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This is a pre-copyedited, author-produced version of an article accepted for publication in European Journal of Preventive Cardiology following peer review. The version of record Kavousi, Pisinger, Barthelemy, Smedt, Koskinas, Marques-Vidal, Panagiotakos, Prescott, Tiberi, Vassiliou, Løchen. Electronic cigarettes and health with special focus on cardiovascular effects: position paper of the European Association of Preventive Cardiology (EAPC). European Journal of Preventive Cardiology (EJPC). 2020:2047487320941993, is available online at: https://doi.org/10.1177/2047487320941993. Background - Tobacco use is the single largest preventable risk factor for premature death of non-communicable diseases and the second leading cause of cardiovascular disease. In response to the harmful effects of tobacco smoking, the use of electronic cigarettes (e-cigarettes) has emerged and gained significant popularity over the past 15 years. E-cigarettes are promoted as safe alternatives for traditional tobacco smoking and are often suggested as a way to reduce or quit smoking. However, evidence suggests they are not harmless. Discussion - The rapid evolution of the e-cigarette market has outpaced the legislator’s regulatory capacity, leading to mixed regulations. The increasing use of e-cigarettes in adolescents and young individuals is of concern. While the long-term direct cardiovascular effects of e-cigarettes remain largely unknown, the existing evidence suggests that the e-cigarette should not be regarded as a cardiovascular safe product. The contribution of e-cigarette use to reducing conventional cigarette use and smoking cessation is complex, and the impact of e-cigarette use on long-term cessation lacks sufficient evidence. Conclusion - This position paper describes the evidence regarding the prevalence of e-cigarette smoking, uptake of e-cigarettes in the young, related legislations, cardiovascular effects of e-cigarettes and the impact of e-cigarettes on smoking cessation. Knowledge gaps in the field are also highlighted. The recommendations from the population science and public health section of the European Association of Preventive Cardiology are presented.

In daily clinical practice, clinicians integrate available data to ascertain the diagnostic and prognostic probability of a disease or clinical outcome for their patients. For patients with suspected or known cardiovascular disease, several anatomical and functional imaging techniques are commonly performed to aid this endeavor, including coronary computed tomography angiography (CCTA) and nuclear cardiology imaging. Continuous improvement in positron emission tomography (PET), single-photon emission computed tomography (SPECT), and CT hardware and software has resulted in improved diagnostic performance and wide implementation of these imaging techniques in daily clinical practice. However, the human ability to interpret, quantify, and integrate these data sets is limited. The identification of novel markers and application of machine learning (ML) algorithms, including deep learning (DL) to cardiovascular imaging techniques will further improve diagnosis and prognostication for patients with cardiovascular diseases. The goal of this position paper of the European Association of Nuclear Medicine (EANM) and the European Association of Cardiovascular Imaging (EACVI) is to provide an overview of the general concepts behind modern machine learning-based artificial intelligence, highlights currently prefered methods, practices, and computational models, and proposes new strategies to support the clinical application of ML in the field of cardiovascular imaging using nuclear cardiology (hybrid) and CT techniques.

Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular function are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.

Commercially available health technologies such as smartphones and smartwatches, activity trackers and eHealth applications, commonly referred to as wearables, are increasingly available and used both in the leisure and healthcare sector for pulse and fitness/activity tracking. The aim of the Position Paper is to identify specific barriers and knowledge gaps for the use of wearables, in particular for heart rate (HR) and activity tracking, in clinical cardiovascular healthcare to support their implementation into clinical care. The widespread use of HR and fitness tracking technologies provides unparalleled opportunities for capturing physiological information from large populations in the community, which has previously only been available in patient populations in the setting of healthcare provision. The availability of low-cost and high-volume physiological data from the community also provides unique challenges. While the number of patients meeting healthcare providers with data from wearables is rapidly growing, there are at present no clinical guidelines on how and when to use data from wearables in primary and secondary prevention. Technical aspects of HR tracking especially during activity need to be further validated. How to analyse, translate, and interpret large datasets of information into clinically applicable recommendations needs further consideration. While the current users of wearable technologies tend to be young, healthy and in the higher sociodemographic strata, wearables could potentially have a greater utility in the elderly and higher-risk population. Wearables may also provide a benefit through increased health awareness, democratization of health data and patient engagement. Use of continuous monitoring may provide opportunities for detection of risk factors and disease development earlier in the causal pathway, which may provide novel applications in both prevention and clinical research. However, wearables may also have potential adverse consequences due to unintended modification of behaviour, uncertain use and interpretation of large physiological data, a possible increase in social inequality due to differential access and technological literacy, challenges with regulatory bodies and privacy issues. In the present position paper, current applications as well as specific barriers and gaps in knowledge are identified and discussed in order to support the implementation of wearable technologies from gadget-ology into clinical cardiology.

This study is an analysis of the 100 most cited articles in mitral valve surgery. A bibliometric analysis is a tool to evaluate research performance in a given field. It uses the number of times a publication is cited by others as a proxy marker of its impact. The most cited paper Carpentier et al. discusses mitral valve repair in terms of restoring the geometry of the entire valve rather than simply narrowing the annulus (Carpentier, J Thorac Cardiovasc Surg 86:23–37, 1983). The first successful mitral valve repair was performed by Elliot Cutler at Brigham and Women’s Hospital in 1923 (Cohn et al., Ann Cardiothorac Surg 4:315, 2015). More recently percutaneous and minimally invasive techniques that were originally designed as an option for high risk patients are being trialled in other patient groups (Hajar, Heart Views 19:160–3, 2018). Comparison of percutaneous method with open repair represents an expanding area of research (Hajar, Heart Views 19:160–3, 2018). This study will analyse the top 100 cited papers relevant to mitral valve surgery, identifying the most influential papers that guide current management, the institutions that produce them and the authors involved.

Endothelial cells (ECs) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper, we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and micro-vascular are well established but they are invasive, time-consuming, and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We, therefore, propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression, and responses to therapy.

Background Chronic kidney disease (CKD) is characterized by dysbiosis, elevated levels of uremic toxins, systemic inflammation, and increased markers of oxidative stress. These factors lead to an increased risk of cardiovascular disease (CVD) which is common among CKD patients. Supplementation with high amylose maize resistant starch type 2 (RS-2) can change the composition of the gut microbiota, and reduce markers of inflammation and oxidative stress in patients with end-stage renal disease. However, the impact of RS-2 supplementation has not been extensively studied in CKD patients not on dialysis. Aerobic exercise training lowers certain markers of inflammation in CKD patients. Whether combining aerobic training along with RS-2 supplementation has an additive effect on the aforementioned biomarkers in predialysis CKD patients has not been previously investigated. Methods The study is being conducted as a 16-week, double-blind, placebo controlled, parallel arm, randomized controlled trial. Sixty stage 3–4 CKD patients (ages of 30–75 years) are being randomized to one of four groups: RS-2 & usual care, RS-2 & aerobic exercise, placebo (cornstarch) & usual care and placebo & exercise. Patients attend four testing sessions: Two baseline (BL) sessions with follow up visits 8 (wk8) and 16 weeks (wk16) later. Fasting blood samples, resting brachial and central blood pressures, and arterial stiffness are collected at BL, wk8 and wk16. A stool sample is collected for analysis of microbial composition and peak oxygen uptake is assessed at BL and wk16. Blood samples will be assayed for p-cresyl sulphate and indoxyl sulphate, c-reactive protein, tumor necrosis factor α, interleukin 6, interleukin 10, monocyte chemoattractant protein 1, malondialdehyde, 8-isoprostanes F2a, endothelin-1 and nitrate/nitrite. Following BL, subjects are randomized to their group. Individuals randomized to conditions involving exercise will attend three supervised moderate intensity (55–65% peak oxygen uptake) aerobic training sessions (treadmills, bikes or elliptical machine) per week for 16 weeks. Discussion This study has the potential to yield information about the effect of RS-2 supplementation on key biomarkers believed to impact upon the development of CVD in patients with CKD. We are examining whether there is an additive effect of exercise training and RS-2 supplementation on these key variables. Trial registration Clinicaltrials.gov Trial registration#NCT03689569. 9/28/2018, retrospectively registered.

Aims Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industry's willingness to invest in this field has declined because of the many challenges involved with bringing new cardiovascular drugs to market, including late-stage failures, escalating regulatory requirements, bureaucracy of the clinical trial business enterprise, and limited patient access after approval. This contrasts with the remaining burden of cardiovascular disease in Europe and in the world. Thus, clinical cardiovascular research needs to adapt to address the impact of these challenges in order to ensure development of new cardiovascular medicines.Methods and results The present paper is the outcome of a two-day workshop held by the Cardiovascular Round Table of the European Society of Cardiology. We propose strategies to improve development of effective new cardiovascular therapies. These can include (i) the use of biomarkers to describe patients who will benefit from new therapies more precisely, achieving better human target validation; (ii) targeted, mechanism-based approaches to drug development for defined populations; (iii) the use of information technology to simplify data collection and follow-up in clinical trials; (iv) streamlining adverse event collection and reducing monitoring; (v) extended patent protection or limited rapid approval of new agents to motivate investment in early phase development; and (vi) collecting data needed for health technology assessment continuously throughout the drug development process (before and after approval) to minimize delays in patient access. Collaboration across industry, academia, regulators, and payers will be necessary to enact change and to unlock the existing potential for cardiovascular clinical drug development.Conclusions A coordinated effort involving academia, regulators, industry, and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.

International audience; Extracellular vesicles (EVs)-particularly exosomes and microvesicles (MVs)-are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized. These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity. EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction. They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies. Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities. However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data. The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis and translational application of EVs focussing on the diagnosis and therapy of the ischaemic heart. This should help to ensure that the data from emerging studies are robust and repeatable, and optimize the pathway towards the diagnostic and therapeutic use of EVs in clinical studies for patient benefit.

Heart attack is mainly caused by the rupture of a vulnerable plaque. IVUS-OCT is a novel medical imaging modality that provides opportunities for accurate assessment of vulnerable plaques in vivo in patients. IVUS provides deep penetration to image the whole necrotic core while OCT enables accurate measurement of the fibrous cap of a plaque owing to its high resolution. In this paper, the authors describe the fundamentals, the technical designs and the applications of IVUS-OCT technology. Results from cadaver specimens are summarized, which indicated the complementary nature of OCT and IVUS for assessment of vulnerable plaques, plaque composition, and stent-tissue interactions. Furthermore, previously reported in vivo animal experiments are reviewed to assess the clinical adaptability of IVUS-OCT. Future directions for this technology are also discussed in this review.

In this article, a critical analysis is performed on differences in citation frequency of basic and clinical cardiovascular papers. It appears that the latter papers are cited at about 40% higher frequency. The differences between the largest number of citations of the most cited papers are even larger. It is also demonstrated that the groups of clinical and basic cardiovascular papers are also heterogeneous concerning citation frequency. It is concluded that none of the existing citation indicators appreciates these differences. At this moment these indicators should not be used for quality assessment of individual scientists and scientific niches with small numbers of scientists.

Objectives Our primary aim was to confirm whether intertwin discordance in ventricular strain and ductus venosus (DV) time intervals predicts twin–twin transfusion syndrome (TTTS). Secondary aims were to create gestational‐age ranges for ventricular strain in uncomplicated monochorionic diamniotic (MCDA) twin pregnancies without selective intrauterine growth restriction (sIUGR) and to characterize the relationship of ventricular strain with gestational age in MCDA twin pregnancies with sIUGR that did not develop TTTS. Methods In the period 2015–2018, we enrolled 150 MCDA twin pregnancies consecutively into this prospective, blinded study of global longitudinal left and right ventricular strain. With the observer blinded to twin pairing and pregnancy outcome, videoclips of the four‐chamber view, which had been recorded during ultrasound surveillance in the usual window for development of TTTS (16–26 completed gestational weeks), underwent offline measurement of strain. Uncomplicated MCDA twin pregnancies, without sIUGR, were used to test the association between strain, gestational age and estimated fetal weight using mixed‐effects multilevel regression. Inter‐rater reliability was tested in 208 strain measurements in 31 fetuses from pregnancies which did not develop TTTS and within‐fetus variation was assessed in 16 such fetuses, in which multiple four‐chamber views were taken on the same day. The effect of sIUGR on strain in otherwise uncomplicated MCDA twin pregnancy was analyzed. MCDA twin pregnancies were defined as ‘pre‐TTTS’ when, having been referred for TTTS evaluation, they did not satisfy Quintero staging criteria, but subsequently developed TTTS requiring laser treatment. MCDA pregnancies which did not develop TTTS comprised the ‘non‐TTTS’ group. Cardiovascular parameters measured in these cases included tissue Doppler parameters and DV early filling time as a percentage of the cardiac cycle (DVeT%). Intertwin strain and DVeT% discordance was compared between non‐TTTS and pre‐TTTS cases, matched for gestational age. Results Paired strain data were available for intertwin comparison in 127/150 MCDA twin pregnancies, comprising 14 pre‐TTTS and 113 non‐TTTS pregnancies, after exclusions. Scans were collected at a median frame rate of 97 (range, 28–220) Hz. Laser therapy was performed at a median gestational age of 20.6 (range, 17.2–26.6) weeks. There were no group differences in right (RV) or left (LV) ventricular strain discordance between 68/113 non‐TTTS and 13/14 pre‐TTTS MCDA twin pregnancies 3.6% was found in eight of 13 pre‐TTTS pregnancies. In non‐TTTS pregnancies, the estimated variability in ventricular strain within each twin during the day was high (RV, 19.7; LV, 12.9). However, within each pair (intertwin variation), variability was low (RV, 5.5; LV, 2.9). Interclass correlation reflecting the proportion of total variability represented by the variability between twin pairs was low (RV, 0.22; LV, 0.18). Both RV (P

Purpose Cardiotoxicity affects 5–16% of cancer patients who receive anthracyclines and/or trastuzumab. Limited research has examined interventions to mitigate cardiotoxicity. We examined the role of statins in mitigating cardiotoxicity by performing a systematic review and meta-analysis of published studies. Methods A literature search was conducted using PubMed, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Central. A random-effect model was used to assess summary relative risks (RR), weighted mean differences (WMD), and corresponding 95% confidence intervals. Testing for heterogeneity between the studies was performed using Cochran’s Q test and the I2 test. Results Two randomized controlled trials (RCTs) with a total of 117 patients and four observational cohort studies with a total of 813 patients contributed to the analysis. Pooled results indicate significant mitigation of cardiotoxicity after anthracycline and/or trastuzumab exposure among statin users in cohort studies [RR = 0.46, 95% CI (0.27–0.78), p = 0.004, $${ }I^{2}$$ I 2 = 0.0%] and a non-significant decrease in cardiotoxicity risk among statin users in RCTs [RR = 0.49, 95% CI (0.17–1.45), p = 0.20, $$I^{2}$$ I 2 = 5.6%]. Those who used statins were also significantly more likely to maintain left ventricular ejection fraction compared to baseline after anthracycline and/or trastuzumab therapy in both cohort studies [weighted mean difference (WMD) = 6.14%, 95% CI (2.75–9.52), p $$I^{2}$$ I 2 = 74.7%] and RCTs [WMD = 6.25%, 95% CI (0.82–11.68, p = 0.024, $$I^{2}$$ I 2 = 80.9%]. We were unable to explore publication bias due to the small number of studies. Conclusion This meta-analysis suggests that there is an association between statin use and decreased risk of cardiotoxicity after anthracycline and/or trastuzumab exposure. Larger well-conducted RCTs are needed to determine whether statins decrease risk of cardiotoxicity from anthracyclines and/or trastuzumab. Trial Registration Number and Date of Registration PROSPERO: CRD42020140352 on 7/6/2020.

Motivation CpG sites within the same genomic region often share similar methylation patterns and tend to be co-regulated by multiple genetic variants that may interact with one another. Results We propose a multi-trait methylation random field (multi-MRF) method to evaluate the joint association between a set of CpG sites and a set of genetic variants. The proposed method has several advantages. First, it is a multi-trait method that allows flexible correlation structures between neighboring CpG sites (e.g. distance-based correlation). Second, it is also a multi-locus method that integrates the effect of multiple common and rare genetic variants. Third, it models the methylation traits with a beta distribution to characterize their bimodal and interval properties. Through simulations, we demonstrated that the proposed method had improved power over some existing methods under various disease scenarios. We further illustrated the proposed method via an application to a study of congenital heart defects (CHDs) with 83 cardiac tissue samples. Our results suggested that gene BACE2, a methylation quantitative trait locus (QTL) candidate, colocalized with expression QTLs in artery tibial and harbored genetic variants with nominal significant associations in two genome-wide association studies of CHD. Availability and implementation https://github.com/chenlyu2656/Multi-MRF. Supplementary information Supplementary data are available at Bioinformatics online.

Objective: To demonstrate differences in cardiovascular structure and function between diabetic and non-diabetic older adults. To investigate associations between acyl-carnitines and cardiovascular function as indexed by imaging measurements. Methods: A community-based cohort of older adults without cardiovascular disease underwent current cardiovascular imaging and metabolomics acyl-carnitines profiling based on current and archived sera obtained fifteen years prior to examination. Results: A total of 933 participants (women 56%, n=521) with a mean age 63±13 years were studied. Old diabetics compared to old non-diabetics had lower myocardial relaxation (0.8±0.2 vs 0.9±0.3, p=0.0039); lower left atrial conduit strain (12±4.3 vs 14±4.1, p=0.045), lower left atrial conduit strain rate (-1.2±0.4 vs -1.3±0.5, p=0.042) and lower ratio of left atrial conduit strain to left atrial booster strain (0.5±0.2 vs 0.7±0.3, p=0.0029). Higher levels of archived short chain acyl-carnitine were associated with present-day impairments in myocardial relaxation (C5:1; OR 1.03, p=0.011), worse left atrial conduit strain function (C5:1; OR 1.03, p=0.037). Increases in hydroxylated acyl-carnitines were associated with worse left atrial conduit strain [(C4-OH; OR 1.05, p=0.0017), (C16:2-OH; OR 1.18, p=0.037)]. Current, archived and changes in long chain acyl-carnitines were associated with cardiovascular functions [(C16; OR 1.02, p=0.002), (C20:3; OR 1.01, p=0.014), (C14:3; OR 1.12, p=0.033), (C18:1; OR 1.01, p=0.018), (C18:2; OR 1.01, p=0.028), (C20:4; OR 1.10, p=0.038)] (all p

Macrophage accumulation and nitrosative stress are known mechanisms underlying age-related cardiovascular pathology and functional decline. The cardiac muscle microenvironment is known to change with age, yet the direct effects of these changes have yet to be studied in-depth. The present study sought to better elucidate the role that biochemical and biomechanical alterations in cardiac tissue have in the altered phenotype and functionality of cardiac resident macrophages observed with increasing age. To accomplish this, naive bone marrow derived macrophages from young mice were seeded onto either functionalized poly-dimethyl-siloxane hydrogels ranging in stiffness from 2kPA to 64kPA or onto tissue culture plastic, both of which were coated with either young or aged solubilized mouse cardiac extracellular matrix (cECM). Both biomechanical and biochemical alterations were found to have a significant effect on macrophage polarization and function. Increased substrate stiffness was found to promote macrophage morphologies associated with pro-inflammatory macrophage activation, increased expression of pro-inflammatory inducible nitric oxide synthase protein with increased nitric oxide secretion, and attenuated arginase activity and protein expression. Additionally, exposure to aged cECM promoted attenuated responsivity to both canonical pro-inflammatory and anti-inflammatory cytokine signaling cues when compared to young cECM treated cells. These results suggest that both biomechanical and biochemical changes in the cardiovascular system play a role in promoting the age-related shift towards pro-inflammatory macrophage populations associated with cardiovascular disease development.

Prehypertension is a risk factor for cardiovascular disease (CVD) and all‐cause mortality. However, it is unclear whether prehypertension combined with diabetes associate with a higher risk for cardiovascular disease and all‐cause mortality. The purpose of this study was to explore the relationship between prehypertension and the risk of CVD and all‐cause mortality was different among individuals with or without diabetes. In the prospective community‐based Kailuan study, 67 344 participants without hypertension or a history of CVD at baseline (2006) were included. Prehypertension was defined as systolic blood pressure of 120–139 mmHg or diastolic blood pressure of 80–89 mmHg. The outcomes were CVD and all‐cause mortality were followed up through December 31, 2017. We performed Cox proportional hazards models to evaluate the relationships between prehypertension and CVD and all‐cause mortality by diabetes status. During a median follow‐up of 11.03 years, 2981 CVD events and 4655 all‐cause mortality occurred. After adjusting age, sex, and other factors, the associations of prehypertension with risk of CVD and all‐cause mortality were significant in participants without diabetes (hazard ratio and 95% confidence interval: 1.54 [1.38–1.71] and 1.27 [1.17–1.38]), but not in participants with diabetes (1.20 [0.93–1.56] and 0.88 [0.73–1.07]). The interactions between prehypertension and diabetes for the risk of CVD and all‐cause mortality were all significant (all p

Key points The impact of SARS‐CoV‐2 infection on autonomic and cardiovascular function in otherwise healthy individuals is unknown.For the first time it is shown that young adults recovering from SARS‐CoV‐2 have elevated resting sympathetic activity, but similar heart rate and blood pressure, compared with control subjects.Survivors of SARS‐CoV‐2 also exhibit similar sympathetic nerve activity and haemodynamics, but decreased pain perception, during a cold pressor test compared with healthy controls.Further, these individuals display higher sympathetic nerve activity throughout an orthostatic challenge, as well as an exaggerated heart rate response to orthostasis.If similar autonomic dysregulation, like that found here in young individuals, is present in older adults following SARS‐CoV‐2 infection, there may be substantial adverse implications for cardiovascular health. Abstract The novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can elicit systemic adverse physiological effects. However, the impact of SARS‐CoV‐2 on autonomic and cardiovascular function in otherwise healthy individuals remains unclear. Young adults who tested positive for SARS‐CoV‐2 (COV+; n = 16, 8 F) visited the laboratory 35 ± 16 days following diagnosis. Muscle sympathetic nerve activity (MSNA), systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were measured in participants at rest and during a 2 min cold pressor test (CPT) and 5 min each at 30° and 60° head‐up tilt (HUT). Data were compared with age‐matched healthy controls (CON; n = 14, 9 F). COV+ participants (18.2 ± 6.6 bursts min−1) had higher resting MSNA burst frequency compared with CON (12.7 ± 3.4 bursts min−1) (P = 0.020), as well as higher MSNA burst incidence and total activity. Resting HR, SBP and DBP were not different. During CPT, there were no differences in MSNA, HR, SBP or DBP between groups. COV+ participants reported less pain during the CPT compared with CON (5.7 ± 1.8 vs. 7.2 ± 1.9 a.u., P = 0.036). MSNA was higher in COV+ compared with CON during HUT. There was a group‐by‐position interaction in MSNA burst incidence, as well as HR, in response to HUT. These results indicate resting sympathetic activity, but not HR or BP, may be elevated following SARS‐CoV‐2 infection. Further, cardiovascular and perceptual responses to physiological stress may be altered, including both exaggerated (orthostasis) and suppressed (pain perception) responses, compared with healthy young adults., Key points The impact of SARS‐CoV‐2 infection on autonomic and cardiovascular function in otherwise healthy individuals is unknown.For the first time it is shown that young adults recovering from SARS‐CoV‐2 have elevated resting sympathetic activity, but similar heart rate and blood pressure, compared with control subjects.Survivors of SARS‐CoV‐2 also exhibit similar sympathetic nerve activity and haemodynamics, but decreased pain perception, during a cold pressor test compared with healthy controls.Further, these individuals display higher sympathetic nerve activity throughout an orthostatic challenge, as well as an exaggerated heart rate response to orthostasis.If similar autonomic dysregulation, like that found here in young individuals, is present in older adults following SARS‐CoV‐2 infection, there may be substantial adverse implications for cardiovascular health.

Aims This study explored the association of coronary artery calcium (CAC) with incident cancer subtypes in the Multi-Ethnic Study of Atherosclerosis (MESA). CAC is an established predictor of cardiovascular disease (CVD), with emerging data also supporting independent predictive value for cancer. The association of CAC with risk for individual cancer subtypes is unknown. Methods and results We included 6271 MESA participants, aged 45–84 and without known CVD or self-reported history of cancer. There were 777 incident cancer cases during mean follow-up of 12.9 ± 3.1 years. Lung and colorectal cancer (186 cases) were grouped based on their strong overlap with CVD risk profile; prostate (men) and ovarian, uterine, and breast cancer (women) were considered as sex-specific cancers (in total 250 cases). Incidence rates and Fine and Gray competing risks models were used to assess relative risk of cancer-specific outcomes stratified by CAC groups or Log(CAC+1). The mean age was 61.7 ± 10.2 years, 52.7% were women, and 36.5% were White. Overall, all-cause cancer incidence increased with CAC scores, with rates per 1000 person-years of 13.1 [95% confidence interval (CI): 11.7–14.7] for CAC = 0 and 35.8 (95% CI: 30.2–42.4) for CAC ≥400. Compared with CAC = 0, hazards for those with CAC ≥400 were increased for lung and colorectal cancer in men [subdistribution hazard ratio (SHR): 2.2 (95% CI: 1.1–4.7)] and women [SHR: 2.2 (95% CI: 1.0–4.6)], but not significantly for sex-specific cancers across sexes. Conclusion CAC scores were associated with cancer risk in both sexes; however, this was stronger for lung and colorectal when compared with sex-specific cancers. Our data support potential synergistic use of CAC scores in the identification of both CVD and lung and colorectal cancer risk.

Involvement of extracellular nicotinamide phosphoribosyltransferase (eNAMPT, i.e., visfatin or pre-B-cell colony-enhancing factor), a cancer metabokine, in chronically hepatitis C virus (HCV)-infected (CHC) patients with sustained virological responses (SVRs) remains elusive. This 8-year prospective cohort study evaluated eNAMPT profiles of 842 consecutive CHC patients, including 519 who had completed an anti-HCV therapy course and pre-therapy and 24-week post-therapy surveys. For 842 patients, pre-therapy associations were HCV RNA, homeostatic model assessment for insulin resistance (HOMA-IR) index, and body mass index with eNAMPT levels, and NAMPT-rs61330082 T allele with total cholesterol levels. NAMPT-rs10953502, NAMPT-rs2058539, and NAMPT-rs61330082 were in a linkage disequilibrium block, which was associated with total cholesterol levels. Compared to pre-therapy levels, at 24 weeks post-therapy, decreased eNAMPT and increased lipid levels were observed in SVR patients (n = 427). Among SVR patients, higher cumulative incidences of cardiovascular events occurred in those with a NAMPT-rs61330082 TT genotype than those with non-TT genotypes (28.2% vs. 8.4%, p < 0.001). NAMPT-rs61330082 TT genotype was independently associated with incident cardiovascular events (95% CI hazard ratio (HR): 1.88–10.37; HR: 4.415); no eNAMPT profiles were associated with incident malignancies. Of CHC patients, hepatic vascular endothelial cells and baseline peripheral leukocytes expressed higher eNAMPT levels than controls, and peripheral eNAMPT-positive leukocyte proportions decreased after SVR. During HCV infection, eNAMPT involvement in glucose metabolism was modulated by HCV RNA linked to lipid metabolism and NAMPT-associated SNPs. Hepatic endothelial cells and peripheral leukocytes potentially secrete eNAMPT. Caution is required for incident cardiovascular events in SVR patients with NAMPT-rs61330082 TT genotype.

Aims The relationship between dyspnoea, coronary artery disease (CAD), and major cardiovascular events (MACE) is poorly understood. This study evaluated (i) the association of dyspnoea with the severity of anatomical CAD by coronary computed tomography angiography (CCTA) and (ii) to which extent CAD explains MACE in patients with dyspnoea. Methods and results From the international COronary CT Angiography EvaluatioN for Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry, 4425 patients (750 with dyspnoea) with suspected but without known CAD were included and prospectively followed for ≥5 years. First, the association of dyspnoea with CAD severity was assessed using logistic regression analysis. Second, the prognostic value of dyspnoea for MACE (myocardial infarction and death), and specifically, the interaction between dyspnoea and CAD severity was investigated using Cox proportional-hazard analysis. Mean patient age was 60.3 ± 11.9 years, 63% of patients were male and 592 MACE events occurred during a median follow-up duration of 5.4 (IQR 5.1–6.0) years. On uni- and multivariable analysis (adjusting for age, sex, body mass index, chest pain typicality, and risk factors), dyspnoea was associated with two- and three-vessel/left main (LM) obstructive CAD. The presence of dyspnoea increased the risk for MACE [hazard ratio (HR) 1.57, 95% confidence interval (CI): 1.29–1.90], which was modified after adjusting for clinical predictors and CAD severity (HR 1.26, 95% CI: 1.02–1.55). Conversely, when stratified by CAD severity, dyspnoea did not provide incremental prognostic value in one-, two-, or three-vessel/LM obstructive CAD, but dyspnoea did provide incremental prognostic value in non-obstructive CAD. Conclusion In patients with suspected CAD, dyspnoea was independently associated with severe obstructive CAD on CCTA. The severity of obstructive CAD explained the elevated MACE rates in patients presenting with dyspnoea, but in patients with non-obstructive CAD, dyspnoea portended additional risk.

Background Despite the clear risks of tobacco use, millions of people continue to smoke. Electronic nicotine delivery systems (ENDS), commonly called e-cigarettes, have been proposed as a substitute for those who are unwilling or unable to quit. Current systematic and narrative reviews on the health effects of ENDS use, particularly respiratory and cardiovascular effects, have come to differing conclusions. Objective We conducted two systematic reviews to critically assess and synthesize available human studies on the respiratory and cardiovascular health effects of ENDS substitution for people who smoke. The primary goal is to provide clinicians with evidence on the health effects of ENDS substitution to inform their treatment recommendations and plans. The twin goal of the reviews is to promote health literacy in ENDS users with facts on the health effects of ENDS. Methods These two reviews will be living systematic reviews. The systematic reviews will be initiated through a baseline review. Studies will be evaluated using the JBI quality assessment tools and a checklist of biases drawn from the Centre for Evidence Based Medicine Catalogue of Bias. A narrative synthesis is planned because of the heterogeneity of data. A search for recently published studies will be conducted every 3 months, and an updated review will be published every 6 months for the duration of the project or possibly longer. Results The baseline and updated reviews will be published in a peer-reviewed journal. The findings of the reviews will be reported in a white paper for clinicians and a fact sheet for people who use ENDS. Conclusions The substitution of ENDS for cigarettes is one way to potentially reduce the risks of smoking. Clinicians and their patients need to understand the potential benefits and possible risks of substituting ENDS for cigarettes. Our living systematic reviews seek to highlight the best and most up-to-date evidence in this highly contentious and fast-moving field of research. Trial Registration PROSPERO CRD42021239094; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=239094 International Registered Report Identifier (IRRID) DERR1-10.2196/29084

Purpose Androgen deprivation therapy (ADT) is the mainstay for the management of metastatic prostate cancer. Available pharmaceutical ADTs include gonadotropin-releasing hormone (GnRH) agonists and antagonists. Here, real-world data are presented from the UK general practitioner Optimum Patient Care Research Database. The study investigated the hypothesis that GnRH antagonists have lower cardiac event rates than GnRH agonists. Methods The incidence of cardiac events following initiation of GnRH antagonist or agonist therapy was investigated in a population-based cohort study conducted in UK primary care between 2010 and 2017. Results Analysis of real-world data from the UK primary care setting showed that relative risk of experiencing cardiac events was significantly lower with degarelix, a GnRH antagonist, compared with GnRH agonists (risk ratio: 0.39 [95% confidence interval 0.191, 0.799]; p = 0.01). Patients that received degarelix as first-line treatment switched treatment more frequently (33.7%), often to a GnRH agonist, than those who initiated treatment with a GnRH agonist (6.7–18.6%). Conclusion Screening for known or underlying vascular disease and identifying those at high risk of a cardiac event is important for risk mitigation in patients with prostate cancer receiving hormone therapy. The GnRH antagonist degarelix conferred a significantly lower risk of cardiac events than GnRH agonists. Prior to treatment, patients should be stratified based on level of cardiovascular (CV) risk, and appropriate lifestyle, and pharmacological interventions to mitigate CV risk should be recommended. CV risk factors and patient response to the intervention should be monitored at regular intervals.

Many relevant aspects of mammal’s cardiac physiology have been mainly investigated in insect models such as Drosophila melanogaster and Periplaneta americana. Cardiac function has been poorly studied in the cockroach Gromphadorhina portentosa, which has some advantages for experimental purposes such as an easier culture, bigger organs and a robust physiology. On the other hand, the study of cardiac physiology in insects has been largely improved since the arrival of digital imaging technologies for recording purposes. In the present work, we introduce a methodology of video recording coupled to an isotonic transducer for a three-dimensional analysis of the heart and intracardiac valves of G. portentosa. We used this methodology for assessing the physiological responses of the cockroach heart upon the application of different cholinergic neurotransmitters (acetylcholine, nicotine and muscarine). We recorded in detail the relationship between intracardiac valves movement, hemolymph flow, diastole and systole. Acetylcholine and nicotine induced a biphasic effect on the cardiac frequency. Acetylcholine increased the diastolic opening. Nicotine at high concentration caused paralysis. Muscarine induced no major effects. These findings suggest a combined action of cholinergic agonists for a finely tuned the cardiac frequency, intracardiac valves function and cardiac cycle. Electronic supplementary material The online version of this article (10.1007/s00359-020-01443-5) contains supplementary material, which is available to authorized users.

Background and purpose Tetramethylpyrazine (TMP) was originally isolated from the traditional Chinese herb ligusticum and the fermented Japanese food natto and has since been synthesized. TMP has a long history of beneficial effects in the treatment of many cardiovascular diseases. Here we have evaluated the therapeutic effects of TMP on pulmonary hypertension (PH) in animal models and in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). Experimental approach Three well-defined models of PH -chronic hypoxia (10% O2 )-induced PH (HPH), monocrotaline-induced PH (MCT-PH) and Sugen 5416/hypoxia-induced PH (SuHx-PH) - were used in Sprague-Dawley rats, and assessed by echocardiography, along with haemodynamic and histological techniques. Primary cultures of rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to study intracellular calcium levels. Western blots and RT-qPCR assays were also used. In the clinical cohort, patients with PAH or CTEPH were recruited. The effects of TMP were evaluated in all systems. Key results TMP (100 mg·kg-1 ·day-1 ) prevented rats from developing experimental PH and ameliorated three models of established PH: HPH, MCT-PH and SuHx-PH. The therapeutic effects of TMP were accompanied by inhibition of intracellular calcium homeostasis in PASMCs. In a small cohort of patients with PAH or CTEPH, oral administration of TMP (100 mg, t.i.d. for 16 weeks) increased the 6-min walk distance and improved the 1-min heart rate recovery. Conclusion and implications Our results suggest that TMP is a novel and inexpensive medication for treatment of PH. Clinical trial is registered with www.chictr.org.cn (ChiCTR-IPR-14005379).

Coronary heart disease is a common diseases of atherosclerosis. Despite the development of noninvasive therapies and the advancement of pharmacological methods and extensive drug regimens, coronary artery bypass grafting surgery is still the ultimate treatment option in many patients. Among the various complications following open heart surgery, one of the common difficulties is pulmonary complications associated with subsequent morbidity and mortality, which should be studied according to preoperative, perioperative, and postoperative factors. Preoperative factors include genetics, age, family history of pulmonary disease, smoking, coexisting disease, etc. Perioperative factors include surgical procedures like sternotomy incision, cardioplegia, and internal mammary artery harvesting; anaesthesia procedure effects like pulmonary collapse, maintenance drugs and morphine administration; and cardiopulmonary bypass pump by systemic inflammatory response syndromes. And finally, postoperative factors, especially mediastinitis and the role of nursing in the intensive care unit. Pulmonary complications after cardiac surgery include atelectasis, pleural effusions, pneumonia, pulmonary oedema, cardiogenic pulmonary oedema, acute respiratory distress syndrome, pulmonary embolism, phrenic nerve injury, pneumothorax, sternal wound infection, and mediastinitis, with different outbreaks in patients reported. Although the preoperative, perioperative, and postoperative factors play an important role in the occurrence of these complications, the preoperative factors, as factors that can be adjusted, should be considered more than the others and explained to the patient, and the preoperative patient’s assessment should be noted. Also, postoperative care with the goal of reducing infections and pulmonary complications should be addressed by the nursing team.

Background: Increased cardiac apoptosis is a hallmark of the elderly, which in turn increases the risk for developing cardiac disease. The overexpression of Omi/HtrA2 mRNA and protein contributes to apoptosis in the aged heart. Heat shock factor 1 (HSF1) is a transcription factor that binds to the promoter of Omi/HtrA2 in the aging myocardium. However, whether HSF1 participates in cardiomyocyte apoptosis via transcriptional regulation of Omi/HtrA2 remains unclear. The present study was designed to investigate whether HSF1 plays a role in Omi/HtrA2 transcriptional regulation and myocardial apoptosis. Methods and Results: Assessment of the hearts of mice of different ages was performed, which indicated a decrease in cardiac function reserve and an increase in mitochondrial apoptosis. Omi/HtrA2 overexpression in the elderly was negatively correlated with left ventricular function after exercise overload and positively correlated with myocardial Caspase-9 apoptosis. Chromatin immunoprecipitation (ChIP) of aging hearts and plasmid transfection/RNA interference of H9C2 cells revealed that enhancement of HSF1 expression promotes Omi/HtrA2 expression by inducing the promoter activity of Omi/HtrA2 while also increasing mitochondrial apoptosis by upregulating Omi/HtrA2 expression. Conclusions: HSF1 acts as a transcriptional factor that induces Omi/HtrA2 expression and Caspase-9 apoptosis in aged cardiomyocytes, while also decreasing cardiac function reserve.

Aims We determined the feasibility and diagnostic performance of segmental 18F-flurpiridaz myocardial blood flow (MBF) measurement by positron emission tomography (PET) compared with the standard territory method, and assessed whether flow metrics provide incremental diagnostic value beyond relative perfusion quantitation (PQ). Methods and results All evaluable pharmacological stress patients from the Phase III trial of 18F-flurpiridaz were included (n = 245) and blinded flow metrics obtained. For each coronary territory, the segmental flow metric was defined as the lowest 17-segment stress MBF (SMBF), myocardial flow reserve (MFR), or relative flow reserve (RFR) value. Diagnostic performances of segmental and territory MBF metrics were compared by receiver operating characteristic (ROC) areas under the curve (AUC). A multiple logistic model was used to evaluate whether flow metrics provided incremental diagnostic value beyond PQ alone. The diagnostic performances of segmental flow metrics were higher than their territory counterparts; SMBF AUC = 0.761 vs. 0.737; MFR AUC = 0.699 vs. 0.676; and RFR AUC = 0.716 vs. 0.635, respectively (P < 0.001 for all). Similar results were obtained for per-vessel coronary artery disease (CAD) ≥70% stenosis categorization and per-patient analyses. Combinatorial analyses revealed that only SMBF significantly improved the diagnostic performance of PQ in CAD ≥50% stenoses, with PQ AUC = 0.730, PQ + segmental SMBF AUC = 0.782 (P < 0.01), and PQ + territory SMBF AUC = 0.771 (P < 0.05). No flow metric improved diagnostic performance when combined with PQ in CAD ≥70% stenoses. Conclusion Assessment of segmental MBF metrics with 18F-flurpiridaz is feasible and improves flow-based epicardial CAD detection. When combined with PQ, only SMBF provides additive diagnostic performance in moderate CAD.

Made available in DSpace on 2022-04-28T19:48:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-12-01 Rationale: Dietary nitrate and nitrite have a notoriously bad reputation because of their proposed association with disease, in particular cancer. However, more recent lines of research have challenged this dogma suggesting that intake of these anions also possess beneficial effects after in vivo conversion to the vital signaling molecule nitric oxide. Such effects include improvement in cardiovascular, renal and metabolic function, which is partly mediated via reduction of oxidative stress. A recent study even indicates that low dose of dietary nitrite extends life span in fruit flies. Methods: In this study, 200 middle-aged Wistar rats of both sexes were supplemented with nitrate or placebo in the drinking water throughout their remaining life and we studied longevity, biochemical markers of disease, vascular reactivity along with careful determination of the cause of death. Results: Dietary nitrate did not affect life span or the age-dependent changes in markers of oxidative stress, kidney and liver function, or lipid profile. Ex vivo examination of vascular function, however, showed improvements in endothelial function in rats treated with nitrate. Neoplasms were not more common in the nitrate group. Conclusion: We conclude that chronic treatment with dietary nitrate does not affect life span in rats nor does it increase the incidence of cancer. In contrast, vascular function was improved by nitrate, possibly suggesting an increase in health span. Department of Physiology and Pharmacology - Karolinska Institutet Department of Biotechnology - Federal University of Paraiba, João Pessoa Department of Veterinary Science - Federal University of Paraiba, João Pessoa Department of Biophysics and Pharmacology - São Paulo State University, São Paulo Department of Biophysics and Pharmacology - São Paulo State University, São Paulo

There is a need for real-time and predictive data on alcohol use both broadly and specific to HIV. However, substance use and HIV data often suffer from lag times in reporting as they are typically measured from surveys, clinical case visits and other methods requiring extensive time for collection and analysis. Social big data might help to address this problem and be used to provide near real-time assessments of people's alcohol use and/or alcohol. This manuscript describes three types of social data sources (i.e., social media data, internet search data, and wearable device data) that might be used in surveillance of alcohol and HIV, and then discusses the implications and potential of implementing them as additional tools for public health surveillance.

Author(s): Hoshino, Shinsuke; Jain, Sonia; Shimizu, Chisato; Roberts, Samantha; He, Feng; Daniels, Lori; Kahn, Andrew; Gordon, John; Burns, Jane; Tremoulet, Adriana | Abstract: Background: Myocardial histology from autopsies of young adults with giant coronary artery aneurysms following Kawasaki disease (KD) shows bridging fibrosis beyond the territories supplied by the aneurysmal arteries. The etiology of this fibrosis is unknown, but persistent, low-level myocardial inflammation and microcirculatory ischemia are both possible contributing factors. To investigate the possibility of subclinical myocardial inflammation or fibrosis, we measured validated biomarkers in young adults with a remote history of KD. Methods: We measured plasma calprotectin, galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and serum procollagen type 1C-terminal propeptide (P1CP) in 91 otherwise healthy young adults with a remote history of KD and in 88 age-similar, healthy controls. KD subjects were stratified by coronary artery aneurysm (CAA) status and history of remote myocardial infarction (MI). Results: After correction for multiple testing, calprotectin, Gal-3, and GDF-15 levels were significantly higher in subjects with persistent CAA (nn=n26) compared with KD subjects with remodeled CAA (nn=n20, pn=n0.005, 0.001, 0.0036, respectively). In a multivariable regression model with CA status as the main predictor and adjusting for sex, MI history, and interval from KD onset, CA status was a significant predictor (Persistent CAA vs KD Normal CA) of calprotectin, Gal-3, GDF-15 and sST2 levels (pn=n0.004, l0.001, 0.007, and 0.049, respectively). Conclusions: These results suggest that ongoing inflammation and fibrosis may be occurring in individuals with persistent CAA. Longitudinal follow-up is needed to clarify the clinical significance of these elevated biomarker levels in this patient population that requires life-long monitoring.