Prognostic importance of emerging cardiac, inflammatory, and renal biomarkers in chronic heart failure patients with reduced ejection fraction and anaemia: RED-HF study

Aims: To test the prognostic value of emerging biomarkers in the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial. Methods and results: Circulating cardiac [N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTnT)], neurohumoral [mid-regional pro-adrenomedullin (MR-proADM) and copeptin], renal (cystatin C), and inflammatory [high-sensitivity C-reactive protein (hsCRP)] biomarkers were measured at randomization in 1853 participants with complete data. The relationship between these biomarkers and the primary composite endpoint of heart failure hospitalization or cardiovascular death over 28 months of follow-up (n = 834) was evaluated using Cox proportional hazards regression, the c-statistic and the net reclassification index (NRI). After adjustment, the hazard ratio (HR) for the composite outcome in the top tertile of the distribution compared to the lowest tertile for each biomarker was: NT-proBNP 3.96 (95% CI 3.16–4.98), hsTnT 3.09 (95% CI 2.47–3.88), MR-proADM 2.28 (95% CI 1.83–2.84), copeptin 1.66 (95% CI 1.35–2.04), cystatin C 1.92 (95% CI 1.55–2.37), and hsCRP 1.51 (95% CI 1.27–1.80). A basic clinical prediction model was improved on addition of each biomarker individually, most strongly by NT-proBNP (NRI +62.3%, P < 0.001), but thereafter was only improved marginally by addition of hsTnT (NRI +33.1%, P = 0.004). Further addition of biomarkers did not improve discrimination further. Findings were similar for all-cause mortality. Conclusion: Once NT-proBNP is included, only hsTnT moderately further improved risk stratification in this group of chronic heart failure with reduced ejection fraction patients with moderate anaemia. NT-proBNP and hsTnT far outperform other emerging biomarkers in prediction of adverse outcome

A rapid (differential) effect of rosuvastatin and atorvastatin on high-sensitivity cardiac Troponin-I in subjects with stable cardiovascular disease

Serum troponin within the normal range is an emerging predictor of cardiovascular mortality. We aimed to determine how rapidly high‐sensitivity troponin‐I (hs‐cTnI) levels are lowered by statin therapy in patients with stable cardiovascular disease. In the RADAR substudy, patients were randomized to atorvastatin 20 mg/day (n = 39) or rosuvastatin 10 mg/day (n = 39) and up‐titrated at 6‐week intervals to 80 mg of atorvastatin or 40 mg of rosuvastatin. Hs‐cTnI concentrations were measured at baseline and at 6 and 18 weeks of follow‐up. Statin treatment resulted in a mean change of serum hs‐cTnI of –8.2% (P = 0.010) after 6 weeks and –12.3% (P = 0.001) after 18 weeks. After 18 weeks, hs‐cTnI levels were lowered by 21.8% with atorvastatin and by 4.1% with rosuvastatin (P = 0.001 and P = 0.133, respectively). During statin therapy, serum hs‐cTnI levels decreased rapidly within weeks of treatment, suggesting an effect beyond long‐term atherosclerosis regression. Mechanisms that mediate this effect require further study

Revisiting the obesity paradox in heart failure:Per cent body fat as predictor of biomarkers and outcome

Aims - Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure. We assessed whether another anthropometric measure, per cent body fat (PBF), reveals different associations with outcome and heart failure biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenesis-2 (sST2)). Methods - In an individual patient dataset, BMI was calculated as weight (kg)/height (m)2, and PBF through the Jackson–Pollock and Gallagher equations. Results - Out of 6468 patients (median 68 years, 78% men, 76% ischaemic heart failure, 90% reduced ejection fraction), 24% died over 2.2 years (1.5–2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4–33.0%) with the Jackson–Pollock equation, and 28.0% (23.8–33.5%) with the Gallagher equation, with an extremely strong correlation (r = 0.996, p 2, third PBF tertile), hs-TnT and sST2, but not NT-proBNP, independently predicted outcome. Conclusion - In parallel with increasing BMI or PBF there is an improvement in patient prognosis and a decrease in NT-proBNP, but not hs-TnT or sST2. hs-TnT or sST2 are stronger predictors of outcome than NT-proBNP among obese patients

Impact of diabetes on the predictive value of heart failure biomarkers

Altres ajuts: This study was funded by the Redes Temáticas de Investigación Cooperativa en Salud (RETICS); Red Cardiovascular (RD12/0042/0047) as part of the Plan Nacional de I+D+I.Patients with diabetes mellitus (DM) have an increased risk of developing heart failure (HF). Further, DM is associated with poor prognosis in patients with HF. Our aim was to determine whether DM has any impact on the predictive value of a multi-biomarker panel in patients with HF. We included 1069 consecutive ambulatory HF patients in the study: age 66.2 ± 12.8 years, 33.5 ± 13.3 left ventricular ejection fraction, 36% diabetic patients. We measured serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), ST2, galectin-3, high-sensitivity C reactive protein (hs-CRP), cystatin-C, soluble transferrin receptor (sTfR), and neprilysin and followed patients for 4.9 ± 2.8 years. Primary endpoints were all-cause and cardiovascular death. During follow-up, 534 patients died; 283 died of cardiovascular causes. Diabetic subjects had higher mortality (57.7 vs. 45.6%, p < 0.001). NTproBNP (p = 0.07), hs-TnT (p < 0.001), galectin-3 (p < 0.001), and cystatin-C (p = 0.001) concentrations were higher in diabetic patients, whereas sTfR levels were lower (p = 0.005). There were no interactions between DM and NTproBNP, hs-TnT, galectin-3, hs-CRP, cystatin-C, sTfR, and neprilysin relative to risk prediction for all-cause or cardiovascular death. By contrast, ST2 significantly interacted with DM for all-cause (p = 0.02) and cardiovascular (p = 0.03) death. In diabetic patients, HRs for ST2 were 1.27 (95% CI 1.16-1.40, p < 0.001) and 1.23 (95% CI 1.09-1.39, p = 0.001) for all-cause and cardiovascular death, respectively. In nondiabetic patients, HRs for ST2 were 1.53 (95% CI 1.35-1.73, p < 0.001) and 1.64 (95% CI 1.31-2.05, p < 0.001) for all-cause and cardiovascular death, respectively. The multivariable Cox regression analysis showed that hs-TnT and ST2 were the only markers that were independently associated with both all-cause and cardiovascular mortality in patients with HF and diabetes. Moreover, in these patients, the combination of these two markers significantly increased discrimination as assessed by the area under the curve. Biomarkers used in the general population to predict the clinical course of heart failure are also useful in patients with diabetes. In these patients, among all the biomarkers analysed only hs-TnT and ST2 were independently associated with both all-cause and cardiovascular mortality

Plasma CCN2/connective tissue growth factor is associated with right ventricular dysfunction in patients with neuroendocrine tumors

<p>Abstract</p> <p>Background</p> <p>Carcinoid heart disease, a known complication of neuroendocrine tumors, is characterized by right heart fibrotic lesions. Carcinoid heart disease has traditionally been defined by the degree of valvular involvement. Right ventricular (RV) dysfunction due to mural involvement may also be a manifestation. Connective tissue growth factor (CCN2) is elevated in many fibrotic disorders. Its role in carcinoid heart disease is unknown. We sought to investigate the relationship between plasma CCN2 and valvular and mural involvement in carcinoid heart disease.</p> <p>Methods</p> <p>Echocardiography was performed in 69 patients with neuroendocrine tumors. RV function was assessed using tissue Doppler analysis of myocardial systolic strain. Plasma CCN2 was analyzed using an enzyme-linked immunosorbent assay. Mann-Whitney U, Kruskal-Wallis, Chi-squared and Fisher's exact tests were used to compare groups where appropriate. Linear regression was used to evaluate correlation.</p> <p>Results</p> <p>Mean strain was -21% ± 5. Thirty-three patients had reduced RV function (strain > -20%, mean -16% ± 3). Of these, 8 had no or minimal tricuspid and/or pulmonary regurgitation (TR/PR). Thirty-six patients had normal or mildly reduced RV function (strain ≤ -20%, mean -25% ± 3). There was a significant inverse correlation between RV function and plasma CCN2 levels (r = 0.47, p < 0.001). Patients with reduced RV function had higher plasma CCN2 levels than those with normal or mildly reduced RV function (p < 0.001). Plasma CCN2 ≥ 77 μg/L was an independent predictor of reduced RV function (odds ratio 15.36 [95% CI 4.15;56.86]) and had 88% sensitivity and 69% specificity for its detection (p < 0.001). Plasma CCN2 was elevated in patients with mild or greater TR/PR compared to those with no or minimal TR/PR (p = 0.008), with the highest levels seen in moderate to severe TR/PR (p = 0.03).</p> <p>Conclusions</p> <p>Elevated plasma CCN2 levels are associated with RV dysfunction and valvular regurgitation in NET patients. CCN2 may play a role in neuroendocrine tumor-related cardiac fibrosis and may serve as a marker of its earliest stages.</p

Interleukin-1 has opposing effects on connective tissue growth factor and tenascin-C expression in human cardiac fibroblasts.

Cardiac fibroblasts (CF) play a central role in the repair and remodeling of the heart following injury and are important regulators of inflammation and extracellular matrix (ECM) turnover. ECM-regulatory matricellular proteins are synthesized by several myocardial cell types including CF. We investigated the effects of pro-inflammatory cytokines on matricellular protein expression in cultured human CF. cDNA array analysis of matricellular proteins revealed that interleukin-1α (IL-1α, 10ng/ml, 6h) down-regulated connective tissue growth factor (CTGF/CCN2) mRNA by 80% and up-regulated tenascin-C (TNC) mRNA levels by 10-fold in human CF, without affecting expression of thrombospondins 1-3, osteonectin or osteopontin. Western blotting confirmed these changes at the protein level. In contrast, tumor necrosis factor α (TNFα) did not modulate CCN2 expression and had only a modest stimulatory effect on TNC levels. Signaling pathway inhibitor studies suggested an important role for the p38 MAPK pathway in suppressing CCN2 expression in response to IL-1α. In contrast, multiple signaling pathways (p38, JNK, PI3K/Akt and NFκB) contributed to IL-1α-induced TNC expression. In conclusion, IL-1α reduced CCN2 expression and increased TNC expression in human CF. These observations are of potential value for understanding how inflammation and ECM regulation are linked at the level of the CF

Adjuvant kjemoterapi ved stadium III tykktarmskreft hos pasienter over 75 år

TITLE Adjuvant chemotherapy for stage III colon cancer in patients older than 75 years. BACKGROUND In Norway, a chronological age limit of 80 years for receiving adjuvant chemotherapy after resection of stage III colon cancer is suggested in the national guidelines. In the United States, nearly 40 % of the 80- year old patients receive adjuvant chemotherapy. The prevalence of colon cancer is increasing, especially in elderly people. OBJECTIVE To study the literature concerning the problem of whether to treat older patients with stage III colon cancer with adjuvant chemotherapy. METHODS A non-systematic literature search for articles in the Pubmed database concerning colon cancer, adjuvant treatment and elderly was conducted. Treatment guidelines were searched in BMJ, UpToDate, the Cochrane database, and in the newest guidelines for treatment of colorectal cancer in Norway. Individual patient cases from a prospective observational cohort study of patients 70 years and older operated for colorectal cancer in Norway were used as clinical examples. RESULTS Many articles, both reviews and original articles, were of interest. Studies show that a minority of elderly patients are offered adjuvant chemotherapy. A general problem is that elderly patients are underrepresented in clinical trials. Many studies have shown that selected elderly have the same survival benefit as younger patients, and acceptable toxicity. Other studies suggest that the benefit of adjuvant chemotherapy decreases with increasing age. CONCLUSION Studies show that selected elderly patients probably have the same benefit of adjuvant chemotherapy as younger patients, but information about effect and toxicity in the elderly is lacking. The heterogeneity of the elderly population is substantial, and the remaining life expectancy varies among individuals with the same chronological age. An individual assessment of each elderly patient, and not their chronological age, should be the determining factor of the treatment decision

Prognostic value of Troponin I elevation after Percutaneous Coronary Intervention

Background. We wanted to examine the prognostic value of elevated cardiac troponin I (cTnI) after percutaneous coronary intervention (PCI) in patients with unstable angina pectoris (UAP), one year after intervention. Material and methods. The charts to 157 patients with UAP who underwent PCI in 2001 were reviewed. We included 103 patients with TnI-values before and after PCI in the study. The patients were divided into two groups, depending on TnI-positive or TnI-negative before PCI. Demographic information was registered, together with TnI-values before and 16 – 24 hours after PCI. We defined events after one year as death (all-cause) or hospitalization with cardiovascular disease (angina pectoris, myocardial infarction, pulmonary edema, new PCI or ACB-operation). Results. Totally 31,1% of the patients had elevated TnI (>0,10ìg/L) after intervention. The pre-PCI TnI-negative patients with a de novo post-PCI TnI-elevation, had a statistically significant higher number of events, compared to those without post-PCI TnI-elevation (50,0% vs. 21,7%; p=0,024). The importance of post-PCI TnI-elevation was confounded by TnI-rise prior to PCI. Interpretation. This study indicates that TnI-elevation after PCI has an important prognostic value in patients with unstable angina pectoris. Especially in patients with de novo TnI-elevation

Totrinns-evaluering av geriatriske pasienter i akuttmottak

Bakgrunn/emne: Vi har i dag en økende andel eldre (>65 år) i befolkningen. Typisk for eldre pasienter er atypiske symptomer, betydelig komorbiditet og polyfarmasi. Dette kan vanskeliggjøre utredning/diagnostikk i akuttmottak. Mange eldre pasienter trenger en bred tilnærming i sykehus. Kunnskapsområdet eldre i akuttmottak oppfattes som et område hvor det kan gjøres betydelige kvalitetsforbedringer. Kunnskapsgrunnlaget: I litteraturen beskriver man et totrinnssystem som er validert for undersøkelse av eldre i mottak. ISAR (Identification of Seniors At Risk) og CGA (Comprehensive Geriatric Assessment) er verktøy som fokuserer på en skrøpelig eldres medisinske, psykologiske og funksjonelle kapasitet. Målet med disse verktøyene er å forbedre diagnostisering og behandling, samt å sette i gang en koordinert og integrert plan for behandling og langsiktig oppfølging. Det er vist at innføring av disse verktøyene i et akuttmottak kan forbedre overlevelse og funksjonalitet. Begrunnet tiltak, metode og organisering: Det ble utført et ikke-systematisk litteratursøk i ulike medisinske databaser på artikler om utredning og diagnostikk av eldre i akuttmottak. Det ble funnet flere artikler som omhandlet dette temaet, og vi valgte ut i fra disse å foreslå to-trinnsevaluering med ISAR og CGA som vårt kvalitetsforbedrende tiltak. Det ble også funnet retningslinjer basert på en omfattende litteraturgjennomgang som viser at eldre har nytte av en bred tilnærming i sykehus. Tiltaket skal innføres på akuttmottaket på et sykehus uten geriatrisk avdeling over en periode på 12 måneder. Man legger opp til en syklisk tilnærming. Resultater/ Vurdering: Innføring av vårt tiltak er viktig for å fange opp de eldre pasientene som trenger en bred tilnærming og diagnostisk tankegang. Totrinns-evaluering med ISAR og CGA kan bidra til en forbedring og bevisstgjøring av sykepleiere og leger. Motstand mot tiltaket og ekstraarbeid for involvert helsepersonell, vil trolig være den største utfordringen i gjennomføringen. Et klart mål for oss var å finne validerte verktøy som kunne brukes i et travelt akuttmottak