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Introduction: Up to 20% of patients presenting with acute coronary syndrome (ACS) have no traditional cardiovascular risk-factors (RFs). Data regarding the determinants, management, and outcomes of these patients are scarce., Objectives: To evaluate the management, outcomes, and time-dependent changes of ACS patients without RFs., Methods: Evaluation of clinical characteristics, management strategies, and outcomes as well as time-dependent changes [by 3 time periods: early (2000-2006), mid (2008-2013), and late (2016-2018)] of ACS patients without RFs (diabetes mellitus, hypertension, dyslipidemia, family history of ischemic heart disease, and smoking) or known coronary artery disease, enrolled in the biennial ACS Israeli Surveys (ACSIS) between 2000 and 2018. We compared ACS patients without RFs (no-RF group) to those with ≥1 RFs (RF group)., Results: Overall, 554/9,683 (5.7%) eligible ACS patients did not have any RFs [median age 63 (IQR 52-76) years, 25% females]. The no-RF group were older, with lower body mass index and prevalence of other cardiovascular comorbidity and chronic kidney disease compared with the RF group. The in-hospital percutaneous coronary intervention rates were lower among the no-RF vs. the RF group (55% vs. 66%, respectively p<0.001). Furthermore, lower rate of guideline-recommended medical therapy upon discharge was prescribed in the no-RF group. The rate of in-hospital complications was greater in the no-RF vs. RF group (31.6% vs. 26.1%, respectively p=0.005). The rates of 30-day major adverse cardiovascular events (MACE; 17.6% vs.12.8%, respectively, p=0.002) and of 30-day and 1-year all-cause mortality (8.4% vs. 4.2%, p<0.001 and 11.4% vs. 7.7%, p=0.003 respectively) were higher among patients with no-RF vs. RF. Following propensity score matching 30-day MACE, 30-day and 1-year mortality risk remained higher in the no-RF group. The rate of 30-day MACE decreased between the early and the late study period in the no-RF group (21.5% vs. 10.5%, p=0.003, respectively)., Conclusions: ACS patients without traditional cardiovascular risk-factors comprise a unique group with reduced prevalence of comorbidities yet significantly worse outcomes. Additional research to identify unique risk-factors and targets for interventions to improve outcomes of this group of patients is warranted., (Copyright © 2021. Published by Elsevier Ltd.)

Aims: Data on the association of cardiorespiratory fitness with survival of cancer patients are limited. This study aimed to evaluate the association between midlife cardiorespiratory fitness and survival after a subsequent cancer diagnosis., Methods: We evaluated 19,134 asymptomatic self-referred adults who were screened in preventive healthcare settings. All subjects were free of cardiovascular disease and cancer at baseline and completed a maximal exercise stress test. Fitness was categorised into age-specific and sex-specific quintiles according to the treadmill time and dichotomised to low (quintiles 1-2) and high fitness groups., Results: The mean age was 50 ± 8 years and 72% were men. During a median follow-up of 13 years (interquartile range 7-16) 517 (3%) died. Overall, 1455 (7.6%) subjects developed cancer with a median time to cancer diagnosis of 6.4 years (interquartile range 3-10). Death from the time of cancer diagnosis was significantly lower among the high fitness group (Plog rank = 0.03). Time-dependent analysis showed that subjects who developed cancer during follow-up were more likely to die (P < 0.001). The association of cancer with survival was fitness dependent such that in the lower fitness group cancer was associated with a higher risk of death, whereas among the high fitness group the risk of death was lower (hazard ratio 20 vs. 15; Pfor interaction = 0.047). The effect modification persisted after applying a 4-year blanking period between fitness assessment and cancer diagnosis (Pfor interaction = 0.003)., Conclusion: Higher midlife cardiorespiratory fitness is associated with better survival among cancer patients. Our findings support fitness assessment in preventive healthcare settings., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: The authors declare no conflicts of interest.

Background: Although cardiorespiratory fitness (CRF) is a strong independent predictor of adverse cardiovascular outcomes, it is not considered as a risk enhancer by current guidelines., Methods: We evaluated asymptomatic self-referred adults aged 40 to 79 years of age, free of cardiovascular disease at baseline, who were screened annually and completed baseline exercise stress test. Baseline CRF was dichotomized into 2 groups: low (metabolic equivalents < 8) and high. The primary endpoint was the composite of death, nonfatal acute coronary syndrome, and stroke after excluding subjects diagnosed with metastatic cancer during follow-up., Results: Study population included 15,445 subjects with median age of 49 years (interquartile range: 44-55). During median follow-up of 8 years 1362 (9%) subjects developed the study endpoint. Kaplan-Meier survival analysis showed that both fitness and atherosclerotic cardiovascular disease (ASCVD) were associated with developing of the study endpoint (P < 0.001 for both). Cox regression model with adjustment for ASCVD risk consistently showed that lower fitness was associated with a significant 23% higher risk to develop the study endpoint (P = 0.001). Continuous net reclassification improvement analysis showed an overall improvement of 11.4% (95% confidence interval, 8%-14.6%; P value < 0.001) in the accuracy of classification when fitness was added to the ASCVD model., Conclusions: Low CRF is a strong independent predictor of the cardiovascular morbidity and mortality in asymptomatic adults. Addition of fitness to the pooled cohort ASCVD risk significantly improves the accuracy of the model., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Men tend to develop cardiovascular disease (CVD) earlier in life than women. Whether this difference is attributable only to gender is a matter of debate. The purpose of this study was to evaluate gender differences in cardiovascular risk in a large cohort of asymptomatic men and women and explore gender-related risk in prespecified risk factor subgroups. We investigated 14,966 asymptomatic men and women free of diabetes, hypertension, or ischemic heart disease who were annually screened. The primary end point of the present study was the occurrence of ischemic or cerebrovascular disease as composite end point. Multivariate Cox proportional hazards regression modeling was used to assess the gender difference regarding CVD and to examine the association between CVD risk factors and gender. Mean age of the study population was 47 ± 10 years and 30% were women. Kaplan-Meier survival analysis showed that at 6.2 ± 3.9 years' follow-up, the rate of CVD events was 6.1% among men compared with 1.8% among women (log-rank p <0.001). Consistently, multivariate analysis demonstrated that male gender was independently associated with a significant threefold increased risk for development of CVD events (hazard ratio 3.05, CI 2.25 to 4.14). The CVD risk associated with male gender was consistent in each risk subset analyzed, including older age, low high-density lipoprotein, impaired fasting glucose, and positive family history for ischemic heart disease (all p values for gender-by-risk factor interactions <0.05). Higher performance on treadmill test had a protective effect regarding CVD development in both men and women. In conclusions, healthy middle-aged men experienced increased risk for the development of CVD events compared with women independently of traditional CVD risk factors. However, better exercise capacity is associated with a protective effect., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: We aimed to evaluate whether reduced cardiovascular fitness has a direct or indirect effect for the development of cardiovascular disease., Methods: We investigated 15,595 men and women who were annually screened in a tertiary medical center. All subjects were free of ischemic heart disease and had completed maximal exercise stress test according to the Bruce protocol at their first visit. Fitness was categorized into age- and sex-specific quintiles (Q) according to Bruce protocol treadmill time with Q1 as lowest fitness. Subjects were categorized at baseline into 3 groups: low fitness (Q1), moderate fitness (Q2-Q4), and high fitness (Q5). The primary end point of the current analysis was the development of a first cardiovascular event during follow-up., Results: Mean age of study patients was 48 ± 10 years, and 73% were men. A total of 679 events occurred during 92,092 person-years of follow-up. Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was significantly higher among subjects with low fitness (P < .001). Low fitness was associated with known cardiovascular risk factors, including hypercholesterolemia (odds ratio [OR] 1.58, 95% CI 1.31-1.89), diabetes mellitus (OR 2.32, 95% CI 1.58-3.41), and obesity (OR 10.46, 95% CI 8.43-12.98). The effect of low fitness on cardiovascular events was no longer significant when including diabetes mellitus, hypercholesterolemia, and obesity as mediators (hazard ratio 0.99, 95% CI 0.82-1.19)., Conclusions: The association between cardiovascular fitness and adverse cardiovascular outcomes may be modulated through traditional cardiovascular risk factors. These findings need to be further validated in prospective clinical trials., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The existence of an independent association between elevated triglyceride (TG) levels, cardiovascular (CV) risk and mortality has been largely controversial. The main difficulty in isolating the effect of hypertriglyceridemia on CV risk is the fact that elevated triglyceride levels are commonly associated with concomitant changes in high density lipoprotein (HDL), low density lipoprotein (LDL) and other lipoproteins. As a result of this problem and in disregard of the real biological role of TG, its significance as a plausible therapeutic target was unfoundedly underestimated for many years. However, taking epidemiological data together, both moderate and severe hypertriglyceridaemia are associated with a substantially increased long term total mortality and CV risk. Plasma TG levels partially reflect the concentration of the triglyceride-carrying lipoproteins (TRL): very low density lipoprotein (VLDL), chylomicrons and their remnants. Furthermore, hypertriglyceridemia commonly leads to reduction in HDL and increase in atherogenic small dense LDL levels. TG may also stimulate atherogenesis by mechanisms, such excessive free fatty acids (FFA) release, production of proinflammatory cytokines, fibrinogen, coagulation factors and impairment of fibrinolysis. Genetic studies strongly support hypertriglyceridemia and high concentrations of TRL as causal risk factors for CV disease. The most common forms of hypertriglyceridemia are related to overweight and sedentary life style, which in turn lead to insulin resistance, metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Intensive lifestyle therapy is the main initial treatment of hypertriglyceridemia. Statins are a cornerstone of the modern lipids-modifying therapy. If the primary goal is to lower TG levels, fibrates (bezafibrate and fenofibrate for monotherapy, and in combination with statin; gemfibrozil only for monotherapy) could be the preferable drugs. Also ezetimibe has mild positive effects in lowering TG. Initial experience with en ezetimibe/fibrates combination seems promising. The recently released IMPROVE-IT Trial is the first to prove that adding a non-statin drug (ezetimibe) to a statin lowers the risk of future CV events. In conclusion, the classical clinical paradigm of lipids-modifying treatment should be changed and high TG should be recognized as an important target for therapy in their own right. Hypertriglyceridemia should be treated.

Background: High-density lipoprotein cholesterol (HDL-C) is a strong inverse predictor of cardiovascular events. The aim of the current study was to evaluate the correlation between changes in HDL-C and subsequent cardiovascular events., Methods: Study population comprised 13,037 subjects free of cardiovascular disease with a mean follow up of 6 ± 3 years. Low HDL-C was defined as < 40 mg/dl for men and <50mg/dl for women. Participants were divided into three groups based on HDL-C levels at the first and second baseline visits: persistently-low HDL-C (LL); persistently-high HDL-C (HH); and those with high HDL-C in a one visit only: intermittently high HDL-C (LH/HL). The primary endpoint was the first occurrence of a cardiovascular event., Results: A total of 529 (4.1%) incident events occurred during follow-up. HDL-C levels increased significantly between the two landmark visits (47.5 ± 12.6 vs. 48.1 ± 12.2, p<0.001). Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was highest among subjects in the LL group (7.6%), and similar among LH/HL and HH groups (3.3% and 4%, respectively; log-rank p=0.001). Multivariate Cox regression analysis, with HDL-C as time-dependent covariate, showed that subjects with persistently low HDL-C during follow up experienced a 51% increased cardiovascular risk compared with subjects with persistently high HDL-C (p=0.026). Subjects with intermittently high HDL-C during follow up experienced similar risk to those with persistently high HDL-C (HR=1.02; p=0.89)., Conclusions: Variations in HDL-C levels during follow-up are associated with subsequent cardiovascular risk. Patients who retain low HDL-C levels are at the cardiovascular highest risk., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The effect of combination of fibrate with statin on major adverse cardiovascular events (MACE) following acute coronary syndrome (ACS) hospitalization is unclear. The main aim of this study was to investigate the 30-day rate of MACE in patients who participated in the nationwide ACS Israeli Surveys (ACSIS) and were treated on discharge with a fibrate (mainly bezafibrate) and statin combination vs. statin alone., Methods: The study population comprised 8,982 patients from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 8,545 (95%) received statin alone and 437 (5%) received fibrate/statin combination. MACE was defined as a composite measure of death, recurrent MI, recurrent ischemia, stent thrombosis, ischemic stroke and urgent revascularization., Results: Patients from the combination group were younger (58.1±11.9 vs. 62.9±12.6 years). However, they had significantly more co-morbidities (hypertension, diabetes), current smokers and unfavorable cardio-metabolic profiles (with respect to glucose, total cholesterol, triglyceride and HDL-cholesterol). Development of MACE was recorded in 513 (6.0%) patients from the statin monotherapy group vs. 13 (3.2%) from the combination group, p = 0.01. 30-day re-hospitalization rate was significantly lower in the combination group: 68 (15.6%) vs. 1691 (19.8%) of patients, respectively; p = 0.03. Multivariable analysis identified the fibrate/statin combination as an independent predictor of reduced risk of MACE with odds ratio of 0.54, 95% confidence interval 0.32-0.94., Conclusion: A significantly lower risk of 30-day MACE rate was observed in patients receiving combined fibrate/statin treatment following ACS compared with statin monotherapy. However, caution should be exercised in interpreting these findings taking into consideration baseline differences between our observational study groups.

Heart failure (HF) poses a major health burden worldwide, and early detection of at-risk populations is of clinical importance. The triglyceride-glucose index (TGI), a surrogate marker of insulin resistance, is thought to be associated with a higher risk of developing cardiovascular disease. Nonetheless, its predictive value for the future development of HF in healthy populations is unknown. We thus investigated the utility of TGI for the prediction of HF development in healthy adults. The study population comprised 19,829 self-referred adults, evaluated annually in a screening program, who were free of baseline diabetes and cardiovascular disease. The TGI was calculated as: ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The primary end-point was the development of any HF. An HF specialist classified all HF events in accordance with guidelines. The mean age was 50±8 years for the cohort, 14,039 (71%) were men, and 2,709 (14%) were obese. Baseline TGI was 8.53±0.54. During a median follow-up of 14 years (IQR 8-18), 193 (1%) subjects developed HF. Univariate Cox regression showed that each 1 unit increase in TGI was associated with a significant 67% increased risk of developing any HF during follow-up (95% CI 1.30-2.16, p<.001). A multivariate model, adjusted for age, sex, baseline hypertension, LDL, obesity, and fitness level consistently showed that each 1 unit increase in TGI was associated with a 39% increased risk of developing HF (95% CI 1.05-1.84, p=.020). The association between the baseline TGI and the development of HF was obesity dependent, such that for obese patients each 1 unit increase in TGI was associated with a significant 61% increase in the risk of HF (95% CI 1.18-2.20, p=.003), while for non-obese subjects the association was non-significant (p NS; p for interaction.018). High TGI in the healthy adult population is associated with an increased risk of HF and is a promising potential marker for the later development of HF. The impact of interventions aiming to decrease TGI on HF outcomes should be assessed. [ABSTRACT FROM AUTHOR]

The left atrium (LA) in heart transplant (HT) recipients is a surgically created chamber from variable portions of donor and recipient. In the non-HT patients there is strong evidence that left atrial volume (LAV) is a robust predictor of cardiovascular outcomes such as atrial fibrillation, stroke, heart failure and cardiovascular death. Thus, we thought to 1) characterize LA size in HT recipients and 2) investigate the implications of "new" LA volume on HT outcomes. First echocardiograms of 248 HT recipients between 2000-2018 were analyzed for LA volume index (LAVi). LAV was assessed employing the biplane Simpson method in the apical 4- and 2-chamber view and indexed to body surface area (LAVi). Patients were categorized by quartiles. The primary end points were: stroke, cardiovascular and all-cause mortality, cardiac allograft vasculopathy and heart failure. Mean and median LAV were 69.3 mL (SD, 29.6) and 65.3 mL [IQR 48.2, 84.3], respectively, and, when indexed (LAVi), 37.2 mL/m2 (SD, 15.7) and 34.6 mL/m2 [IQR 25.9, 45.6], respectively. Baseline patient and donor clinical, demographic and hemodynamic parameters were similar. Outcomes, assessed by each LAVi quartile were shown to have similar cumulative probabilities. Kaplan-Meier analyses for each outcome, were similar too (Figure). Notably, with an emphasis on the enlarged LA volume of this cohort, the hazard of stroke, was low. Consistent with these findings, atrial fibrillation episodes were very rare (excluding perioperative/rejection) with a total of 7 patients experiencing paroxysmal atrial fibrillation. In contrast to what is known in non-HT patients, no association was demonstrated for LAV and cardiovascular adverse events. As all patients undergo a "MAZE procedure" during HT, our findings suggest that pulmonary vein isolation and cardiac denervation provide significant prophylaxis against cardiovascular events in HT patients, neutralizing the risks that are typically associated with significant enlargement of LA volumes. [ABSTRACT FROM AUTHOR]