Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial.

BACKGROUND: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP). METHODS: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and ≥160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury. RESULTS: The trial comprised 17 160 patients; mean age, 64.0±6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9; P<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (Pinteractions=0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 (95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. CONCLUSIONS: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01730534.

Position Paper on the Management of Pregnancy-Associated Superficial Venous Thrombosis. Balkan Working Group for Prevention and Treatment of Venous Thromboembolism.

Venous thromboembolism (VTE) is a multifactorial disease that can possibly affect any part of venous circulation. The risk of VTE increases by about 2 fold in pregnant women and VTE is one of the major causes of maternal morbidity and mortality. For decades superficial vein thrombosis (SVT) has been considered as benign, self-limiting condition, primarily local event consequently being out of scope of well conducted epidemiological and clinical studies. Recently, the approach on SVT has significantly changed considering that prevalence of lower limb SVT is twice higher than both deep vein thrombosis (DVT) and pulmonary embolism (PE). The clinical severity of SVT largely depends on the localization of thrombosis, when it concerns the major superficial vein vessels of the lower limb and particularly the great saphenous vein. If untreated or inadequately treated, SVT can potentially cause DVT or PE. The purpose of this review is to discuss the complex interconnection between SVT and risk factors in pregnancy and to provide evidence-based considerations, suggestions, and recommendations for the diagnosis and treatment of this precarious and delicate clinical entity.

The Impact of Bariatric Surgery on Diabetes and Other Cardiovascular Risk Factors.

Introduction: Nowadays, obesity is a major worldwide health problem due to its serious consequences and toits increasing prevalence. Bariatric surgery has demonstrated a sustained weight loss and an efficient long-term control of the co-morbidities associated with obesity. The objective of our study was to compare cardiovascular risk factors before and after bariatric surgery. Material and Method: We have retrospectively studied 59 consecutive patients scheduled for bariatric surgery (gastric sleeve) in Ponderas Academic Hospital between January and March 2016, excluding the ones that didn't commit to respect the follow-up terms. The preoperative, 6 and 12 postoperative months blood tests and anthropometric measurements were comparatively analyzed. Results: BMI, waist circumference and total body weight decreased by 38%, 31%, and 41%; Glycemia, triglycerides and LDL cholesterol decreased by 16%, 37% and 9% respectively; HDL cholesterol increased by 18%. The decline was statistically significant for all variables (P 0.001) except for LDL cholesterol. The need for antihypertensive treatment was reduced by 60% and for lipid lowering treatment diminished by 21%. In diabetic patients glycated hemoglobin (HbA1c) decreased by 28% and the necessity for antidiabetic medical treatment dropped by 69%. Conclusions: Weight loss obtained by bariatric surgery in this study, improved the metabolic syndrome in all its components, obesity, hyperglycemia/type 2 diabetes, hypertension, and dyslipidemia, thus reducing the cardiovascular risk.

Acute Myocardial Infarction Mortality Rates and Trends in Romania between 1994 and 2017.

Introduction: The current study aimed to assess recent acute myocardial infarction (AMI) mortality rates and trends in Romania between 1994 and 2017. This dataset is a necessity in the context of the current improvement of emergency protocols, medical addressability, and modernization of hospital infrastructure. Materials and Methods: The study is a retrospective analysis of an anonymized mortality database containing all deaths registered in Romania during 1994-2017. AMI crude mortality rates (CMR) and age-standardized mortality rates (ASMR) were calculated using the European Standard Population. Poisson regression was used for calculating the annual percentage change (APC) in mortality, subsequently used to make mortality predictions through the year 2030. Results: There were 197,152 AMI deaths in women (39.3% of total AMI), and 304,644 (60.7%) in men. Mortality rates were higher in men as compared with women for the entire time covered by the study. Based on the 1994-2017 ASMR dynamics, predictions for the year 2030 showed an overall AMI ASMR of 70.9 (95% CI 69.9-71.9), with gender analysis showing 46.8 (95% CI 45.8-47.9) in women and 104.1 (95% CI 102.3-105.8) in men. Conclusion: Acute myocardial infarction age-standardized mortality rates decreased significantly in Romania between 1994 and 2017 in close correlation to the implementation of national healthcare programs.

Perspectives on hypertension's prevalence, treatment and control in a high cardiovascular risk East European country: data from the SEPHAR III survey.

OBJECTIVES: To estimate the trend in arterial hypertension's prevalence, awareness, treatment, and control in Romania, starting from the latest national survey Study for the Evaluation of Prevalence of Hypertension and Cardiovascular Risk in Romania III that has a crucial importance for the development of prevention strategies at national level. METHODS: A representative sample of 1970 Romanian adults (mean age 48.38 years, age range 18-80 years, 52.5% women, 72.58% response rate), was enrolled. During the two study visits, three blood pressure (BP) measurements were performed at 1-min interval. Hypertension was defined as study SBP at least 140 mmHg and/or study DBP at least 90 mmHg at both study visits or previously diagnosed hypertension, regardless of BP values. BP control was defined as SBP less than 140 mmHg and DBP less than 90 mmHg in hypertensive patients. RESULTS: General hypertension prevalence is 45.1% (19.1% newly diagnosed hypertension, 80.9% awareness of hypertension), increasing with age, regardless of sex and area of residence. Although the majority (72.2%) of hypertensive patients were treated (51.9% with two or more drugs), only 30.8% of them had controlled BP values. Following the evolution from the last 11 years, it is expected that in 2020 the prevalence of hypertension to be up to 44%, the awareness up to 96.2%, treatment of hypertension up to 83.7%, and BP control up to 36.6%. CONCLUSION: Hypertension's prevalence in Romania is on the rise despite the increase in awareness, treatment, and control. Possible explanations of this trend might be the increasing incidence of unhealthy lifestyle and diet, including high salt intake, and a general increase in the prevalence of obesity, diabetes mellitus, and dyslipidemia.

Dysfunctional high-density lipoproteins have distinct composition, diminished anti-inflammatory potential and discriminate acute coronary syndrome from stable coronary artery disease patients.

There is a stringent need to find means for risk stratification of coronary artery diseases (CAD) patients. We aimed at identifying alterations of plasma high-density lipoproteins (HDL) components and their validation as dysfunctional HDL that could discriminate between acute coronary syndrome (ACS) and stable angina (SA) patients. HDL2 and HDL3 were isolated from CAD patients' plasma and healthy subjects. ApolipoproteinAI (apoAI), apoAII, apoCIII, malondialdehyde (MDA), myeloperoxidase (MPO), ceruloplasmin and paraoxonase1 (PON1) were assessed. The anti-inflammatory potential of HDL subfractions was tested by evaluating the secreted inflammatory molecules of tumor necrosis factor α-activated endothelial cells (EC) upon co-incubation with HDL2 or HDL3. We found in ACS versus SA patients: 40% increased MPO, MDA, apoCIII in HDL2 and HDL3, 35% augmented apoAII in HDL2, and in HDL3 increased ceruloplasmin, decreased apoAII (40%) and PON1 protein and activity (15% and 25%). Co-incubation of activated EC with HDL2 or HDL3 from CAD patients induced significantly increased levels of secreted inflammatory molecules, 15-20% more for ACS versus SA. In conclusion, the assessed panel of markers correlates with the reduced anti-inflammatory potential of HDL subfractions isolated from ACS and SA patients (mostly for HDL3 from ACS) and can discriminate between these two groups of CAD patients.

Hyperglycemia Determines Increased Specific MicroRNAs Levels in Sera and HDL of Acute Coronary Syndrome Patients and Stimulates MicroRNAs Production in Human Macrophages.

We aimed to determine the levels of microRNAs (miRNAs) in sera and HDL of acute coronary syndrome (ACS) compared to stable angina (SA) patients with/without hyperglycemia, and evaluate comparatively the functional effect of these sera on the processing machinery proteins (Drosha, DGCR8, Dicer) and miRNAs production in human macrophages. MiRNAs levels in sera and HDL from 35 SA and 72 ACS patients and 30 healthy subjects were measured by using microRNA TaqMan assays. MiR-223, miR-92a, miR-486, miR-122, miR-125a and miR-146a levels were higher in the hyperglycemic ACS compared to normoglycemic sera. MiR-223 and miR-486 prevailed in HDL2, while miR-92a predominated in HDL3, all three miRNAs discriminating between ACS and SA patients; their levels were increased in HDL from hyperglycemic ACS patients versus normoglycemic ones. The incubation of human macrophages with sera from ACS and SA patients showed that all patients' sera induced an increase of Drosha, DGCR8 and Dicer expressions and of selected miRNAs levels compared to control sera, the effect being higher in the case of hyperglycemic versus normoglycemic ACS sera. The addition of glucose to SA and ACS sera increased Drosha, DGCR8 and Dicer expression and miRNAs levels in the exposed macrophages. In conclusion, hyperglycemia is associated with increased miR-223, miR-92a, miR-486 levels in HDL, which discriminate between ACS and SA patients. Exposure of human macrophages to ACS compared to SA sera determines the upregulation of Drosha, DGCR8 and Dicer expression and the increase of selected miRNAs production, the effect being augmented by an increased glucose concentration.

MiR-486 and miR-92a Identified in Circulating HDL Discriminate between Stable and Vulnerable Coronary Artery Disease Patients.

Small non-coding microRNAs (miRNAs) are implicated in gene regulation, including those involved in coronary artery disease (CAD). Our aim was to identify whether specific serum miRNAs present in the circulating lipoproteins (Lp) are associated with stable or vulnerable CAD patients. A cardiovascular disease-focused screening array was used to assess miRNAs distribution in sera collected from 95 CAD patients: 30 with stable angina (SA), 39 with unstable angina (UA), 26 at one month after myocardial infarction (MI) and 16 healthy control subjects. We found that miR-486, miR-92a and miR-122 presented the highest expression in CAD sera. These miRNA together with miR-125a, miR-146a and miR-33a were further individually analyzed by TaqMan assays. The results were consistent with PCR-array screening data that all of these miRNAs were significantly increased in CAD patients compared to controls. Using a binary logistic regression model, we established that miR-486 and miR-92a in association with some high-density lipoprotein (HDL) components can designate vulnerable CAD patients. Further, all classes of Lp were isolated from sera by density gradient ultracentrifugation. Analysis of the selected miRNAs in each Lp class showed that they were associated mainly with HDL, miR-486 and miR-92a having the highest levels. In UA and MI patients, miR-486 prevailed in HDL2, while miR-92a prevailed in HDL3, and their levels discriminate between stable and vulnerable CAD patients. We identified two circulating miRNAs that in association with some lipid metabolism biomarkers can be used as an additional tool to designate vulnerable CAD patients.

Takotsubo cardiomyopathy and transient thyrotoxicosis during combination therapy with interferon-alpha and ribavirin for chronic hepatitis C.

BACKGROUND: Thyroid dysfunction is a common complication of chronic hepatitis C (CHC) and its therapy. Takotsubo cardiomyopathy (TCM) is a multifactorial, stress related cardiomyopathy, rarely reported in association with thyrotoxicosis. Simultaneous occurrence of TCM and thyrotoxicosis due to hepatitis C and its treatment has never been reported. CASE PRESENTATION: A 47-year-old woman was admitted for acute chest pain, dyspnea, palpitations and diaphoresis. She had been diagnosed with CHC and had undergone 7 months of IFNα and Ribavirin therapy. At admission electrocardiogram (ECG) showed ST segment elevation, negative T waves and troponin was elevated suggesting ST segment elevation myocardial infarction (STEMI). Echocardiography demonstrated left ventricular apical akinesia and ballooning, with a left ventricular ejection fraction (LVEF) of 35%. Contrast angiography showed normal epicardial coronaries, yet a ventriculogram revealed left ventricular apical ballooning, consistent with TCM. Cardiac MRI showed left ventricle apical ballooning and no late enhancement suggesting the absence of any edema, scar or fibrosis in the left myocardium. She was diagnosed with non-autoimmune destructive thyroiditis: TSH=0.001 mU/L, free T4=2.41 ng/dl, total T3=199 ng/dl and negative thyroid antibodies. The thyroid ultrasonography showed a diffuse small goiter, no nodules and normal vascularization of the parenchyma. Following supportive treatment she experienced a complete recovery after a few weeks and she successfully completed her antiviral treatment, with no thyroid or cardiovascular dysfunction ever since. In patients treated with IFNα for CHC, the prevalence of thyroid dysfunction varies between 2.5-45.3% of cases. TCM is a stress related cardiomyopathy characterized by elevated cardiac enzymes, normal coronary angiography and an acute, transient, left ventricular apical dysfunction that mimics myocardial infarction. Most of the patients survive the initial acute event, typically recover normal ventricular function within one to four weeks and have a favorable outcome, as was the case with our patient. Thyrotoxicosis induced stress cardiomyopathy is rare and has been mostly reported in association with Graves' disease, thyroid storm, thyrotoxicosis factitia or following radioiodine therapy for toxic multinodular goiter. CONCLUSION: Routine thyroid screening should be done in patients receiving IFN-alpha and Ribavirin for CHC and thyrotoxicosis should be considered as a possible and treatable underlying cause of TCM.

Impact of associated significant aortic regurgitation on left ventricular remodeling and hemodynamic impairment in severe aortic valve stenosis.

OBJECTIVES: The left ventricular (LV) response to combined pressure and volume overload [aortic stenosis (AS) and aortic regurgitation (AR)] versus pressure overload (isolated AS)has not been systematically studied. We aimed to assess LV remodeling, functional and hemodynamic consequences inpatients with mixed aortic valve disease versus patients with isolated AS. METHODS: We enrolled 181 patients (67 ± 9 years,109 men) with severe AS (aortic valve area indexed to body surface area <0.6 cm 2 /m 2 ) who underwent preoperative cardiac catheterization and a complete echocardiogram. Pulmonary capillary wedge pressure (PCWP), LV end-diastolic pressure (LVEDP) and pulmonary artery pressure (PAP) were measured. RESULTS: One hundred and ten patients (group A)had isolated severe AS (AR 0­1) and 71 patients (group B)had mixed aortic valve disease (severe AS plus AR 2­3). Patients in group B were younger and in a higher New York Heart Association class (p < 0.01). Severity of AS was similar in both groups. Patients in group B had a higher indexed LV mass, a lower LV ejection fraction, and higher PCWP, LVED Pand PAP (all p ≤ 0.01). CONCLUSIONS: Patients with severe AS and significant AR are more symptomatic than patients with isolated severe AS. The increased burden due to the combined lesion induces pronounced LV remodeling and more severe hemodynamic consequences.

Prognostic role of left atrial volume in elderly patients with symptomatic stable chronic heart failure: comparison with left ventricular diastolic dysfunction and B-type natriuretic peptide.

BACKGROUND: Left atrial (LA) volume and B-type natriuretic peptide (BNP) represent powerful outcome predictors in patients with heart failure (HF). AIM: To assess the comparative prognostic role of LA volume (indexed to body surface area, LAVi), left ventricular diastolic dysfunction (LVDD) and BNP levels on long-term outcome in patients with symptomatic but stable chronic HF. methods: We studied consecutively 46 patients with symptomatic stable chronic HF (73 +/- 10 years, 30 men), in sinus rhythm, without significant valvular disease. Echocardiographic measurements included: LV mass, LV volumes and ejection fraction, and LAVi. LVDD was graded using a comprehensive Doppler algorithm. Blood taken before echocardiography was assayed for BNP levels. Primary end point was combined: all-cause mortality and hospitalization for worsening HF. RESULTS: During 20 +/- 14 months of follow-up 19 events occurred: 8 deaths, and 11 hospitalizations for HF. In univariate analyses LAVi, LVDD, BNP levels, LV ejection fraction, LV volumes, and LV mass were significant outcome predictors (P < 0.05). At multivariate regression LAVi was the only independent predictor of outcome (hazard ratio: 1.03 per 1 ml/m(2) increase, 95% CI: 1.01-1.06, P = 0.02). CONCLUSION: Although directly related to LVDD and to BNP levels, only LAVi emerged as an independent outcome predictor in this cohort of elderly patients with symptomatic stable chronic HF.