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Metformin improves cardiovascular prognosis in patients with diabetes mellitus, compared to alternative glucose-lowering drugs, despite similar glycemic control. Direct cardiovascular protective properties have therefore been proposed, and studied in preclinical models of myocardial infarction. We now aim to critically assess the quality and outcome of these studies. We present a systematic review, quality assessment and meta-analysis of the effect of metformin in animal studies of experimental myocardial infarction. Through a comprehensive search in Pubmed and EMBASE, we identified 27 studies, 11 reporting on ex vivo experiments and 18 reporting on in vivo experiments. The primary endpoint infarct size as percentage of area at risk was significantly reduced by metformin in vivo (MD -18.11[-24.09,-12.14]) and ex vivo (MD -18.70[-25.39, -12.02]). Metformin improved the secondary endpoints left ventricular ejection fraction (LVEF) and left ventricular end systolic diameter. A borderline significant effect on mortality was observed, and there was no overall effect on cardiac hypertrophy. Subgroup analyses could be performed for comorbidity and timing of treatment (infarct size and mortality) and species and duration of ischemia (LVEF), but none of these variables accounted for significant amounts of heterogeneity. Reporting of possible sources of bias was extremely poor, including randomization (reported in 63%), blinding (33%), and sample size calculation (0%). As a result, risk of bias (assessed using SYRCLE's risk of bias tool) was unclear in the vast majority of studies. We conclude that metformin limits infarct-size and improves cardiac function in animal models of myocardial infarction, but our confidence in the evidence is lowered by the unclear risk of bias and residual unexplained heterogeneity. We recommend an adequately powered, high quality confirmatory animal study to precede a randomized controlled trial of acute administration of metformin in patients undergoing reperfusion for acute myocardial infarction.

Atherosclerosis is the major cause of cardiovascular disease (CVD). Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. In patients with atherosclerotic CVD, leukocytes have a hyperinflammatory phenotype. We hypothesize that immune cell reprogramming in these patients occurs at the level of myeloid progenitors. We included 13 patients with coronary artery disease due to severe atherosclerosis and 13 subjects without atherosclerosis in an exploratory study. Cytokine production capacity after ex vivo stimulation of peripheral blood mononuclear cells (MNCs) and bone marrow MNCs was higher in patients with atherosclerosis. In BM-MNCs this was associated with increased glycolysis and oxidative phosphorylation. The BM composition was skewed towards myelopoiesis and transcriptome analysis of HSC/GMP cell populations revealed enrichment of neutrophil- and monocyte-related pathways. These results show that in patients with atherosclerosis, activation of innate immune cells occurs at the level of myeloid progenitors, which adds exciting opportunities for novel treatment strategies.

Breast cancer (BC) patients have an increased risk of developing cancer therapy-related cardiac dysfunction (CTRCD) and cardiovascular morbidity, which seems to have a substantial prognostic impact. Oncologists, in collaboration with dedicated cardiologists, have the opportunity to perform cardiovascular risk stratification. Despite guideline recommendations, strategies to detect cardiac damage at an early stage are not structurally implemented in clinical practice. The perspectives of oncology professionals regarding cardiac surveillance in BC patients have not been qualitatively evaluated. We aim to explore the perceptions of oncology professionals regarding cardiac surveillance in BC patients and, more specifically, the influencing factors of delivering cardiac surveillance. A qualitative study with semi-structured interviews was conducted and thematically analyzed. Twelve oncology professionals participated in this study. Four themes were selected to answer the study objectives: (1) sense of urgency, (2) multidisciplinary collaboration, (3) patient burden, and (4) practical tools for cardiac surveillance. Most professionals did not feel the need to deliver cardiac surveillance as they considered the incidence of CTRCD as rare. Multidisciplinary collaboration was also perceived as unnecessary, and cardiac surveillance was considered disproportionately burdensome with respect to its benefits. Nevertheless, professionals affirmed the need for practical tools to deliver cardiac surveillance. Most professionals are currently unaware of CTRCD incidence and cardiac surveillance benefits. Encouraging multidisciplinary collaboration and improving their knowledge of cardiotoxic effects of treatments and possibility of early detection can lead to structured cardiac surveillance for breast cancer patients.

•Inflammation is a key driver in the pathogenesis of aortic valve stenosis (AS).•CHIANTI is a placebo-controlled, randomized trial of low-dose colchicine in AS.•Advanced CT and 18F-NaF PET-CT imaging offer new insights into AS pathophysiology. Aortic valve stenosis (AS) is one of the most common valvular heart diseases worldwide. Its prevalence increases with age and is expected to rise further as the population ages. Untreated severe AS carries a 2-year mortality rate exceeding 50%. Furthermore, surveillance and management of AS impose a significant burden on healthcare systems. Therefore, effective pharmacological strategies are urgently needed to slow or halt the progression of AS. Inflammation plays a central role in the pathogenesis of both atherosclerosis and AS. Anti-inflammatory therapy with low-dose colchicine reduces cardiovascular events in patients with coronary artery disease, but its efficacy has not been tested in AS. Colchicine and Inflammation in Aortic Stenosis (CHIANTI) is an investigator-initiated, placebo-controlled, double-blind, multicenter, randomized trial involving 150 patients with moderate AS. After confirming tolerance during a two-week run-in phase, eligible participants underwent coronary computed tomography (CT) angiography, 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)-CT, and echocardiography. Thereafter, participants were randomized 1:1 to colchicine 0.5 mg once daily or a matching placebo. All baseline imaging is repeated after 24 months. The primary endpoint is the change in aortic valve calcium score on CT. Secondary endpoints are (1) the change in aortic valve 18F-NaF uptake on PET-CT and corrected for target-to-background ratio, and (2) the change in peak aortic jet velocity on echocardiography. The CHIANTI trial evaluates whether anti-inflammatory therapy with low-dose colchicine can slow or halt the progression of moderate AS. If successful, it would offer the first effective pharmacological treatment for AS. Registered on ClinicalTrials.gov (https://clinicaltrials.gov/), ID: NCT05162742.

Background: The Myval balloon-expandable (BE) valve has shown encouraging early clinical data in terms of safety and efficacy. Comparative data with other well-established contemporary valves are nonetheless still scarce. This study aims to compare the performance of the Myval BE valve with the Evolut self-expanding (SE) valve. Methods: In this retrospective single-center study, 223 patients with symptomatic severe aortic stenosis (AS) were included and treated with the Myval BE valve (n = 120) or with the Evolut SE valve (n = 103). Then, 91 pairs were compared after matching. Clinical outcomes were evaluated at 30 days and 1 year. Echocardiographic follow-up was performed at 30 days. Results: Procedural complications were rare in both groups. At the 30-day follow-up, no significant difference in cardiac death (Myval: 1% vs. Evolut: 2%, p = 0.56), stroke (2% vs. 4%, p = 0.41) and myocardial infarction (1% vs. 3%, p = 0.31) was observed. A permanent pacemaker implantation (PPI) was significantly less needed in the Myval group (4% vs. 15%, p = 0.01). At 1 year, cardiac death (2% vs. 4%, p = 0.41) and the stroke rate (7% vs. 5%, p = 0.76) were similar. Moderate–severe paravalvular leakage (PVL) was also comparable in both groups (1% vs. 4%, p = 0.17). Conclusion: Safety and efficacy outcomes were comparable between the two valves, except for a higher PPI rate for the Evolut SE valve. Up to 1-year follow-up, clinical outcomes showed acceptable rates of stroke and cardiac death with both valves. Valve hemodynamics were excellent with a low rate of moderate–severe PVL in both groups.

ObjectivesTo investigate: (1) the prevalence of left ventricular hypertrophy (LVH) in elderly primary care patients with long-standing asymptomatic hypertension, and (2) the diagnostic value of ECG as a screening tool in the detection of LVH compared with echocardiography in this specific patient population.Design and settingsA cross-sectional study in five general practices in the south-east of the Netherlands.ParticipantsPatients with primary care-managed hypertension, aged between 60 and 85 years, without known heart failure.Primary and secondary outcome measuresBetween June 2010 and January 2013, the patients underwent structured interviews, blood pressure assessment, laboratory testing, ECGs and echocardiograms. The primary outcome was to investigate the ability of ECG to detect LVH, compared with echocardiography as a reference test (gold standard).ResultsFour hundred and twenty-two patients (44% male; ages 70±7 years) who underwent ECG and echocardiographic assessment to determine LVH were included. The median duration of hypertension was 10 (4–15) years. The overall prevalence of LVH was 44%, which increased with age (p<0.001); up to 60% of patients were ≥75 years. ECG intimated LVH in 47 patients (11%) but in only 26 of those (55%) was LVH confirmed by echocardiography. The sensitivity of ECG for detecting LVH was poor (14%).ConclusionsAsymptomatic primary care patients with long-standing hypertension have a high prevalence of previously undetected LVH, which increases with age. ECG is inadequate for detecting LVH in these patients. Early detection of LVH could potentially create more awareness for the optimal regulation of hypertension and compliance to therapy. Therefore, echocardiography should be considered a screening device for the detection of LVH in this population.

[This corrects the article DOI: 10.1371/journal.pone.0183664.].

Background Various breast cancer (BC) treatments, such as chemotherapy and targeted therapies, increase cardiotoxicity-risk and lead to premature ischemic heart disease and heart failure among survivors. Reducing this adverse risk through early recognition and (preventive) treatment is therefore important. Conversely, we feel that screening for cardiotoxicity is currently insufficiently standardized in daily practice. A fundamental first step in identifying areas of improvement is providing an overview of current practice. Objective This study aims to describe current cardiac surveillance for women with BC during and after cardiotoxic cancer treatment, using routinely collected hospital data in the Netherlands. The study also describes hospital variation in cardiac surveillance. Methods This observational study was performed on claims data provided by Statistics Netherlands. From the data, newly diagnosed BC patients in 2013 ( N  = 16,040) were selected and followed up until 2015. Healthcare utilization analyses were performed for all cardiac and oncologic healthcare activities but with a specific focus on cardiac surveillance healthcare activities. In addition, differences between types and individual hospitals were evaluated. Results Almost one third of all BC patients received high risk cardiotoxic treatments ( N  = 5157), but cardiac surveillance was rarely performed. Cardiac care provided to patients mainly consisted of ECGs (52.0%) and MUGA scans (26.5%). Cardiac MRI was performed in 0.7% of the patients, echocardiography in 17.7%, and measurement of Troponin and NT-proBNP in 5.1 and 5.8%, respectively. Moreover, we observed a substantial variation in cardiac surveillance between different hospital types and between individual hospitals. Conclusion This study shows that women treated for BC with cardiotoxic treatments do not receive recommended cardiac surveillance. Standardized approaches in clinical care are lacking, resulting in low rates of diagnostic testing and a substantial variation in surveillance between hospitals. A structured approach and increased interprofessional collaboration could lead to tailored cardiac surveillance for early detection of cardiotoxicity and therefore start of treatment.

Background Thoracic radiotherapy may damage the myocardium and arteries, increasing cardiovascular disease (CVD) risk. Women with a high local breast cancer (BC) recurrence risk may receive an additional radiation boost to the tumor bed. Objective We aimed to evaluate the CVD risk and specifically ischemic heart disease (IHD) in BC patients treated with a radiation boost, and investigated whether this was modified by age. Methods We identified 5260 BC patients receiving radiotherapy between 2005 and 2016 without a history of CVD. Boost data were derived from hospital records and the national cancer registry. Follow-up data on CVD events were obtained from Statistics Netherlands until December 31, 2018. The relation between CVD and boost was evaluated with competing risk survival analysis. Results 1917 (36.4%) received a boost. Mean follow-up was 80.3 months (SD37.1) and the mean age 57.8 years (SD10.7). Interaction between boost and age was observed for IHD: a boost was significantly associated with IHD incidence in patients younger than 40 years but not in patients over 40 years. The subdistribution hazard ratio (sHR) was calculated for ages from 25 to 75 years, showing a sHR range from 5.1 (95%CI 1.2–22.6) for 25-year old patients to sHR 0.5 (95%CI 0.2–1.02) for 75-year old patients. Conclusion In patients younger than 40, a radiation boost is significantly associated with an increased risk of CVD. In absolute terms, the increased risk was low. In older patients, there was no association between boost and CVD risk, which is likely a reflection of appropriate patient selection.

Large prospective studies in patients with type 2 diabetes mellitus have demonstrated that metformin treatment improves cardiovascular prognosis, independent of glycemic control. Administration of metformin potently limits infarct size in murine models of myocardial infarction. This study examined, for the first time in humans, whether metformin limits ischemia-reperfusion (IR) injury in vivo using a well-validated forearm model of endothelial IR-injury. Twenty-eight healthy volunteers (age 41±6 years, 10 male/16 female) were randomized between pretreatment with metformin (500 mg three times a day for 3 days) or no treatment in a Prospective Randomized Open Blinded Endpoint study. Brachial artery flow mediated dilation (FMD) was measured before and after 20 minutes of forearm ischemia and 20 minutes of reperfusion. FMD analysis was performed offline by investigators blinded for the treatment arm. Baseline FMD did not differ between metformin pretreatment and no pretreatment (6.9±3.6% and 6.1±3.5%, respectively, p = 0.27, n = 26). FMD was significantly lower after forearm IR in both treatment arms (4.4±3.3% and 4.3±2.8%, respectively, P<0.001 in both conditions). A linear mixed model analysis revealed that metformin treatment did not prevent the decrease in FMD by IR. A 3 day treatment with metformin in healthy, middle-aged subjects does not protect against endothelial IR-injury, measured with brachial artery FMD after forearm ischemia. Further studies are needed to clarify what mechanism underlies the cardiovascular benefit of metformin treatment. ClinicalTrials.gov NCT01610401.