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BACKGROUND N-terminal pro-brain natriuretic peptide (Nt-proBNP) and N-terminal pro-atrial natriuretic peptide (Nt-proANP) are strong cardiovascular risk markers in patients with chronic heart failure, as well as in the general population. We investigated whether high Nt-proBNP or Nt-proANP could also predict the composite endpoint (CEP) of cardiovascular death, non-fatal stroke or non-fatal myocardial infarction in patients with hypertension and left ventricular (LV) hypertrophy. METHODS After 2 weeks of placebo treatment, clinical, laboratory and echocardiographic variables were assessed in 183 hypertensive participants in the LIFE echo substudy with electrocardiographic LV hypertrophy. Nt-proBNP and Nt-proANP were measured by immunoassay at baseline. The patients were followed for 60 +/- 5 months. RESULTS Using Cox regression analysis, the 25 CEP were predicted by ln(Nt-proBNP) (hazard ratio 1.61 per 2.73-fold increase, P < 0.01) as well as ln(Nt-proANP) (hazard ratio 2.93, P < 0.05). Nt-proBNP above the median value of 21.8 pmol/ml was associated with higher incidence of CEP (19.6 versus 7.7%, P < 0.05). Nt-proBNP above the median value was associated with higher incidence of CEP in the 123 patients without history of diabetes or cardiovascular disease (14.8 versus 4.3%, P < 0.05), but the association was insignificant in the 60 patients with a history of diabetes or cardiovascular disease (26.3 versus 18.2%, NS). Nt-proANP showed the same tendency. CONCLUSION Nt-proBNP, more than Nt-proANP, strongly predicts cardiovascular events in patients with hypertension and LV hypertrophy, especially in patients without diabetes or clinically overt cardiovascular disease.

Heart failure (HF) treatment guidelines of the ESC recommend ACE-inhibitors (ACE-I) as first-line treatment and beta-blockers added if patients remain symptomatic. CARMEN explored the need for combined treatment for remodelling and order of introduction by comparing the ACE-I enalapril against carvedilol and their combination.In a parallel-group, 3-arm study of 18 months duration, 572 mild heart failure patients were randomly assigned to carvedilol (N = 191), enalapril (N = 190) or their combination (N = 191). In the latter, carvedilol was up-titrated before enalapril. Left ventricular (LV) remodelling was assessed by transthoracic echocardiography (biplane, modified Simpson) at baseline and after 6, 12 and 18 months of maintenance therapy. Primary comparisons considered the change in LV end-systolic volume index (LVESVI) from baseline to month 18 between the combination and enalapril, and between carvedilol and enalapril.In the first primary comparison, LVESVI was reduced by 5.4 ml/m2 (p = 0.0015) in favour of combination therapy compared to enalapril. The second primary comparison tended to favour carvedilol to enalapril (NS). In the within treatment arm analyses, carvedilol significantly reduced LVESVI by 2.8 ml/m2 (p = 0.018) compared to baseline, whereas enalapril did not. LVESVI decreased by 6.3 ml/m2 (p = 0.0001) with combination therapy. All three arms showed similar safety profiles and withdrawal rates.CARMEN is the first study to demonstrate that early combination of ACE-I and carvedilol reverses LV remodelling in patients with mild to moderate HF and LV systolic dysfunction. The results of the CARMEN study support a therapeutic strategy in which the institution of beta-blockade should not be delayed.

Summary objective N-terminal B-type natriuretic peptide (NT-pro-BNP) is secreted from the cardiac ventricles in response to volume expansion and pressure overload, and serum levels are elevated in systolic heart failure. The aim of this study was to evaluate the influence of thyroid function on NT-pro-BNP. design Patients with overt or subclinical thyroid disease were evaluated before and after treatment for their dysthyroid state. patients Seventeen overt and 21 subclinical hypothyroid patients together with six subclinical and 13 overt hyperthyroid patients without cardiac disease were included. Subclinical states had, by definition, free T4 and free T3 estimates within reference ranges. measurements Serum levels of NT-pro-BNP and thyroid hormones were measured, and in 31 patients resting cardiac output was measured by impedance cardiography in the untreated state. results NT-pro-BNP levels were more than four times higher in hyperthyroid than hypothyroid patients, with mean values of 30 and 7 pmol/l, respectively (P

Background Studies on the effect of heart failure clinics have been encouraging and convincing with respect to reduced hospitalizations, improved quality of life, and reduced cost. However, previous results have been derived from patient populations either recently discharged and with specific exclusion criteria or from heart transplant lists. We here report the establishment of a heart failure clinic that offers an integrated approach to both diagnosing and managing heart failure patients, the baseline characteristics of the first 283 patients treated, and the impact on heart failure hospitalizations during establishment. Methods Since September 1, 1999, a heart failure clinic has been in operation at Frederiksberg University Hospital. The clinic was designed with both a diagnostic and a therapeutic unit. The diagnostic unit offers open access to all patients with suspected heart failure, either through referral from general practitioners or from the medical departments of the hospital. In the case of confirmed systolic heart failure, the patient is referred to the therapeutic unit for (1) uptitration and optimization of medical therapy and thorough information and education. In addition, the unit offers a rapid access track and the possibility of intravenous diuretic treatment. Results During the 21 months of operation, a total of 460 patients were referred to the clinic. Of these, 320 (70%) were found to have clinical evidence of heart failure, and 283 (88% of the patients with heart failure) had left ventricular systolic dysfunction (defined by an ejection fraction of ≤45%). These patients were seen in the clinic for education, control of fluid retention, and uptitration of medications. These patients with left ventricular dysfunction were predominantly elderly (aged 72.7 ± 10.7 y) and most often male (73%). Ischemic heart disease was the most common etiology (55%). Before referral, most patients with left ventricular dysfunction had been treated with none or only low-dose angiotensin-converting enzyme inhibitor (55%), and fewer than one third received β-blockers (29%). During the first year of operation of the clinic, there was a 23% decline of heart failure-related hospital admissions to the department of cardiology (from 396 to 306). Conclusion Patients with systolic heart failure are not always optimally treated. The establishment of a heart failure clinic, which offers the combination of diagnosing and managing congestive heart failure, appears to be efficient both in terms of therapy optimization and with respect to a concomitant decline in hospitalization for heart failure. (Am Heart J 2002;144:e2.)

Background/Objective: The aim of the Frederiksberg Heart Failure Study was to describe the epidemiology of heart failure in the general population among persons older than 50 years. This paper describes some aspects of the methodology of this study, especially regarding population sampling. Methods: From 1997 to 2000, a random sample of 1,088 women and men aged 50–89 years from the municipality of Frederiksberg (city of Copenhagen, Denmark) were invited to participate in the study; 764 subjects (70.2%) were examined (57% female). To optimize scientific information across age groups, we used age-stratified sampling, attempting to have at least 150 subjects in each age decade, i.e. 50–59 years (n = 240), 60–69 years (n = 208), 70–79 years (n = 190) and 80–89 years (n = 126). Each participant filled in a questionnaire and was submitted to an echocardiographic examination, an ECG and collection of blood samples. The group of invited subjects (divided into participants and nonparticipants) was compared with the background population with regard to hospital admissions due to cardiovascular diseases and mortality 1 year before and 1 year after sampling. Results: As a result of the sampling strategy, the sampling proportion increased from 2.86% in the age class 50–59 years to 4.43% in the age class 80–89 years, with no evidence of a sex difference. The participation proportion systematically decreased with age, from 75.2% in the age class 50–59 years to 57.5% in the age class 80–89 years, with no sex difference. Both participants and nonparticipants had admission rates for cardiovascular diseases similar to that of the background population during the year before sampling. However, the rate of admission was significantly increased (p = 0.025) during the year after the time of sampling, and this applied equally to participants and nonparticipants. The 1-year mortality rate was increased in the sample after sampling (p = 0.014). However, participants had a 1-year mortality rate very close to that of the background population, whereas nonparticipants had a 1-year mortality rate more than three times higher than that of the participants (p < 0.001). In terms of methodology, the echocardiographic assessment was examined as follows: the interobserver variability between two independent observers in measuring the ejection fraction by means of echocardiography was calculated, and overall agreement was found to be 93.2% (kappa value = 0.786), corresponding to a very good level of agreement. The interobserver coefficient of variation was 4.9%. Conclusion: In this population-based study, the increased mortality and admission rates among nonparticipants suggest that subjects who agree to participate in a study on heart failure are a biased sample, in that they represent relatively healthy subjects. The fact that the participation rate declined with age indicates a systematic age effect in this bias. Standard methods to assess how representative of the corresponding background population a study population is should be agreed upon for future studies.

OBJECTIVES The purpose of the study was to investigate the effects of beta 1 -blockade on left ventricular (LV) size and function for patients with chronic heart failure. BACKGROUND Large-scale trials have shown that a marked decrease in mortality can be obtained by treatment of chronic heart failure with beta-adrenergic blocking agents. Possible mechanisms behind this effect remain yet to be fully elucidated, and previous studies have presented insignificant results regarding suspected LV antiremodeling effects. METHODS In this randomized, placebo-controlled and double-blind substudy to the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF), 41 patients were examined with magnetic resonance imaging three times in a six-month period, assessing LV dimensions and function. RESULTS Decreases in both LV end-diastolic volume index (150 ml/m 2 at baseline to 126 ml/m 2 after six months, p = 0.007) and LV end-systolic volume index (107 ml/m 2 to 81 ml/m 2 , p = 0.001) were found, whereas LV ejection fraction increased in the metoprolol CR/XL group (29% to 37%, p = 0.005). No significant changes were seen in the placebo group regarding these variables. Left ventricular stroke volume index remained unchanged, whereas LV mass index decreased in both groups (175 g/m 2 to 160 g/m 2 in the placebo group [p = 0.005] and 179 g/m 2 to 164 g/m 2 in the metoprolol CR/XL group [p = 0.01]). CONCLUSIONS This study is the first randomized study to demonstrate that the beta 1 -blocker metoprolol CR/XL has antiremodeling effects on the LV in patients with chronic heart failure and consequently provides an explanation for the highly significant decrease in mortality from worsening heart failure found in the MERIT-HF trial.

OBJECTIVE: Impairment of left ventricular diastolic function, possibly caused by increased collagen cross-linking of the cardiac muscle, is common in patients with type 1 diabetes even without coronary artery disease. Advanced glycation end products (AGEs) cross-link tissue collagen and are found within myocardial fibers. The aim of this study was to examine for a possible association between circulating AGEs and left ventricular cardiac function. RESEARCH DESIGN AND METHODS: Left ventricular diastolic and systolic function were assessed by M-mode and Doppler echocardiography in 52 patients with type 1 diabetes, age 40 +/- 13 (mean +/- SD) years, diabetes duration 17 +/- 13 years, and HbA1c 8.3 +/- 1.1%. Serum levels of AGEs and N epsilon-(carboxymethyl)lysine (CML) were measured by newly developed competitive immunoassays. RESULTS: A positive correlation was found between serum levels of AGEs and isovolumetric relaxation time (IVRT), r = 0.46 (P < 0.0008), and left ventricular diameter during diastole, r = 0.37 (P < 0.008). The systolic parameters did not correlate with serum levels of AGEs. Stepwise regression analysis showed that 21% of the IVRT variation could be explained by serum levels of AGEs (F = 11.4, P < 0.002), whereas serum levels of CML, HbA1c, albumin excretion rate, diabetes duration, and mean arterial blood pressure were of no importance. AGE levels were significantly increased in men compared with women (P < 0.03) and present or former smokers (P < 0.04). CONCLUSIONS: Increased serum levels of AGEs, unlike serum levels of CML, are associated with heart stiffness in patients with type 1 diabetes, possibly mediated by the cross-linking properties of AGEs.

Endothelial dysfunction is a well-established aspect of the pathophysiology of patients with systolic heart failure. We have previously reported that patients who have had multiple current or previous hospital admissions for decompensated heart failure have consistently shown abnormal levels of plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and soluble E-selectin (E-sel, an index of endothelial activation), as well as other indices of endothelial perturbation.To investigate if endothelial abnormalities extend to CHF outpatients who have only been recently diagnosed or have relatively mild or few, stable symptoms (at baseline), given the better prognosis in these patients, we performed a cross-sectional analysis of CHF patients, where vWf and E-sel levels (as indices of endothelial perturbation) were measured (ELISA) and related to left ventricular ejection fraction (LVEF), exercise capacity (6-min walk test) and N-terminal pro-Brain Natiuretic Peptide (NT-proBNP).There were no statistically significant differences in vWf and E-sel levels amongst patients with systolic heart failure compared to controls. Plasma NT-proBNP levels in patients with CHF were significantly elevated compared to controls (p0.0001). Among the patients with CHF, higher NT-proBNP levels correlated with poorer LVEF [Spearman r=-0.244, p0.004] and shorter 6-min walk distance [Spearman r=-0.226, p=0.045] but not NYHA class. Plasma vWf or E-sel levels did not correlate with LVEF, 6-min walk test or NYHA class. NT-proBNP levels correlated weakly with E-sel [Spearman r=-0.211, p=0.015] but not vWf.The present observation suggests that stable CHF outpatients with few symptoms may in fact have less severe endothelial perturbation, as reflected by plasma indices such as vWf and E-selectin. There was limited association of endothelial indices to LVEF, exercise capacity, NYHA class and NT-proBNP levels.

Ramipril 10 mg/day reduced regurgitation in chronic mitral regurgitation secondary to mitral valve prolapse in patients with sinus rhythm.

ObjectiveTo evaluate the influence of a history of arterial hypertension on the efficacy of the angiotensin converting enzyme (ACE) inhibitor trandolapril in patients with acute myocardial infarction (AMI) and left ventricular dysfunction.MethodsA retrospective analysis of data from the Trandolapril

Aim The aim of this study was to estimate the prognostic information to be gained from ventricular fibrillation in patients with myocardial infarction. Methods and results We studied 4259 consecutive patients with myocardial infarction admitted to one centre in 1977–1988. Five hundred and twenty-eight (12·4%) of the patients had ventricular fibrillation in hospital. The following risk factors were included in multivariate models to estimate their importance for 30-day and long-term (median 7 year) prognosis: age, gender, ventricular fibrillation, congestive heart failure, pulmonary oedema, cardiogenic shock, other cardiac arrest and atrial fibrillation. We found that the odds ratio for death on days 6–30 was 6·34 (3·55–11·30, 95% confidence limits, P

Background— Renal dysfunction is an important prognostic factor in heart failure (HF), but whether this dysfunction progresses to end-stage renal disease (ESRD) is unknown. Therefore, we examined incidence and predictors of ESRD in outpatients with HF. Methods and Results— Patients with systolic HF were identified in The Danish Heart Failure database and new-onset ESRD from the Danish Registry on Dialysis. Renal function was estimated by The Chronic Kidney Disease Epidemiology Collaboration equation and patients grouped by estimated glomerular filtration rate (eGFR)—group I: ≥60 mL/min per 1.73 m 2 , group II: 30 to 59 mL/min per 1.73 m 2 , group III: 15 to 29 mL/min per 1.73 m 2 , group IV: 2 . Cox hazard models for time to ESRD, to death, and the composite end point of ESRD or death were constructed and predictors of ESRD identified. A total of 8204 patients were included in the analyses. Median age was 70 years (Q, 61–77), 28% were women, median left ventricular ejection fraction was 30% (Q, 24–40), and median eGFR was 68 (Q, 51–85) mL/min per 1.73 m 2 . Forty-one patients developed ESRD (1.3/1000 patient-years). Baseline eGFR group II ( P P P P =0.049), need of diuretics, and age P =0.016) were associated with time to ESRD. Conclusions— ESRD is rare in outpatients with systolic HF and is mainly observed in patients with an eGFR 2 . A low eGFR, age

AIMS: Low prevalence of detectable cardiac troponin in healthy people and low-risk patients previously curtailed its use. With a new high-sensitive cardiac troponin assay (hs-cTnT), concentrations below conventional detection may have prognostic value, notably in combination with N-terminal pro-B-type natriuretic peptide (NT-pro-BNP). METHODS AND RESULTS: Biomarker concentrations were determined from serum obtained at enrolment in the CLARICOR trial involving 4197 patients with stable coronary artery disease (CAD) followed for 2.6 years. Serum hs-cTnT was detectable (above 3 ng/l) in 78% and above the conventional 99th percentile (13.5 ng/l) in 23%. Across all levels of hs-cTnT there was a graded increase in the risk of cardiovascular death after adjustment for known prognostic indicators: hazard ratio (HR) per unit increase in the natural logarithm of the hs-cTnT level, 1.49; 95% confidence interval (CI), 1.23-1.81; similarly for all-cause mortality (HR 1.48, 95% CI 1.29-1.70) and myocardial infarction (HR 1.37, 95% CI 1.13-1.67). Increasing values of hs-cTnT were associated with increased mortality across all values of NT-pro-BNP, but this was particularly prominent when NT-pro-BNP >400 ng/l. CONCLUSIONS: In patients with stable CAD, any detectable hs-cTnT level is significantly associated with all-cause mortality, cardiovascular death, and myocardial infarction after adjustment for traditional risk factors and NT-pro-BNP. Excess mortality is particularly pronounced in patients with NT-pro-BNP >400 ng/l.

UNLABELLED: The objective of this study is to describe the agreement between randomized trial outcome assessment by committee and outcomes entirely identified through public registers.METHODS: In the CLARICOR trial, 4,372 patients with stable coronary heart disease received a short course of clarithromycin versus placebo and were followed up for 2.6 years. The pertinent hospital records and death certificates had originally been evaluated by the adjudication committee using common definitions of outcomes mapped into a 6-category list. We now mechanically converted the International Classification of Diseases-coded diagnoses of the public registries into the same categories. After cross-tabulation of the committee diagnoses with National Patient Register diagnoses and Register of Causes of Death, we calculate agreement and compare the estimated intervention effects of the 2 data sets.RESULTS: With public register data, the protocol-specified categories were slightly more frequent. Overall agreement was 74% for hospital discharges and 60% for cause of death, but the intervention effect, expressed as a hazard ratio, stayed within 4% of the value originally obtained with the adjudication committee (P≥ .35).CONCLUSIONS: Our results show a modest agreement between formal adjudication and outcomes deducible from public registers. However, the estimated intervention effect did not differ noticeably between the 2 data sources. If studies on a wide range of public registers confirm these findings, register outcomes may be considered as a replacement for adjudication committees.

Aims This study was designed to evaluate a new NT-proBNP monitoring concept in outpatients with systolic heart failure (HF). Methods and results This was a multicentre, prospective randomized open-label blinded endpoint study. A total of 407 systolic HF patients were allocated to either clinical management (n = 208) or clinical management + NT-proBNP monitoring (n = 199) and followed for 2.5 years. If NT-proBNP increased >30%, a clinical checklist was completed and treatment initiated. The patients were matched at randomization and were 73 years old, 25% were females, 85% were NYHA class I–II, LVEF was 30%, and NT-proBNP 1955 pg/mL. NT-proBNP monitoring did not improve outcome, the hazard ratio for the primary composite endpoint (death or a cardiovascular admission) being 0.96 [95% confidence interval (CI) 0.71–1.29, P = 0.766]. NT-proBNP monitoring did not induce a significant change in the pharmacological strategy (P > 0.05 for all comparisons). In patients in whom NT-proBNP increased >30% (25% of the patients) during follow-up, a higher frequency of admission (69% vs. 47%, P = 0.002), a higher number of admission days (14 vs. 5 days, P = 0.003) and number of admissions (2 vs. 1, P = 0.009), and a lower quality of life (P = 0.032) and a poorer functional class (37% vs. 18% in NYHA class III–IV, P < 0.001) were observed. Conclusions Adding serial measurements of NT-proBNP to optimal clinical management was not associated with a change in pharmacological strategy and did not improve outcome. However, survivors in whom NT-proBNP increased >30% showed a poorer functional class, clinical outcome, and quality of life. Trial registration www.centerwatch: 173491 (NorthStar).

Background Outpatient follow-up in specialized heart failure clinics (HFCs) is recommended by current guidelines and implemented in most European countries, but the optimal duration of HFC programmes has not been established. Nor is it known whether all or only high-risk patients, e.g. identified by NT-proBNP, might benefit from an extended HFC follow-up. Methods and results In a multi-centre setting, we randomly assigned 921 clinically stable systolic heart failure (HF) outpatients on optimal medical therapy to undergo either an extended follow-up in the HFC ( n = 461) or referral back to their general practitioner (GP) ( n = 460). The primary composite endpoint was death or a cardiovascular admission. Secondary endpoints included mortality, an HF admission, quality of life, number of days admitted, and number of admissions. The median age of the patients was 69 years; 23% were females; the median left ventricular ejection fraction was 0.30; and the median NT-proBNP was 801 pg/mL; 89% were in NYHA class I–II. The median follow-up was 2.5 years. Time-to-event did not differ between groups (HFC vs. GP) (HR: 1.17, 95% CI: 0.95–1.45, P = 0.149). The two groups did not differ with respect to any of the secondary endpoints at the follow-up ( P > 0.05 for all). In high-risk patients identified by NT-proBNP ≥1000 pg/mL, no benefit from HFC follow-up was found ( P = 0.721). Conclusion Irrespective of the level of NT-proBNP stable HF patients on optimal medical therapy do not benefit from long-term follow-up in a specialized HFC in a publicly funded universal access healthcare system. Heart failure patients on optimal medical therapy with mild or moderate symptoms are safely managed by their personal GP. Trial Registration: www.Centerwatch.com: 173491 (NorthStar).

Patients with diabetes mellitus have a high morbidity and mortality from acute myocardial infarction, the reason for which is not fully understood. The relationship between congestive heart failure symptoms, left ventricular ejection fraction, and long-term mortality was examined in 578 hospital survivors of acute myocardial infarction, 47 of whom had Type 2 (non-insulin-dependent) diabetes mellitus. None of the patients were treated with insulin. The prevalence of congestive heart failure during hospitalization was similar in patients with and without diabetes, although mean diuretic dose was higher in the former patients. Left and right ventricular ejection fraction was measured with radionuclide ventriculography in the second week after acute myocardial infarction. At discharge from the coronary care unit, patients with and without diabetes had similar left ventricular ejection fraction (with diabetes: median 46% vs without diabetes: median 43%; p = 0.89). Median right ventricular ejection fraction (62%) was within normal limits in both groups and did not differ statistically. Survival data were obtained for all patients. The 5-year mortality was increased in patients with diabetes compared with non-diabetic patients independent of left ventricular ejection fraction. Univariate analysis showed that the cumulative 5-year mortality rate was 53% in the group with diabetes compared with 43% in the non-diabetic group (p = 0.007). Using multivariate regression analysis presence of diabetes was found to have a significant association with long-term mortality after myocardial infarction, that was independent of age, history of hypertension, congestive heart failure symptoms during hospitalization or of either left or right ventricular ejection fractions at discharge. We conclude that the excess mortality in patients with non-insulin-dependent diabetes mellitus is not explained by available risk markers after myocardial infarction. Even though left ventricular ejection fraction and serum creatinine did not differ significantly, the apparent higher dose of Frusemide in patients with than without non-insulin-dependent diabetes mellitus might indicate that heart failure, it present, is more severe in patients with than in those without diabetes. The importance of diastolic dysfunction in this context needs to be determined.

Objective Individuals with diabetes mellitus (DM) have a considerably elevated risk of developing serious health problems including cardiovascular disease (CVD). Long-term elevated levels of blood glucose in nondiabetic individuals may also be associated with increased risk of CVD. The aim of this study was to investigate the relationships between glycated haemoglobin A1c (HbA1c) and CVD, DM and all-cause mortality. Subjects and design The Copenhagen City Heart Study is a prospective study of individuals from the Danish general population. The cohort was followed for 10 years via national registers with respect to incident CVD, DM and all-cause mortality. Follow-up was 100% complete. Results A total of 5127 subjects were included, of whom 597 had DM. In the nondiabetic population, HbA1c was significantly associated with incident CVD events in both univariate [hazard ratio (HR) 1.38, 95% CI 1.11–1.71] and multivariate analyses (HR 1.31, 95% CI 1.05–1.64). In the nondiabetic population, increased levels of HbA1c were correlated with developing DM. There was a threefold increase in risk of incident DM per unit increase in HbA1c with a univariate HR of 3.83 (95% CI 1.96–7.51). This relationship was essentially unchanged after multivariate adjustments (HR 4.19, 95% CI 2.01–8.71). Furthermore, we found that net reclassification improvement for diagnosed DM and CVD was significantly improved with the addition of HbA1c in the analyses. Although not statistically significant, we found a strong trend towards an association between HbA1c and all-cause mortality (HR 1.21, 95% CI 0.99–1.47). We did not find the same associations amongst the population with DM. Conclusion In the Danish general population, HbA1c was strongly associated with CVD in individuals without DM.

Aim α-Defensins are part of the innate immune system. Low-grade inflammation seems to play a crucial role in development and progression of chronic heart failure (CHF). The aims of the present study were to compare plasma levels of α-defensins in CHF patients and healthy controls and to examine the predictive ability of α-defensins, alone and combined with N-terminal pro brain natriuretic peptide (NT-proBNP), with respect to all-cause mortality. Methods and results In a prospective observational study lasting 2.6 years we examined the prognostic value of plasma α-defensins with respect to mortality in 194 CHF patients, and compared plasma levels with those of 98 age-matched healthy controls. α-Defensin levels were twice as high among CHF patients in New York Heart Association (NYHA) functional class III–IV than in patients in NYHA class I–II and healthy controls (P = 0.001). The absolute increase in risk of mortality for patients with α-defensin levels in the upper tertile vs. the lowest tertile was 30% (P = 0.002). After adjusting for potential confounders including NT-proBNP, plasma α-defensins remained independently associated with an increased risk of all-cause mortality (hazard ratio 1.65, 95% confidence interval 1.19–2.28, P = 0.002) per 1 standard deviation increment in Ln (natural logarithm)-transformed α-defensin values. The combination of high α-defensins and NT-proBNP levels provided incremental prognostic information independent of well-known prognostic biomarkers in heart failure. Conclusion Plasma α-defensins appear to have prognostic information regarding mortality among patients with CHF and seem to provide incremental information to established clinical risk markers.

OBJECTIVES--To evaluate dependence of posture and exercise on the degree of mitral regurgitation using combined first pass and equilibrium radionuclide cardiography. DESIGN--24 patients with clinically stable chronic mitral regurgitation and sinus rhythm were studied by first pass list mode and simultaneous multigated frame mode equilibrium radionuclide cardiography using red cells labelled with technetium-99m. RESULTS--When patients changed posture from supine to sitting upright, left ventricular volumes decreased considerably. Regurgitation tended to increase in patients with valve prolapse but decreased in patients with ischaemic heart disease and dilated cardiomyopathy. During submaximal bicycle exercise cardiac output increased without dilatation of the left ventricle. The increase in left ventricular forward stroke volume was more pronounced than that in the total stroke volume, leading to a considerable decrease in the regurgitant flow through the mitral valve. The repeatability and observer variability of radionuclide determination of regurgitation was acceptable, with limits of agreement within about 10%. CONCLUSIONS--Change in posture induces a normal haemodynamic response in most patients with chronic mitral regurgitation; the effect of posture on regurgitation depends on the underlying disease. Mild to moderate exercise causes no deterioration in the severity of regurgitation.

All admissions to a coronary care unit (CCU) in Copenhagen County were prospectively registered over a 10-year period, from 1979 to 1988, i.e. after the introduction of CCUs but before the era of intervention with thrombolytic or prophylactic medical treatment. The catchment area remained nearly constant throughout the study period; all patients with MI were admitted to the CCU regardless of age and concomitant diseases, and treatment and discharge policy of the department was unchanged. A total of 4176 MI admissions were registered. During the study period, the age-specific incidence of MI decreased in males above 50 years of age, but was virtually unchanged in females, increasing the proportion of women in the MI population from 26 to 33%. In-hospital and 30-day mortality was unchanged. The occurrence of atrial fibrillation during the admission increased significantly (from 11 to 18%), while the incidence of ventricular fibrillation, heart failure and pulmonary oedema was unchanged.

The safety of treatment with digoxin in patients with acute myocardial infarction (MI) was investigated in 584 hospital survivors of MI. All patients were examined by radionuclide ventriculography, with determination of left ventricular ejection fraction (LVEF), close to the time of discharge. Clinical data were collected on admission. All patients were followed up with regard to death (median 6.2 years, range 3.9-7.8 years). Patients treated with digoxin (N = 172 (29%) were older (median 66 vs 59 years; (P < 0.001), had a higher incidence of diabetes (13% vs 7%; P = 0.025), and a lower LVEF (0.33 vs 0.49; P < 0.001). As expected, clinical heart failure was more frequent among them (84% vs 14%; P < 0.001), than in patients not receiving digoxin. The 1- and 5-year mortality of patients treated with digoxin was 38% and 74% compared to 8% and 26% in patients not receiving digoxin (P < 0.001). The increased risk associated with digoxin therapy remained statistically significant when patients were stratified according to the presence or absence of heart failure or atrial fibrillation/flutter during hospitalization, or to LVEF above or below 0.45 at discharge. In a proportional hazard model including age, LVEF, diabetes mellitus, heart failure, atrial fibrillation or flutter, ventricular fibrillation, gender, dose of furosemide at discharge and calcium antagonists and digoxin treatment as covariates, digoxin was independently associated with an increased risk of death (relative risk 1.8 (95% confidence limit 1.2-2.5)). We conclude that administration of digoxin may be harmful in hospital survivors of MI.

Objective In clinical trials, agreement on outcomes is of utmost importance for valid estimation of intervention effects. As there is limited knowledge about adjudicator agreement in cardiology, we examined the level of agreement among three cardiology specialists adjudicating all possible events in a randomized controlled clinical trial of patients with stable coronary heart disease. Study Design and Setting All information (hospital records, death certificates, etc.) was forwarded to two randomly selected blinded adjudicators. If they disagreed, the third arbiter had to choose the more likely of the two alternatives. Files of 5,475 nonfatal and 362 fatal events were evaluated. Results For nonfatal outcomes, pairwise kappa values ranged from 0.75 to 0.80. The three adjudicators had 4.3%, 9.5%, and 6.1% of their nonfatal outcome classifications overruled by their arbiter. If stable angina pectoris, unstable angina pectoris, and acute myocardial infarction were treated as one, agreement increased minimally. For fatal outcomes, the pairwise kappa values ranged from 0.65 to 0.90. The three adjudicators had 12%, 9%, and 10% of their death classifications overruled. Conclusion Specialists in cardiology can attain a reasonably high agreement on outcomes in patients with stable coronary heart disease.

Objectives: To elucidate potential mechanisms for the clarithromycin-induced excess mortality observed in the CLARICOR trial during 2.6 year follow-up of patients with stable coronary artery disease. Methods: Cox analyses using out-of-hospital death as a proxy for sudden death compared to in-hospital (nonsudden) death. Result: In 100 of 189 (53%) cardiovascular (CV) deaths in which it was possible to examine the question, there was a strong association between place of death and the classification of CV death as sudden or not-sudden. The excess mortality in the clarithromycin group was confined to sudden CV death in patients not on statins at trial entry (HR: 2.61, 95% CI: 1.69–4.05, p < 0.0005). Other categories of deaths showed no marked drug-placebo difference. Conclusions: Short-term clarithromycin administration was significantly associated with increased risk of sudden CV death in stable coronary heart disease patients not using statins.

Background This study was designed to assess whether pharmacologically treated depression was associated with increased mortality risk in systolic heart failure (SHF) patients. Methods Patients ( n =3346) with SHF (left ventricular ejection fraction≤0.45) and primarily New York Heart Association (NYHA) classes II–III (78%) were recruited from a clinical database used in 20 heart failure clinics in Denmark. The association between pharmacologically treated depression identified by at least one prescription of an antidepressant and mortality risk was evaluated. Results Follow-up time was 540days (range: 30–1600days). 539 patients died. For 243 patients (7%) an antidepressant had been prescribed at least once. In a Cox Proportional Hazard Model, pharmacologically treated depression was associated with a 49% increased mortality risk (Hazard ratio: 1.49, 95% confidence interval: 1.03–2.16) after adjustment for traditional confounders. Three months after the baseline visit in the heart failure clinic, these patients received lower doses of beta-blockers than patients without antidepressant therapy ( p =0.006). Female sex ( p p =0.007) were associated with the prescription of an antidepressant. Conclusions Our analyses suggest that pharmacologically treated depression is associated with a 49% increased mortality risk, and that these high-risk patients receive lower doses of beta-blockers than patients with no antidepressant therapy.

The use of magnetic resonance (MR) velocity mapping in the quantification of aortic valvular blood flow was examined in 10 patients with angiographically verified aortic regurgitation. MR velocity mapping succeeded in identifying and quantifying the regurgitation in all patients, and the regurgitant volume determined with MR velocity mapping agreed well with the grade obtained by aortic root angiography (p < 0.02). The accuracy in quantification of the aortic valvular flow rate was demonstrated by a significant correlation between the stroke volume (ml) measured by MR velocity mapping and calculated from MR imaging of the left ventricular end-diastolic and end-systolic volumes in eight patients (Y = 0.89 x X + 11, r = 0.97, p < 0.001). This finding was confirmed by a good agreement between the net cardiac output (L/min) quantified with MR velocity mapping and simultaneous 125I-indicator dilution measurement in all subjects (Y = 0.89 x X + 0.08, r = 0.82, p < 0.01). In conclusion, MR velocity mapping may be used as a noninvasive tool in the quantification of aortic regurgitation.

Accessible online at: www.karger.com/journals/hed Type 2 diabetes increases the risk of coronary heart disease by a factor of 2–4. Haffner et al. [1] demonstrated that the 7-year mortality among type 2 diabetics without established ischemic heart disease (IHD) was similar to that of nondiabetics who had experienced a prior myocardial infarction (MI). The combination of type 2 diabetes and IHD further increased mortality by a factor of 2 [1]. Other long-term post-MI studies have demonstrated an approximately double mortality rate in diabetics versus nondiabetics [2]. The poor prognosis in diabetes is probably mainly due to both the high frequency of risk factors for IHD as well as more widespread coronary artery disease in diabetics, as also demonstrated in two articles in this issue of Heart Drug [3, 4]. Conventional pharmacological treatment modalities, such as fibrinolysis, ASA, statins, beta-blockers and ACE inhibitors, have proven their efficacy in high-risk patients with diabetes, IHD, or both, and a general pattern is that for any given treatment the effect is greater in diabetics than in nondiabetics, i.e. numbers needed to treat are smaller among diabetics. Despite this fact, diabetics are in general treated to a lesser extent than nondiabetics [2, 5]. This might simply be because physicians do not realize the severity of the diabetic disease, and because of problems with compliance in these patients due to the many drugs prescribed. In case of an acute MI, the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction I (DIGAMI I) study [6] suggested a beneficial effect on survival of acute glucose-insulin infusion in diabetics. This hypothesis is now being tested prospectively in the larger, ongoing DIGAMI II study, which also focuses on long-term glycemic control. The beneficial effect of prolonged good glycemic control on the development of IHD in diabetics has been a matter of controversy. In large prospective trials, both in type 1 diabetics – Diabetes Control and Complications Trial (DCCT) [7] – and type 2 diabetics – United Kingdom Prospective Diabetes Study (UKPDS) [8] – good glycemic control tended to, but did not conclusively demonstrate a beneficial effect on the development of cardiovascular disease (CVD). However, in the UKPDS trial in type 2 diabetics, the patients were at low risk of CVD, and established CVD at entry was an exclusion criterion. In contrast, in the follow-up of the Kumamoto trial [9] good glycemic control in type 2 diabetics conclusively demonstrated reduced events of CVD, and in the UKPDS a subgroup of overweight patients demonstrated a quite substantial benefit from metformin treatment on the devel

Aims We evaluated the applicability and prognostic importance of oral glucose tolerance testing (OGTT) among outpatients with systolic heart failure (SHF). Methods and results Consecutive patients with SHF and left ventricular ejection fraction (LVEF) ≤ 45% referred to a heart failure clinic (n= 413) were included in this study. An OGTT was conducted in patients without a history of diabetes. Information on NYHA class, aetiology of SHF, LVEF, treatment, and biochemical parameters were collected at baseline. The survival status was obtained after a median follow-up time of 591 days. Of the 413 patients, 82 (20%) had known diabetes. Of the remaining 331 patients, 227 (69%) agreed to undergo an OGTT. Among the tested subjects, 136 (60%) were classified as having normal glucose tolerance (NGT), 51 (23%) impaired glucose tolerance (IGT), and 40 (18%) newly diagnosed diabetes. Assuming a similar prevalence of unrecognized diabetes among the patients who refused OGTT, the prevalence of diabetes in the total population was 34%. If only fasting blood glucose had been used, 16 of the 40 newly diagnosed diabetic patients would have been undiagnosed. During follow-up, 24 (29%) patients with known diabetes, 6 (15%) of the newly diagnosed diabetic patients, 9 (18%) of those with IGT, and 13 (9%) patients with NGT died. Patients with diabetes had higher mortality rate compared with non-diabetic patients [multivariate hazard ratio 1.89 (1.02–3.59); P = 0.047]. Conclusion It is feasible to perform diabetes screening using OGTT in outpatients with SHF. A substantial proportion of patients tested were found to have unrecognized diabetes. The presence of diabetes was associated with a higher mortality rate.

Background. Patients with stable coronary artery disease (CAD) have a poor prognosis. The aim of the study was to evaluate the extent to which serum high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement alone or together could be prognostic biomarkers in patients with stable CAD. Materials and methods. During the 2.6-year follow-up period 270 patients among the 4264 patients with stable CAD in the CLARICOR trial suffered myocardial infarction (MI) and 377 died (187 cardiovascular deaths (CVD)). Results. Serum NT-proBNP was significantly associated with MI (hazard ratio (HR), 1. 65 (refers to a 2.72 fold increase in serum level, p = 0.0005), CVD (HR, 2.42, p

Cardiac natriuretic peptides, BNP and NT-proBNP can be used to screen for left ventricular systolic dysfunction in patients with symptoms suggestive of heart failure. Using the cut-off values recommended in the article, the sensitivity and negative predictive values are high in patients aged75 years, but have lower sensitivity at older age. In addition, natriuretic peptides are prognostic markers for mortality and cardiovascular hospitalization. BNP/NT-proBNP measurement may also be of value in follow-up on heart failure patients.

Udgivelsesdato: 2010-Jun-7 Abstract Objectives. Patients with chronic heart failure (CHF) have an exaggerated immune response, endothelial damage/dysfunction, and increased risk of diabetes mellitus (DM). The inter-relationship(s) between indices of complement activation (soluble membrane attack complex, sMAC), inflammation (hsCRP), endothelial activation (soluble E-selectin, sEsel)), endothelial damage/dysfunction (von Willebrand factor, vWf) and insulin resistance (IR) and prognosis in CHF remains unknown. Design. We investigated the association(s) between plasma sMAC, hsCRP, sEsel, vWf and IR (assessed by homeostatic model assessment, HOMA) in a prospective study including a total of 193 patients with CHF, and assessed whether high levels of these biomarkers had a prognostic impact. Biomarker levels in CHF patients were compared to 100 age-matched controls. Results. Plasma sMAC levels were elevated in patients with CHF due to ischemic heart disease (IHD) as compared with CHF patients with non-ischemic ethiology (p=0.02), but were not predictive of survival or progression of CHF. A moderate strong relation between sMAC and sEsel levels was found beta=0.33 (p

The study evaluated the use of age-related decision limits for N-terminal pro-B-type natriuretic peptide (NT-proBNP), for ruling out suspected systolic dysfunction in symptomatic patients in primary care, compared with the present standards.Data were obtained from 5508 patients from 10 studies in the UK, New Zealand, Europe, and USA. All have had NT-proBNP analysis and echocardiography. The median age was 62 years (range 18-100 years) with a prevalence of reduced left ventricular systolic function (left ventricular ejection fractionor =40%) of 18%. In a receiver operating characteristic curve analysis, overall area under the curve (AUC) was 0.89. When looking at different age groups, AUC was highest (0.95) for50 years, intermediate (0.90) for 50-75 years, and lowest (0.82) for75 years. Using optimized decision limits, sensitivity, specificity, and negative predictive values (NPVs) were:50 years (50 ng/L): 99.2, 57.2, and 99.7%; 50-75 years (75 ng/L): 95.9, 51.0, and 96.8%; and75 years (250 ng/L): 87.9, 53.7, and 92.4%, respectively. Using only a single decision value (125 ng/L for all ages) gave sensitivities of 89.1, 91.9, and 94.3%; specificities of 84.0, 69.1, and 29.3% and NPVs of 97.7, 97.6, and 93.4%. A decision value of 400 ng/L for all ages gave much lower sensitivities.In a large population of patients in primary care, the use of age-stratified NT-proBNP decision limits considerably improves performance over current standards, with an excellent NPV for exclusion of reduced left ventricular systolic function.

Udgivelsesdato: 2010-Apr The association observed between coronary heart disease (CHD) and Chlamydia (Chlamydophila) pneumoniae antibodies prompted, during the 1990s, several primary and secondary prevention trials with various antibiotics. In our CLARICOR trial, a randomized placebo-controlled trial in 4372 patients with stable CHD, a brief clarithromycin regimen was followed, unexpectedly, by increased long-term mortality. We now compare C. pneumoniae antibody levels at entry with population levels, with the patients' individual histories, and with their subsequent outcomes. IgG antibody levels were somewhat raised, but elevated IgA and IgG titers were unrelated to entry data (including prior acute myocardial infarction), except for an association with smoking and with not using statins. Hazards of mortality and of other outcomes tended to slightly increase with IgA and decrease with IgG titers, but the unfavorable clarithromycin effect was unrelated to antibody levels and remains unexplained. Smoking-related lung disease probably underlies the link between heart disease and increased IgG titers.

The value of thrombolytic therapy in myocardial infarction is well established, while any beneficial effect of adjunct therapy is more uncertain. In a double-blind, randomized, parallel-group study the effect of combined intravenous infusions of streptokinase and isosorbide dinitrate (ISDN) on enzyme-estimated infarct size was investigated. One hundred consecutive patients with strong clinical and electrocardiographic suspicion of myocardial infarction, admitted to the coronary care unit within 8 hours after the onset of symptoms, were given a streptokinase infusion of 1.5 million units for 1 hour and a titrated dose of ISDN or placebo for 48 hours. From isoenzyme B of creatine kinase (CK-B) values measured every 4 hours, the infarct size was calculated and the possible presence of reperfusion was evaluated. The infarct size in patients receiving ISDN infusion was reduced (p = 0.04, one-sided test) compared with placebo. By subdividing the patients according to whether or not reperfusion had occurred, the infarct size appeared to be similar following ISDN and placebo in patients with reperfusion (419 versus 369 U/L), whereas the infarct size in patients not reperfused was markedly reduced after treatment with ISDN (223 versus 1320 U/L, p = 0.003). In conclusion, the present study demonstrates that the infarct size may be reduced by other means than reperfusion and it supports the use of combined infusion of thrombolytic agents and nitrates in patients with suspected myocardial infarction.

Aims It is unclear whether subclinical vascular damage adds significantly to Systemic Coronary Risk Evaluation (SCORE) risk stratification in healthy subjects. Methods and results In a population-based sample of 1968 subjects without cardiovascular disease or diabetes not receiving any cardiovascular, anti-diabetic, or lipid-lowering treatment, aged 41, 51, 61, or 71 years, we measured traditional cardiovascular risk factors, left ventricular (LV) mass index, atherosclerotic plaques in the carotid arteries, carotid/femoral pulse wave velocity (PWV), and urine albumin/creatinine ratio (UACR) and followed them for a median of 12.8 years. Eighty-one subjects died because of cardiovascular causes. Risk of cardiovascular death was independently of SCORE associated with LV hypertrophy [hazard ratio (HR) 2.2 (95% CI 1.2–4.0)], plaques [HR 2.5 (1.6–4.0)], UACR ≥ 90th percentile [HR 3.3 (1.8–5.9)], PWV > 12 m/s [HR 1.9 (1.1–3.3) for SCORE ≥ 5% and 7.3 (3.2–16.1) for SCORE < 5%]. Restricting primary prevention to subjects with SCORE ≥ 5% as well as subclinical organ damage, increased specificity of risk prediction from 75 to 81% ( P < 0.002), but reduced sensitivity from 72 to 65% ( P = 0.4). Broaden primary prevention from subjects with SCORE ≥ 5% to include subjects with 1% ≤ SCORE < 5% together with subclinical organ damage increased sensitivity from 72 to 89% ( P = 0.006), but reduced specificity from 75 to 57% ( P < 0.002) and positive predictive value from 11 to 8% ( P = 0.07). Conclusion Subclinical organ damage predicted cardiovascular death independently of SCORE and the combination may improve risk prediction.

Congestive heart failure (CHF) has been associated with elevated biomarker levels reflecting chronic low-grade inflammation. YKL-40 is a biomarker with increasing levels in patients with cardiovascular disease (CVD) of increasing severity. Furthermore, YKL-40 is associated with all-cause and cardiovascular mortality. We investigated plasma YKL-40 levels in patients with CHF and evaluated the possible predictive value with respect to overall mortality and recurrent cardiovascular outcomes.Plasma YKL-40 was measured in 194 CHF patients and in 117 age-matched individuals without CVD.Median YKL-40 levels were approximately 77% higher in patients with CHF (106 (IQR, 66-184) ng/ml vs. 60 (IQR, 42-97) ng/ml, p0.0001). We found a trend towards an association of YKL-40 levels with urinary albumin/creatinine ratio (UACR) (beta = 0.12, p = 0.08). YKL-40 levels were not predictive of overall mortality (p = 0.59), major cardiovascular events (p = 0.23) or events of incompensation (p = 0.56).Plasma YKL-40 levels are elevated in patients with CHF but show no association with other clinical or paraclinical variables. YKL-40 levels were not predictive of overall mortality or incident cardiovascular events. Most likely, elevated YKL-40 levels in CHF patients are explained by the presence of concomitant diseases but a role of YKL-40 in low-grade inflammation is not excluded.

Udgivelsesdato: 2010-Feb In the CLARICOR trial, significantly increased cardiovascular (CV) and all-cause mortality in stable patients with coronary heart disease were observed after a short course of clarithromycin. We report on the impact of statin treatment at entry on the CV and all-cause mortality. The multicenter CLARICOR trial randomized patients to oral clarithromycin (500 mg daily; n = 2172) versus matching placebo (daily; n = 2201) for 2 weeks. Patients were followed through public databases. In the 41% patients on statin treatment at entry, no significant effect of clarithromycin was observed on CV (hazard ratio [HR], 0.68, 95% confidence interval [CI], 0.38-1.22; P = 0.20) or all-cause mortality (HR, 1.08; 95% CI, 0.71-1.65; P = 0.72) at 2.6-year follow up. In the patients not on statin treatment at entry, clarithromycin was associated with a significant increase in CV (HR, 1.90; 95% CI, 1.34-2.67; P = 0.0003; statin-clarithromycin interaction P = 0.0029) and all-cause mortality (HR, 1.33; 95% CI, 1.05-1.67; P = 0.016; statin-clarithromycin interaction P = 0.41). Multivariate analysis and 6-year follow up confirmed these results. Concomitant statin treatment in stable patients with coronary heart disease abrogated the observed increased CV mortality associated with 2 weeks of clarithromycin.

The objective of the present study was to test the hypothesis that circulating levels of insulin-like growth factor-I (IGF-I) are inversely associated with inflammatory processes in an elderly background population.We conducted a population-based study comprising 629 individuals, aged 50-89 years. Associations between plasma IGF-I versus interleukin 6 (IL-6) and the acute phase proteins high sensitive C-reactive protein (hsCRP) and YKL-40 were evaluated by linear regression analyses. Subsequently, the population was dichotomised at a CRP level of 3.0 mg/L and the associations were re-evaluated in the two subgroups.Adjusted for confounding variables, plasma IGF-I was inversely related to IL-6, hsCRP and YKL-40 (all P0.001). The strongest association was found for YKL-40 with a 34% reduction in YKL-40 per twofold increase in IGF-I. A significant inverse association between IGF-I and all markers of inflammation persisted in individuals with hsCRP below 3.0 mg/L whereas only YKL-40 was significantly associated with IGF-I in individuals with hsCRP above 3.0 mg/L.The data support the hypothesis of an inverse association between GH/IGF-I signalling and inflammation, and suggest that the relationship between the IGF-I and inflammation might be more predominant in healthy individuals with a low inflammatory activity.

Udgivelsesdato: 2008-Oct BACKGROUND: Randomized clinical trials have shown that newly discharged and symptomatic patients with chronic heart failure (CHF) benefit from follow-up in a specialized heart failure clinic (HFC). Clinical stable and educated patients are usually discharged from the HFC when on optimal therapy. It is unknown if risk stratification using natriuretic peptides could identify patients who would benefit from longer-term follow-up. Furthermore, data on the use of natriuretic peptides for monitoring of stable patients with CHF are sparse. AIMS: The aims of this study are to test the hypothesis that clinical stable, educated, and medical optimized patients with CHF with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels > or = 1,000 pg/mL benefit from long-term follow-up in an HFC and to assess the efficacy of NT-proBNP monitoring. METHODS: A total of 1,250 clinically stable, medically optimized, and educated patients with CHF will be enrolled from 18 HFCs in Denmark. The patients will be randomized to treatment in general practice, to a standard follow-up program in the HFC, or to NT-proBNP monitoring in the HFC. The patients will be followed for 30 months (median). RESULTS: Data will be collected from 2006 to 2009. At present (March 2008), 720 patients are randomized. Results expect to be presented in the second half of 2010. CONCLUSIONS: This article outlines the design of the NorthStar study. If our hypotheses are confirmed, the results will help cardiologists and nurses in HFCs to identify patients who may benefit from long-term follow-up. Our results may also indicate whether patients with CHF will benefit from adding serial NT-proBNP measurements to usual clinical monitoring.

The study aim was to determine whether urine albumin/creatinine ratio (UACR), high-sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (Nt-proBNP) added to risk prediction based on HeartScore and history of diabetes or cardiovascular disease. A Danish population sample of 2460 individuals was divided in three groups: 472 subjects receiving cardiovascular medication or having history of diabetes, prior myocardial infarction or stroke, 559 high-risk subjects with a 10-year risk of cardiovascular death above 5% as estimated by HeartScore, and 1429 low-moderate risk subjects with estimated risk below 5%. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (CEP) occurred in 204 subjects. CEP was predicted in all three groups by UACR (HRs: 2.1, 2.1 and 2.3 per 10-fold increase, all P0.001) or by hsCRP (HRs: 1.9, 1.9 and 1.7 per 10-fold increase, all P0.05), but not by Nt-proBNP (HRs: 1.1, 2.6 and 3.7 per 10-fold increase, last two P0.001) (P0.05 for interaction). In the low-moderate risk group, pre-specified gender adjusted (men/women) cutoff values of UACRor =0.73/1.06 mg mmol(-1) or hsCRPor =6.0/7.3 mg l(-1) identified a subgroup of 16% who experienced one-third of the CEPs. In the patient group, combined absence of high UACR and high Nt-proBNPor =110/164 pg ml(-1) (men/women) identified a subgroup of 52% who experienced only 15% of the CEPs. Additional use of UACR and hsCRP in subjects with low-moderate risk and UACR and Nt-proBNP in subjects with known diabetes of cardiovascular disease changed HeartScore risk classification significantly in 19% of the population.

Background C-reactive protein (CRP), a marker of inflammation, and insulin resistance (IR), a metabolic disorder, are closely related. CRP and IR have both been identified as significant risk factors of cardiovascular disease (CVD) after adjustment for conventional CVD risk factors. It is not clear whether CRP predicts CVD independent of IR. Design Prospective population-based study. Methods Two thousand three hundred and fifty-seven Danish men and women, recruited from the general population, aged 41–72 years, without major CVD at baseline were studied. Traditional and new risk factors were recorded at baseline. CRP was determined by a high-sensitivity assay, and IR was determined by the homoeostasis model assessment (HOMA-IR) method. Results Over a median follow-up of 9.4 years, the incidence of the prespecified CV event, defined as the composite event of CV death, nonfatal ischaemic heart disease and nonfatal stroke, amounted to 222 cases. In Cox proportional-hazard models, adjusted for age, sex, smoking habit, total cholesterol, waist circumference, levels of triglycerides and high-density lipoprotein-cholesterol, systolic and diastolic blood pressures, physical activity and HOMA-IR, the hazard ratio (95% confidence interval) of a CV event was 1.33 (1.14–1.55; 0.001) per standard deviation increase in log-transformed CRP level. In the same model, the hazard ratio of a CV event was 1.11 (1.02–1.21; P < 0.05) per standard deviation increase in HOMA-IR level. Conclusion In a general Danish population free of major CVD at baseline, both CRP and IR were significantly related to risk of CVD.

Several studies have documented the importance of troponin elevation as a prognostic marker in end-stage renal disease (ESRD). The reason for the elevated concentrations is not clarified. We do not know whether the different assays recognize the same patients within ESRD populations. The aim of this study was to compare concentrations of troponin measured by four different assays in a cohort of patients with ESRD, to investigate whether haemodialysis affects troponin concentrations, and to compare the prognostic potential of the different assays.We included 109 patients on chronic haemodialysis. Serum cardiac troponin T (cTnT) was measured pre- and postdialysis using Elecsys 2010 and troponin I (cTnI) using Access AccuTnI, Dimension RxL and AIA-600II.The cTnT assay had the highest percentage of elevated concentrations for all chosen cut-offs with a reduction in percentage of patients with elevated concentrations during haemodialysis. Elecsys 2010 and AIA-600II demonstrated a significant increased mortality with raised concentrations of troponin.The diverging results in previous studies are most likely based on substantial differences in the analytical performance of the assays. The prognostic value of cTnT appears superior to cTnI, which amplifies the prognostic significance of this cardiovascular marker in patients with ESRD.

The objective was to evaluate the prevalence of paroxysmal atrial fibrillation (PAF) in patients with heart failure (HF) due to systolic dysfunction.We included 79 patients (age 68 years, LVEF 30%) with HF and sinus-rhythm (SR) referred to a HF outpatient clinic. A 48 hours Holter ECG and a follow-up ECG were performed. RESULTS. One patient had one episode of PAF. Thirty-two (41%) patients had episodes of irregular atrial runs (AR). The numbers of QRS complexes during AR were 7.2+/-2.9 (mean+/-SD). Patients with AR were older than patients with SR, p =0.02 and more often of female sex, p =0.04. Multivariate logistic regression analysis showed that age and female sex were independently correlated with AR with adjusted OR of 1.1 (per year, 95% CI 1.02-1.14, p =0.01) and 4.0 (1.05-15.07, p =0.04), respectively. The presence of AR did not predict development of new-onset AF.Outpatients with HF due to systolic dysfunction did not present with PAF during 48 hours Holter, but had several episodes of AR. The clinical and prognostic importance of AR deserves further investigation.

The purpose of this analysis is to evaluate the cost effectiveness of ezetemibe coadministration compared to a shift to higher doses of simvastatin or to a more potent statin.The calculations are based on a Markov model in which a patient who does not attain the desired cholesterol outcome with simvastatin treatment is treated either with ezetemibe coadministration, or with increased simvastatin doses, or with a more potent statin. Calculations are conducted for a total of 72 different patient types followed over the remainder of their lives.Ezetemibe coadministration evaluated over the entire lifetime will be somewhat more expensive than simvastatin titration but must, however, be seen in relation to improved survival and increased quality of life. For the typical patient, treatment will be associated with costs of between DKK 50,000 and 100,000 per gained year of life, which cannot be deemed too expensive in relation to other interventions provided by the Health Authorities. For some patient types who receive treatment with a potent statin (atorvastatin), savings will also be possible here as well as an increase in life expectancy and quality of life.The results of the study indicate that ezetemibe coadministration is cost effective. The results are sustainable even with quite significant changes of the estimates used and taking into account uncertainties in the material and methods.

Although the metabolic syndrome (MetS) is positively associated with high-sensitivity C-reactive protein (hsCRP), negatively associated with N-terminal pro-brain natriuretic peptide (Nt-proBNP) and inconsequently related to urine albumin/creatinine ratio (UACR) they are all associated with cardiovascular events. Therefore, we wanted to determine the influence of MetS on the predictive values of UACR, hsCRP and Nt-proBNP. On the basis of the definition of MetS by the International Diabetes Federation, a Danish population sample of 1983 apparently healthy subjects was divided into three groups: 530 subjects without any elements of MetS, 1093 subjects with some elements of MetS and 360 subjects with MetS. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (composite cardiovascular end point, CEP) occurred in 204 subjects. In Cox-regression analyses adjusting for age, gender and smoking, all three cardiovascular risk markers predicted CEP independently of MetS. Despite no significant interaction with MetS, high log(hsCRP) was associated with CEP primarily in subjects without any elements of MetS (hazard ratio (HR)=4.5 (1.5-14.0), P0.01), log(Nt-proBNP) primarily in subjects with some elements of MetS (HR=3.0 (1.6-5.6), P0.01), and logUACR independently of elements of MetS. Pre-specified gender-adjusted (men/women) cutoff values of hsCRPor = 6.0/7.3 mg l(-1) predicted CEP in subjects without elements of MetS with positive and predictive values of 11.5 and 98%, respectively. UACRor = 0.73/1.06 mg mmol(-1) predicted CEP in subjects with MetS with positive and predictive values of 23.5 and 93%, respectively. In apparently healthy subjects, high hsCRP was associated with CEP primarily in subjects without MetS, high Nt-proBNP in subjects with elements of MetS and UACR independently of MetS.

Background: Endothelial dysfunction is present in patients with heart failure (HF) due to left ventricular systolic dysfunction, as well as in patients with atrial fibrillation (AF) who have normal cardiac function. It is unknown whether AF influences the degree of endothelial dysfunction in patients with systolic HF. Methods: We measured levels of plasma von Willebrand factor (vWF) and E-selectin (as indexes of endothelial damage/dysfunction and endothelial activation, respectively; both enzyme-linked immunosorbent assay) in patients with AF and HF (AF-HF), who were compared to patients with sinus rhythm and HF (SR-HF), as well as in age-matched, healthy, control subjects. We also assessed the relationship of vWF and E-selectin to plasma N-terminal pro B-type natriuretic peptide (NTpro-BNP), a marker for HF severity and prognosis. Results: One hundred ninety patients (73% men; mean age, 69.0 10.1 years [ SD]) with systolic HF were studied, who were compared to 117 healthy control subjects: 52 subjects (27%) were in AF, while 138 subjects (73%) were in sinus rhythm. AF-HF patients were older than SR-HF patients (p 0.046), but left ventricular ejection fraction and New York Heart Association class were similar. There were significant differences in NT-proBNP (p < 0.0001) and plasma vWF (p 0.003) between patients and control subjects. On Tukey post hoc analysis, AF-HF patients had significantly increased NT-proBNP (p < 0.001) and vWF (p 0.0183) but not E-selectin (p 0.071) levels when compared to SR-HF patients. On multivariate analysis, the presence of AF was related to plasma vWF levels (p 0.018). Plasma vWF was also significantly correlated with NT-proBNP levels (Spearman r 0.139; p 0.017). Conclusions: There is evidence of greater endothelial damage/dysfunction in AF-HF patients when compared to SR-HF patients. The clinical significance of this is unclear but may have prognostic value. (CHEST 2008; 133:1203–1208)

Screening of general populations with amino-terminal pro-B-type natriuretic peptides (NT-proBNP) holds promise for the detection of significant underlying cardiac structural and functional abnormalities, as well as for the early detection of the propensity to develop future cardiovascular events. In comparative studies to date, NT-proBNP performs at least as well as BNP in the detection of heart disease and prognostication in the general population. In some studies and subgroups, NT-proBNP appears to outperform BNP in population screening. More needs to be learned about noncardiac sources of NT-proBNP variation in "apparently well" populations. Better understanding of these factors may allow optimization of thresholds for screening of apparently well patients and concomitant delineation of patient populations in whom NT-proBNP screening is less appropriate.