MiRNA-21a, miRNA-145, and miRNA-221 Expression and Their Correlations with WNT Proteins in Patients with Obstructive and Non-Obstructive Coronary Artery Disease.

MicroRNAs and the WNT signaling cascade regulate the pathogenetic mechanisms of atherosclerotic coronary artery disease (CAD) development. OBJECTIVE: To evaluate the expression of microRNAs (miR-21a, miR-145, and miR-221) and the role of the WNT signaling cascade (WNT1, WNT3a, WNT4, and WNT5a) in obstructive CAD and ischemia with no obstructive coronary arteries (INOCA). METHOD: The cross-sectional observational study comprised 94 subjects. The expression of miR-21a, miR-145, miR-221 (RT-PCR) and the protein levels of WNT1, WNT3a, WNT4, WNT5a, LRP6, and SIRT1 (ELISA) were estimated in the plasma of 20 patients with INOCA (66.5 [62.8; 71.2] years; 25% men), 44 patients with obstructive CAD (64.0 [56.5; 71,0] years; 63.6% men), and 30 healthy volunteers without risk factors for cardiovascular diseases (CVD). RESULTS: Higher levels of WNT1 (0.189 [0.184; 0.193] ng/mL vs. 0.15 [0.15-0.16] ng/mL, p < 0.001) and WNT3a (0.227 [0.181; 0.252] vs. 0.115 [0.07; 0.16] p < 0.001) were found in plasma samples from patients with obstructive CAD, whereas the INOCA group was characterized by higher concentrations of WNT4 (0.345 [0.278; 0.492] ng/mL vs. 0.203 [0.112; 0.378] ng/mL, p = 0.025) and WNT5a (0.17 [0.16; 0.17] ng/mL vs. 0.01 [0.007; 0.018] ng/mL, p < 0.001). MiR-221 expression level was higher in all CAD groups compared to the control group (p < 0.001), whereas miR-21a was more highly expressed in the control group than in the obstructive (p = 0.012) and INOCA (p = 0.003) groups. Correlation analysis revealed associations of miR-21a expression with WNT1 (r = -0.32; p = 0.028) and SIRT1 (r = 0.399; p = 0.005) protein levels in all CAD groups. A positive correlation between miR-145 expression and the WNT4 protein level was observed in patients with obstructive CAD (r = 0.436; p = 0.016). Based on multivariate regression analysis, a mathematical model was constructed that predicts the type of coronary lesion. WNT3a and LRP6 were the independent predictors of INOCA (p < 0.001 and p = 0.002, respectively). CONCLUSIONS: Activation of the canonical cascade of WNT-ß-catenin prevailed in patients with obstructive CAD, whereas in the INOCA and control groups, the activity of the non-canonical pathway was higher. It can be assumed that miR-21a has a negative effect on the formation of atherosclerotic CAD. Alternatively, miR-145 could be involved in the development of coronary artery obstruction, presumably through the regulation of the WNT4 protein. A mathematical model with WNT3a and LRP6 as predictors allows for the prediction of the type of coronary artery lesion.

Relationship of Acylcarnitines to Myocardial Ischemic Remodeling and Clinical Manifestations in Chronic Heart Failure.

BACKGROUND: Progressive myocardial remodeling (MR) in chronic heart failure (CHF) leads to aggravation of systolic dysfunction (SD) and clinical manifestations. Identification of metabolomic markers of these processes may help in the search for new therapeutic approaches aimed at achieving reversibility of MR and improving prognosis in patients with CHF. METHODS: To determine the relationship between plasma acylcarnitine (ACs) levels, MR parameters and clinical characteristics, in patients with CHF of ischemic etiology (n = 79) and patients with coronary heart disease CHD (n = 19) targeted analysis of 30 ACs was performed by flow injection analysis mass spectrometry. RESULTS: Significant differences between cohorts were found for the levels of 11 ACs. Significant positive correlations (r > 0.3) between the medium- and long-chain ACs (MCACs and LCACs) and symptoms (CHF NYHA functional class (FC); r = 0.31-0.39; p < 0.05); negative correlation (r = -0.31-0.34; p < 0.05) between C5-OH and FC was revealed. Positive correlations of MCACs and LCACs (r = 0.31-0.48; p < 0.05) with the left atrium size and volume, the right atrium volume, right ventricle, and the inferior vena cava sizes, as well as the pulmonary artery systolic pressure level were shown. A negative correlation between C18:1 and left ventricular ejection fraction (r = -0.31; p < 0.05) was found. However, a decrease in levels compared to referent values of ACs with medium and long chain lengths was 50% of the CHF-CHD cohort. Carnitine deficiency was found in 6% and acylcarnitine deficiency in 3% of all patients with chronic heart disease. CONCLUSIONS: ACs may be used in assessing the severity of the clinical manifestations and MR. ACs are an important locus to study in terms of altered metabolic pathways in patients with CHF of ischemic etiology and SD. Further larger prospective trials are warranted and needed to determine the potential benefits to treat patients with CV diseases with aberrate AC levels.

Pre-discharge and early post-discharge management of patients hospitalized for acute heart failure: A scientific statement by the Heart Failure Association of the ESC.

Acute heart failure is a major cause of urgent hospitalizations. These are followed by marked increases in death and rehospitalization rates, which then decline exponentially though they remain higher than in patients without a recent hospitalization. Therefore, optimal management of patients with acute heart failure before discharge and in the early post-discharge phase is critical. First, it may prevent rehospitalizations through the early detection and effective treatment of residual or recurrent congestion, the main manifestation of decompensation. Second, initiation at pre-discharge and titration to target doses in the early post-discharge period, of guideline-directed medical therapy may improve both short- and long-term outcomes. Third, in chronic heart failure, medical treatment is often left unchanged, so the acute heart failure hospitalization presents an opportunity for implementation of therapy. The aim of this scientific statement by the Heart Failure Association of the European Society of Cardiology is to summarize recent findings that have implications for clinical management both in the pre-discharge and the early post-discharge phase after a hospitalization for acute heart failure.

Target Metabolome Profiling-Based Machine Learning as a Diagnostic Approach for Cardiovascular Diseases in Adults.

Metabolomics is a promising technology for the application of translational medicine to cardiovascular risk. Here, we applied a liquid chromatography/tandem mass spectrometry approach to explore the associations between plasma concentrations of amino acids, methylarginines, acylcarnitines, and tryptophan catabolism metabolites and cardiometabolic risk factors in patients diagnosed with arterial hypertension (HTA) (n = 61), coronary artery disease (CAD) (n = 48), and non-cardiovascular disease (CVD) individuals (n = 27). In total, almost all significantly different acylcarnitines, amino acids, methylarginines, and intermediates of the kynurenic and indolic tryptophan conversion pathways presented increased (p < 0.05) in concentration levels during the progression of CVD, indicating an association of inflammation, mitochondrial imbalance, and oxidative stress with early stages of CVD. Additionally, the random forest algorithm was found to have the highest prediction power in multiclass and binary classification patients with CAD, HTA, and non-CVD individuals and globally between CVD and non-CVD individuals (accuracy equal to 0.80 and 0.91, respectively). Thus, the present study provided a complex approach for the risk stratification of patients with CAD, patients with HTA, and non-CVD individuals using targeted metabolomics profiling.

Cardiac remodelling - Part 2: Clinical, imaging and laboratory findings. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology.

In patients with heart failure, the beneficial effects of drug and device therapies counteract to some extent ongoing cardiac damage. According to the net balance between these two factors, cardiac geometry and function may improve (reverse remodelling, RR) and even completely normalize (remission), or vice versa progressively deteriorate (adverse remodelling, AR). RR or remission predict a better prognosis, while AR has been associated with worsening clinical status and outcomes. The remodelling process ultimately involves all cardiac chambers, but has been traditionally evaluated in terms of left ventricular volumes and ejection fraction. This is the second part of a review paper by the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology dedicated to ventricular remodelling. This document examines the proposed criteria to diagnose RR and AR, their prevalence and prognostic value, and the variables predicting remodelling in patients managed according to current guidelines. Much attention will be devoted to RR in patients with heart failure with reduced ejection fraction because most studies on cardiac remodelling focused on this setting.

Cardiac remodelling - Part 1: From cells and tissues to circulating biomarkers. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology.

Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling.

Анализ влияния коморбидной сердечно-сосудистой патологии на течение и Ð¸ÑÑ Ð¾Ð´Ñ‹ COVID-19 у Ð³Ð¾ÑÐ¿Ð¸Ñ‚Ð°Ð»Ð¸Ð·Ð¸Ñ€Ð¾Ð²Ð°Ð½Ð½Ñ‹Ñ Ð¿Ð°Ñ†Ð¸ÐµÐ½Ñ‚Ð¾Ð² в первую и вторую волну пандемии в Евразийском регионе.

Цель:  Ð˜Ð·ÑƒÑ‡ÐµÐ½Ð¸Ðµ особенностей клинического течения новой коронавирусной инфекции и  влияния сопутствующих заболеваний на исход заболевания у госпитализированных больных с инфекцией SARS-CoV-2 в первую и вторую волны пандемии.Методы и результаты.  Для оценки особенностей течения COVID-19 в Евразийском регионе были созданы международные регистры АКТИВ 1 и во время второй волны пандемии АКТИВ 2. Набор больных в регистр АКТИВ 1 проводили с 29.06.20 по 29.10.20, набрано 5 397 пациентов. Прием пациентов на учет в АКТИВ 2 проводили с 01.11.20 до 30.03.21, набрано 2 665 больных.Результаты. Госпитальная летальность снизилась в  Ð¿ÐµÑ€Ð¸Ð¾Ð´ второй волны пандемии и  ÑÐ¾ÑÑ‚Ð°Ð²Ð¸Ð»Ð° 4,8 % против 7,6 % в  Ð¿ÐµÑ€Ð¸Ð¾Ð´ первой волны. В  Ð¿ÐµÑ€Ð¸Ð¾Ð´ второй волны пациенты были старше, имели больше сопутствующих заболеваний и поступали в стационар в более тяжелом состоянии, пациенты имели более высокий уровень полиморбидности. В период второй волны пандемии увеличилась заболеваемость бактериальной пневмонией и сепсисом, но реже встречались тромбозы глубоких вен и «Ñ†Ð¸Ñ‚Ð¾ÐºÐ¸Ð½Ð¾Ð²Ñ‹Ð¹ шторм¼. Наиболее неблагоприятными для прогноза смертности, как в первую, так и во вторую волны эпидемии были сочетания сопутствующих заболеваний: артериальная гипертензия (АГ) + хроническая сердечная недостаточность (ХСН) + сахарный диабет (СД) + ожирение, АГ + ишемическая болезнь сердца (ИБС) + ХСН + СД, АГ + ИБС + ХСН + ожирение.Заключение. Ð£ пациентов во вторую волну пандемии наблюдалось более обширное поражение ткани легких, чаще возникала фебрильная лихорадка, были выше уровни С-реактивного белка и  Ñ‚Ñ€Ð¾Ð¿Ð¾Ð½Ð¸Ð½Ð°, ниже уровни гемоглобина и лимфоцитов. Это, вероятно, связано с различной тактикой госпитализации пациентов в первую и вторую волны пандемии в странах, принявших участие в формировании регистров АКТИВ 1 и АКТИВ 2.

[Анализ влияния коморбидной сердечно-сосудистой патологии на течение и Ð¸ÑÑ Ð¾Ð´Ñ‹ COVID-19 у Ð³Ð¾ÑÐ¿Ð¸Ñ‚Ð°Ð»Ð¸Ð·Ð¸Ñ€Ð¾Ð²Ð°Ð½Ð½Ñ‹Ñ Ð¿Ð°Ñ†Ð¸ÐµÐ½Ñ‚Ð¾Ð² в первую и вторую волну пандемии в Евразийском регионе].

Цель:  Ð˜Ð·ÑƒÑ‡ÐµÐ½Ð¸Ðµ особенностей клинического течения новой коронавирусной инфекции и  влияния сопутствующих заболеваний на исход заболевания у госпитализированных больных с инфекцией SARS-CoV-2 в первую и вторую волны пандемии.Методы и результаты.  Для оценки особенностей течения COVID-19 в Евразийском регионе были созданы международные регистры АКТИВ 1 и во время второй волны пандемии АКТИВ 2. Набор больных в регистр АКТИВ 1 проводили с 29.06.20 по 29.10.20, набрано 5 397 пациентов. Прием пациентов на учет в АКТИВ 2 проводили с 01.11.20 до 30.03.21, набрано 2 665 больных.Результаты. Госпитальная летальность снизилась в  Ð¿ÐµÑ€Ð¸Ð¾Ð´ второй волны пандемии и  ÑÐ¾ÑÑ‚Ð°Ð²Ð¸Ð»Ð° 4,8 % против 7,6 % в  Ð¿ÐµÑ€Ð¸Ð¾Ð´ первой волны. В  Ð¿ÐµÑ€Ð¸Ð¾Ð´ второй волны пациенты были старше, имели больше сопутствующих заболеваний и поступали в стационар в более тяжелом состоянии, пациенты имели более высокий уровень полиморбидности. В период второй волны пандемии увеличилась заболеваемость бактериальной пневмонией и сепсисом, но реже встречались тромбозы глубоких вен и «Ñ†Ð¸Ñ‚Ð¾ÐºÐ¸Ð½Ð¾Ð²Ñ‹Ð¹ шторм¼. Наиболее неблагоприятными для прогноза смертности, как в первую, так и во вторую волны эпидемии были сочетания сопутствующих заболеваний: артериальная гипертензия (АГ) + хроническая сердечная недостаточность (ХСН) + сахарный диабет (СД) + ожирение, АГ + ишемическая болезнь сердца (ИБС) + ХСН + СД, АГ + ИБС + ХСН + ожирение.Заключение. Ð£ пациентов во вторую волну пандемии наблюдалось более обширное поражение ткани легких, чаще возникала фебрильная лихорадка, были выше уровни С-реактивного белка и  Ñ‚Ñ€Ð¾Ð¿Ð¾Ð½Ð¸Ð½Ð°, ниже уровни гемоглобина и лимфоцитов. Это, вероятно, связано с различной тактикой госпитализации пациентов в первую и вторую волны пандемии в странах, принявших участие в формировании регистров АКТИВ 1 и АКТИВ 2.

Angiotensin-Converting Enzyme Inhibitor Therapy Effects in Patients With Heart Failure With Preserved and Mid-Range Ejection Fraction.

BACKGROUND: There is hypothesis that endothelial function enhancement is strongly associated with better outcome and functional class improvement in heart failure with preserved ejection fraction (HFpEF) and heart failure with mid-range ejection fraction (HFmrEF) patients. Perindopril is the only angiotensin-converting enzyme inhibitor (ACEI) drug with proven positive effect on the endothelium in coronary artery disease (CAD) patients. In patients with HFpEF and HFmrEF, its impact is still unknown. The aim of this study was to assess perindopril's influence on endothelial dysfunction markers in these groups of patients. METHODS: We included 60 patients with HFpEF and HFmrEF. At the baseline, endothelial dysfunction biomarkers were measured by IFA and echocardiographic parameters (left atrial volume index (LAVI), ejection fraction (EF), left ventricular mass index (LVMI), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-diastolic volume (LVEDV)) were studied. In patients with no history of previous ACEI or angiotensin II receptor blockers (ARBs) therapy, perindopril was prescribed for 12 months. If patient was treated with ARB or ACEI drug other than perindopril before the study, after 48-h withdrawal period, previous drug was replaced by perindopril. RESULTS: After 12-month therapy with perindopril, E-selectin decreased from 57.25 to 46.05 ng/mL and from 56.55 to 47.6 ng/mL in HFpEF and HFmrEF patients, respectively (P < 0.05). Significant reductions from 0.99 to 0.76 pg/mL (P < 0.05) and from 1.08 to 0.97 pg/mL (P < 0.05) in endothelin-1 level were shown in patients with HFpEF and HFmrEF. CONCLUSION: The 12-month therapy with perindopril leads to LAVI reduction in HFmrEF patients and potential endothelial dysfunction markers decrease in HFpEF and HFmrEF patients.

Relationship between the plasma acylcarnitine profile and cardiometabolic risk factors in adults diagnosed with cardiovascular diseases.

The development of cardiovascular diseases (CVDs) is often asymptomatic. Identification of initial indicators of cardiometabolic disruption may assist in its early detection. The objective was to determine the relationships between plasma acylcarnitines (ACs) and cardiometabolic risk factors in adults with and without CVDs. The AC profile in human plasma of healthy controls [non-CVD group, n = 13)] and individuals diagnosed with CVDs (CVD group, n = 34) were compared. A targeted analysis of 29 ACs was performed using flow injection analysis-tandem mass spectrometry. There were significant direct correlations (p < 0.05) between ACs and cardiometabolic risk factors. Comparing the groups after adjustment for covariates, showed that the ACs that were best differentiated (p < 0.05) between the two groups and that presented "good" diagnostic accuracy were carnitine [30.7 (25.5-37.7) vs. 37.7 (32.3-45.0) µM], the short-chain ACs: acetylcarnitine [8.9 (7.4-10.2) vs. 11.9 (9.2-14.4) µM] and isovalerylcarnitine [0.10 (0.06-0.13) vs. 0.13 (0.10-0.16) µM], and the medium-chain ACs: hexanoylcarnitine [0.04 (0.03-0.05) vs. 0.06 (0.05-0.07) µM] and decenoylcarnitine [0.18 (0.12-0.22) vs. 0.22 (0.17-0.32) µM]. This assessment contributes to the identification of the unique metabolic features exhibited in association with cardiometabolic risk in adults diagnosed with CVD. The altered metabolites have the potential to be used as biomarkers for early detection of CVD.

A double-blind, randomized, placebo-controlled study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee.

OBJECTIVE: To evaluate the efficacy and safety of duloxetine in the treatment of chronic pain due to osteoarthritis of the knee. METHODS: This was a 13-week, randomized, double-blind, placebo-controlled trial in patients meeting American College of Rheumatology clinical and radiographic criteria for osteoarthritis of the knee. At baseline, patients were required to have a ≥ 4 weekly mean of the 24-hour average pain ratings. Patients were randomized to either duloxetine 60 mg once daily (QD) or placebo. At week 7, the duloxetine dosage was increased, in a blinded fashion, to 120-mg QD in patients reporting < 30% pain reduction. The primary efficacy measure was Brief Pain Inventory (BPI) 24-hour average pain. Secondary efficacy measures included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); Clinical Global Impressions of Severity (CGI-S). Safety and tolerability was also assessed. RESULTS: Of the total (n = 256) patients, 111 (86.7%) in placebo group and 93 (72.7%) in duloxetine group completed the study. Patients treated with duloxetine had significantly (P ≤ 0.001) greater improvement at all time points on BPI average pain and had significantly greater improvement on BPI pain severity ratings (P ≤ 0.05), WOMAC total (P = 0.044) and physical functioning scores (P = 0.016), and CGI-S (P = 0.009) at the study endpoint. Frequency of treatment-emergent nausea, constipation, and hyperhidrosis were significantly higher in the duloxetine group (P ≤ 0.05). Significantly more duloxetine-treated patients discontinued the trial because of adverse events (P = 0.002). CONCLUSIONS: Treatment with duloxetine 60 mg to 120 mg QD was associated with significant pain reduction and improved function in patients with pain due to osteoarthritis of the knee.

Pathogenesis of sudden unexpected death in a clinical trial of patients with myocardial infarction and left ventricular dysfunction, heart failure, or both.

BACKGROUND: The frequency of sudden unexpected death is highest in the early post-myocardial infarction (MI) period; nevertheless, 2 recent trials showed no improvement in mortality with early placement of an implantable cardioverter-defibrillator after MI. METHODS AND RESULTS: To better understand the pathophysiological events that lead to sudden death after MI, we assessed autopsy records in a series of cases classified as sudden death events in patients from the VALsartan In Acute myocardial infarctioN Trial (VALIANT). Autopsy records were available in 398 cases (14% of deaths). We determined that 105 patients had clinical circumstances consistent with sudden death. On the basis of the autopsy findings, we assessed the probable cause of sudden death and evaluated how these causes varied with time after MI. Of 105 deaths considered sudden on clinical grounds, autopsy suggested the following causes: 3 index MIs in the first 7 days (2.9%); 28 recurrent MIs (26.6%); 13 cardiac ruptures (12.4%); 4 pump failures (3.8%); 2 other cardiovascular causes (stroke or pulmonary embolism; 1.9%); and 1 noncardiovascular cause (1%). Fifty-four cases (51.4%) had no acute specific autopsy evidence other than the index MI and were thus presumed arrhythmic. The percentage of sudden death due to recurrent MI or rupture was highest in the first month after the index MI. By contrast, after 3 months, the percentage of presumed arrhythmic death was higher than recurrent MI or rupture (chi(2)=23.3, P<0.0001). CONCLUSIONS: Recurrent MI or cardiac rupture accounts for a high proportion of sudden death in the early period after acute MI, whereas arrhythmic death may be more likely subsequently. These findings may help explain the lack of benefit of early implantable cardioverter-defibrillator therapy.

Fatal myocardial rupture after acute myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: the VALsartan In Acute myocardial iNfarcTion Trial (VALIANT).

BACKGROUND: Myocardial rupture is a relatively rare and usually fatal complication of myocardial infarction (MI). Early recognition of patients at greatest risk of myocardial rupture provides an opportunity for early intervention. METHODS: VALIANT was a double-blind, randomized, controlled trial comparing valsartan, captopril, and their combination in high-risk patients post-MI. Myocardial rupture was identified by autopsy (available in 138/589 patients dying within 30 days of index MI), echocardiography, direct surgical visualization, or presence of hemopericardium. An independent clinical end points committee reviewed medical records for all deaths or suspected nonfatal cardiovascular events. RESULTS: Rupture was identified in 45 (0.31%) patients enrolled in VALIANT, occurring 9.8 +/- 6.0 days after the qualifying MI. Rupture accounted for 7.6% (45/589) of all deaths occurring in the first 30 days of follow-up and 24% (33/138) of deaths in which autopsies were obtained. Compared with survivors, rupture was associated with increased age, hypertension, increased Killip class, lower estimated glomerular filtration rate, and Q wave MI, and inversely related to beta-blocker and diuretic use. Compared with patients who died of other causes within 30 days, patients with myocardial rupture were more likely to have had an inferior MI, Q wave MI, or hypertension; to have used oral anticoagulants; or to have received thrombolytic therapy. CONCLUSIONS: Although rare, myocardial rupture accounted for nearly one fourth of all deaths within the first 30 days after high-risk MI, suggesting an estimated incidence of approximately 1% within the first 30 days. A number of clinical characteristics may identify post-MI patients at higher risk of myocardial rupture.

Effect of nateglinide on the incidence of diabetes and cardiovascular events.

BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS: In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS: After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Effect of valsartan on the incidence of diabetes and cardiovascular events.

BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Oral levosimendan in patients with severe chronic heart failure --the PERSIST study.

BACKGROUND: Intravenous levosimendan improves symptoms in acutely decompensated heart failure. AIMS: To evaluate the effects of oral levosimendan in severe chronic heart failure (CHF). METHODS: 307 patients with NYHA IIIB-IV CHF were randomly assigned, double-blind, to levosimendan 1 mg once or twice daily or placebo for at least 180 days. An exploratory primary end-point, the Patient Journey, a composite consisting of repeated symptom assessments, worsening heart failure and mortality during 60 days was used. Minnesota Living with Heart Failure quality of life score (MLHFQoL) and NT-proBNP were assessed repeatedly. RESULTS: Patients assigned to a lower dose of levosimendan had more severe CHF at baseline. No differences in symptoms emerged and worsening heart failure events and death were similar resulting in a similar Patient Journey score with levosimendan and placebo (p=0.567). Compared to placebo, a net improvement of 3-4 points in MLHFQoL at several time-points in favour of the combined levosimendan groups was observed (p<0.001) which was accompanied by a substantial and persistent reduction in NT-proBNP (-30-40%) (p<0.001). CONCLUSION: Levosimendan improved QoL and decreased NT-proBNP but did not improve the Patient Journey composite in patients with severe CHF. Further research with this compound is warranted to clarify safety and efficacy.

Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial.

BACKGROUND: A prior diagnosis of diabetes mellitus is associated with adverse outcomes after acute myocardial infarction (MI), but the risk associated with a new diagnosis of diabetes in this setting has not been well defined. METHODS AND RESULTS: We assessed the risk of death and major cardiovascular events associated with previously known and newly diagnosed diabetes by studying 14,703 patients with acute MI enrolled in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Patients were grouped by diabetic status: previously known diabetes (insulin use or diagnosis of diabetes before MI, n=3400, 23%); newly diagnosed diabetes (use of diabetic therapy or diabetes diagnosed at randomization [median 4.9 d after infarction], but no known diabetes at presentation, n=580, 4%); or no diabetes (n=10,719). Patients with newly diagnosed diabetes were younger and had fewer comorbid conditions than did patients with previously known diabetes. At 1 year after enrollment, patients with previously known and newly diagnosed diabetes had similarly increased adjusted risks of mortality (hazard ratio [HR] 1.43; 95% confidence interval [CI], 1.29 to 1.59 and HR, 1.50; 95% CI, 1.21 to 1.85, respectively) and cardiovascular events (HR, 1.37; 95% CI, 1.27 to 1.48 and HR, 1.34; 95% CI, 1.14 to 1.56). CONCLUSIONS: Diabetes mellitus, whether newly diagnosed or previously known, is associated with poorer long-term outcomes after MI in high-risk patients. The poor prognosis of patients with newly diagnosed diabetes, despite having baseline characteristics similar to those of patients without diabetes, supports the idea that metabolic abnormalities contribute to their adverse outcomes.