European Journal of Preventive Cardiology

To assess the associations of baseline and long-term gamma-glutamyltransferase (GGT) activity with risk of heart failure (HF), ventricular arrhythmias (VAs) and atrial fibrillation (AF).

GGT measurements were made in a prospective cohort of 1780 men free of HF and cardiac arrhythmias at baseline. Correction for within-person variability was made using data from repeat measurements taken several years apart.

During an average follow-up of 22 years, 222 HF, 56 VA and 336 AF events occurred. The regression dilution ratio of log_e GGT was 0.68 (95% confidence interval (CI): 0.61–0.74). Serum GGT was log-linearly associated with risk of HF, VAs and AF. In analyses adjusted for established risk factors, the hazard ratios (HRs) (95% CIs) for HF, VAs and AF per 1 SD higher baseline log_e GGT values were 1.25 (1.07–1.45), 1.37 (1.04–1.80) and 1.04 (0.92–1.18), respectively. After correction for within-person variability, the corresponding HRs were 1.38 (1.11–1.73), 1.58 (1.06–2.37) and 1.06 (0.88–1.27), respectively. These findings remained consistent in analyses accounting for incident coronary heart disease and the development of impaired renal function. In a meta-analysis of five population-based studies, the fully adjusted relative risks for HF per 1 SD higher baseline and long-term GGT values were 1.28 (1.20–1.35) and 1.43 (1.31–1.56), respectively. In a pooled analysis of two studies, the corresponding risks for AF were 1.09 (1.02–1.16) and 1.14 (1.03–1.25), respectively.

GGT is positively and log-linearly associated with future risk of HF, VAs and AF. Further research is needed in order to assess the causal relevance of these findings.

Peak oxygen uptake is an independent predictor of mortality in patients with coronary artery disease (CAD). However, patients with CAD are not always capable of reaching peak effort, and therefore submaximal gas exchange variables such as the oxygen uptake efficiency slope (OUES) have been introduced. Baseline exercise capacity as expressed by OUES provides prognostic information and this parameter responds to training. Therefore, we aimed to assess the prognostic value of post-training OUES in patients with CAD.

We included 960 patients with CAD (age 60.6 ± 9.5 years; 853 males) who completed a cardiac rehabilitation program between 2000 and 2011. The OUES was calculated before and after cardiac rehabilitation and information on mortality was obtained. The relationships of post-training OUES with all-cause and cardiovascular (CV) mortality was assessed by Cox proportional hazards regression analyses. Receiver operator characteristic curve analysis was performed in order to obtain the optimal cut-off value.

During 7.37 ± 3.20 years of follow-up (range: 0.45–13.75 years), 108 patients died, among whom 47 died due to CV reasons. The post-training OUES was related to all-cause (hazard ratio: 0.50, p < 0.001) and CV (hazard ratio: 0.40, p < 0.001) mortality. When significant covariates, including baseline OUES, were entered into the Cox regression analysis, post-training OUES remained related to all-cause and CV mortality (hazard ratio: 0.40, p < 0.01 and 0.26, p < 0.01, respectively). In addition, the change in OUES due to exercise training was positively related to mortality (hazard ratio: 0.49, p < 0.01).

Post-training OUES has stronger prognostic value compared to baseline OUES. The lack of improvement in exercise capacity expressed by OUES after an exercise training program relates to a worse prognosis and can help distinguish patients with favorable and unfavorable prognoses.

Recent findings revealed negative effects of deregulated molecular circadian rhythm in coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). Physical exercise training (ET) has been shown to promote anti-diabetic and anti-atherogenic responses in skeletal muscle of these patients, but the role of the circadian clock-machinery remains unknown. This study investigated whether mRNA expression of clock genes in skeletal muscle of CAD and T2DM patients is influenced by physical ET intervention.

Nineteen patients with CAD and T2DM (age 64 ± 5 years) were randomised to either six months of ET (four weeks of in-hospital ET followed by a five-month ambulatory programme) or usual care. At the beginning of the study, after four weeks and after six months parameters of metabolic and cardiovascular risk factors, and physical exercise capacity were assessed. Gene expression was measured in skeletal muscle biopsies by quantitative real-time polymerase chain reaction (PCR).

A selection of clock genes and associated components (circadian locomoter output cycle kaput protein (CLOCK), period (PER) 1, cryptochrome (CRY) 2 and aminolevulinate-deltA-synthase-1 (ALAS1)) was reliably measured and used for further analysis. A time-dependent effect in gene expression was observed in CLOCK (p = 0.013) and a significant interaction between time and intervention was observed for ALAS1 (p = 0.032; p = 0.014) as a result of ET.

This is the first study to analyse clock gene expression in skeletal muscles of patients with CAD and T2DM participating in a long-lasting exercise intervention. ET, as one of the cornerstones in prevention and rehabilitation of CAD and T2DM, exerts no effects on CLOCK genes but meaningful effects on the clock-associated gene ALAS1.

Cardiac troponin T (cTnT), measured with a high-sensitivity (hs) assay, is associated with cognitive decline, but the underlying mechanism is unknown. We investigated the association of hs-cTnT with cognitive function and decline, and studied whether this association was independent of cardiovascular diseases or risk factors, and N-terminal pro-brain natriuretic peptide (NT-proBNP).

We studied 5407 participants (mean age 75.31 years) from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), who all had cardiovascular diseases or risk factors thereof. Participants with pre-existent advanced clinical heart failure were excluded. Hs-cTnT and NT-proBNP obtained after 6 months of follow-up were related with cognitive function, tested repeatedly during a mean follow-up of 3.2 years. Participants with higher hs-cTnT performed worse at baseline on Stroop test (mean baseline score (standard error (SE)) lowest vs highest third 65.91 (1.16) vs 69.40 (1.10) seconds, p < 0.001), Letter–Digit Coding test (23.35 (0.32) vs 22.40 (0.31) digits coded, p < 0.001), immediate Picture–Word Learning test (9.45 (0.09) vs 9.31 (0.08) pictures remembered, p = 0.002) and delayed Picture–Word Learning test (10.33 (0.12) vs 10.10 (0.12) pictures remembered, p = 0.013). Furthermore, participants with higher hs-cTnT had steeper decline on Stroop test (mean annual change (SE) lowest vs highest third 0.34 (0.12) vs 1.06 (0.12) seconds, p = 0.013), Letter–Digit Coding test (–0.29 (0.03) vs −0.46 (0.03) digits coded, p < 0.001), immediate Picture–Word Learning test (0.01 (0.01) vs −0.06 (0.01) pictures remembered, p < 0.001) and delayed Picture–Word Learning test (–0.03 (0.01) vs −0.12 (0.02) pictures remembered, p = 0.001). Associations were independent of cardiovascular diseases risk factors or Apolipoprotein E genotype. Further adjusting for NT-proBNP levels revealed the same results.

Higher levels of hs-cTnT associate with worse cognitive function and steeper cognitive decline in older adults independent of cardiovascular diseases, risk factors and NT-proBNP.

The aim of this study was to investigate whether polypill-based care for the prevention of cardiovascular disease (CVD) is associated with a change in lifestyle risk factors when compared with usual care, among patients with CVD or high calculated cardiovascular risk.

We conducted an individual participant data meta-analysis of three trials including patients from Australia, England, India, Ireland, the Netherlands and New Zealand that compared a strategy using a polypill containing aspirin, statin and antihypertensive therapy with usual care in patients with a prior CVD event or who were at high risk of their first event. Analyses investigated any differential effect on anthropometric measures and self-reported lifestyle behaviours.

Among 3140 patients (75% male, mean age 62 years and 76% with a prior CVD event) there was no difference in lifestyle risk factors in those randomised to polypill-based care compared with usual care over a median of 15 months, either across all participants combined, or in a range of subgroups. Furthermore, narrow confidence intervals (CIs) excluded any major effect; for example differences between the groups in body mass index was −0.1 (95% CI −0.2 to 0.1) kg/m², in weekly duration of moderate intensity physical activity was −2 (−26 to 23) minutes and the proportion of smokers was 16% vs 17% (RR 0.98, 0.84 to 1.15) at the end of trial.

This analysis allays concern that polypill-based care may lead to neglect of lifestyle risk factors, at least among high-risk patients. Maximally effective preventive approaches should address lifestyle factors alongside pharmaceutical interventions, as recommended by major international guidelines.

Serum cystatin C, a novel marker of renal function has been shown to be superior to serum creatinine in predicting renal function decline and adverse outcomes of chronic kidney disease (CKD). Our aim was to investigate the association between cystatin C and retinopathy in adults without diabetes.

We examined 1725 Indian adults, aged 40–80 years who participated in the Singapore Indian Eye Study (2007–2009) and were free of diabetes mellitus. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² determined from serum cystatin C (CKD-eGFR_cys, n = 199), and serum creatinine (CKD-eGFR_cr, n = 81). Retinopathy was assessed from digital fundus photographs of both eyes by trained graders using the modified Airlie House classification. The associations of CKD defined by the two markers alone and in combination (confirmed CKD, eGFR_cr <60 and eGFR_cys <60, n = 58) with retinopathy were examined using logistic regression models adjusted for potential confounding factors including preexisting cardiovascular disease and albuminuria.

The prevalence of retinopathy among those with CKD-eGFR_cr and CKD-eGFR_cys was 9.9% and 8.5%, respectively. In separate models, the associations of retinopathy with both CKD-eGFR_cys (odds ratio (OR) (95% confidence interval (CI)) = 2.18 (1.14–4.16)) and CKD-eGFR_cr were significant (OR (95% CI) = 2.63 (1.10–6.28)). In models including both markers, compared to optimal kidney function (eGFR_cr ≥60 and eGFR_cys ≥60), confirmed CKD was associated with a fourfold higher odds of retinopathy (OR (95% CI) = 4.01 (1.52–10.60)).

In a population-based sample of Indian adults without diabetes, CKD defined by both cystatin C and creatinine was strongly associated with retinopathy.

Hypertension complicated with left ventricular hypertrophy (LVH) and diastolic dysfunction is one of the most common risks for heart failure with preserved ejection fraction (HFpEF). This study was designed to evaluate the influences of long-term beta-blocker prescription in these patients.

This retrospective analysis included eligible patients diagnosed with hypertension, LVH (left ventricular (LV) mass index >125 g/m² for men and >110 g/m² for women) and suspected diastolic dysfunction (E/E’ ratio between 8 and 15) and without clinical signs or symptoms of heart failure in our hospital medical record database (January 2005–December 2009). A total of eligible 1498 patients were enrolled, of whom 803 received beta-blocker prescription and 695 accepted non-beta-blocker therapy.

With a median follow-up of 7.2 years, the new-onset symptomatic HFpEF occurred in 48 of 803 patients in the beta-blocker group (6.0%) and 92 of 695 patients in the non-beta-blocker group (13.2%, p < 0.001). Beta-blockers also generated more prominent improvement in diastolic function and LVH. And Cox proportional hazards model revealed that beta-blocker (hazard ratio (HR) 0.327, 95% confidence interval (CI): 0.121–0.540, p = 0.009) or angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) exposure (HR 0.422, 95% CI: 0.210–0.699, p = 0.015) was associated with a reduced risk of new onset of symptomatic HFpEF, and the elevation of LVMI (HR 1.210, 95% CI: 1.069–1.362, p = 0.040) or E/E’ (HR 1.398, 95% CI: 1.306–1.541, p = 0.032) was associated with a high risk of new onset of symptomatic HFpEF.

Long-term beta-blocker exposure was associated with protective effects in terms of the incidence of new-onset symptomatic HFpEF, LV diastolic dysfunction and LVH, which might be beneficial for the delay of HFpEF progression.

Resting heart rate is a surrogate marker associated with achieved exercise capacity, which has been observed in patients with sinus rhythm. The aim of this study was to examine and compare the relationships between resting heart rate and peak oxygen consumption in atrial fibrillation and sinus rhythm.

A total of 2160 consecutive patients undergoing cardiopulmonary exercise testing in our single-hospital cohort were divided into two groups according to rhythm status: an atrial fibrillation group (N = 320) and a sinus rhythm group (N = 1840). In the total cohort and sinus rhythm group, resting heart rate was negatively correlated with percentage of predicted peak oxygen consumption (P_trend < 0.0001); in atrial fibrillation patients, this correlation was apparently positive (P_trend = 0.032). Multivariate analysis of the total cohort showed a significant interaction between resting heart rate and rhythm status for peak oxygen consumption after adjustments for age, sex, ejection fraction, structural heart diseases and heart rate-lowering drugs. In the sinus rhythm group, resting heart rate was an independent, negative contributing factor for peak oxygen consumption, even after the adjustments for patient background. However, in the atrial fibrillation group, resting heart rate was a weak positive or non-independent contributing factor for peak oxygen consumption after the same adjustments.

The impact of resting heart rate on exercise capacity differed completely between atrial fibrillation and sinus rhythm, suggesting that heart rate control may need to be managed differently for atrial fibrillation and sinus rhythm, in light of exercise capacity that is related to quality of life and prognosis.

Atrial fibrillation (AF) affects about 3.2% of the adult population in the western world and incurs an annual stroke risk of 4.5%. The use of oral anticoagulant (OAC) drugs significantly reduces this risk. OAC drugs seem to be under-utilized, but little is known about why their use is restrained in routine clinical management. The aim of this study was to assess this issue and, from these data, to estimate the proportion of patients with AF in a general population who were eligible for treatment with OAC drugs.

Retrospective study of medical records.

The study included all identified patients with AF in a well-defined catchment area of 65,532 people, among whom 1616 (3.2%) had documented AF. Of the patients with AF, 588 (36%) were originally reported not to be receiving OAC drugs. The patient-responsible physicians (n = 24) were requested to complete a standardized questionnaire to assess the reason for restraining the use of OAC drugs for each individual patient.

Of the 588 patients originally reported not to be receiving OAC drugs, eight were shown to be using OAC drugs and seven were lost to follow up. Thus the reason for restraining OAC drugs was finally assessed in 573 patients. The primary reasons were: lack of indication, 26%; declined general condition, 14%; a history of bleeding, 12%; assumed poor compliance, 11%; repeated falls, 6%; and reason unknown, 9%.

This is, to our knowledge, the first study to assess the reasons for restraining the use of OAC drugs in a geographically well-defined population including all hospital-based and non-hospital-based healthcare. Applying CHA₂DS₂-VASc and new strategies for OAC drugs to our study data indicated that between 72 and 88% of all patients with AF are eligible for treatment with OAC drugs.

Obesity and physical inactivity in children correlate with the presence of cardiovascular risk factors. The aim of this prospective, randomised, interventional study was to examine the long term impact of additional physical exercise lessons at school on fitness and cardiovascular risk factors.

We randomly assigned 366 5th and 6th grade students class-wise into an intervention group that participated in one-daily physical exercise unit at school and a control group, participating in conventional school sports twice a week. The intervention duration was 4 years. At baseline and yearly follow-up, anthropometric measurements, body coordination tests, spiroergometry, questionnaires and blood samples were performed.

A total of 236 children qualified for analysis of the intervention effect after 4 years. At the beginning students of the intervention and control groups had similar values for fitness assessed by peak oxygen uptake. Peak oxygen uptake was significantly better in the intervention group at first and second follow-up. After 4 years we found no difference in fitness any longer. Students in the intervention group were more likely to have healthy body mass index percentiles in comparison to the control group (within 10th to 90th percentile: intervention 86.4%, control 78.2%, P = 0.13).

Over a period of 1–2 years, additional physical exercise lessons at school resulted in an improvement of fitness. However, long-term follow-up failed to demonstrate ongoing improvement of performance in the intervention compared with the control group. Nevertheless, the intervention group had lower rates of body mass index above the 90th percentile throughout the entire follow-up. Therefore more physical exercise units at school seem justified.

Patients with high-grade (≥70%) carotid artery stenosis (CAS) rank in the highest risk category for future cardiovascular (CV) events, but the quality of cardiovascular risk management in this patient group is unknown.

Cross-sectional retrospective study.

Data were collected for all patients diagnosed with high-grade CAS in Östergötland county, Sweden between 1 January 2009 and 31 July 2012 regarding the quality of cardiovascular risk management, co-morbidity and outcomes during the 2-year follow-up period after a diagnosis of CAS with a carotid ultrasound scan. Patients were included regardless of whether they underwent carotid endarterectomy (CEA).

A total of 393 patients with CAS were included in the study; 133 (33.8%) underwent CEA and 260 (66.2%) were assigned to a conservative management (CM) group. In both groups of patients the prescription of platelet inhibitors, statins and antihypertensive drugs increased significantly (p < 0.001) after diagnosis. However treatment targets were not met in the majority of patients and the low-density lipoprotein level was on target in only 13.5% of patients. During follow-up, low-density lipoprotein levels were not measured in 19.8% of patients who underwent CEA and 44.2% of patients in the CM group (p < 0.001); HbA1c was not measured in 24.4% of patients with diabetes in the CEA group and in 18.8% of patients in the CM group (p = 0.560). There was no documentation of counselling on diet, exercise, smoking cessation or adherence to medication. The combined clinical event rate (all-cause mortality, cardiovascular mortality and non-fatal cardiovascular events) was high in both groups (CEA 36.8% and CM 36.9%; p = 1.00) with no difference in the occurrence of ipsilateral ischaemic stroke.

The clinical event rate was high in patients with high-grade CAS and the management of cardiovascular risk was deficient in all aspects.