metformin -4.8 ± 15.6 mmHg vs. placebo 4.6 ± 15.7 mmHg; P=0.02) and reduced concentration of thiobarbituric acid reactive substances (TBARs), a biomarker for oxidative stress (p=0.04). In the on-per protocol analysis (n=56), metformin resulted in a greater reduction of LVMI (metformin -3.1 ± 1.9 g/m1.7 vs. placebo -1.2 ± 2.7 g/m1.7; P=0.005), and greater weight reduction of 4.2kgs (p=0.001). Conclusions: Metformin treatment significantly reduced LVMI, office SBP, body weight and oxidative stress. These results reveal a novel mechanism for the cardioprotective effect of metformin and raise the possibility of using metformin in nondiabetic patients with CAD. Disclosure M. Mohan: None. S. Al-Talabany: None. A.M. McKinnie: None. I. Mordi: None. J.S. Singh: None. S.J. Gandy: None. A. Choy: None. J.G. Houston: None. J. George: None. A.D. Struthers: Research Support; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca. C.C. Lang: None.
Abstract Background Primary prevention of cardiovascular events in people with Type 2 diabetes mellitus (T2DM) needs to improve due to risk of cardiovascular events. A major problem in T2DM is the high incidence of silent yet potentially lethal cardiac abnormalities, namely myocardial ischaemia (MI), left ventricular hypertrophy (LVH), left ventricular systolic dysfunction (LVSD), left ventricular diastolic dysfunction (LVDD), and left atrial enlargement (LAE). All these independently predict cardiovascular events and mortality. There is not a single study with comprehensive enough cardiac phenotyping to document the prevalence of all the aforementioned 5 cardiac abnormalities. To improve primary prevention of cardiovascular disease in diabetes, we need to first identify the type of silent cardiac abnormality and treat accordingly. However cardiac phenotyping in all people with T2DM would be prohibitively expensive. Purpose Our study examines the prevalence of all 5 cardiac abnormalities, and the accuracy of biomarkers in identifying them in a cohort of patients with well-controlled T2DM and blood pressure (BP) with no known cardiovascular symptom or disease. Methods This is a cross-sectional study of randomly selected patients with T2DM with no known cardiovascular symptom or disease, clinic BP or average 24-hour BP ≤140/80mmHg, and HbA1c ≤64mmol/mol. Patients with renal impairment, atrial fibrillation, moderate to severe valvular heart disease were excluded. All participants underwent transthoracic echocardiogram, electrocardiogram and dobutamine stress echocardiogram (DSE). Those who did not tolerate DSE or whose DSE was inconclusive, a myocardial perfusion scan or computed tomography coronary angiogram was done. Biomarkers such as BNP, NT-proBNP, high-sensitivity cardiac Troponin I (hs-cTnI), and high sensitivity cardiac Troponin T (hs-cTnT) were measured. Results Of 246 participants (mean age 66 years, 63% male), 141 (57.3%) had silent cardiac abnormalities. 90 (36.6%) had 1 cardiac abnormality, 44 (17.9%) had 2 cardiac abnormalities and 7 (2.8%) had 3 cardiac abnormalities. The most prevalent abnormality was LAE, n=106 (43.1%); followed by LVH, n=71 (28.9%); LVDD, n=13 (5.3%); MI, n=8 (3.3%); LVSD, n=1 (0.4%). Both NT-proBNP and hs-cTnI performed best in detecting silent cardiac abnormalities with p-values of 0.02 and 0.0004, and AUC 0.66 and 0.68 respectively. Increasing NT-proBNP (p=0.002) and hs-cTnI (p=0.002) levels correlated to increasing number of concomitant cardiac abnormalities. Our key new finding is that biomarkers identify those with multiple silent cardiac abnormalities. Conclusion BNP and high-sensitivity cardiac Troponin appear to identify those with multiple silent cardiac abnormalities which may make them useful screening tests so that cardiac investigations are focused on this high-risk subset, with a view to intensifying potential therapies on this subset to reduce the cardiotoxic effect of diabetes. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Chief Scientist Office
Patients with type 2 diabetes mellitus are at a higher risk of developing heart failure compared with the healthy population. In recent landmark clinical trials, sodium-glucose co-transporter 2 (SGLT2) inhibitor therapies improve blood glucose control and also reduce cardiovascular events and heart failure hospitalisations in patients with type 2 diabetes. Intriguingly, such clinical benefits have also been seen in patients with heart failure in the absence of type 2 diabetes although the underlying mechanisms are not clearly understood. Potential pathways include improved glycaemic control, diuresis, weight reduction and reduction in blood pressure, but none fully explain the observed improvements in clinical outcomes. More recently, novel mechanisms have been proposed to explain these benefits that include improved cardiomyocyte calcium handling, enhanced myocardial energetics, induced autophagy and reduced epicardial fat. We provide an up-to-date review of cardiac-specific SGLT2 inhibitor–mediated mechanisms and highlight studies currently underway investigating some of the proposed mechanisms of action in cardiovascular health and disease.
Objectives: The aims of this study were to determine predictors of survival after hospital discharge and to describe the impact of intensive care unit admission on health-related quality of life at 6 months after hospital discharge in older adults admitted to intensive care units. Design: Prospective longitudinal observational study with administered questionnaire. Settings and Patients: Patients 65 yrs of age and older who were admitted to the medical, surgical, and coronary intensive care units for >24 hrs in a large urban teaching hospital system from August 2007 to May 2008 with a follow-up period ending April 2009. Interventions: Administered questionnaire to patients or proxies. Measurements and Main Results: Four hundred eighty-four patients 65 yrs old and older were enrolled. Data were collected on demographics, comorbidities, intensive care unit admission diagnoses, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment score, Glasgow Coma Scale score at intensive care unit admission, intensive care unit interventions, and disposition after hospital discharge. A health-related quality of life survey was administered to patients, their proxies, or caregivers at intensive care unit admission, and to hospital survivors at 6 months after hospital discharge. Three hundred sixty-seven (75.8%) and 318 (65.7%) of enrolled patients were alive at hospital discharge and at 6 months, respectively. Mean age of survivors was 77.8 ± 8.5. Independent predictors of death at 6 months were: number of days during the 30 days before hospitalization that the patient felt their "physical health was not good" on the health-related quality of life survey [odds ratio = 1.08; confidence interval 1.04–1.12], a higher Acute Physiology and Chronic Health Evaluation II score [odds ratio = 1.09; 95% confidence interval 1.06–1.12], and chronic pulmonary disease as a comorbidity [odds ratio = 2.22; 95% confidence interval 1.04–4.78]. Of the 318 survivors at 6 months after hospital discharge, 297 (93.4%) completed the health-related quality of life questionnaire. When assessing whether changes in health-related quality of life over time were affected by age in our study cohort of 65 yrs old and older, we found that the oldest survivors, age 86.3 yrs old and older, had worse health-related quality of life over time, including more days spent with poor physical health (p < .004) and mental health (p < .001), while the youngest survivors, age 65–69.3 yrs old, showed improvement in health-related quality of life with fewer days spent with poor physical health (p < .004) and mental health (p < .001) at follow-up compared to baseline. These differences remained after adjusting for severity of illness and other potential confounders. Conclusions: One-third of adults 65 yrs old and older admitted to the intensive care unit die within 6 months of hospital discharge. Among survivors at 6 months, health-related quality of life has significantly worsened over time in the oldest patients but improved in the youngest. Our study in a large cohort of mixed intensive care unit patients identifies additional prognostic factors and significant quality of life information in intensive care unit survivors well after hospital discharge. This additional information may guide clinicians in their discussions with patients, families, and other providers as they decide on what treatments and interventions to pursue.
Abstract Background Heart failure (HF) is an important manifestation of Type 2 Diabetes (T2D). The development of HF in T2D may be preceded by Stage B HF. Asymptomatic left ventricular impairment, especially left ventricular diastolic dysfunction (LVDD), is a defining early feature of Stage B HF. Detection of Stage B HF is crucial as it provides an opportune target for intervention with cardio-protective therapy to prevent the development of symptomatic HF in T2D. The risk of T2DM is higher in South Asian populations resulting in increased risk of macrovascular and microvascular complications. The prevalence of Stage B HF in South Asian patients with T2DM is not known. Purpose (i) To compare the prevalence of Stage B HF in South Asians in India compared with White Europeans in Scotland; (ii) To test the role of NT-proBNP in identifying Stage B HF Methods This study involved the comparison between two independently conducted, cross-sectional studies. The patients were asymptomatic patients with T2DM with no prior history of cardiovascular disease from Chennai, India (n=246) and Tayside, Scotland (n=246). All patients underwent transthoracic echocardiogram (echo) examination to detect the presence of structural and functional echo features of Stage B HF: left atrial enlargement (LAE), left ventricular hypertrophy (LVH), LVDD and LV systolic dysfunction (LVSD). Receiver operating curves (ROC) were used to determine the predictive ability of NT-proBNP to predict LAE/LVDD/LVD/LVSD. Results The prevalence of Stage B HF was high in South-Asian patients with T2DM (median age of 55 [49, 62] with a high prevalence of LVDD (5% had LVH, 7.3% had LAE, 70% had LVDD and 0% had LVSD (Figure 1B). 10% of the South Asian patients had at least 2 factors contributing to Stage B HF and these patients had higher NT-proBNP titres (703.4 [500.0, 949.2] vs 423.7 [35.0, 754.2], p<0.001). ROC curves show that NT-proBNP can predict these participants with 2 or more echo features [Figure 2B, AUC: 0.7043 (0.6159, 0.7928) p<0.05]. The prevalence of Stage B HF among White Europeans (median age of 67 [61, 72].) was lower compared with South Asian patients: 15% had LVH, 13% had LAE, 19% had LVDD and 2% had LVSD (Figure 1A). 8% of White Europeans had at least 2 factors contributing to Stage B HF and these had higher NT-proBNP titres (368.9 [154.6, 1087.8] vs 186.8 [79.7, 411.5], p=0.02). ROC curves show that NT-proBNP can predict participants with 2 or more factors [Figure 2A, AUC: 0.6399 (0.5122, 0.7676) p<0.05]. Conclusion Our study has shown that South Asian patients with T2DM have a high prevalence of Stage B HF compared with White Europeans and that the predominant Stage B HF feature is LVDD. We also found that NTproBNP could potentially be used to detect Stage B HF and help identify at-risk patients for cardio-protective therapy such as SGLT2 inhibitor therapy that has been shown to prevent the development of future HF events. Funding Acknowledgement Type of funding sources: None.
Genetic defects in the Wnt-1 signaling pathway contribute to human tumor progression and are especially prevalent in colorectal cancer. We screened mouse C57MG cells to isolate mRNAs induced by Wnt-1 and identified Stra6, an mRNA known to be up-regulated by retinoic acid. Up-regulation of Stra6 mRNA was also observed in hyperplastic mammary tissue and mammary gland tumors from transgenic mice expressing Wnt-1 and in human tumors that frequently harbor defects in Wnt-1 signaling. Stimulation of C57MG cells with retinoic acid plus Wnt-1 resulted in expression of Stra6 transcript to levels greatly exceeding that observed with either stimulus alone. This synergy could be explained in part by the up-regulation of retinoic acid receptor-gamma that was observed in response to Wnt-1 signaling. Accordingly, treatment of human colorectal cancer cell lines with retinoic acid resulted in the up-regulation of Stra6 mRNA and accumulation of Stra6 protein at the cell membrane. The data support a model in which Wnt-1 signaling synergizes with retinoids to activate retinoic acid receptor-gamma-responsive genes in human cancers.
OBJECTIVE To determine the effects of dapagliflozin in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM) on left ventricular (LV) remodeling using cardiac MRI. RESEARCH DESIGN AND METHODS We randomized 56 patients with T2DM and HF with LV systolic dysfunction to dapagliflozin 10 mg daily or placebo for 1 year, on top of usual therapy. The primary end point was difference in LV end-systolic volume (LVESV) using cardiac MRI. Key secondary end points included other measures of LV remodeling and clinical and biochemical parameters. RESULTS In our cohort, dapagliflozin had no effect on LVESV or any other parameter of LV remodeling. However, it reduced diastolic blood pressure and loop diuretic requirements while increasing hemoglobin, hematocrit, and ketone bodies. There was a trend toward lower weight. CONCLUSIONS We were unable to determine with certainty whether dapagliflozin in patients with T2DM and HF had any effect on LV remodeling. Whether the benefits of dapagliflozin in HF are due to remodeling or other mechanisms remains unknown.
Abstract Introduction Epicardial adipose tissue (EAT) accumulation is associated with adverse outcome in heart failure with preserved ejection fraction, however its role in HF with reduced ejection fraction (HFrEF) is less clear. The relationship between EAT thickness and their impact on patients who have diabetes and heart failure remains unclear. SGLT2 inhibitors such as dapagliflozin improve outcomes in heart failure and diabetes, however their mechanism of benefit is not well understood. The aim of our study was to assess whether dapagliflozin reduced EAT in patients with type 2 diabetes and HFrEF. Methods We performed an analysis of individuals with type 2 diabetes and HFrEF who were randomised to receive either dapagliflozin or a placebo for 12 months as part of the REFORM trial. Participants had cardiac magnetic resonance (CMR) scans at baseline and at 12 months. Epicardial fat was measured utilizing 4-chamber cine images to quantify adipose tissue between the myocardium and the visceral layer of the pericardium. This assessment was carried out using the single end-diastolic image, with measurements conducted by evaluators blinded to the randomisation status of participants. Results 47 participants completed the stud. At baseline, not only EAT thickness and BMI level (placebo: 33, dapagliflozin 32, p=0.49) but also heart rate (74.39 bpm vs. 77.61 bpm, p=0.35), systolic blood pressure (132.75 mmHg vs. 135.00 mmHg, p=0.63), diastolic blood pressure (71.39 mmHg vs. 74.04 mmHg, p=0.33) and age (67 vs. 66, p=0.79) were comparable between the two groups. 23 randomised to placebo and 24 to dapagliflozin. Baseline EAT was similar in both groups (placebo: 11.54 cm², dapagliflozin 11.74 cm², p=0.414). After 12 months of treatment dapagliflozin caused a significant reduction in EAT compared to placebo (1.21 cm² vs. 0.09 cm², p=0.007). Conclusion Dapagliflozin significantly reduced epicardial adipose tissue compared to placebo in patients with type 2 diabetes and HFrEF. The reduction in EAT may play a role in the beneficial effects of dapagliflozin in heart failure patients.4 Ch CMRBox plot
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