Helge Røsjø

Prognostic value of cardiac troponin i measured with a highly sensitive assay in patients with stable coronary artery disease

OBJECTIVES The aims of this study were to assess the prognostic value of cardiac troponin I levels, measured with a new high-sensitivity assay, in low-risk patients with stable coronary artery disease (CAD) and to contrast its determinants and prognostic merit with that of high-sensitivity cardiac troponin T (hs-TnT). BACKGROUND New, highly sensitive cardiac troponin assays permit evaluation of the association between troponin levels and outcomes in patients with stable CAD. METHODS High-sensitivity cardiac troponin I (hs-TnI) levels at baseline were assessed in 3,623 patients with stable CAD and preserved systolic function enrolled in the PEACE (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy) trial. RESULTS In total, 98.5% of patients had hs-TnI concentrations higher than the detection level (1.2 pg/ml). hs-TnI correlated moderately with hs-TnT (r = 0.44) and N-terminal pro-B-type natriuretic peptide (r = 0.39) but only weakly with age (r = 0.17) and estimated glomerular filtration rate (r = -0.11). During a median follow-up period of 5.2 years, 203 patients died of cardiovascular causes or were hospitalized for heart failure, and 209 patients had nonfatal myocardial infarctions. In analyses adjusting for conventional risk markers, N-terminal pro-B-type natriuretic peptide, and hs-TnT, hs-TnI levels in the fourth compared with the 3 lower quartiles were associated with the incidence of cardiovascular death or heart failure (hazard ratio: 1.84; 95% confidence interval: 1.30 to 2.61; p < 0.001). [corrected]. There was a [corrected] weaker association with nonfatal myocardial infarction (hazard ratio: 1.37; 95% confidence interval: 0.98 to 1.92; p = 0.066). [corrected]. In the same models, hs-TnT concentrations were associated with the incidence of cardiovascular death or heart failure but not of myocardial infarction. CONCLUSIONS In patients with stable CAD, hs-TnI concentrations are associated with cardiovascular risk independently of conventional risk markers and hs-TnT. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]; NCT00000558).

Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

Abstract Aims Contemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation. Methods and results In a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed. Conclusion In patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function.

Prognostic value of circulating chromogranin A levels in acute coronary syndromes

Aims To determine whether circulating levels of chromogranin A (CgA) provide prognostic information independently of conventional risk markers in acute coronary syndromes (ACSs). Methods and results We measured circulating CgA levels on day 1 in 1268 patients (median age 67 years, 70% male) with ACS admitted to a single coronary care unit of a Scandinavian teaching hospital. The merit of CgA as a biomarker was evaluated after adjusting for conventional cardiovascular risk factors. During a median follow-up of 92 months, 389 patients (31%) died. The baseline CgA concentration was strongly associated with increased long-term mortality [hazard ratio per 1 standard deviation increase in logarithmically transformed CgA level: 1.57 (1.44–1.70), P < 0.001], heart failure hospitalizations [1.54 (1.35–1.76), P < 0.001], and recurrent myocardial infarction (MI) [1.27 (1.10–1.47), P < 0.001], but not stroke. After adjustment for conventional cardiovascular risk markers, the association remained significant for mortality [hazard ratio 1.28 (1.15–1.42), P < 0.001] and heart failure hospitalization [hazard ratio 1.24 (1.04–1.47), P = 0.02], but not recurrent MI. Conclusion CgA is an independent predictor of long-term mortality and heart failure hospitalizations across the spectrum of ACSs and provides incremental prognostic information to conventional cardiovascular risk markers.

Circulating MicroRNAs and Aerobic Fitness - The HUNT-Study

Aerobic fitness, measured as maximal oxygen uptake (VO2max), is a good indicator of cardiovascular health, and a strong predictor of cardiovascular mortality. Biomarkers associated with low VO2max may therefore represent potential early markers of future cardiovascular disease (CVD). The aim of this study was to assess whether circulating microRNAs (miRs) are associated with VO2max-level in healthy individuals. In a screening study, 720 miRs were measured in serum samples from healthy individuals (40–45 yrs) with high (n = 12) or low (n = 12) VO2max matched for gender, age and physical activity. Candiate miRs were validated in a second cohort of subjects with high (n = 38) or low (n = 38) VO2max. miR-210 and miR-222 were found to be higher in the low VO2max-group (p<0.05). In addition, miR-21 was increased in male participants with low VO2max (p<0.05). There were no correlations between traditional risk factors for CVD (blood pressure, cholesterol, smoking habit, or obesity) and miR-21, miR-210 and miR-222. DIANA-mirPath identified 611 potential gene-targets of miR-21, miR-210 and miR-222, and pathway analysis indicated alterations in several important signaling systems in subjects with low VO2max. Potential bias involve that blood was collected from non-fasting individuals, and that 8 performed exercise within 24 h before sampling. In conclusion, we found that miR-210, miR-21, and miR-222 were increased in healthy subjects with low VO2max. The lack of association between these three miRs, and other fitness related variables as well as traditional CVD risk factors, suggests that these miRs may have a potential as new independent biomarkers of fitness level and future CVD.

The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls.

Objective Gut microbiota could influence gut, as well as hepatic and biliary immune responses. We therefore thoroughly characterised the gut microbiota in primary sclerosing cholangitis (PSC) compared with healthy controls (HC) and patients with ulcerative colitis without liver disease. Design We prospectively collected 543 stool samples. After a stringent exclusion process, bacterial DNA was submitted for 16S rRNA gene sequencing. PSC and HC were randomised to an exploration panel or a validation panel, and only significant results (p<0.05, QFDR<0.20) in both panels were reported, followed by a combined comparison of all samples against UC. Results Patients with PSC (N=85) had markedly reduced bacterial diversity compared with HC (N=263, p<0.0001), and a different global microbial composition compared with both HC (p<0.001) and UC (N=36, p<0.01). The microbiota of patients with PSC with and without IBD was similar. Twelve genera separated PSC and HC, out of which 11 were reduced in PSC. However, the Veillonella genus showed a marked increase in PSC compared with both HC (p<0.0001) and UC (p<0.02). Using receiver operating characteristic analysis, Veillonella abundance yielded an area under the curve (AUC) of 0.64 to discriminate PSC from HC, while a combination of PSC-associated genera yielded an AUC of 0.78. Conclusions Patients with PSC exhibited a gut microbial signature distinct from both HC and UC without liver disease, but similar in PSC with and without IBD. The Veillonella genus, which is also associated with other chronic inflammatory and fibrotic conditions, was enriched in PSC.

Prognostic usefulness of circulating high-sensitivity troponin T in aortic stenosis and relation to echocardiographic indexes of cardiac function and anatomy.

The new high-sensitivity cardiac troponin T (hs-cTnT) assay seems to provide important prognostic information in patients with stable cardiovascular disease. To understand the merit of hs-cTnT more closely in stable cardiovascular disease, we performed extensive echocardiographic characterization of 57 patients with aortic stenosis and myocardial hypertrophy and related hs-cTnT levels to prognosis and echocardiographic indexes of myocardial structure and function. The hs-cTnT levels were above the assays detection limit in all patients, correlated with echocardiographic indexes of structure and function, most notably with left ventricular mass, and demonstrated prognostic utility of similar strength as N-terminal pro-B-type natriuretic peptide. In conclusion, these findings indicate that hs-cTnT may provide prognostic information in patients with aortic stenosis, and that left ventricular mass is an important determinant of TnT levels in stable patients as measured by the new highly sensitive assay.

Rationale and Design of the Prevention of Cardiac Dysfunction during an Adjuvant Breast Cancer Therapy (PRADA) Trial

Objective: The PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) study is a randomized, placebo-controlled, double-blind trial to determine whether angiotensin receptor blockers (ARB), or beta-blockers or their combination may prevent the development of left ventricular (LV) dysfunction in patients on standard adjuvant treatment for early breast cancer. Methods: Following surgical resection, 120 breast cancer patients scheduled for adjuvant epirubicin-containing chemotherapy and, if indicated, trastuzumab, will be included. They will be randomized to an ARB (candesartan), a beta-blocker (metoprolol) and matching placebos in a 2 × 2 factorial design. The primary objective of the PRADA study is to assess whether prophylactic ARB and/or beta-blockers may prevent a reduction in LV ejection fraction (EF) after adjuvant treatment of early breast cancer, as evaluated by serial cardiovascular magnetic resonance (CMR) performed at randomization, after the first chemotherapy cycle and on its completion, and for subgroups, on completion of radiotherapy or trastuzumab. Secondary outcome measures include echocardiographic indices of LV diastolic dysfunction, structural myocardial alterations assessed by CMR and changes in cardiac biomarkers. Conclusion: PRADA may provide new information on the prophylactic effect of ARB and beta-blockers in patients with early breast cancer regarding the risk of developing cardiac dysfunction from adjuvant cancer treatment.

Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial.

To assess the association between circulating levels of chromogranin A (CgA) and outcome in a large population of patients with chronic heart failure (HF).

Impaired endothelial function in persons with obstructive sleep apnoea: impact of obesity

Objective Obstructive sleep apnoea (OSA) and obesity are both associated with endothelial dysfunction, which precedes the development of atherosclerosis. As obesity is highly prevalent in OSA, we wanted to test the hypothesis that OSA is associated with endothelial dysfunction independently of obesity. Design Cross-sectional, population-based study. Setting Norwegian university hospital. Patients Seventy-one subjects (median age 44 years, 35% female) were recruited from a population-based study in Norway. Participants were categorised as obese (body mass index (BMI) ≥30 kg/m2), non-obese (BMI<30 kg/m2) with OSA (apnoea–hypopnoea index (AHI)≥10), or non-obese without OSA (AHI<5). Interventions None. Main outcome measures Endothelial function measured by brachial artery ultrasound and expressed as percentage of flow-mediated dilation (FMD%). Results When non-obese subjects without OSA were used as the reference (FMD% (mean±SD) 10.1±6.3), endothelial function was found to be impaired in subjects with OSA (FMD% 6.4±3.2) (p=0.003). FMD% did not differ between obese (6.0±3.4) and non-obese (6.7±3.1) OSA subjects (p=0.3). By univariate linear regression analysis, AHI, BMI, gender and baseline brachial artery diameter were significantly associated with FMD%. When these variables were entered into a multivariate model, only AHI was significantly associated with FMD%. Conclusions OSA is associated with endothelial dysfunction independently of obesity and conventional risk factors.

Cardiac troponin T levels and exercise stress testing in patients with suspected coronary artery disease: the Akershus Cardiac Examination (ACE) 1 study

Whether reversible ischaemia in patients referred for exercise stress testing and MPI (myocardial perfusion imaging) is associated with changes in circulating cTn (cardiac troponin) levels is controversial. We measured cTnT with a sensitive assay before, immediately after peak exercise and 1.5 and 4.5 h after exercise stress testing in 198 patients referred for MPI. In total, 19 patients were classified as having reversible myocardial ischaemia. cTnT levels were significantly higher in patients with reversible myocardial ischaemia on MPI at baseline, at peak exercise and after 1.5 h, but not at 4.5 h post-exercise. In patients with reversible ischaemia on MPI, cTnT levels did not change significantly after exercise stress testing [11.1 (5.2–14.9) ng/l at baseline compared with 10.5 (7.2–16.3) ng/l at 4.5 h post-exercise, P=0.27; values are medians (interquartile range)]. Conversely, cTnT levels increased significantly during testing in patients without reversible myocardial ischaemia [5.4 (3.0–9.0) ng/l at baseline compared with 7.5 (4.6–12.4) ng/l, P<0.001]. In conclusion, baseline cTnT levels are higher in patients with MPI evidence of reversible myocardial ischaemia than those without reversible ischaemia. However, although cTnT levels increase during exercise stress testing in patients without evidence of reversible ischaemia, this response appears to be blunted in patients with evidence of reversible ischaemia. Mechanisms other than reversible myocardial ischaemia may play a role for acute exercise-induced increases in circulating cTnT levels.