Ragnhild Wergeland

Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients.

OBJECTIVES This study was initiated to determine whether heart transplant recipients (HTRs) with cardiac allograft vasculopathy (CAV) have increased levels of high-sensitivity C-reactive protein (hsCRP) and to examine whether an increase in hsCRP after heart transplantation predicts the development of CAV. Furthermore, the effect of pravastatin on plasma levels of hsCRP in HTRs was investigated. BACKGROUND The relationship between CAV and hsCRP, as well as the effect of statins on hsCRP in HTRs, has not been well established. METHODS On referral for their annual angiographic control study, 150 consecutive HTRs (mean 6.5 years since transplantation) were included. Plasma levels of hsCRP were measured before angiography and compared with patients with (n = 52) and without (n = 98) CAV. In 49 of these patients, we additionally analyzed hsCRP in blood samples stored from their six-month visit after the transplantation procedure. Furthermore, in a randomized, crossover study, hsCRP was analyzed in 17 male HTRs before and after six weeks of treatment with 20 mg pravastatin. RESULTS Median levels of CRP were elevated among patients with CAV compared with those with normal angiograms [3.86 (1.78 to 7.00) vs. 1.08 (0.72 to 2.13) mg/l, p < 0.001]. Prospectively evaluated hsCRP levels from six months to follow-up were significantly higher among those who developed CAV compared with those with normal angiograms [+2.76 (1.56 to 5.00) vs. +0.07 (-0.57 to 0.41) mg/l, p < 0.001]. On multivariate analysis, the increase in hsCRP was the only significant predictor of CAV. Six weeks of treatment with pravastatin significantly reduced hsCRP levels by 25%, without any relation to changes in lipid values. CONCLUSIONS Elevated plasma levels of CRP are associated with angiographic evidence of CAV, and the increase in hsCRP is a strong predictor of development of CAV. Statin treatment reduces levels of hsCRP and should be used in HTRs, regardless of their lipid levels.

Absence of enhanced systemic inflammatory response at 18 weeks of gestation in women with subsequent pre-eclampsia

Objective To compare indicators of systemic inflammatory response in the second trimester in women who developed pre‐eclampsia with normal pregnancies.

Effect of Thalidomide on Cardiac Remodeling in Chronic Heart Failure Results of a Double-Blind, Placebo-Controlled Study

Background— Inflammation and matrix degradation may play a pathogenic role in chronic heart failure (CHF), and therefore, we examined whether thalidomide, a drug with potential immunomodulating and matrix-stabilizing properties, could improve left ventricular (LV) function in patients with CHF secondary to idiopathic dilated cardiomyopathy (IDCM) or coronary artery disease (CAD). Methods and Results— Fifty-six patients with CHF and an LV ejection fraction (LVEF) <40% who were already on optimal conventional cardiovascular treatment were randomized to thalidomide (25 mg QD increasing to 200 mg QD) or placebo and followed up for 12 weeks. Our main findings were as follows: (1) During thalidomide treatment but not during placebo, there was a marked increase in LVEF (≈7 EF units) along with a significant decrease in LV end-diastolic volume and heart rate. (2) This improvement in LVEF was accompanied by a decrease in matrix metalloproteinase-2 without any changes in its endogenous tissue inhibitor, suggesting a matrix-stabilizing net effect. (3) Thalidomide also induced a decrease in total neutrophil count and an increase in plasma levels of tumor necrosis factor-α, suggesting both proinflammatory and antiinflammatory effects. (4) The effect of thalidomide on LVEF was more marked in IDCM than in CAD, possibly partly reflecting that the former group was able to tolerate a higher thalidomide dosage. Conclusions— Although our results must be confirmed in larger studies that also examine the effects on morbidity and mortality, our findings suggest a role for thalidomide in the management of CHF in addition to traditional cardiovascular medications.

Probrain natriuretic peptide and C-reactive protein as markers of acute rejection, allograft vasculopathy, and mortality in heart transplantation

Background. N-terminal probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) are useful in risk stratification of patients with congestive heart failure. They could also be markers of distinctly altered hormonal and immunological milieus, but the combined prognostic value of these biomarkers in heart transplant (HTx) recipients has not been assessed previously. Methods. We sought to assess the individual and combined value of NT-proBNP and CRP as markers of acute rejection, cardiac allograft vasculopathy (CAV) and all-cause mortality in HTx recipients. We evaluated 101 patients for acute rejection and 210 patients for CAV and all-cause mortality. Patients evaluated for rejection had serial endomyocardial biopsies and plasma sampling performed during the first year postHTx. All other patients had plasma samples taken upon inclusion at an annual visit. Median follow-up for CAV and all-cause mortality was 2.2 years and 5.4 years, respectively. Results. Altogether, 1131 biopsy procedures were performed, and increased NT-proBNP and CRP levels were not useful markers of acute cellular rejection. In total, 78 (37%) patients developed CAV, and 39 (19%) patients died. Neither biomarker was a predictor of CAV, but both were independent predictors of mortality. When combining both biomarkers, elevated levels of both NT-proBNP and CRP identified patients at highest risk for CAV (HR 2.10, P=0.01) and all-cause mortality (HR 3.14, P=0.01). Conclusions. In HTx recipients, NT-proBNP and CRP are not useful as markers of acute cellular rejection during the first year postHTx, but combined analysis adds significantly to their predictive value for development of CAV and all-cause mortality.

Soluble Glycoprotein 130 Predicts Fatal Outcomes in Chronic Heart Failure Analysis From the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)

Background— Glycoprotein 130 (gp130) is the common signal-transducing receptor subunit of the interleukin-6 (IL-6) family, which may be involved in the progression of heart failure (HF). We hypothesized that soluble gp130 would provide prognostic information beyond that of IL-6 in a population with HF from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Methods and Results— The associations of soluble gp130 and IL-6 with morbidity, mortality, and mode of death were assessed by immunoassays in a subset of 1452 patients enrolled in the CORONA trial, which included patients with HF, aged ≥60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. In multivariable analyses, including C-reactive protein, IL-6, troponin T, and N-terminal pro-B-type natriuretic peptide, elevated soluble gp130 (fifth quintile versus all lower quintiles) was associated with all-cause mortality (hazard ratio, 1.47 [1.11–1.93]; P =0.006), cardiovascular mortality (hazard ratio, 1.38 [1.01–1.87]; P =0.042), and death from worsening HF (hazard ratio, 1.85 [1.09–3.14]; P =0.002), but not with the primary end point (composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke; hazard ratio, 1.12 [0.84–1.50]; P =0.44). Plasma IL-6 was not associated with outcomes in multivariable analyses. Conclusions— Marked elevations in soluble gp130 are associated with total and cardiovascular mortality, as well as deaths from worsening HF, in elderly patients with HF of ischemic cause Clinical Trial Registration— URL: . Unique identifier: [NCT00206310][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00206310&atom=%2Fcirchf%2F6%2F1%2F91.atomBackground— Glycoprotein 130 (gp130) is the common signal-transducing receptor subunit of the interleukin-6 (IL-6) family, which may be involved in the progression of heart failure (HF). We hypothesized that soluble gp130 would provide prognostic information beyond that of IL-6 in a population with HF from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Methods and Results— The associations of soluble gp130 and IL-6 with morbidity, mortality, and mode of death were assessed by immunoassays in a subset of 1452 patients enrolled in the CORONA trial, which included patients with HF, aged ≥60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. In multivariable analyses, including C-reactive protein, IL-6, troponin T, and N-terminal pro-B-type natriuretic peptide, elevated soluble gp130 (fifth quintile versus all lower quintiles) was associated with all-cause mortality (hazard ratio, 1.47 [1.11–1.93]; P=0.006), cardiovascular mortality (hazard ratio, 1.38 [1.01–1.87]; P=0.042), and death from worsening HF (hazard ratio, 1.85 [1.09–3.14]; P=0.002), but not with the primary end point (composite of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke; hazard ratio, 1.12 [0.84–1.50]; P=0.44). Plasma IL-6 was not associated with outcomes in multivariable analyses. Conclusions— Marked elevations in soluble gp130 are associated with total and cardiovascular mortality, as well as deaths from worsening HF, in elderly patients with HF of ischemic cause Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Prognostic value of cardiac troponin T in patients with moderate to severe heart failure scheduled for cardiac resynchronization therapy.

BACKGROUND Predicting response to cardiac resynchronization therapy (CRT) is challenging. Highly sensitive cardiac troponin T (hsTnT) might predict response to CRT and identify patients at a high risk of experiencing severe cardiovascular events. We investigated whether baseline levels of hsTnT were associated with response to CRT and with severe cardiovascular events after long-term follow-up. METHODS Eighty-one consecutive patients were included according to the current guidelines for CRT. Biochemical, functional, and clinical parameters were assessed at baseline and at 3, 6, and 12 months of follow-up; and mortality/cardiac transplantation after 46 ± 6 months of follow-up was investigated. Cardiac magnetic resonance imaging and echocardiography were used to assess left ventricular function including viability and remodeling. RESULTS Seventy-five patients completed 12 months of follow-up; and after a follow-up of 46 ± 6 months, a total of 15 patients died, 13 of these from cardiovascular causes, and 7 underwent heart transplantation. Baseline hsTnT <15 ng/L predicted response to CRT and was associated with a more favorable outcome with regard to severe cardiovascular events. Multivariate analysis found that presence of transmural scar tissue/fibrosis on magnetic resonance imaging and use of statins were independently associated with higher concentrations of hsTnT at baseline. There was a strong correlation between hsTnT and N-terminal pro-B-type natriuretic peptide levels. CONCLUSIONS Highly sensitive TnT levels were elevated in the majority of heart failure patients who were scheduled for CRT. The HsTnT levels predicted response to CRT as well as long-time survival.

High-sensitive troponin T and N-terminal-brain-natriuretic-peptide predict outcome in symptomatic aortic stenosis.

Abstract Objectives. Aortic stenosis (AS) and atherosclerosis share similarities when it comes to risk factors and disease progression. Like in other heart diseases, we hypothesized that biomarkers like high-sensitive troponin T (hsTnT), N-terminal-pro-brain-natriuretic-peptide (NT-proBNP) and high-sensitive C-reactive protein (hsCRP) could be useful in risk stratification. Design. A total of 136 patients (57% men, mean age 74 years), referred for evaluation of AS (valve area 0.62 cm2, left ventricular ejection fraction 64%) were consecutively enrolled in the study. The relationship between hsTnT, hsCRP and NT-proBNP, different echocardiographic parameters of AS and cardiac function were investigated as well as their relation to all-cause mortality. Results. In contrast to hsCRP, hsTnT and NT-proBNP were individually correlated with prognosis. Regression analysis identified diabetes and the combination of hsTnT and NT-proBNP as significant predictors of all-cause mortality. When analyzing patients without surgery separately, only the combination of hsTnT and NT-proBNP were identified as a significant predictor of all-cause mortality in multivariable analysis. Conclusion. The combination of NT-proBNP and hsTnT came out as the strongest predictor of outcome irrespective of surgical treatment or not and could be of particular interest in risk-stratification in AS-patients. The results should be confirmed in prospective studies both in symptomatic and asymptomatic patients.

Inflammation and coronary angiography in asymptomatic type 2 diabetic subjects

Objective. Coronary artery disease (CAD) is prevalent in patients with type 2 diabetes mellitus (T2DM) and because it is often asymptomatic and extensive in comparison with CAD in subjects without diabetes, it represents a diagnostic challenge. The objective of the study was to investigate the prevalence of CAD in asymptomatic T2DM patients utilizing angiography and to investigate its association with cardiovascular (CV) risk factors, the metabolic syndrome and markers of inflammation. Material and methods. Eighty‐two patients with T2DM without symptoms of CAD, and with ⩾1 CV risk factor (hypertension, dyslipidaemia, premature familial CAD, smoking or microalbuminuria) underwent a diagnostic stress test and coronary angiography irrespective of stress test results. Stenosis detected in the main coronary arteries ⩾50% of lumen diameter was categorized as one‐, two‐ or three‐vessel disease. Inflammatory markers were analysed in fasting samples. Results. Fifteen men and two women had significant CAD (21%) (1‐vessel disease, n = 10; 2‐ or 3‐vessel disease, n = 7). Patients with 2‐ or 3‐vessel disease were significantly older and had a longer duration of diabetes, but the prevalence of other traditional CV risk factors or the metabolic syndrome was similar among those with 1‐vessel and those with 2‐ or 3‐vessel disease. Sensitivity for CAD of the stress test was low (0.35). The mean level of the pro‐inflammatory marker interleukin‐6 was elevated in patients with 2‐ to 3‐vessel CAD as compared to patients with no or 1‐vessel CAD (p<0.05). Conclusions. Significant CAD was found in 21% of asymptomatic patients with T2DM with ⩾1 CV risk factor. Inflammatory markers may be helpful in identifying patients that are likely to have significant CAD, but larger studies are warranted.

MicroCRP: a highly sensitive CRP method applied in the monitoring of renal allograft recipients

A new ultrasensitive fluoroimmunometric assay for C-reactive protein (CRP), called MicroCRP assay, has a lower detection limit of 0.05 mg/l, and a CV of 7.6% at concentration 0.25 mg/l. The microCRP levels in healthy adults show a skewed distribution, median 0.90 mg/l and mean 1.4 mg/l, with 2.5th and 97.5th percentiles of 0.17 and 4.7 mg/l, respectively, and no gender-related or age differences. Serial microCRP was applied in the monitoring of 37 renal allograft recipients. The operative trauma gave rise to an initial CRP peak, usually on day 2 after transplantation, with a return to preoperative value 1 week after surgery. There were significant CRP elevations (>25%) in all cases of rejections, indicating 100% sensitivity. The microCRP values started to increase about 3 days (range -1 to 9 days) before the rise in creatinine. The microCRP peak tended to be higher in rejection episodes with a vascular component, compared with episodes of cellular rejection (p=0.05). A rise in microCRP at days 7-12 after transplantation seems to predict the risk of rejections later on, and probably reflects the primary immune response to the graft. Recipients without this primary CRP response (only 6 of 37 patients) subsequently had uncomplicated courses. Tracking of values below the traditional lower limit is essential in order to recognize the different CRP peaks. Serial monitoring of microCRP is well suited for clinical use and provides clinical information previously unattainable with other assay systems.

Elevated serum uric acid levels following heart transplantation predict all-cause and cardiac mortality.

We evaluated the relationship between elevated serum uric acid (SUA) and mortality as well as cardiac allograft vasculopathy (CAV) among 184 heart transplant (HTx) recipients. We also measured inflammatory, neurohormonal, and oxidative stress markers to explore pathophysiological mechanisms.