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Aims To evaluate the extent of left atrial (LA) fibrosis in patients with a recent stroke without atrial fibrillation and controls without established cardiovascular disease. Methods and results This prospectively designed study used cardiac magnetic resonance to detect LA late gadolinium enhancement as a proxy for LA fibrosis. Between 2019 and 2021, we consecutively included 100 patients free of atrial fibrillation with recent ischaemic stroke ( Conclusion LA fibrosis was more extensive in patients with stroke than in age- and sex-matched controls. A similar extent of LA fibrosis was observed in patients with stroke of undetermined aetiology and stroke classified as attributable to large- or small-vessel disease. Our findings suggest that LA structural abnormality is more frequent in patients with stroke than in controls independent of aetiological classification.

The prognostic significance of incidental non-sustained ventricular tachycardia (NSVT) in subjects without apparent heart disease is unknown. We aimed to evaluate short- and long-term prognosis of NSVT in the Copenhagen Holter Study cohort. From the study, 678 middle-aged and elderly subjects had minimum 48 hours of Holter-recording, laboratory testing and physician-based examination and questionnaire performed. Median follow-up time was 14.7 years. NSVT was defined as runs of minimum three premature ventricular complexes. The primary end-point was a combination of cardiovascular mortality, acute myocardial infarction, coronary revascularization or stroke. Secondary endpoints were all-cause mortality and components of the primary end-point. We found that 72 (10.6%) had minimum one NSVT event on 48-hour Holter-recording. The primary end-point occurred more frequently in patients with NSVT than those without: 38.3 versus 17.7 events per 1,000 patient-years, hazard ratio 2.1, 95% CI 1.37 to 3.20 after adjustment for risk factors. Secondary end-points also occurred more frequently in the NSVT-group. A shorter-term follow-up revealed similar event rates for the primary outcome; 47.5 versus 21.2 events per 1,000 patient-years, hazard ratio 1.9, 95% CI 0.69 to 5.24. Besides stroke other secondary end-points occurred more frequently in the short-term follow-up. The prognosis in subjects with NSVT was not dependent of the length of the VT. In conclusion, incidental asymptomatic NSVT on Holter-recording in subjects without apparent or manifest structural heart disease is associated with increased risk of mortality and cardiovascular events, however the increased risk is not imminent but with a slow and steady pace over time.

Aims Remote dielectric sensing (ReDS) enables quick estimation of lung fluid content. To examine if ReDS is superior to other methods in detecting acute heart failure. Methods and results We included consecutive patients with dyspnoea from the emergency departments at Bispebjerg Hospital, Copenhagen, and performed ReDS, low-dose chest computed tomography (CT), echocardiogram, lung ultrasound, NT-Pro-brain natriuretic peptide (NT-proBNP), and a Boston score evaluation (chest X-ray and clinical signs). ReDS values >35% were used as a cut-off to diagnose pulmonary congestion. Acute heart failure was adjudicated by experts’ review of health records but independently of ReDS values. Sub-analyses investigated ReDS in acute heart failure patients with congestion on CT. We included 97 patients within a median of 4.8 h from admittance: 25 patients (26%) were ReDS-positive and 39 (40%) had adjudicated acute heart failure (21 with and 18 without CT congestion). Heart failure patients had median ReDS 33%, left ventricular ejection fraction 48%, and NT-proBNP 2935 ng/L. A positive ReDS detected heart failure with 46% sensitivity, 88% specificity, and 71% accuracy. The AUC for ReDS was like the Boston score (P = 0.88) and the lung ultrasound score (P = 0.74). CT-congested heart failure patients had higher ReDS values than patients without heart failure (median 38 vs. 28%, P < 0.001). Heart failure patients without CT-congestion had ReDS values like patients without heart failure (mean 30 vs. 28%, P = 0.07). Conclusion ReDS detects acute heart failure similarly to the Boston score and lung ultrasound score, and ReDS primarily identifies the acute heart failure patients who have congestion on a chest CT.

Objective: To identify ECG changes in sinus rhythm that may be used to predict subsequent development of new AF. Method: We identified prospective and retrospective cohort or case control studies evaluating ECG patterns from a 12-lead ECG in sinus rhythm taken in hospital or community predicting subsequent development of new AF. For each identified ECG predictor, we then identify absolute event rates and pooled risk ratios (RR) using an aggregate level random effects meta-analysis. Results: We identified 609,496 patients from 22 studies. ECG patterns included P wave terminal force V1 (PTFV1), interatrial block (IAB) and advanced interatrial block (aIAB), abnormal P wave axis (aPWA), PR prolongation and atrial premature complexes (APCs). Pooled risk ratios reached significance for each of these; PTFV1 RR 1.48 (95% CI 1.04–2.10), IAB 2.54 (95% CI 1.64–3.93), aIAB 4.05 (95% CI 2.64–6.22), aPWA 1.89 (95% CI 1.25–2.85), PR prolongation 2.22 (95% CI 1.27–3.87) and APCs 3.71 (95% CI 2.23–6.16). Diabetes reduced the predictive value of PR prolongation. Conclusion: APC and aIAB were most predictive of AF, while IAB, PR prolongation, PTFV1 and aPWA were also significantly associated with development of AF. These support their use in a screening tool to identify at risk cohorts who may benefit from further investigation, or following stroke, with empirical anticoagulation.

IntroductionDespite workup for the aetiology of ischaemic stroke, about 25% of cases remain unexplained. Paroxysmal atrial fibrillation is typically suspected but often not detected. Even if atrial fibrillation (AF) is detected, the quantitative threshold of clinically relevant AF remains unclear. Emerging evidence suggests that left atrial (LA) functional and structural abnormalities may convey a risk of ischaemic stroke in which AF is only one of several features. These abnormalities have been termed ‘atrial cardiomyopathy’. This study uses cardiac magnetic resonance (CMR) to evaluate atrial cardiomyopathy among patients with stroke of undetermined aetiology compared with those with an attributable mechanism and controls without established cardiovascular disease.Methods and analysisThis cross-sectional and prospective cohort study included 100 patients with recent ischaemic stroke and 50 controls with no established cardiovascular disease. The study will assess LA structural and functional abnormalities with CMR. Inclusion began in March 2019, and follow-up is planned to be complete in January 2023. There are two scheduled follow-ups: (1) 18 months after individual inclusion, counting from the index diagnostic MRI of the brain, (2) end of study follow-up at 18 months after inclusion of the last patient, assessing the incidence of recurrent ischaemic stroke, AF and cardiovascular death. The primary endpoint is the extent of CMR-assessed atrial fibrosis in the LA at baseline. The study is powered to detect a difference of 6% fibrosis between stroke of undetermined aetiology and stroke of known mechanism with a SD of 9%, a significance level of 0.05, and power of 80%.Ethics and disseminationThis study has been approved by the Danish National Committee on Health Research Ethics (H-18055313). All participants in the study signed informed consent. Results from the study will be published in peer-reviewed journals regardless of the outcome.Trial registration numberNCT03830983.

BackgroundDiastolic dysfunction is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and is associated with overweight, glucose dysregulation and coronary artery disease (CAD). The GLP-1 receptor agonist, liraglutide, has shown to induce weight loss and improve metabolic factors, thus modulating factors associated with diastolic dysfunction. We have previously reported the effects of liraglutide on systolic function, and in this current study we explore the effects of liraglutide on diastolic function parameters in patients with stable CAD, preserved left ventricular ejection fraction (LVEF), and newly diagnosed T2DM.MethodsThirty subjects were randomized to liraglutide or placebo intervention for 12 + 12-weeks in this double-blind cross-over study. 2D-echocardiography using tissue velocity imaging was used for assessment of diastolic function parameters. Early diastolic filling velocity (E), late atrial filling velocity (A), E-wave deceleration time (EDT) and E/A ratio was assessed from the pulse wave (PW)-Doppler velocity recording of the mitral inflow. Peak early diastolic annular velocities (e′) was measured from color tissue doppler images.ResultsLiraglutide, when compared to placebo, induced a significant reduction in average e′ and lateral e′ velocities (– 0.57 cm/s [– 1.05 to − 0.08] and –0.74 cm/s [–1.32 to –0.15], respectively). Adjusted for the concomitant increase in HR (+ 6.16 bpm [0.79 to 11.54], the changes were not significant. No significant changes in other diastolic function parameters were observed.ConclusionsLiraglutide therapy did not improve any diastolic function parameters in subjects with T2DM, CAD, and preserved LVEF. Instead, a deterioration in e’ was observed, which was associated to an increase in heart rate induced by liraglutide therapy.Trial registrationClinical Trial Registration:http://www.clinicaltrials.gov(unique identifier: NCT01595789) (first submitted May 8, 2012)

Introduction: Hypotensive events and drops in systolic blood pressure (SBP-drop) are frequent in patients with acute heart failure (AHF). We investigated SBP-drop and associations with outcomes and whether treatment with the vasodilator serelaxin affected the association between SBP-drops and outcomes. Methods: Analyses of data from four randomized, controlled trials investigating serelaxin as an intervention in patients hospitalized with AHF. Main inclusion criteria were SBP 125-180 mmHg, pulmonary congestion, elevated NT-proBNP. SBP-drops (predefined as an SBP-value below 100 mmHg and/or a drop of 40 mmHg from baseline) were prospectively registered during the first 48 hours of hospitalization. Outcomes were a composite outcome (worsening heart failure, hospital readmission for heart failure or all-cause mortality through 14 days) and 180-day mortality. Results: Overall, 2558/11226 (23%) patients had an SBP-drop, with a median time from randomization to event of 15 (6-25) hours. In multivariable analyses, SBP-drop was associated with 180-day mortality (hazard ratio 1.21, 95% CI 1.05-1.39; p=0.009) and the composite outcome (1.29 (1.13-1.49); p Conclusions: SBP-drops in hospitalized patients treated for AHF is an independent risk factor for adverse short- and long-term outcomes, and its occurrence highlights the need for careful monitoring and urgent treatment. However, in patients treated with serelaxin under careful observation, SBP-drops were not associated with worse outcome.

Objectives To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker’s clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable. Methods The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient’s entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers. Results Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes. Conclusions For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.

Background and purpose Diagnosing heart failure (HF) remains difficult in the acute setting where multiple diagnoses are in play. Objective evidence of pulmonary congestion by chest X-ray (CXR) is one criteria for the recent universal definition of heart failure (UniHF). But, since CXR is known to have a low diagnostic value, we hypothesized that a chest CT (CT) would outdo the CXR to diagnose decompensated HF in acute breathless patients. This study's primary objective was to examine if the CT has higher accuracy than the CXR to diagnose HF in the acute setting; and, secondly, to identify what pre-test characteristics would predict a false negative CXR or CT. Methods We performed a single-centre, prospective observational study and included consecutive adult patients with dyspnoea in the emergency department. Patients underwent immediate clinical examination, blood tests, CXR, CT and an echocardiogram. Congestion on CXR and CT was defined as the congruent verdict by two expert thorax radiologists, blinded to each others reading and all other clinical data. The absence of congestion was defined as the congruent verdict of “no congestion”. Congestion of CXR and CT was held up against UniHF ascertained by an expert panel of cardiologists where the pulmonary congestion component primarily was based on elevated filling pressures from the simultaneous comprehensive echocardiogram. Univariate- and multivariate logistic analyses identified factors associated with a false negative chest x-ray and CT. Results Of 228 patients with a mean age of 74,5 years, 129 (56,5%) were male, 98 (43%) had UniHF, and 139 (61.0%) had pulmonary disease. Congestion on the CXR diagnosed UniHF with a 54% sensitivity and 95% specificity, with almost similar figures for the CT with 54% and 99% respectively. A marginally better performance of the CT was shown by a significantly lower Akaike Information Criterion for pulmonary congestion by CT than for CXR. However, the net reclassification improvement by CT was 4% (p:0.5586). The CXR and CT were false negative for UniHF in 46% (45/98) for both modalities (Table 1). The only independent pre-test predictor of a false negative radiology examination in multivariable logistic regression analysis was NT-proBNP (CXR: OR 1.670 per log(BNP), p: Conclusions For the first time, CT has been directly compared with CXR to diagnose HF in consecutive breathless patients from the emergency department. The chest CT was marginally more specific than the CXR to diagnose HF, but with a similar sensitivity. Approximately half the patients obeying the universal definition of HF have no definite congestion on CXR nor CT, and these can only be identified by a high proBNP. Funding Acknowledgement Type of funding sources: None. Table 1

Background Low grade inflammation (LGI) is significantly associated with microvascular complications in diabetes mellitus (DM). Reduced and impaired Heart rate variability (HRV) is a strong marker of autonomic dysfunction and neuropathy and strongly associated with microvascular disease in DM. New studies and observations indicate that the diabetic neuropathic process starts early during pre-diabetes. On the other hand, HRV and LGI are closely interrelated. Our aim was to evaluate whether LGI or hyperglycemia (i.e. high HbA1c) is associated with the autonomic dysfunction or reduced HRV among people with diabetes and pre-diabetes. Methods and materials This study is based on The Copenhagen Holter Study, in which 678 community dwelling subjects aged 55 – 75 years who were free of previous cardiovascular disease, except from well controlled hypertension, and who underwent a 48-hours Holter recording. Analysis of HRV including night-time HRV were available for 653 participants and this population included 133 people with well-controlled and newly recognized T2DM (mean HbA1c 55 mmol/mol (7.2%)) and 386 people with pre-diabetes defined as HbA1c between 39 mmol/mol (5.7%) and 47 mmol/mol (6.4%). We selected high-sensitive CRP, as markers of LGI. As measures of HRV we used the standard deviation of normal-to-normal (N-N) beats (SDNN), the root mean square of N-N beats (RMSSD) which has been acknowledged to be best linked to vagal parasympathetic tone, and the mean time between N-N complexes (meanNN) which represents the average 24-hour heart rate (60.000/meanNN = average 24-hour HR in beats/min) Results Measures of HRV were associated with HgbA1c among both people with T2DM and pre-diabetes. Among people with pre-diabetes HbA1c was inversely associated with 24-hour RMSSD (r=−0.11, p=0.03) and night-time SDNN (r=−0,13, p>0.01), while among T2DM HgbA1c was only associated with 24-hour RMSSD (r=−0.21, p=0.02). These association stayed significant when adjusted for sex, age, BMI, smoking, HOMA-ir, hs-CRP and systolic blood pressure in multiple linear regression (Table 1). LGI was only associated with HRV in diabetes. HbA1c was not associated with any measures of HRV or LGI among people with normal glucose metabolism. Conclusion HRV is closely and inversely associated with HbA1c in both diabetes and prediabetes, but only in diabetes LGI is associated with HRV. This indicates that the process of autonomic dysfunction/neuropathy starts at an early phase during pre-diabetes and probably provoked by postprandial hyperglycemia, while in diabetes both HbA1c and LGI are associated with HRV showing that LGI is activated later in the disease process probably provoked by long-term postprandial hyperglycemia, indicating treatment of hyperglycemia and postprandial hyperglycemia in the prediabetes state may be helpful. Funding Acknowledgement Type of funding sources: None.

Background: Excessive supraventricular ectopic activity (ESVEA), defined as ≥720 premature atrial contractions (PAC) per day or any runs of ≥20 PACs, has been proposed as a surrogate marker for paroxysmal atrial fibrillation (PAF). Objective: We aimed to estimate the prognostic impact of ESVEA on the future development of PAF in consecutive patients referred to ambulatory cardiac monitoring. Methods: The cohort consists of a population with comorbidities referred to 48-hour ambulatory electrocardiogram aged 30–98 (n = 1316) between 2009 and 2011. After exclusion of known or current atrial fibrillation (AF) (n = 527) and patients with pacemakers (n = 7), 782 patients were included, with a median follow-up of 8.1 years. Events of incident AF and death were retrieved from patient records. Results: Mean age was 58.6 ± 15.5 years and 56.5% were women. A total of 101 patients had ESVEA at baseline (12.9%). During follow-up, 69 (8.9%) developed incidental AF. Twenty-three patients with ESVEA developed AF (23%). Incidence rate of AF in patients with and without ESVEA was 37.1/1000 person-years and 9.1 per 1000 person-years, respectively (P < .001). ESVEA was associated with incident AF after adjustment for potential confounders in Cox regression analysis (hazard ratio [HR]: 2.39; 95% confidence interval [CI]: 1.40–4.09) and in competing risk analysis with death as competing risk (subdistribution HR: 2.35; 95% CI: 1.30–4.17). Conclusion: ESVEA increases the risk of incident AF substantially in a population referred to ambulatory cardiac monitoring.

Background and aims Atherosclerosis in obesity and type 2 diabetes (T2DM) is associated with low-grade inflammation (LGI) and dyslipidemia, where especially small, dense lipoprotein particles are atherogenic. The glucagon-like peptide-1 receptor agonist, liraglutide, reduces cardiovascular events by poorly understood mechanisms. We investigated the effect of liraglutide combined with metformin on LGI and lipoprotein density profiles in patients with stable coronary artery disease (CAD) and newly diagnosed T2DM. Methods We conducted a randomized, double-blind, placebo-controlled, cross-over trial over a 12 + 12-week period, with ≥2-week wash-out. Intervention: liraglutide/metformin vs. placebo/metformin. Lipoproteins were separated by continuous density gradient ultracentrifugation, and LDL divided into five subfractions between 226 and 270 A, considering particle size ≤255 A as the atherogenic pattern. Plasma C-reactive protein and tumor necrosis factor-α were assessed by the enzyme-linked immunosorbent-assay. Results 28 out of 41 randomized patients completed all visits. Intention-to-treat analysis was performed but one patient had statin dosage and was excluded from the analysis. 95% of the patients were on statin therapy. Overall, liraglutide did not affect lipid subfractions or markers of LGI compared to placebo. The combination of liraglutide and metformin reduced the total LDL subfractions, primarily by reducing the most atherogenic subfraction LDL 5 , and reduced CRP but not TNF-α. Explorative analyses suggested that the subfraction LDL 5 during the wash-out period rebounded significantly at least in a per-protocol analysis of the sub-group of patients starting the liraglutide therapy. Conclusions In patients with CAD and newly diagnosed T2DM on stable statin therapy, liraglutide combined with metformin may improve the atherogenic LDL lipid profile and CRP.

Elevated levels of non-esterified fatty acids (NEFA) play a role in insulin resistance, impaired beta-cell function and they are a denominator of the abnormal atherogenic lipid profile that characterizes obese patients with type 2 diabetes (T2DM). We hypothesized that the GLP-1 receptor agonist liraglutide, in combination with metformin, would reduce lipolysis. In a randomized, double-blind, placebo-controlled, cross-over trial, 41 T2DM patients with coronary artery disease were randomized and treated with liraglutide-metformin vs placebo-metformin during 12- + 12-week periods with a wash-out period of at least 2 weeks before and between the intervention periods. NEFA kinetics were estimated using the Boston Minimal Model of NEFA metabolism, with plasma NEFA and glucose levels measured during a standard 180-minute frequently sampled intravenous glucose tolerance test. Liraglutide-metformin reduced estimates of lipolysis. Furthermore, placebo-metformin increased estimates of lipid oxidation, while treatment with liraglutide eliminated this effect. We conclude that liraglutide exerts a clinically relevant reduction in estimates of lipolysis and lipid oxidation which is explained, in part, by improved insulin secretion, as revealed by an intravenous glucose tolerance test.

Background Low heart rate variability (HRV) reflects cardiac autonomic neuropathy, which is associated with increased cardiovascular mortality in people with type 2 diabetes mellitus (T2DM). Measuring HRV is challenged by environmental noise, mental stress and physical activity during daytime. Night-time HRV during sleep may be a more valid tool to measure cardiac autonomic neuropathy and therefore may improve prediction of cardiovascular (CV) events in low-risk people with T2DM. Methods Copenhagen Holter Study included 678 community-dwelling participants aged 55-75 years who were free of previous CV disease. Day and night-time HRV were available for 653 participants. The population included 133 people with well-controlled T2DM and newly recognized T2DM (mean HbA1c 55 mmol/mol [7.2%]). HRV is defined as standard deviation for the mean value of normal-to-normal complexes (SDNN). Night-time HRV measurements were pre-defined from 2:00 to 2:15 AM. Cardiovascular events were defined as CV death, myocardial infarction, stroke or coronary revascularization. Results Median follow-up time was 14.4 years. During this period, 245 death and 149 CV events (CV death 36, myocardial infarction 42, revascularisation procedures 46, stroke 70) occurred in total. Among people with T2DM, 41 CV events were observed (CV death 13, myocardial infarction 13, revascularisation procedures 17, stroke 18). Night-time SDNN was inversely associated with CV events in people with T2DM, (hazard ratio [HR]: 0.74 95% confidence interval [CI]:0.61-0.89) for each 10-millisecond increment in SDNN after adjustment for the conventional risk factors sex, age, LDL cholesterol, smoking, systolic blood pressure and by also including glucose CRP and NT-proBNP in adjustment. Twenty-four-hour HRV was not associated with CV events, but associated with all-cause mortality in people with T2DM. Conventional risk factors had a receiver operating characteristic (ROC) value of 0.704 (95% CI 0.602-0.806) to predict CV events in people with T2DM. The prediction of CV events by conventional risk factors was improved in people with T2DM by the addition of night-time SDNN; ROC 0.765 (95% CI 0.669-0.862), p = 0.037, but ROC was not improved by addition of CRP and NT-proBNP in the model. In people with T2DM and night-time SDNN ≤30 ms, the 10-year risk of CV death and CV event rate was 12% and 45%, respectively, which re-allocated them to a 'very high-risk' group according to current guidelines. Conclusion Reduced night-time HRV predicts increased risk of CV events in people with well-controlled T2DM, thus night-time HRV may add to traditional risk factors in predicting CV events in people with T2DM.

Asymptomatic aortic stenosis (AS) is a frequent condition that may cause hyponatremia due to neurohumoral activation. We examined if hyponatremia heralds poor prognosis in patients with asymptomatic AS, and whether AS in itself is associated with increased risk of hyponatremia. The study question was investigated in 1,677 individuals that had and annual plasma sodium measurements in the SEAS (Simvastatin and Ezetimibe in AS) trial; 1,873 asymptomatic patients with mild-moderate AS (maximal transaortic velocity 2.5 to 4.0 m/s) randomized to simvastatin/ezetimibe combination versus placebo. All-cause mortality was the primary endpoint and incident hyponatremia (P-Na+

Introduction Low Heart rate variability (HRV) reflects cardiac autonomic neuropathy, associated with increased cardiovascular mortality in type 2 diabetes (T2DM) patients. Measuring HRV is challenged by environmental noise, mental stress and physical activity during the day-time. Thus, measuring night-time HRV during sleep may be a better tool to predict cardiovascular (CV) events in low risk T2DM patients without previous cardiovascular disease. Methods Copenhagen Holter Study included 678 community dwelling subjects aged 55–75 years free of previous cardiovascular disease. Day- and night-time HRV were available for 653. The population included 133 well-controlled T2DM patients (mean HbA1c 7.2%). Median follow- up was 14.4 years. HRV is defined as standard deviation for the mean value of normal-to-normal complexes (SDNN). Night-time HRV measurements were pre-defined from 2:00 to 2:15 AM. CV events were defined as CV death, myocardial infarction, stroke, or coronary revascularization. Results The rate of CV events was 17 and 31 per 1000 patient-year in patients without and with T2DM, respectively (p=0.015). Night-time SDNN was inversely associated with CV events in T2DM patients with a HR of 0.74 (0.61–0.89), P=0.001, for each 10 ms increment in SDNN, after adjustment for sex, age, LDL, smoking, systolic BP, glucose, CRP and NT pro-BNP (table 1). Twenty-four-hours HRV was not associated with cardiovascular events (table 1). Conventional risk factors had an AUC of 0.704 (95% CI 0.602–0.806) to predict CV events in T2DM. Prediction was improved by the addition of night-time SDNN; AUC 0.765 (95% CI 0.669–0.862), P=0.037, but not by CRP or NT-proBNP (Figure 1). In subjects with well-controlled T2DM and night-time SDNN ≤30 ms, the 10-year risk of CV death and CV even-rate were 12% and 45%, respectively. This allocates these T2DM patients in a “very high-risk” group, and more aggressive targets for blood-pressure and lipids according to the current guidelines. Conclusion Reduced night-time HRV associates with increased risk of CV events in persons with well-controlled T2DM. We observed improved risk prediction of cardiovascular events in T2DM by night-time HRV, which may have therapeutic consequences. Figure 1. ROC Curve Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Danish Heart Foundation

Background High-sensitive cardiac Troponin T (hsTnT) is the most frequently used biomarker for the detection of cardiomyocyte injury. Severe aortic stenosis (AS) leads to an increased left ventricular load, with the potential of myocardial injury reflected by increased TnT levels. However, there is a lack of studies showing the prevalence and prognostic role of elevated hsTnT in patients with asymptomatic AS. Purpose To examine the association between the hsTnT levels and AS severity in asymptomatic AS patients. We hypothesized that patients with more severe AS will have elevated hsTnT levels and that hsTnT levels are associated with a higher risk for aortic valve events (AVE) and all-cause mortality (ACM). Methods We performed a post-hoc analysis in 1739 asymptomatic patients with mild to moderate-severe AS, enrolled in the randomized, double-blinded SEAS-study (Simvastatin and Ezetimibe in Aortic Stenosis). All patients had available hsTnT blood samples measured at baseline (Year 0) and Year 1. We defined moderate to severe (mod-severe) AS as a transaortic maximal outflow velocity (Vmax)>3.5 m/s combined with aortic valve area (AVA)14 ng/L was high according to assay (Roche, Elecsys Troponin T hs on cobas e 601). Linear multivariable regression model examined the association of hsTnT levels to clinical and echocardiographic variables. Cox multivariable regression model evaluated competing risks and hazard ratios (HR) of outcomes while adjusting for relevant variables, including a Framingham 10-years risk score of cardiovascular diseases. The competing risks were either ACM or AVE, i.e. the first of AVR, cardiovascular death and heart failure due to AS progression. Results At baseline, hsTnT was high in 26% (453/1739) patients; 25% (380/1529) in non-severe and 35% (73/210) in mod-severe AS. Relative TnT change over one year was 17% (mean 1.17, SD 1.01); 15% in non-severe vs. 32% in mod-severe AS, and neither associated to AS severity, hsTnT at baseline or lipid-lowering treatment. In multivariable linear regression analysis, there were significant correlations between hsTnT at baseline and age, male gender, creatinine, left ventricular mass index and BMI (all p In multivariable Cox regression analyses, a high hsTnT at baseline was associated with AVE 1.61 [95% CI 1.29–1.99]. In contrast, hsTnT at baseline was not associated to all-cause mortality (see figure). Conclusions In asymptomatic AS patients without severe AS, high-sensitive Troponin T is not associated with AS severity in cross-sectional analyses, and its levels do not change substantially during one year of follow-up. However, patients with hsTnT >14 ng/l had a sixty percent higher independent risk of subsequent aortic valve events. Multivariable Cox regression Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Acknowledgements: Main sponsor (SEAS): MSD Singapore Company, LLC, partnership between Merck & Co. Inc. and Schering-Plough Corporation. Blood analysis sponsor: Roche

ObjectiveTo assess if 12 novel circulating biomarkers, when added to ‘standard predictors’ available in general practice, could improve the 10-year prediction of cardiovascular events and mortality in patients with stable coronary heart disease.DesignThe patients participated as placebo receiving patients in the randomised clarithromycin for patients with stable coronary artery disease (CLARICOR) trial at a random time in their disease trajectory.SettingFive Copenhagen University cardiology departments and a coordinating centre.Participants1998 participants with stable coronary artery disease.OutcomesDeath and composite of myocardial infarction, unstable angina pectoris, cerebrovascular disease and death.ResultsWhen only ‘standard predictors’ were included, 83.4% of all-cause death predictions and 68.4% of composite outcome predictions were correct. Log(calprotectin) and log(cathepsin-S) were not associated (p≥0.01) with the outcomes, not even as single predictors. Adding the remaining 10 biomarkers (high-sensitive assay cardiac troponin T; neutrophil gelatinase-associated lipocalin; osteoprotegerin; N-terminal pro-B-type natriuretic peptide; tumour necrosis factor receptor 1 and 2; pregnancy-associated plasma protein A; endostatin; YKL40; cathepsin-B), which were all individually significantly associated with the prediction of the two outcomes, increased the figures to 84.7% and 69.7%.ConclusionWhen ‘standard predictors’ routinely available in general practices are used for risk assessment in consecutively sampled patients with stable coronary artery disease, the addition of 10 novel biomarkers to the prediction model improved the correct prediction of all-cause death and the composite outcome by Trial registration numberNCT00121550.

Elevated pregnancy-associated plasma protein A (PAPP-A) is associated with mortality in acute coronary syndromes. Few studies have assessed PAPP-A in stable coronary artery disease (CAD) and results are conflicting. We assessed the 10-year prognostic relevance of PAPP-A levels in stable CAD. The CLARICOR trial was a randomized controlled clinical trial including outpatients with stable CAD, randomized to clarithromycin versus placebo. The placebo group constituted our discovery cohort (n = 1.996) and the clarithromycin group the replication cohort (n = 1.975). The composite primary outcome was first occurrence of cardiovascular event or death. In the discovery cohort, incidence rates (IR) for the composite outcome were higher in those with elevated PAPP-A (IR 12.72, 95% Confidence Interval (CI) 11.0−14.7 events/100 years) compared to lower PAPP-A (IR 8.78, 8.25−9.34), with comparable results in the replication cohort. Elevated PAPP-A was associated with increased risk of the composite outcome in both cohorts (discovery Hazard Ratio (HR) 1.45, 95% CI 1.24−1.70; replication HR 1.29, 95% CI 1.10−1.52). In models adjusted for established risk factors, these trends were attenuated. Elevated PAPP-A was associated with higher all-cause mortality in both cohorts. We conclude that elevated PAPP-A levels are associated with increased long-term mortality in stable CAD, but do not improve long-term prediction of death or cardiovascular events when added to established predictors.

Background The inflammatory biomarker YKL‐40 has previously been studied as a potential risk marker in cardiovascular disease. We aimed to assess the prognostic reclassification potential of serum YKL‐40 in patients with stable coronary artery disease. Methods and Results The main study population was the placebo group of the CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) trial. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all‐cause mortality. We used Cox proportional hazards regression models adjusted for C‐reactive protein level and baseline cardiovascular risk factors. Improvement in prediction by adding serum YKL‐40 to the risk factors was calculated using the Cox‐Breslow method and c‐statistic. A total of 2200 patients were randomized to placebo, with a follow‐up duration of 10 years. YKL‐40 was associated with an increased risk of the composite outcome (hazard ratio per unit increase in (YKL‐40) 1.13, 95% CI 1.03–1.24, P =0.013) and all‐cause mortality (hazard ratio 1.32, 95% CI 1.17–1.49, P Conclusions Higher serum YKL‐40 was independently associated with an increased risk of adverse cardiovascular outcomes and mortality. Addition of YKL‐40 did not improve risk prediction in patients with stable coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT00121550.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (n = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (DMD), actin-associated LIM protein (PDLIM3), and fukutin (FKTN)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (p = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (p = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.

Background P-wave duration (P-DURATION) and P-wave area (P-AREA) have been linked to risk of atrial fibrillation (AF), but they do not improve the efficacy of Framingham AF risk score. We suggest the incorporation of both variables in one index, the P-wave area/P-wave duration (P-AREA(/)DURATION) index, which may be considered an expression of the average amplitude of the P wave that reflects aspects of P-wave morphology. Objective To assess the prognostic value of P-wave area/P-wave duration index (P(AREA/DURATION)index) in lead II together with other P-wave indices (PWIs) in incidence of AF in the Copenhagen Holter Study. Methods The study included 632 men and women, between 55 and 75 years with no apparent heart disease or AF. Baseline standard 12-lead Electrocardiography (ECGs) were analyzed manually. Results The median follow-up time was 14.7 (14.5;14.9) years. A total of 68 cases of AF and 233 cases of death were recorded. The restricted cubic spline method showed a U-shaped association between P(AREA/DURATION)and rate of AF. The lowest quintile of P(AREA/DURATION)index in lead II was associated with increased rate of AF, HR 2.80 (1.64-4.79). The addition of the new index to the Framingham model for AF improved the model in this population. The P(AREA)in lead II in its lowest quintile was also associated with increased rate of AF, HR 2.16 (1.25-3.75), but did not improve the Framingham model. P(DURATION)and P-wave terminal force (PTF) were not significantly associated with AF. Conclusion A flat P wave as expressed by a small P(AREA/DURATION)index in lead II is associated with increased rate of incident AF beyond known AF risk factors.

Background and aims: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease. Methods: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs. Results: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05–1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07–1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events. Conclusions: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.

A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10−6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10−6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF., Common genetic variants in structural proteins contribute to risk of atrial fibrillation (AF). Here, using whole-exome sequencing, the authors identify rare truncating variants in TTN that associate with familial and early-onset AF and show defects in cardiac sarcomere assembly in ttn.2-mutant zebrafish.

Background and Purpose— Low serum potassium is associated with stroke in populations with cardiovascular disease, hypertension, and diabetes mellitus but has not been studied in a mainly healthy population. We aimed to study the relation between serum potassium and incident stroke and mortality in the Malmö Preventive Project, a large cohort with screening in early mid-life and follow-up >25 years. Methods— Serum potassium measurements and covariates were available in 21 353 individuals (79% men, mean age 44 years). Mean follow-up time was 26.9 years for stroke analyses and 29.3 years for mortality analyses. There were 2061 incident stroke events and 8709 deaths. Cox regression analyses adjusted for multiple stroke risk factors (age, sex, height, weight, systolic blood pressure, fasting blood glucose, serum sodium, current smoking, prevalent diabetes mellitus, prevalent coronary artery disease, and treatment for hypertension) were fitted. Results— There was an independent, linear association between serum potassium, per mmol/L increase, and both stroke (hazard ratio, 1.33; 95% confidence interval, 1.17–1.52; P P Conclusions— Serum potassium, measured in early mid-life, was linearly associated with both incidence of ischemic stroke and intracerebral hemorrhage and all-cause mortality. An interaction with serum sodium implies that factors related to electrolyte balance and incident hypertension may be mediating factors.

Background: Atrial fibrillation is the most common sustained arrhythmia and is associated with cardiovascular morbidity and mortality. The few studies conducted on short-term effects of air pollution on episodes of atrial fibrillation indicate a positive association, though not consistently. Objectives: The aim of this study was to evaluate the long-term impact of traffic-related air pollution on incidence of atrial fibrillation in the general population. Methods: In the Danish Diet, Cancer, and Health cohort of 57,053 people 50–64 years old at enrollment in 1993–1997, we identified 2,700 cases of first-ever hospital admission for atrial fibrillation from enrollment to end of follow-up in 2011. For all cohort members, exposure to traffic-related air pollution assessed as nitrogen dioxide (NO2) and nitrogen oxides (NOx) was estimated at all present and past residential addresses from 1984 to 2011 using a validated dispersion model. We used Cox proportional hazard model to estimate associations between long-term residential exposure to NO2 and NOx and risk of atrial fibrillation, after adjusting for lifestyle and socioeconomic position. Results: A 10 μg/m3 higher 10-year time-weighted mean exposure to NO2 preceding diagnosis was associated with an 8% higher risk of atrial fibrillation [incidence rate ratio: 1.08; 95% confidence interval (CI): 1.01, 1.14] in adjusted analysis. Though weaker, similar results were obtained for long-term residential exposure to NOx. We found no clear tendencies regarding effect modification of the association between NO2 and atrial fibrillation by sex, smoking, hypertension or myocardial infarction. Conclusion: We found long-term residential traffic-related air pollution to be associated with higher risk of atrial fibrillation. Accordingly, the present findings lend further support to the demand for abatement of air pollution. Citation: Monrad M, Sajadieh A, Christensen JS, Ketzel M, Raaschou-Nielsen O, Tjønneland A, Overvad K, Loft S, Sørensen M. 2017. Long-term exposure to traffic-related air pollution and risk of incident atrial fibrillation: a cohort study. Environ Health Perspect 125:422–427; http://dx.doi.org/10.1289/EHP392

Background and Purpose— Stroke is independently associated with the common conditions of hypokalemia and supraventricular ectopy, and we hypothesize that the combination of excessive supraventricular ectopic activity and hypokalemia has a synergistic impact on the prognosis in terms of stroke in the general population. Methods— Subjects (55–75 years old) from the Copenhagen Holter Study cohort (N=671) with no history of atrial fibrillation or stroke were studied—including baseline values of potassium and ambulatory 48-hour Holter monitoring. Excessive supraventricular ectopic activity is defined as ≥30 premature atrial complexes per hour or any episodes of runs of ≥20. Hypokalemia was defined as plasma-potassium ≤3.6 mmol/L. The primary end point was ischemic stroke. Cox models were used. Results— Hypokalemia was mild (mean, 3.4 mmol/L; range, 2.7–3.6). Hypokalemic subjects were older (67.0±6.94 versus 64.0±6.66 years; P P P Conclusions— The combination of hypokalemia and excessive supraventricular ectopy carries a poor prognosis in terms of stroke.

AIMS The aims of the study were to investigate the effects of the GLP-1 receptor agonist liraglutide as add-on to metformin on insulin sensitivity (Si) and glucose effectiveness (Sg) in addition to its positive effects on beta-cell function in overweight/obese patients with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). METHODS The design of the study was a randomized, double-blind, placebo-controlled, cross-over trial in patients with stable CAD and newly diagnosed well-controlled T2DM. Patients were treated with liraglutide/metformin vs placebo/metformin for a 12 + 12-week period with ≥2-week wash-out. First phase insulin secretion (AIRg), Si and Sg were estimated by the Bergman Minimal Model, enabling calculation of beta-cell function; Disposition Index (DI) = AIRg × Si. A total of 30 patients from among 41 randomized were available for paired analysis. RESULTS Baseline characteristics were: HbA1c 47 mmol/mol (SD 6), BMI 31.6 kg/m2 (SD 4.8), fasting plasma-glucose 6.9 mmol/L (IQR 6.1; 7.4) and HOMA-IR 4.9 (IQR 3.0; 7.5). Liraglutide treatment improved AIRg by 3-fold, 497 mU × L-1 × min (IQR 342; 626, P

Background The prognostic significance of incidental non-sustained ventricular tachycardia (NSVT) in subjects without manifest heart disease is unknown. Aim We aimed to evaluate the short- and long-term prognosis of NSVT. Methods Data from 678 subjects from Copenhagen Holter study were analyzed. All had at least 48 hours of Holter recording. NSVT was defined as runs of at least three premature ventricular complexes. All were followed up to 16 years. The primary end-point was defined as a combination of cardiovascular mortality, acute myocardial infarction, coronary revascularization, or stroke. Results 72 (10.6%) had at least one event of VT. The primary end-point occurred more frequently in patients with NSVT: 38.3 versus 17.7 events per 1000 patient-years: HR and 95% CI: 2.06 (1.37–3.20) after relevant adjustments. In a shorter-term follow-up period of up to two-year there were few events: HR and 95% CI: 1.9 (0.69–5.24). The prognosis in subjects with NSVT was not dependent of the length of the VT (p for interaction 0.9), but of the background risk profile. Table 1. Results of the Cox proportional Hazard models showing risk of cardiovascular events in different groups of subjects with incidental ventricular tachycardia on ambulatory ECG recording Model 1 p Model 2 p Interaction All VT 2.02 (1.32–3.10) 0.001 1.95 (1.2–3.02) 0.003 VT (3 complexes) 1.79 (0.98–3.27) 0.057 1.84 (1.0–3.38) 0.04 0.91 VT (4–9 complexes) 1.94 (1.13–3.32) 0.016 1.78 (1.06–3.22) 0.029 VT and high risk score* 2.84 (1.79–4.49) Conclusions Incidental NSVT in subjects without manifest heart disease is associated with increased risk of mortality and CV-events, however the increased risk is not imminent but with a slow pace over time. Acknowledgement/Funding Danish Heart Foundation

Background Hyperinsulinemia aggravates insulin resistance and cardio-vascular disease. How the insulinotropic glucagon-like peptide-1 receptor agonist liraglutide in a physiologic post-prandial setting may act on pancreatic alpha and beta-cell function in patients with coronary artery disease (CAD) and type 2 diabetes (T2DM) is less clear. Methods Insulin resistant patients with established CAD and newly diagnosed well-controlled T2DM were recruited to a placebo-controlled, cross-over trial with two treatment periods of 12 weeks and a 2 weeks wash-out period before and in-between. Treatment was liraglutide or placebo titrated from 0.6 mg q.d. to 1.8 mg q.d. within 4 weeks and metformin titrated from 500 mg b.i.d to 1000 mg b.i.d. within 4 weeks. Before and after intervention in both 12 weeks periods insulin, C-peptide, glucose, and glucagon were measured during a meal test. Beta-cell function derived from the oral glucose tolerance setting was calculated as changes in insulin secretion per unit changes in glucose concentration (Btotal) and whole-body insulin resistance using ISIcomposite. Results Liraglutide increased the disposition index [Btotal × ISIcomposite, by 40% (n = 24, p Conclusions The insulinotropic drug liraglutide may without increasing the insulin concentration reduce postprandial glucose but not glucagon excursions and improve beta-cell function in newly diagnosed and well-controlled T2DM. Trial registration Clinicaltrials.gov ID: NCT01595789

Background: Evidence for treating hypertension in patients with asymptomatic aortic valve stenosis is scarce. We used data from the SEAS trial (Simvastatin Ezetimibe in Aortic Stenosis) to assess what blood pressure (BP) would be optimal. Methods: A total of 1767 patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease were analyzed. Outcomes were all-cause mortality, cardiovascular death, heart failure, stroke, myocardial infarction, and aortic valve replacement. BP was analyzed in Cox models as the cumulative average of serially measured BP and a time-varying covariate. Results: The incidence of all-cause mortality was highest for average follow-up systolic BP ≥160 mm Hg (4.3 per 100 person-years; 95% confidence interval [CI], 3.1–6.0) and lowest for average systolic BP of 120 to 139 mm Hg (2.0 per 100 person-years; 95% CI, 1.6–2.6). In multivariable analysis, all-cause mortality was associated with average systolic BP P =0.033) and BP of 120 to 129 mm Hg (HR, 1.6; P =0.039). Conclusions: Optimal BP seems to be systolic BP of 130 to 139 mm Hg and diastolic BP of 70 to 90 mm Hg in these patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease or diabetes mellitus. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00092677.

Background: Studies have found long-term exposure to traffic noise to be associated with higher risk for hypertension, ischemic heart disease and stroke. We aimed to investigate the novel hypothesis that traffic noise increases the risk of atrial fibrillation (A-fib). Methods: In a population-based cohort of 57,053 people aged 50–64 years at enrolment in 1993–1997, we identified 2692 cases of first-ever hospital admission of A-fib from enrolment to end of follow-up in 2011 using a nationwide registry. The mean follow-up time was 14.7 years. Present and historical residential addresses were identified for all cohort members from 1987 to 2011. For all addresses, exposure to road traffic and railway noise was estimated using the Nordic prediction method and exposure to air pollution was estimated using a validated dispersion model. We used Cox proportional hazard model for the analyses with adjustment for lifestyle, socioeconomic position and air pollution. Results: A 10 dB higher 5-year time-weighted mean exposure to road traffic noise was associated with a 6% higher risk of A-fib (incidence rate ratio (IRR): 1.06; 95% confidence interval (95% CI): 1.00–1.12) in models adjusted for factors related to lifestyle and socioeconomic position. The association followed a monotonic exposure–response relationship. In analyses with adjustment for air pollution, NOx or NO2, there were no statistically significant associations between exposure to road traffic noise and risk of A-fib; IRR: 1.04; (95% CI: 0.96–1.11) and IRR: 1.01; (95% CI: 0.94–1.09), respectively. Exposure to railway noise was not associated with A-fib. Conclusion: Exposure to residential road traffic noise may be associated with higher risk of A-fib, though associations were difficult to separate from exposure to air pollution. Keywords: Arrhythmia, Traffic noise, Cohort, Epidemiology

Objective: We investigated the association among increased levels of plasma homocysteine (Hcy), all-cause mortality, and cardiovascular events. Methods: Hcy was measured in 670 middle-aged and elderly subjects with no previous manifest cardiovascular disease. The follow-up period was 15 years. Results: Subjects with Hcy ≥ 10.8 μmol/l (n = 231) had a significant higher incidence of all-cause mortality (p