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Background Changes in the protein composition of low-density lipoprotein (LDL) particles induce a shift in their electronegativity, a phenomenon implicated in both pro-inflammatory and pro-atherogenic signalling (1). While high levels of LDL foster the build-up of atherosclerotic plaques, and as such the susceptibility for the development of acute coronary syndromes (ACS), LDL levels assessed at the time of presentation fail to associate with fatal events following the index event (2). Experimental data suggest that altered LDL electronegativity exerts functional effects on both the myocardium and vasculature (1,3). Purpose We aimed to study the association between LDL electronegativity, assessed at the time of acute presentation, and all-cause mortality following the index ACS. Methods We designed a case-cohort study in 2'619 ACS patients prospectively recruited in the investigator-driven, multicentre SPUM-ACS study (ClinicalTrials.gov Identifier: NCT01000701). Plasma LDL levels were quantified at baseline and LDL was chromatographically resolved into 5 subfractions (L1-L5), with the L1/L5 ratio serving as a proxy for overall LDL electronegativity. By employing least-squares ordinary regression models determinants of plasma L1, L5, and the L1/5 ratio were studied, and the association with mortality of both LDL levels and its electronegativity were estimated using weighted Cox regression models. Results Cases and controls showed similar lipid profiles, but distinct LDL electronegativity, demonstrated by an increase in the L1/L5 ratio in cases vs. controls (P Conclusions In contemporary patients with ACS, LDL electronegativity independently predicts fatal events after the acute event, while LDL levels do not. Our results suggest that LDL quality rather than quantity provides predictive utility for premature death within 1 year after the index ACS. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science FoundationSwiss Heart FoundationTheodor-Ida Herzog StiftungFoundation for Cardiovascular Research – Zurich Heart House

Introduction/Purpose High-intensity statin after acute coronary syndrome (ACS) may cause reduced physical activity because of statin-associated muscle symptoms. We aimed to assess the association between statin intensity and physical activity one year after ACS. Methods We studied patients from the Special Program University Medicine-Acute Coronary Syndromes (SPUM-ACS) study, a large multicenter prospective Swiss cohort. In a cross-sectional assessment one year after the index ACS, we identified high-intensity, low/moderate intensity, and no statin users. Physical activity was assessed with the International Physical Activity Questionnaire (IPAQ). Using a multivariable adjusted negative binomial hurdle model, metabolic equivalent-minutes per week (MET-min/week) were first stratified into sedentary and physically active categories, and then analyzed continuously among physically active patients. Models were adjusted for age, sex, education, body mass index, depression, type of ACS, pre-existing chronic disease, premature coronary heart disease, LDL-cholesterol, anti-hypertensive treatment, cardiac rehabilitation, and follow-up medical visits after hospital discharge. Results Among the 2274 patients included in the SPUM-ACS cohort, 1222 (53.7%) were on high intensity statin, 890 (39.1%) on low/moderate intensity statin, and 162 (7.1%) were not on statin. Compared to no statin users, low/moderate intensity statin users were more likely to be physically active than sedentary, with a fully adjusted odds ratio (OR) of 2.78, 95% confidence interval (CI) 1.11–6.93. A similar association was found when comparing non-users with high-intensity statin users, with a fully adjusted OR of 4.18, 95% CI 1.65–10.60. Among physically active patients, physical activity level median scores were 2792.5 MET-min/week in no statin category, 2712.0 and 2839.5 in moderate/low statin category and high statin category respectively (p=0.307), showing no statistically significant difference with median ratios of 1.02, 95% CI 0.84–1.22 and 1.06, 95% CI of 0.88–1.27 for low/moderate intensity and high-intensity statin use, respectively. Conclusion One year after an ACS, neither low/moderate nor high-intensity statin was associated with reduced physical activity compared to no statin use. These findings go against the belief that statin therapy may lead to reduced physical activity among ACS patients because of associated muscular symptoms. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Center for primary care and public health (Unisanté)

Introduction Conflicting data exist upon whether patients presenting with acute coronary syndromes (ACS) during on- or off-hours differ regarding outcomes. Moreover, definitions of on- and off-hours vary in literature. The notion of a weekend effect with increased mortality has been raised, mostly seen in relation to lesser use of invasive treatment. Purpose This multi-center study investigated the baseline characteristics and associated outcomes of patients presenting with ACS undergoing coronary angiography on weekdays compared to those presenting on weekends or holidays. Methods Data from the prospective SPUM-ACS (Special Program University Medicine Acute Coronary Syndromes and Inflammation) Cohort were examined, with patients recruited between 2009 and 2012. Patients were divided into two groups according to whether they presented for coronary angiography for ACS on workdays (Monday-Friday, 00:00–23:59) or on rest days (Saturday or Sunday, 00:00–23:59, and public holidays shared by all centers). Time of presentation was defined as time point of catheter sheath insertion. Results From a total of 2168 patients (21.4% females), 1828 (84.3%) presented on workdays, 340 (15.7%) on rest days without difference in female/male ratio. On rest days, patients more often showed signs of advanced heart failure (Killip Class III–IV 3.9% vs. 7.1%, p=0.009). Patients presented more frequently with ST-segment elevation ACS (STE-ACS) than non-ST-segment elevation ACS (STE-ACS on workdays vs. rest days: 50.4% vs. 65.0%, p In- and out-of-hospital time delay metrics did not differ between groups, apart from symptom onset-to-balloon time, which was shorter on rest days (598 vs. 520 min, p=0.040). There was a trend towards more frequent use of percutaneous (89.2% vs. 92.6%, p=0.053) or surgical (3.3% vs 5.0%, p=0.131) revascularization on rest days. 30-day all-cause mortality was higher on rest days for any ACS (1.75% vs 3.82%, p=0.007) and for STE-ACS only (2.39% vs 4.98%, p=0.019, Fig. 1). Notably, the same trend was seen when comparing only patients presenting with Killip Class III/IV, both for any ACS (11.27% vs. 20.83%, p=0.119) and for STE-ACS (14.00% vs. 26.32%, p=0.114). On rest days, female patients showed higher 30-day all-cause mortality than males for any ACS (7.46% vs 2.93%, p=0.042); the same trend was observed for STE-ACS (8.89% vs. 3.98%, p=0.088). Conclusions On rest days, patients more often presented with STE-ACS and more frequently showed signs of advanced heart failure, with similar use of invasive revascularization as for patients presenting on workdays. This might contribute to higher early mortality observed in ACS patients on rest days. These differences persisted within the subgroups STE-ACS and Killip Class III/IV. Interestingly, female patients showed increased early mortality on rest days compared to males. Thus, patients presenting with ACS on rest days warrant particular attention. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation (SNSF)

Background Despite substantial improvement in secondary preventive therapy, the burden of recurrent cardiovascular (CV) events remains high. Peripheral artery disease (PAD), is a potential marker of increased residual ischemic risk in acute coronary syndrome (ACS) patients suggesting greater net clinical benefit from intensified individualized therapy. Purpose We aimed to assess the prevalence and cardiovascular (CV) outcomes of peripheral arterial disease (PAD) in 4'787 patients with acute coronary syndromes (ACS) in the Swiss prospective multicenter SPUM study. Methods PAD was defined according to international guidelines. The composite primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), i.e., stroke, myocardial infarction (MI) and death at 1 year. Adjusted Cox proportional hazards regression models were used to estimate the risk associated with PAD and outcomes. Results Out of 4'787 ACS patients, 285 patients (6.0%) had PAD. These patients were older (70.1±10.6 vs 63.3±12.4, p Conclusions Among a real-world cohort of ACS patients, the coexistence of PAD, a very-high CV risk phenotype, is associated with significantly increased rates of MACCE, but no difference in major bleeding events. These observations might help clinicians to further stratify this very-high risk population and to identify patients who may derive the greatest benefit from more intense secondary prevention therapies. Funding Acknowledgement Type of funding sources: None.

Background Increasing evidence indicates that cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol) is a causal risk factor for major adverse cardiovascular events (MACE) independent from other lipid fractions. To date, the relationship between remnant cholesterol (remnant-C) levels and cardiovascular (CV) outcomes after acute coronary syndromes (ACS) in patients with adequate low-density lipoprotein cholesterol (LDL-C) control is uncertain. Purpose This study evaluated the contribution of remnant-C to residual lipid risk after ACS. Methods Nested within 4'787 ACS patients in the prospective multicentre SPUM-ACS study (NCT0100070) we examined all patients presenting with LDL-C levels Results Eighty-seven (11.5%) patients had an event, 14 (1.9%) patients withdrew consent, and 5 (0.7%) patients were lost to follow up at 12 months. In multivariable-adjusted analyses, remnant-C (hazard ratio [HR]: 1.63; 95% confidence interval [CI]: 1.04 to 2.74; per log2 increase; p=0.020), triglycerides (HR: 1.41; 95% CI: 1.04 to 1.96; per log2 increase; p=0.017), and low high-density lipoprotein (HDL)-C (HR: 0.56; 95% CI: 0.33 to 0.86; per log2 increase; p Conclusion In patients who develop ACS with LDL-C levels Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Swiss National Science FoundationSwiss Heart Foundation

Background The association between heavy weekly alcohol consumption or binge drinking and the risk of major adverse cardiovascular events (MACE) after acute coronary syndromes (ACS) is still unclear. Purpose To determine the risks of MACE at one year follow up according to baseline alcohol consumption, especially in patients with heavy weekly alcohol consumption or binge drinking. Methods We analyzed data of 6053 patients hospitalized in 4 Swiss centres for an ACS and followed over 12 months. Data on alcohol consumption were collected at baseline and at one year follow up after ACS. Binge drinking was defined as the consumption of ≥6 units of alcohol on one occasion, for the 12-months period preceding the one-year follow up. We defined MACE as a composite of cardiac death, myocardial infarction, stroke or clinically indicated target vessel coronary revascularization. We applied Cox regression to assess the risk of MACE associated with heavy alcohol weekly consumption (>14 standard units/week) compared to light consumption ( Results At baseline, 817 (13.4%) patients reported heavy weekly alcohol consumption and 717 (11.8%) reported to have at least one episode of binge drinking per month. The risk for MACE at one year follow up was not increased in those with heavy weekly consumption compared to light consumption (8.7% vs. 8.5%, HR 0.96, 95% CI 0.69–1.33, P=0.80) or no consumption (8.7% vs. 10.3%, HR 1.26, 95% CI 0.88–1.80, P=0.21). However, the risk of MACE was higher in those reporting binge drinking with less than one episode a month (9.4% vs. 7.7%, HR 1.67, 95% CI 1.32–2.12, P Conclusion In contrast to regular heavy alcohol consumption, binge drinking behavior is associated with significant increased risk of MACE 12 months after ACS. Funding Acknowledgement Type of funding sources: None.

Background Smoking and depression are two risk factors for acute coronary syndrome (ACS) that often go hand-in-hand, as smokers are more likely to be depressed and people that are depressed are more likely to be smokers. Smoking cessation in depressed patients with ACS may worsen depressive symptoms, which could increase the risk of recurrence of cardiac events and decrease adherence to other cardiac risk-reducing lifestyle changes. Purpose We aimed to investigate the evolution of depression according to smoking cessation one-year after ACS. Furthermore, we investigated if there was a higher incidence of one-year depression among ACS smokers who quit in comparison to continuous smokers. Method Data from 1,822 patients with ACS of the Swiss multicenter SPUM-ACS cohort study were analysed over a one-year follow-up period. Participants were classified in three groups based on smoking status one-year post-ACS – continuous smokers, smokers who quit within the year post-ACS, and non-smokers. Depression status at baseline and at one-year after the index ACS event was assessed with the Center for Epidemiologic Studies Depression scale (CES-D) and antidepressant drug use. A multivariate adjusted logistic regression model was used to calculate the risk ratio (RR) between groups. Results In comparison to depressed smokers who continued to smoke one year post-ACS, depressed smokers who quit smoking had an adjusted RR of 2.02 (95% CI 1.04–3.92) of improving their depression. Among 543 non-depressed ACS smokers, new depression at one-year was found in 57/266 (21.4%) smokers who quit, and 68/277 (24.6%) continuous smokers, with an adjusted RR of 0.89 (95% CI 0.58–1.36) of incidence of new depression. Conclusion Smokers with depression at the time of ACS who quit smoking improved more frequently their depression compared to those who continued smoking. Although not statistically significant, there was a smaller incidence of new depression among smokers who quit after ACS in comparison to continuous smokers. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation

Background C-reactive protein measured by high sensitivity assays (hsCRP) is an established biomarker of systemic inflammation and a cut-off at 2 mg/L has been widely studied and proposed to identify patients at residual inflammatory risk (RIR). Purpose It remains unclear how many patients remain at residual inflammatory risk (RIR) at 12 months after acute coronary syndromes (ACS) in a contemporary real-world cohort and if RIR is associated with cardiovascular outcome. Methods Patients included in the SPUM-ACS cohort (NCT01000701) with a primary diagnosis of ACS referred for coronary angiography between 2009 and 2012 and available hsCRP measurements at baseline and at 1 year follow-up. High RIR was defined as hsCRP ≥2mg/L. Patients were divided into four groups: persistently high RIR, increased RIR (first low-, then high hsCRP), attenuated RIR (first high-, then low hsCRP), or persistently low RIR. Adjudicated major adverse cardiac and cerebrovascular events (MACCE) at 365 days were defined as the composite of MI, clinically indicated coronary revascularization or stroke. Logistic regression models were used to evaluate associations between MACCE and RIR groups and continuous long-term GRACE risk score. Adjustment was made for long-term GRACE risk score. Results 1209 patients had available serial biomarker measurements (baseline and 12 months) with clinical and demographic data. Among those, 295 (24.4%) patients (UA 3.4%, NSTEMI 47.5%, STEMI 49.2%) fell in the category persistently high RIR (delta hsCRP median (IQR): −2.3 (−9.9; 0.3) (mg/L) and 72 (5.96%) patients (UA 8.3%, NSTEMI 47.2%, STEMI 44.4%) were in category increased RIR (delta hsCRP median (IQR): +2.45 (1.2; 8.35) (mg/L). Conversely, 390 (32.26%) patients (UA 3.3%, NSTEMI 46.9%, STEMI 49.7%) fell in the category attenuated RIR (delta hsCRP median (IQR): −3.55 (−10; −2) (mg/L) and 452 (37.38%) patients (UA 5.5%, NSTEMI 33.2%, STEMI 61.3%) were in category persistently low RIR (delta hsCRP median (IQR): −0.2 (−0.6; 0.1) (mg/L). Of 90 MACCE, 31 (10.5%) were found in the persistently high RIR group yielding a significantly higher event rate (adjusted HR: 1.71, (95% CI 1.08; 2.7), p-value: 0.02) compared with the three other groups combined (increased RIR: 3 (4.2%), attenuated RIR 30 (7.7%), persistent low RIR 26 (5.8%)). Of note, in that group the long-term GRACE risk score was significantly higher compared with the three other groups (adjusted HR: 1.1, (95% CI 1.0; 1.17), p-value: 0.04). Conclusion Residual inflammatory risk at 12 months after an ACS is found in nearly a third of patients. Patients with persistently elevated hsCRP throughout the first year post-ACS suffered most adverse events warranting studies of anti-inflammatory drugs in these patients. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Swiss Heart Foundation, Swiss National Science Foundation

Background Hypertension is a recognized cardiovascular (CV) risk factor and, although many highly effective antihypertensive drugs have been developed, most patients fail to achieve recommended blood pressure target levels. This may increase major adverse CV events after acute coronary syndromes (ACS) such as acute kidney injury (AKI) and cardiac death (CD). Purpose We assessed the prognostic value of uncontrolled hypertension (UH) and elevated NT-proBNP among 2,168 all-comer patients admitted to 4 Swiss University Hospitals for acute coronary syndromes (ACS) enrolled in the prospective multicenter SPUM registry. Methods Patients with UH defined as a systolic blood pressure≥140 mmHg, and a NT-proBNP>900 ng/l were considered for the analysis. The composite primary endpoint was AKI and CD. Adjusted Cox proportional hazards regression models were implemented to determine risk prediction for UH and elevated NT-proBNP levels. Results Out of 2,168 ACS patients, 235 patients (10.8%) showed UH and NT-proBNP>900 ng/l (Fig. 1A). Compared to the general ACS population, those with UH and elevated NT-proBNP were more likely to be older (41.7% vs 20.0%, p Conclusions Among a real-world cohort of ACS patients, coexistence of UH with elevated levels of NT-proBNP confers increased risk for AKI and CD up to one year after ACS. These observations might help clinicians to identify ACS patients at risk using simple clinical parameters and biomarkers and to target them for more intense preventive therapies. Figure 1. A: GRADE1 = 140–159 mmHg and/or 90–99 mmHg; GRADE2 = 160–179 mmHg and/or 100–109 mmHg; GRADE3 = ≥180 mmHg and/or ≥110 mmHg; ISH (isolate systolic hypertension) = ≥140 mmHg and Funding Acknowledgement Type of funding source: None

Introduction Current guidelines recommend angiography within 24 hours of hospitalisation for patients with non-ST elevation myocardial infarction (NSTEMI). The recent VERDICT study found that angiography within 12 hours of hospitalisation was associated with improved cardiovascular outcomes among high-risk patients. We aimed to obtain a real-world perspective of the impact of angiography timing on one-year outcomes of patients admitted with NSTEMI. Methods Data was obtained from the SPUM-ACS registry, a cohort of consecutive patients hospitalised with acute coronary syndromes in four university hospitals in Switzerland between 2009 and 2017. Patients without a door-to-catheter (DTC) time and those with life-threatening features were excluded. Cox proportional hazards models evaluated the impact of DTC time on the primary endpoint, defined as one-year major adverse cardiovascular events (MACE: cardiovascular mortality, myocardial infarction, stroke), and on one-year all-cause mortality. Results Of 2,672 NSTEMI patients, 1,832 met the inclusion criteria. Among them, 1,464 patients underwent angiography within 12 hours of admission (12h group) while 368 patients underwent angiography between 12 and 24 hours (12–24h group). After 2:1 propensity score matching, 736 patients from the 12h group and 368 patients from the 12–24h group were deemed equivalent in terms of main baseline clinical characteristics. Multiple logistic regression identified admission out-of-hours (night or weekend) as the most significant factor associated with delayed angiography. Cox models found no significant association between early angiography and one-year MACE (12h group: n=57 (7.7%) vs. 12–24h group: n=27 (7.3%), HR: 1.050, 95% CI 0.637- 1.733, p=0.847), or one-year all-cause mortality (12h group: n=25 (3.4%) vs. 12–24h group: n=17 (4.6%), HR: 1.514, 95% CI 0.774- 2.962, p=0.225) (Figure 1A). After stratification based on GRACE score (>140 vs. ≤140), there was no significant difference in one-year MACE or one-year all-cause mortality in the 12h group compared with the 12–24h group (p for interaction=0.601 and 0.463, respectively) (Figure 1A + 1B). Figure 1 Conclusion In an unselected real-world cohort of NSTEMI patients, angiography within 12 hours of hospitalisation was not associated with improved one-year outcomes when compared with angiography between 12 and 24 hours, even among patients with an elevated GRACE score.

Aims We aimed to identify a novel biomarker involved in the early events leading to an acute coronary syndrome (ACS) and evaluate its role in diagnosis and risk stratification. Methods and results Biomarker identification was based on gene expression profiling. In coronary thrombi of ACS patients, cysteine-rich angiogenic inducer 61 (Cyr61, CCN1) gene transcripts were highly up-regulated compared with peripheral mononuclear cells. In a murine ischaemia-reperfusion model (I/R), myocardial Cyr61 expression was markedly increased compared with the controls. Cyr61 levels were determined in human serum using an enzyme-linked immunosorbent assay. Cohorts of ACS (n = 2168) referred for coronary angiography, stable coronary artery disease (CAD) (n = 53), and hypertrophic obstructive cardiomyopathy (HOCM) patients (n = 15) served to identify and evaluate the diagnostic and prognostic performance of the biomarker. Cyr61 was markedly elevated in ST-elevation myocardial infarction patients compared with non-ST-elevation myocardial infarction/unstable angina or stable CAD patients, irrespective of whether coronary thrombi were present. Cyr61 was rapidly released after occlusion of a septal branch in HOCM patients undergoing transcoronary ablation of septal hypertrophy. Cyr61 improved risk stratification for all-cause mortality when added to the reference GRACE risk score at 30 days (C-statistic 0.88 to 0.89, P = 0.001) and 1 year (C-statistic 0.77 to 0.80, P

Subclinical thyroid dysfunction comprises subclinical hypothyroidism (SHypo), defined as elevated thyroid-stimulating hormone (TSH) by normal free thyroxine (FT4), and subclinical hyperthyroidism (SHyper) with decreased or undetectable TSH and normal FT4. Up to 10% of the elderly have SHypo, which is usually asymptomatic. Individual participant data (IPD) analyses of prospective cohort studies from the international Thyroid Studies Collaboration show that SHypo is associated with increased coronary heart disease (CHD) mortality [hazard ratio (HR) 1,58 for TSH ≥ 10 mIU/L, 95% CI 1.10-2.27), as well as increased risk of stroke, and heart failure (HF) for both higher and lower TSH. Small studies found that SHypo affects carotid intima media thickness (CIMT), diastolic function, peripheral vascular resistance, endothelial function, and lipid profile. SHyper is associated with increased risk of atrial fibrillation (AF) (HR 1.68, 95% CI 1.16-2.43) and CHD events (HR 1.21, 95% CI 0.99-1.46). The TSH threshold for initiating treatment is unclear. In the absence of large randomized controlled trials, the best evidence suggests SHypo therapy should be started at TSH ≥ 10 mIU/L, and SHyper therapy at TSH < 0.1 mIU/L. Recommendations on screening are discordant, but most guidelines advocate that thyroid function should be checked in those at risk for hypothyroidism, those over 60, and those with known CHD and HF. This review updates current evidence on the association between thyroid dysfunction and cardiovascular disease, as well as on screening and treatment of subclinical thyroid dysfunction.

Decreasing testosterone levels with ageing is a well-known condition in older men named 'low T', 'manopause', or hypogonadism. Observational studies suggested an association between low endogenous testosterone levels and a high cardio-metabolic profile (increased blood pressure, dyslipidaemia, insulin resistance, atherosclerosis, thrombosis), as well as a modest increase in total and cardiovascular (CV) mortality. Controversies persist regarding the need for screening 'low T' in older men, as well as what precisely should be the indication(s) for testosterone replacement therapy. So far, no data have shown that normalization of testosterone levels reduce CV events. Although testosterone replacement therapy seems to have beneficial effects on male quality of life or physical condition, some data suggest serious adverse events, such as CV events. In addition, there is a lack of consensus on the threshold for treatment indication in men with non-specific symptoms or borderline levels of testosterone. Available data from clinical practice setting suggest an increase in testosterone prescription over time and possible overtreatment. In recent years, pharmaceutical companies have promoted 'low T' as a treatable disease, suggesting that testosterone replacement may help restore energy, positive mood and sexuality, and despite ageing. Currently, well-designed, adequately powered randomized controlled trials are needed to assess the impact of testosterone replacement therapy on CV clinically relevant CV outcomes within age-specific ranges to strengthen the evidence for clinical practice guidelines.

ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation : The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).