Cardiovascular outcomes after curative prostate cancer treatment: A population-based cohort study.

Objective: To investigate differences in cardiovascular disease (CVD) morbidity and mortality after radical prostatectomy or definitive radiotherapy with or without androgen deprivation therapy (ADT). Materials and methods: We used population-based data from the Cancer Registry of Norway, the Norwegian Patient Registry and the Norwegian Cause of Death Registry including 19 289 men ≤80 years diagnosed with non-metastatic prostate cancer during 2010-2019. Patients were treated with radical prostatectomy or definitive radiotherapy. We used competing risk models to compare morbidity from overall CVD, acute myocardial infarction (AMI), cerebral infarction, thromboembolism, and CVD-specific mortality for the overall cohort and stratified by prognostic risk groups. Results: After a median follow-up time of 5.4 years (IQR 4.6 years), there were no differences in adjusted rates of AMI, cerebral infarction, and CVD-specific death between radical prostatectomy and definitive radiotherapy in any of the prognostic risk groups. Rates of overall CVD (0.82; 95% CI 0.76-0.89) and thromboembolism (0.30; 95% CI 0.20-0.44) were lower for definitive radiotherapy than radical prostatectomy during the first year of follow-up. After this overall CVD rates (1.19; 95% CI 1.11-1.28) were consistently higher across all risk groups in patients treated with definitive radiotherapy, but there were no differences regarding thromboembolism. Conclusions: During the first years after treatment, no differences were found in rates of AMI, cerebral infarction, and CVD-specific death between radiotherapy and radical prostatectomy in any of the prognostic risk groups. This suggests that ADT use in combination with radiotherapy may not increase the risks of these outcomes in a curative setting. The increased overall CVD rate for definitive radiotherapy after the first year indicates a possible relationship between definitive radiotherapy and other CVDs than AMI and cerebral infarction.

Plasma methylmalonic acid predicts risk of acute myocardial infarction and mortality in patients with coronary heart disease: A prospective 2-cohort study.

BACKGROUND: Elevated plasma methylmalonic acid (MMA) is reported in patients with established coronary heart disease (CHD) and is considered a marker of vitamin B12 deficiency. Moreover, MMA-dependent reactions have been linked to alterations in mitochondrial energy metabolism and oxidative stress, key features in the pathophysiology of cardiovascular diseases (CVDs). OBJECTIVES: We examined whether plasma MMA prospectively predicted the long-term risk of acute myocardial infarction (AMI) and mortality. METHODS AND RESULTS: Using Cox modeling, we estimated hazard ratios (HRs) for endpoints according to per 1-SD increment of log-transformed plasma MMA in two independent populations: the Western Norway Coronary Angiography Cohort (WECAC) (patients evaluated for CHD; n = 4137) and the Norwegian Vitamin Trial (NORVIT) (patients hospitalized with AMI; n = 3525). In WECAC and NORVIT, 12.8% and 18.0% experienced an AMI, whereas 21.8% and 19.9% died, of whom 45.5% and 60.3% from CVD-related causes during follow-up (range 3-11 years), respectively. In WECAC, age- and gender-adjusted HRs (95% confidence interval) were 1.18 (1.09-1.28), 1.25 (1.18-1.33), and 1.28 (1.17-1.40) for future AMI, total mortality, and CVD mortality, respectively. Corresponding risk estimates were 1.19 (1.10-1.28), 1.22 (1.14-1.31), and 1.30 (1.19-1.42) in NORVIT. These estimates were only slightly attenuated after multivariable adjustments. Across both cohorts, the MMA-risk association was stronger in older adults, women, and non-smokers. CONCLUSIONS: Elevated MMA was associated with an increased risk of AMI and mortality in patients with suspected or verified CHD.

Individual Patient Data Meta-analysis of Drug-eluting Versus Bare-metal Stents for Percutaneous Coronary Intervention in Chronic Versus Acute Coronary Syndromes.

New-generation drug-eluting stents (DES) strongly reduce restenosis and repeat revascularization compared with bare-metal stents (BMS) for percutaneous coronary intervention. There is residual uncertainty as to whether other prognostically relevant outcomes are affected by DES versus BMS concerning initial presentation (chronic coronary syndrome [CCS] vs acute coronary syndrome [ACS]). We performed an individual patient data meta-analysis of randomized trials comparing new-generation DES versus BMS (CRD42017060520). The primary outcome was the composite of cardiac death or myocardial infarction (MI). Outcomes were examined at maximum follow-up and with a 1-year landmark. Risk estimates are expressed as hazard ratio (HR) with 95% confidence interval (CI). A total of 22,319 patients were included across 14 trials; 7,691 patients (34.5%) with CCS and 14,628 patients (65.5%) with ACS. We found evidence that new-generation DES versus BMS consistently reduced the risk of cardiac death or MI in both patients with CCS (HR 0.83, 95% CI 0.70 to 0.98, p <0.001) and ACS (HR 0.83, 95% CI 0.75 to 0.92, p <0.001) (p-interaction = 0.931). This benefit was mainly driven by a similar reduction in the risk of MI (p-interaction = 0.898) for both subsets (HRCCS 0.80, 95% CI 0.65 to 0.97; HRACS 0.79, 95% CI 0.70 to 0.89). In CCS and ACS, we found a time-dependent treatment effect, with the benefit from DES accumulating during 1-year follow-up, without offsetting effects after that. In conclusion, patients with CCS were slightly underrepresented in comparative clinical trials. Still, they benefited similarly to patients with ACS from new-generation DES instead of BMS with a sustained reduction of cardiac death or MI because of lower event rates within 1 year.

A Clinical Description of Chronic Pain in a General Population Using ICD-10 and ICD-11 (The HUNT Pain Examination Study).

The purpose was to present a total description, distribution, and ranking of chronic pain conditions in the general population. This was based on structured clinical examinations of a random sample from a population-based survey (HUNT3) with a calculated oversampling of participants with chronic pain. Supplemented with access to hospital reports, the examination was performed by experienced physicians and psychologists using a consistent definition of chronic pain as well as ICD-10- and the new ICD-11-classification. The main findings were that a higher proportion of the 551 participants had chronic pain assessed by clinical examination (399) than by self-report in a survey the same day (337). Among those with examination-verified chronic pain estimated from HUNT3 to represent 27.9% of the general population, 63% had chronic primary pain, 81% musculoskeletal pain, and 77% more than one chronic pain condition. When separating chronic primary from chronic secondary pain according to ICD-11, the weighted prevalence was 17.7% for chronic pain conditions of unknown and 10.2% of known cause. When all the participants' conditions were accounted for, the most prevalent was nonspecific low back (10.8%) and neck pain (7.6%). Participants with chronic primary pain did not have significantly more psychopathology than those with chronic secondary pain: 14.5% versus 12.5%. PERSPECTIVE: Since this study confirms the high prevalence in self-report surveys and indicates that two thirds of chronic pain conditions cannot be explained by underlying diseases, this huge health and societal problem should be solved primarily on a public health level directed toward prevention and rehabilitation.

Drug-Eluting or Bare-Metal Stents for Left Anterior Descending or Left Main Coronary Artery Revascularization.

Background New-generation drug-eluting stents (DES) reduce target-vessel revascularization compared with bare-metal stents (BMS), and recent data suggest that DES have the potential to decrease the risk of myocardial infarction and cardiovascular mortality. We evaluated the treatment effect of DES versus BMS according to the target artery (left anterior descending [LAD] and/or left main [LM] versus other territories [no-LAD/LM]). Methods and Results The Coronary Stent Trialist (CST) Collaboration gathered individual patient data of randomized trials of DES versus BMS for the treatment of coronary artery disease. The primary outcome was the composite of cardiac death or myocardial infarction. Hazard ratios (HRs) with 95% CIs were derived from a 1-stage individual patient data meta-analysis. We included 26 024 patients across 19 trials: 13 650 (52.4%) in the LAD/LM and 12 373 (47.6%) in the no-LAD/LM group. At 6-year follow-up, there was strong evidence that the treatment effect of DES versus BMS depended on the target vessel (P-interaction=0.024). Compared with BMS, DES reduced the risk of cardiac death or myocardial infarction to a greater extent in the LAD/LM (HR, 0.76; 95% CI, 0.68-0.85) than in the no-LAD/LM territories (HR, 0.93; 95% CI, 0.83-1.05). This benefit was driven by a lower risk of cardiac death (HR, 0.83; 95% CI, 0.70-0.98) and myocardial infarction (HR, 0.74; 95% CI, 0.65-0.85) in patients with LAD/LM disease randomized to DES. An interaction (P=0.004) was also found for all-cause mortality with patients with LAD/LM disease deriving benefit from DES (HR, 0.86; 95% CI, 0.76-0.97). Conclusions As compared with BMS, new-generation DES were associated with sustained reduction in the composite of cardiac death or myocardial infarction if used for the treatment of LAD or left main coronary stenoses. Registration URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42017060520.

Drug-Eluting or Bare-Metal Stents for Left Anterior Descending or Left Main Coronary Artery Revascularization

BACKGROUND: New-generation drug-eluting stents (DES) reduce target-vessel revascularization compared with bare-metal stents (BMS), and recent data suggest that DES have the potential to decrease the risk of myocardial infarction and cardiovascular mortality. We evaluated the treatment effect of DES versus BMS according to the target artery (left anterior descending [LAD] and/or left main [LM] versus other territories [no-LAD/LM]). METHODS AND RESULTS: The Coronary Stent Trialist (CST) Collaboration gathered individual patient data of randomized trials of DES versus BMS for the treatment of coronary artery disease. The primary outcome was the composite of cardiac death or myocardial infarction. Hazard ratios (HRs) with 95% CIs were derived from a 1-stage individual patient data meta-analysis. We included 26 024 patients across 19 trials: 13 650 (52.4%) in the LAD/LM and 12 373 (47.6%) in the no-LAD/LM group. At 6-year follow-up, there was strong evidence that the treatment effect of DES versus BMS depended on the target vessel (P interaction=0.024). Compared with BMS, DES reduced the risk of cardiac death or myocardial infarction to a greater extent in the LAD/LM (HR, 0.76; 95% CI, 0.68­0.85) than in the no-LAD/LM territories (HR, 0.93; 95% CI, 0.83­1.05). This benefit was driven by a lower risk of cardiac death (HR, 0.83; 95% CI, 0.70­0.98) and myocardial infarction (HR, 0.74; 95% CI, 0.65­0.85) in patients with LAD/LM disease randomized to DES. An interaction (P=0.004) was also found for all-cause mortality with patients with LAD/LM disease deriving benefit from DES (HR, 0.86; 95% CI, 0.76­0.97). CONCLUSIONS: As compared with BMS, new-generation DES were associated with sustained reduction in the composite of cardiac death or myocardial infarction if used for the treatment of LAD or left main coronary stenoses.

Is the ongoing obesity epidemic partly explained by concurrent decline in cigarette smoking? Insights from a longitudinal population study. The Tromsø Study 1994-2016.

The increase of obesity coincides with a substantial decrease in cigarette smoking. We assessed post-cessation weight change and its contribution to the obesity epidemic in a general population in Norway. A total of 14,453 participants (52.6% women), aged 25-54 years in 1994, who attended at least two of four surveys in the Tromsø Study between 1994 and 2016, were included in the analysis. Hereof 77% participated in both the first and the last survey. Temporal trends in mean body mass index (BMI), prevalence of obesity (BMI ≥ 30 kg/m2) and daily smoking were estimated with generalized estimation equations. We assessed BMI change by smoking status (ex-smoker, quitter, never smoker, daily smoker), and also under a scenario where none quit smoking. In total, the prevalence of daily smoking was reduced over the 21 years between Tromsø 4 (1994-1995) and Tromsø 7 (2015-2016) by 22 percentage points. Prevalence of obesity increased from 5 - 12% in 1994-1995 to 21-26% in 2015-2016, where obesity in the youngest (age 25-44 in 1994) increased more than in the oldest (p < 0.0001). Those who quit smoking had a larger BMI gain compared to the other three smoking subgroups over the 21 years (p < 0.0001). The scenario where none quit smoking would imply a 13% reduction in BMI gain in the population, though substantial age-related differences were noted. We conclude that smoking cessation contributed to the increase in obesity in the population, but was probably not the most important factor. Public health interventions should continue to target smoking cessation, and also target obesity prevention.

Analyses of Increased Mortality in New and Known Diabetes in Patients with Coronary Disease Enrolled in the NORSTENT Randomized Study.

BACKGROUND: NORSTENT trial randomized 9,013 patients to percutaneous coronary intervention with drug-eluting stents (DES) or bare-metal stents (BMS) with a 5-year follow-up. Among the patients, 5,512 had measured either fasting glucose level or percent glycated hemoglobin (HbA1c) at the index procedure. That cohort constitutes the present study population analyzing mortality and evaluating treatment heterogeneity of randomized stent in diabetic versus nondiabetic subgroups. RESULTS: The cohort consisted of 4,174 (75.7%) patients without diabetes, 716 (13.0%) with known diabetes, and 622 (11.3%) with no diabetes in history but elevated fasting glucose level >7.0 mmol/L or HbA1c >6.5% and therefore defined as new diabetes. Patients with known diabetes had a significantly increased all-cause (hazard ratio [HR] 1.99, 95% CI 1.51-2.62, p < 0.001), cardiac (subhazard ratio [SHR] 2.47, 95% CI 1.55-3.93, p < 0.001), and noncardiac (SHR 1.74, 95% CI 1.23-2.44, p = 0.002) mortality after adjustment for baseline variables. In the follow-up of 5 years, patients with new diabetes, however, had a marginally increased all-cause (HR 1.40, 95% CI 1.01-1.93, p = 0.043) and significantly increased noncardiac mortality (SHR 1.52, 95% CI 1.06-2.20, p = 0.025), but no increase in cardiac mortality (SHR 1.06, 95% CI 0.53-2.12, p = 0.86) after the same adjustment. The majority of the mortality was cardiac in the first 1-2 years after intervention; thereafter, noncardiac mortality dominated. However, the time period for when noncardiac mortality became the dominating cause varied considerably and significantly between the groups. There was no heterogeneity in mortality in response to randomized stent between diabetics and nondiabetics. CONCLUSION: Known diabetes has increased cardiac and noncardiac mortality in contrast to new diabetes which is only associated with increased noncardiac mortality during the 5-year follow-up. Diabetic and nondiabetic patients have the same response to the treatment with BMS or DES.

The Effect of Drug-Eluting Stents on Target Lesion Revascularization in Native Coronary Arteries: Results from the NORSTENT Randomized Study.

BACKGROUND: The NORSTENT trial randomized 9,013 patients to percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) or bare-metal stent (BMS) with 5-year follow-up. No difference was found in the composite primary outcome of death from any cause and nonfatal spontaneous myocardial infarction after a median of 5 years of follow-up. Secondary outcomes included repeat revascularizations, which were reduced by DES. We report the occurrence of target lesion revascularization (TLR) in time and across demographic and clinical subgroups in patients with lesions in native coronary arteries (n = 8,782). RESULTS: Clinically driven TLR was performed on 488 (5.6%) of the 8,782 patients during 5 years of follow-up. Male gender, older age, visible thrombus in the lesion, and larger stent diameter were associated with less TLR; multivessel disease and longer stents were associated with a higher risk of TLR. There was a substantial and highly significant reduction of the risk of any TLR after 5 years in the DES group (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.36-0.52], p < 0.001). The effect of DES on TLR was limited in time to the first 2 years in the study with no evidence of a later rebound effect. The reduction in TLR after DES insertion was consistent across subgroups defined by gender, age, diabetes status, renal function, and lesion and stent characteristics. The number needed to treat with DES (vs. BMS) to prevent 1 TLR ranged from 4 to 110 across clinically relevant subgroups. CONCLUSION: DES have a time-limited effect on the rate of TLR, but with a substantial and highly significant reduction in the first 2 years after the procedure. This effect was found to be consistent across all important clinical subgroups.

Employment status three years after percutaneous coronary intervention and predictors for being employed: A nationwide prospective cohort study.

BACKGROUND: Vocational support is recommended for patients in cardiac rehabilitation (CR), as returning to work is important in patients social readjusting after an acute coronary event. Information is lacking on whether CR leads to higher long-term employment after percutaneous coronary intervention (PCI). AIMS: The aims of this study were to determine employment status three years after PCI, to compare employment status between CR participants and CR non-participants and to assess predictors for employment. METHODS: We included first-time PCI patients from the NorStent trial, who were of working age (<63 years; n = 2488) at a three-year follow-up. Employment status and CR participation were assessed using a self-report questionnaire. Propensity score method was used in comparing employment status of CR participants and CR non-participants. RESULTS: Seventy per cent of participants who were <60 years of age at the index event were employed at follow-up and CR participation had no effect on employment status. Being male, living with a partner and attaining higher levels of education were associated with a higher chance of being employed, while being older, prior cardiovascular morbidity and smoking status were associated with lower chance of being employed at follow-up. CONCLUSION: Because a significant number of working-age coronary heart disease patients are unemployed three years after coronary revascularization, updated incentives should be implemented to promote vocational support. Such programmes should focus on females, patients lacking higher education and patients who are living alone, as they are more likely to remain unemployed.

Drug-eluting or bare-metal stents for percutaneous coronary intervention: a systematic review and individual patient data meta-analysis of randomised clinical trials

Background New-generation drug-eluting stents (DES) have mostly been investigated in head-to-head non-inferiority trials against early-generation DES and have typically shown similar efficacy and superior safety. How the safety profile of new-generation DES compares with that of bare-metal stents (BMS) is less clear.Methods We did an individual patient data meta-analysis of randomized clinical trials to compare outcomes after implantation of new-generation DES or BMS among patients undergoing percutaneous coronary intervention. The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random-effects meta-analysis and examined at maximum follow-up and a 1-year landmark. Risk estimates are reported as hazard ratios (HRs) with 95% CIs. This study is registered in PROSPERO, number CRD42017060520.Findings We obtained individual data for 26 616 patients in 20 randomized trials. Mean follow-up was 3·2 (SD 1·8) years. The risk of the primary outcome was reduced in DES recipients compared with BMS recipients (HR 0·84, 95% CI 0·78­0·90, p<0·001) owing to a reduced risk of myocardial infarction (0·79, 0·71­0·88, p<0·001) and a possible slight but non-significant cardiac mortality benefit (0·89, 0·78­1·01, p=0·075). All-cause death was unaffected (HR with DES 0·96, 95% CI 0·88­1·05, p=0·358), but risk was lowered for definite stent thrombosis (0·63, 0·50­0·80, p<0·001) and target-vessel revascularization (0·55, 0·50­0·60, p<0·001). We saw a time-dependent treatment effect, with DES being associated with lower risk of the primary outcome than BMS up to 1 year after placement. While the effect was maintained in the longer term, there was no further divergence from BMS after 1 year. Interpretation The performance of new-generation DES in the first year after implantation means that BMS should no longer be considered the gold standard for safety. Further development of DES technology should target improvements in clinical outcomes beyond 1 year. (AU)

Drug-eluting or bare-metal stents for percutaneous coronary intervention: a systematic review and individual patient data meta-analysis of randomised clinical trials.

BACKGROUND: New-generation drug-eluting stents (DES) have mostly been investigated in head-to-head non-inferiority trials against early-generation DES and have typically shown similar efficacy and superior safety. How the safety profile of new-generation DES compares with that of bare-metal stents (BMS) is less clear. METHODS: We did an individual patient data meta-analysis of randomised clinical trials to compare outcomes after implantation of new-generation DES or BMS among patients undergoing percutaneous coronary intervention. The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random-effects meta-analysis and examined at maximum follow-up and a 1-year landmark. Risk estimates are reported as hazard ratios (HRs) with 95% CIs. This study is registered in PROSPERO, number CRD42017060520. FINDINGS: We obtained individual data for 26 616 patients in 20 randomised trials. Mean follow-up was 3·2 (SD 1·8) years. The risk of the primary outcome was reduced in DES recipients compared with BMS recipients (HR 0·84, 95% CI 0·78-0·90, p<0·001) owing to a reduced risk of myocardial infarction (0·79, 0·71-0·88, p<0·001) and a possible slight but non-significant cardiac mortality benefit (0·89, 0·78-1·01, p=0·075). All-cause death was unaffected (HR with DES 0·96, 95% CI 0·88-1·05, p=0·358), but risk was lowered for definite stent thrombosis (0·63, 0·50-0·80, p<0·001) and target-vessel revascularisation (0·55, 0·50-0·60, p<0·001). We saw a time-dependent treatment effect, with DES being associated with lower risk of the primary outcome than BMS up to 1 year after placement. While the effect was maintained in the longer term, there was no further divergence from BMS after 1 year. INTERPRETATION: The performance of new-generation DES in the first year after implantation means that BMS should no longer be considered the gold standard for safety. Further development of DES technology should target improvements in clinical outcomes beyond 1 year. FUNDING: Bern University Hospital.

Elevated plasma cystathionine is associated with increased risk of mortality among patients with suspected or established coronary heart disease.

BACKGROUND: Elevated circulating cystathionine levels are related to atherosclerotic cardiovascular disease, a leading cause of death globally. OBJECTIVE: We investigated whether plasma cystathionine was associated with mortality in patients with suspected or established coronary heart disease (CHD). METHODS: Data from 2 independent cohorts of patients with suspected stable angina pectoris (SAP) (3033 patients; median 10.7 y follow-up; 648 deaths) or acute myocardial infarction (AMI) (3670 patients; median 7.0 y follow-up; 758 deaths) were included. Hazard ratios with 95% CIs per SD increment of log-transformed cystathionine were calculated using Cox regression modeling. Endpoint data was obtained from a national health registry. RESULTS: Among patients with SAP, there was a positive association between plasma cystathionine and death (age- and sex-adjusted HRs [95% CI] per SD: 1.23 [1.14, 1.32], 1.29 [1.16, 1.44], and 1.17 [1.05, 1.29] for total, cardiovascular, and noncardiovascular mortality, respectively). Corresponding risk estimates were 1.28 (1.19, 1.37) for all-cause, 1.33 (1.22, 1.45) for cardiovascular, and 1.19 (1.06, 1.34) for noncardiovascular death among AMI patients. In both cohorts, estimates were slightly attenuated after multivariate adjustments for established CHD risk factors. Subgroup analyses showed that the relation between cystathionine and all-cause mortality in SAP patients was stronger among nonsmokers and those with lower plasma concentration of pyridoxal-5'-phosphate (P-interaction ≤ 0.01 for both). CONCLUSIONS: Elevated plasma cystathionine is associated with both cardiovascular and noncardiovascular mortality among patients with suspected or established CHD. The joint risk associations of high plasma cystathionine with lifestyle factors and impaired vitamin B-6 status on mortality need further investigation. This trial was registered at clinicaltrials.gov as NCT00354081 and NCT00266487.

Cardiac rehabilitation and symptoms of anxiety and depression after percutaneous coronary intervention.

Background Anxiety and depression are related to coronary heart disease, and psychological support is recommended in cardiac rehabilitation. Purpose The aims of this study were: to compare the prevalence of anxiety and depression with respect to cardiac rehabilitation participation among patients who have been treated with percutaneous coronary intervention; to examine prevalence of anxiety and depression among percutaneous coronary intervention patients compared to the general population; and to identify predictors of symptomatic anxiety and depression among percutaneous coronary intervention patients. Methods We included 9013 patients undergoing first-time percutaneous coronary intervention. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale in a representative sample of 775 patients at baseline and after three years of follow-up, and in the entire cohort at three-year follow-up. Results Cardiac rehabilitation participants had more anxiety and depression than cardiac rehabilitation non-participants at baseline, and both groups had a more anxiety than the general population. The levels of anxiety and depression fell significantly during three years of follow-up, but the changes did not differ between cardiac rehabilitation participants and cardiac rehabilitation non-participants. Three years after percutaneous coronary intervention the prevalence of anxiety was 32% ( p < 0.001), higher among cardiac rehabilitation participants compared to cardiac rehabilitation non-participants. Female gender and younger age were associated with anxiety, whereas older age, lower levels of education and cardiovascular morbidity were associated with depression. Conclusion The levels of anxiety and depression were prevalent among percutaneous coronary intervention patients and the levels were not affected by cardiac rehabilitation participation. Anxiety is prevalent among female and younger patients, whereas depression is related to older age and cardiovascular co-morbidity.

Plasma cystathionine and risk of acute myocardial infarction among patients with coronary heart disease: Results from two independent cohorts.

BACKGROUND: Cystathionine is a thio-ether and a metabolite formed from homocysteine during transsulfuration. Elevated plasma cystathionine levels are reported in patients with cardiovascular disease; however prospective relationships with acute myocardial infarction (AMI) are unknown. We investigated associations between plasma cystathionine and AMI among patients with suspected and/or verified coronary heart disease (CHD). METHODS: Subjects from two independent cohort studies, the Western Norway Coronary Angiography Cohort (WECAC) (3033 patients with stable angina pectoris; 263 events within 4.8 years of median follow-up) and the Norwegian Vitamin Trial (NORVIT) (3670 patients with AMI; 683 events within 3.2 years of median follow-up) were included. RESULTS: In both cohorts, plasma cystathionine was associated with several traditional CHD risk factors (P < 0.001). Comparing the cystathionine quartile 4 to 1, age and gender adjusted hazard ratios (95% confidence intervals) for AMI were 2.08 (1.43-3.03) and 1.41 (1.12-1.76) in WECAC and NORVIT, respectively. Additional adjustment for traditional risk factors slightly attenuated the risk estimates, which were generally stronger in both cohorts among non-smokers, patients with higher age, and lower BMI or PLP status (P-interaction ≤ 0.04). Risk associations also tended to be stronger in patients not treated with B-vitamins. Additionally, in a subset of 80 WECAC patients, plasma cystathionine associated strongly negatively with glutathione, an important antioxidant and positively with lanthionine, a marker of H2S production (P < 0.001). CONCLUSIONS: Plasma cystathionine is associated with increased risk of AMI among patients with either suspected or verified coronary heart disease, and is possibly related to altered redox homeostasis.

Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles.

BACKGROUND: Although choline metabolism has been associated with atherosclerotic heart disease, less research attention has been paid to the associations of choline and its oxidative metabolite betaine with cardiac arrhythmias. METHODS AND RESULTS: We evaluated associations of plasma concentrations and dietary intakes of choline and betaine with long-term atrial fibrillation (AF) risk in a community-based cohort, HUSK ([the Hordaland Health Study] n=6949), and validated the findings in 2 patient cohorts: the Western Norway Coronary Angiography Cohort (n=4164) and the NORVIT (Norwegian B-Vitamin) Trial (n=3733). Information on AF was obtained from the CVDNOR (Cardiovascular Disease in Norway) project. In HUSK, WECAC (Western Norway Coronary Angiography Cohort), and NORVIT, 552, 411, and 663 AF cases were identified during a median follow-up time of 10.9, 7.3, and, 8.7 years, respectively. Plasma concentrations of choline and betaine were significantly positively associated with later AF risk after multivariable adjustments in HUSK. Such associations were independently replicated in the 2 external prospective patient cohorts. The pooled hazard ratio was 1.13 (95% confidence interval 1.08-1.19, P<0.001) and 1.16 (95% confidence interval 1.10-1.22, P<0.001) per SD increment for log-transformed choline and betaine, respectively. Moreover, dietary intake of choline was marginally associated with AF risk (pooled hazard ratio 1.29, 95% confidence interval 1.01-1.66, fifth versus first quintile), whereas no significant association was observed between dietary betaine and AF risk. CONCLUSIONS: Our findings indicate that plasma concentrations as well as dietary intake of choline, but not betaine, are associated with subsequent risk of AF, suggesting a potential role of choline metabolism in the pathogenesis of AF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov.Unique identifier: NCT00671346.

Cardiac rehabilitation after percutaneous coronary intervention: Results from a nationwide survey.

AIM: The purpose of this study was to estimate the proportion of Norwegian coronary heart disease patients participating in cardiac rehabilitation programmes after percutaneous coronary intervention, and to determine predictors of cardiac rehabilitation participation. METHODS: Participants were patients enrolled in the Norwegian Coronary Stent Trial. We assessed cardiac rehabilitation participation in 9013 of these patients who had undergone their first percutaneous coronary intervention during 2008-2011. Of these, 7068 patients (82%) completed a self-administered questionnaire on cardiac rehabilitation participation within three years after their percutaneous coronary intervention. RESULTS: Twenty-eight per cent of the participants reported engaging in cardiac rehabilitation. Participation rate differed among the four regional health authorities in Norway, varying from 20%-31%. Patients undergoing percutaneous coronary intervention for an acute coronary syndrome were more likely to participate in cardiac rehabilitation than patients with stable angina (odds ratio 3.2; 95% confidence interval 2.74-3.76). A multivariate statistical model revealed that men had a 28% lower probability ( p<0.001) of participating in cardiac rehabilitation, and the odds of attending cardiac rehabilitation decreased with increasing age ( p<0.001). Contributors to higher odds of cardiac rehabilitation participation were educational level >12 years (odds ratio 1.50; 95% confidence interval 1.32-1.71) and body mass index>25 (odds ratio 1.19; 95% confidence interval 1.05-1.36). Prior coronary artery bypass graft was associated with lower odds of cardiac rehabilitation participation (odds ratio 0.47; 95% confidence interval 0.32-0.70) Conclusion: The estimated cardiac rehabilitation participation rate among patients undergoing first-time percutaneous coronary intervention is low in Norway. The typical participant is young, overweight, well-educated, and had an acute coronary event. These results varied by geographical region.

Neopterin as an Effect Modifier of the Cardiovascular Risk Predicted by Total Homocysteine: A Prospective 2-Cohort Study.

BACKGROUND: Plasma total homocysteine (tHcy) is related to plasma neopterin, an indicator of interferon-γ-mediated immune activation, and both biomarkers positively predict cardiovascular risk. We examined whether the association between tHcy and subsequent risk of acute myocardial infarction (AMI) was modified by systemic concentrations of neopterin and C-reactive protein among patients with coronary heart disease. METHODS AND RESULTS: By Cox modeling, we explored the association between tHcy and risk of AMI in 4164 patients with suspected stable angina pectoris. Subgroup analyses were performed according to median levels of neopterin and C-reactive protein. A replication study was performed among 3749 patients with AMI at baseline. Median follow-up was 7.3 and 8.3 years among patients with stable angina pectoris and AMI, respectively. tHcy and neopterin correlated in both cohorts (rs=0.34 and rs=0.30 among stable angina pectoris and AMI patients, respectively, both P<0.001). tHcy predicted AMI in both cohorts, independent of B-vitamin treatment. However, significant risk associations were confined to patients with plasma neopterin above the median (hazard ratios [95% confidence interval] per 1-SD increment of log-transformed tHcy 1.38 [1.26-1.50] and 1.18 [1.10-1.26] among stable angina pectoris and AMI patients, respectively) (Pint<0.005 in both cohorts). Further, adding information on the interaction between tHcy and neopterin improved model discrimination and reclassification. tHcy and C-reactive protein were weakly related, and no effect modification was found by C-reactive protein. CONCLUSIONS: Among patients with coronary heart disease, tHcy predicted risk of AMI only in subjects with concomitantly elevated plasma neopterin. Our results motivate further research on the relationship between homocysteine metabolism, cellular immune activation, and atherothrombosis.

B Vitamins and Hip Fracture: Secondary Analyses and Extended Follow-Up of Two Large Randomized Controlled Trials.

Elevated plasma homocysteine levels are associated with increased risk of fractures in observational studies. However, it is unsettled whether homocysteine-lowering treatment affects fracture risk. The aim of this study was to investigate the effect of an intervention with B vitamins on the risk of hip fracture in a secondary analysis of combined data from two large randomized controlled trials originally designed to study cardiovascular diseases. Both trials had identical design, intervention, and primary objective. Based on a two-by-two factorial design, the intervention consisted of a daily capsule with either (1) folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg); (2) folic acid (0.8 mg) plus vitamin B12 (0.4 mg); (3) vitamin B6 alone (40 mg); or (4) placebo. The participants were followed with respect to hip fracture during the trial or during an extended follow-up (from the trial start for each patient until the end of 2012). No statistically significant association was found between folic acid plus vitamin B12 treatment and the risk of hip fracture, neither during the trial (median 3.3 years; hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.48 to 1.59) nor during the extended follow-up (median 11.1 years; HR 1.08; 95% CI, 0.84 to 1.40). Nor were there significant differences in the risk of hip fracture between groups receiving versus not receiving vitamin B6 during the trial (HR 1.42; 95% CI, 0.78 to 2.61). However, during the extended follow-up, those receiving vitamin B6 showed a significant 42% higher risk of hip fracture (HR 1.42; 95% CI, 1.09 to 1.83) compared to those not receiving vitamin B6 . In conclusion, treatment with folic acid plus vitamin B12 was not associated with the risk of hip fracture. Treatment with a high dose of vitamin B6 was associated with a slightly increased risk of hip fracture during the extended follow-up (in-trial plus post-trial follow-up). © 2017 American Society for Bone and Mineral Research.

Percutaneous Coronary Intervention as a Trigger for Stroke.

Percutaneous coronary intervention (PCI) is a plausible triggering factor for stroke, yet the magnitude of this excess risk remains unclear. This study aimed to quantify the transient change in risk of stroke for up to 12 weeks after PCI. We applied the case-crossover method, using data from the Norwegian Patient Register on all hospitalizations in Norway in the period of 2008 to 2014. The relative risk (RR) of ischemic stroke was highest during the first 2 days after PCI (RR 17.5, 95% confidence interval [CI] 4.2 to 72.8) and decreased gradually during the following weeks. The corresponding RR was 2.0 (95% CI 1.2 to 3.3) 4 to 8 weeks after PCI. The RR for women was more than twice as high as for men during the first 4 postprocedural weeks, RR 10.5 (95% CI 3.8 to 29.3) and 4.4 (95% CI 2.7 to 7.2), respectively. Our results were compatible with an increased RR of hemorrhagic stroke 4 to 8 weeks after PCI, but the events were few and the estimates were very imprecise, RR 3.0 (95% CI 0.8 to 11.1). The present study offers new knowledge about PCI as a trigger for stroke. Our estimates indicated a substantially increased risk of ischemic stroke during the first 2 days after PCI. The RR then decreased gradually but stayed elevated for 8 weeks. Increased awareness of this vulnerable period after PCI in clinicians and patients could contribute to earlier detection and treatment for patients suffering a postprocedural stroke.