SuPAR is associated with death and adverse cardiovascular outcomes in patients with suspected coronary artery disease.

BACKGROUND: The inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is associated with presence and severity of coronary artery disease (CAD) and incident death and myocardial infarction (MI). We sought to validate this finding in a further cohort of patients with suspected CAD. METHODS: Plasma suPAR was available in 1635 patients (73% with CAD) undergoing coronary angiography at a single regional Danish hospital between 2003 and 2005. Patients were followed for adverse cardiovascular outcomes of death, cardiac death and MI over a median follow-up of 4.2 years. RESULTS: In multivariate Cox models, adjusted for established cardiovascular risk factors, the biomarkers C-reactive protein, troponin-T and N-terminal-pro brain natriuretic peptide and the number of stenotic vessels, suPAR was independently associated with the combined endpoint of death/MI, hazard ratio (HR) 1.88; cardiovascular death, HR 2.01; and non-fatal MI, HR 1.53; (all p ≤ .037) per doubling of suPAR concentration. A plasma cutoff for suPAR ≥ 3.5 ng/mL was also significantly associated with death/MI, HR 1.51; p = .005. The C-statistic for the multivariate model predicting death/MI improved from 0.712 to 0.730 (p for difference .008) after inclusion of suPAR. However, suPAR was not associated with presence or extent of CAD (p > .05). CONCLUSION: These results validate previous findings that demonstrate suPAR to be an independent predictor of death/MI in patients with suspected or known CAD, however suPAR was not associated with presence or extent of CAD in our cohort. Probably because suPAR reflects end organ damage rather than the degree of atherosclerosis. BRIEF SUMMARY: We demonstrate that the inflammatory biomarker soluble urokinase plasminogen activator receptor is an independent predictor of death/myocardial infarction in patients with suspected or known coronary artery disease, but is not associated with the presence or severity of coronary artery disease.

Early Versus Standard Care Invasive Examination and Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: The optimal timing of invasive coronary angiography (ICA) and revascularization in patients with non-ST-segment elevation acute coronary syndrome is not well defined. We tested the hypothesis that a strategy of very early ICA and possible revascularization within 12 hours of diagnosis is superior to an invasive strategy performed within 48 to 72 hours in terms of clinical outcomes. METHODS: Patients admitted with clinical suspicion of non-ST-segment elevation acute coronary syndrome in the Capital Region of Copenhagen, Denmark, were screened for inclusion in the VERDICT trial (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) ( ClinicalTrials.gov NCT02061891). Patients with ECG changes indicating new ischemia or elevated troponin, in whom ICA was clinically indicated and deemed logistically feasible within 12 hours, were randomized 1:1 to ICA within 12 hours or standard invasive care within 48 to 72 hours. The primary end point was a combination of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure. RESULTS: A total of 2147 patients were randomized; 1075 patients allocated to very early invasive evaluation had ICA performed at a median of 4.7 hours after randomization, whereas 1072 patients assigned to standard invasive care had ICA performed 61.6 hours after randomization. Among patients with significant coronary artery disease identified by ICA, coronary revascularization was performed in 88.4% (very early ICA) and 83.1% (standard invasive care). Within a median follow-up time of 4.3 (interquartile range, 4.1-4.4) years, the primary end point occurred in 296 (27.5%) of participants in the very early ICA group and 316 (29.5%) in the standard care group (hazard ratio, 0.92; 95% CI, 0.78-1.08). Among patients with a GRACE risk score (Global Registry of Acute Coronary Events) >140, a very early invasive treatment strategy improved the primary outcome compared with the standard invasive treatment (hazard ratio, 0.81; 95% CI, 0.67-1.01; P value for interaction=0.023). CONCLUSIONS: A strategy of very early invasive coronary evaluation does not improve overall long-term clinical outcome compared with an invasive strategy conducted within 2 to 3 days in patients with non-ST-segment elevation acute coronary syndrome. However, in patients with the highest risk, very early invasive therapy improves long-term outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02061891.

Soluble urokinase plasminogen activator receptor for risk prediction in patients admitted with acute chest pain.

BACKGROUND: Plasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict mortality in several clinical settings, but the long-term prognostic importance of suPAR in chest pain patients admitted on suspicion of non-ST-segment elevation acute coronary syndrome (NSTEACS) is uncertain. METHODS: suPAR concentrations were measured on admission in 449 consecutive chest pain patients in a single center between January 3, 2005, and February 14, 2006. Patients were followed for all-cause mortality from discharge until July 28, 2011. RESULTS: The diagnoses at discharge comprised high-risk NSTEACS [non-ST elevation myocardial infarction or unstable angina with electrocardiogram (ECG) abnormalities] in 77 patients (17.2%) and low-risk NSTEACS without evidence of myocardial ischemia in 257 (57.2%) of patients. Another 115 (25.6%) of patients received other diagnoses. During a median follow-up of 5.7 years (range, 0.01-6.6 years) there were 162 (36.1%) deaths. suPAR was predictive of mortality independent of age, sex, smoking, final diagnosis for the hospitalization, comorbidities (diabetes, hypertension, previous myocardial infarction, and heart failure), and variables measured on the day of admission (renal function, inflammatory markers, and markers of myocardial ischemia) with a hazard ratio (95% CI) of 1.93 (1.48-2.51) per SD increase in log-transformed suPAR, P < 0.0001. The use of suPAR improved the predictive accuracy of abnormal ECG findings and increased troponin concentrations regarding all-cause mortality (c statistics, 0.751-0.805; P < 0.0001). CONCLUSIONS: suPAR is a strong predictor of adverse long-term outcomes and improves risk stratification beyond traditional risk variables in chest pain patients admitted with suspected NSTEACS.

Association of clopidogrel treatment with risk of mortality and cardiovascular events following myocardial infarction in patients with and without diabetes.

CONTEXT: Pharmacodynamic studies have shown that persistently high platelet reactivity is common in patients with diabetes in spite of clopidogrel treatment. Clinical trials have not convincingly demonstrated that clopidogrel benefits patients with diabetes as much patients without diabetes. OBJECTIVES: To estimate the clinical effectiveness associated with clopidogrel treatment after myocardial infarction (MI) in patients with diabetes. DESIGN, SETTING, AND PATIENTS: By individual-level linkage of the Danish nationwide administrative registries between 2002-2009, patients who were hospitalized with incident MI and who had survived and not undergone coronary artery bypass surgery 30 days after discharge were followed up for as long as 1 year (maximally until December 31, 2009). Adjusted for age, sex, comorbidity, calendar year, concomitant pharmacotherapy, and invasive interventions, hazard ratios that were associated with clopidogrel in patients with and without diabetes were analyzed by Cox proportional-hazard models and propensity score-matched models. MAIN OUTCOME MEASURES: All-cause mortality, cardiovascular mortality, and a composite end point of recurrent MI and all-cause mortality. RESULTS: Of the 58,851 patients included in the study, 7247 (12%) had diabetes and 35,380 (60%) received clopidogrel. In total, 1790 patients (25%) with diabetes and 7931 patients (15%) without diabetes met the composite end point. Of these, 1225 (17%) with and 5377 (10%) without diabetes died. In total, 978 patients (80%) with and 4100 patients (76%) without diabetes died of events of cardiovascular origin. For patients with diabetes who were treated with clopidogrel, the unadjusted mortality rates (events/100 person-years) were 13.4 (95% CI, 12.8-14.0) vs 29.3 (95% CI, 28.3-30.4) for those not treated. For patients without diabetes who were treated with clopidogrel, the unadjusted mortality rates were 6.4 (95% CI, 6.3-6.6) vs 21.3 (95% CI, 21.0-21.7) for those not treated. However, among patients with diabetes vs those without diabetes, clopidogrel was associated with less effectiveness for all-cause mortality (HR, 0.89 [95% CI, 0.79-1.00] vs 0.75 [95% CI, 0.70-0.80]; P for interaction, .001) and for cardiovascular mortality (HR, 0.93 [95% CI, 0.81-1.06] vs 0.77 [95% CI, 0.72-0.83]; P for interaction, .01) but not for the composite end point (HR, 1.00 [95% CI, 0.91-1.10] vs 0.91 [95% CI, 0.87-0.96]; P for interaction, .08). Propensity score-matched models gave similar results. CONCLUSION: Among patients with diabetes compared with patients without diabetes, the use of conventional clopidogrel treatment after MI was associated with lower reduction in the risk of all-cause death and cardiovascular death.

Prognostic Value of Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes.

BACKGROUND: Severity and extent of coronary artery disease (CAD) assessed by invasive coronary angiography (ICA) guide treatment and may predict clinical outcome in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). OBJECTIVES: This study tested the hypothesis that coronary computed tomography angiography (CTA) is equivalent to ICA for risk assessment in patients with NSTEACS. METHODS: The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial evaluated timing of treatment in relation to outcome in patients with NSTEACS and included a clinically blinded coronary CTA conducted prior to ICA. Severity of CAD was defined as obstructive (coronary stenosis ≥50%) or nonobstructive. Extent of CAD was defined as high risk (obstructive left main or proximal left anterior descending artery stenosis and/or multivessel disease) or non-high risk. The primary endpoint was a composite of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or heart failure. RESULTS: Coronary CTA and ICA were conducted in 978 patients. During a median follow-up time of 4.2 years (interquartile range: 2.7 to 5.5 years), the primary endpoint occurred in 208 patients (21.3%). The rate of the primary endpoint was up to 1.7-fold higher in patients with obstructive CAD compared with in patients with nonobstructive CAD as defined by coronary CTA (hazard ratio [HR]: 1.74; 95% confidence interval [CI]: 1.22 to 2.49; p = 0.002) or ICA (HR: 1.54; 95% CI: 1.13 to 2.11; p = 0.007). In patients with high-risk CAD, the rate of the primary endpoint was 1.5-fold higher compared with the rate in those with non-high-risk CAD as defined by coronary CTA (HR: 1.56; 95% CI: 1.18 to 2.07; p = 0.002). A similar trend was noted for ICA (HR: 1.28; 95% CI: 0.98 to 1.69; p = 0.07). CONCLUSIONS: Coronary CTA is equivalent to ICA for the assessment of long-term risk in patients with NSTEACS. (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes [VERDICT]; NCT02061891).

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: In patients with non-ST-segment elevation acute coronary syndrome (NSTEACS), coronary pathology may range from structurally normal vessels to severe coronary artery disease. OBJECTIVES: The purpose of this study was to test if coronary computed tomography angiography (CTA) may be used to exclude coronary artery stenosis ≥50% in patients with NSTEACS. METHODS: The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial (NCT02061891) evaluated the outcome of patients with confirmed NSTEACS randomized 1:1 to very early (within 12 h) or standard (48 to 72 h) invasive coronary angiography (ICA). As an observational component of the trial, a clinically blinded coronary CTA was conducted prior to ICA in both groups. The primary endpoint was the ability of coronary CTA to rule out coronary artery stenosis (≥50% stenosis) in the entire population, expressed as the negative predictive value (NPV), using ICA as the reference standard. RESULTS: Coronary CTA was conducted in 1,023 patients-very early, 2.5 h (interquartile range [IQR]: 1.8 to 4.2 h), n = 583; and standard, 59.9 h (IQR: 38.9 to 86.7 h); n = 440 after the diagnosis of NSTEACS was made. A coronary stenosis ≥50% was found by coronary CTA in 68.9% and by ICA in 67.4% of the patients. Per-patient NPV of coronary CTA was 90.9% (95% confidence interval [CI]: 86.8% to 94.1%) and the positive predictive value, sensitivity, and specificity were 87.9% (95% CI: 85.3% to 90.1%), 96.5% (95% CI: 94.9% to 97.8%) and 72.4% (95% CI: 67.2% to 77.1%), respectively. NPV was not influenced by patient characteristics or clinical risk profile and was similar in the very early and the standard strategy group. CONCLUSIONS: Coronary CTA has a high diagnostic accuracy to rule out clinically significant coronary artery disease in patients with NSTEACS.

S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes.

OBJECTIVE: The multifunctional Ca2+-binding protein S100A4 (also known as Mts1 and Fsp1) is involved in fibrosis and tissue remodeling in several diseases including cancer, kidney fibrosis, central nervous system injury, and pulmonary vascular disease. We previously reported that S100A4 mRNA expression was increased in hypertrophic rat hearts and that it has pro-cardiomyogenic effects in embryonic stem cell-derived embryoid bodies. We therefore hypothesized that S100A4 could play a supportive role in the injured heart. METHODS AND RESULTS: Here we verify by quantitative real-time PCR and immunoblotting that S100A4 mRNA and protein is upregulated in hypertrophic rat and human hearts and show by way of confocal microscopy that S100A4 protein, but not mRNA, appears in cardiac myocytes only in the border zone after an acute ischemic event in rat and human hearts. In normal rat and human hearts, S100A4 expression primarily colocalizes with markers of fibroblasts. In hypertrophy elicited by aortic banding/stenosis or myocardial infarction, this expression is increased. Moreover, invading macrophages and leucocytes stain strongly for S100A4, further increasing cardiac levels of S100A4 protein after injury. Promisingly, recombinant S100A4 protein elicited a robust hypertrophic response and increased the number of viable cells in cardiac myocyte cultures by inhibiting apoptosis. We also found that ERK1/2 activation was necessary for both the hypertrophy and survival effects of S100A4 in vitro. CONCLUSIONS: Along with proposed angiogenic and cell motility stimulating effects of S100A4, these findings suggest that S100A4 can act as a novel cardiac growth and survival factor and may have regenerative effects in injured myocardium.

Recurrent acute pancreatitis due to eosinophilic gastroenteritis. Case report and literature review.

CONTEXT: Eosinophilic gastroenteritis is characterized by eosinophilic infiltration of any gastrointestinal segment from the esophagus to the rectum, most commonly, the stomach and the duodenum. Clinical manifestations range from non-specific gastrointestinal complaints to more specific symptoms such as protein-losing enteropathy, malabsorption, luminal obstruction and eosinophilic ascites. CASE REPORT: We report the case of a 35-year-old woman with recurrent gastric outlet obstruction due to eosinophilic infiltration of the stomach and the duodenum. There was a history of two episodes of acute pancreatitis as well as eosinophilia of bone marrow and ascites. CONCLUSIONS: Although unusual, eosinophilic gastroenteritis may be complicated by symptomatic acute pancreatitis. Seven previous cases have been reported in the literature, and a comparison was made. The pancreatitis is probably due to duct obstruction, but some cases of eosinophilic gastroenteritis have pancreatic tissue eosinophilia. Most cases respond to medical treatment, and surgery is usually unnecessary.

Relationship Between Two Common Lipoprotein Lipase Variants and the Metabolic Syndrome and Its Individual Components.

BACKGROUND: Common lipoprotein lipase (LPL) variants are important determinants of triglycerides (TG) and high-density lipoprotein (HDL) cholesterol (C) concentrations. High TG/low HDL-C tend to cluster with hypertension, glucose intolerance, and abdominal obesity and comprise the metabolic syndrome (MetS). The role of LPL variants as a cause of MetS is unclear. This study investigated the relationship between two common LPL variants and the presence of MetS and its individual components. METHODS: Cross-sectional study, including 2348 Danish women (50.7%) and men, age 41-72 years, without known cardiovascular disease. Carrier status for the two common LPL variants: 447Ter (low TG/high HDL-C) and 291Ser (high TG/low HDL-C) was determined. The prevalence of MetS according to the National Cholesterol Education Program criteria was 16.6%. RESULTS: Of the 2348 participants, 19.8% had the 447Ter variant and 4.9% had the 291Ser variant. Compared with the reference variant, the prevalence of MetS was lower in carriers of the 447Ter variant (11.2% vs. 17.9%, P < 0.001) but with no difference in carriers of the 291Ser variant (18.4% vs. 16.5%, P = 0.59). Adjusted for age, sex, smoking, physical activity, alcohol consumption, and highest sex-specific insulin quartile, the relative risk of MetS was 0.63 (95% confidence interval [CI] 0.45-0.89, P < 0.01) for carriers of the 447Ter variant and 1.20 (95% CI 0.70-2.03, P > 0.05) for carriers of the 291Ser variant. Both LPL variants were associated with high TG/low HDL-C (P < 0.01), but not with the MetS components waist circumference, hypertension, and glucose intolerance (P > 0.05). CONCLUSION: The two common LPL variants were associated with MetS through their effect on high TG/low HDL-C.

The inflammatory marker suPAR after cardiac arrest.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is released in response to inflammatory stimuli, and plasma levels are associated with long-term outcomes. The ischemia/reperfusion injury caused by cardiac arrest (CA) and resuscitation triggers an inflammatory response. This pilot study aimed at investigating suPAR levels in relation to outcome after CA and mild induced hypothermia. METHODS: suPAR levels were measured at 6, 36, and 72 hours in patients treated with hypothermia after CA. suPAR levels were analyzed in relation to survival after 6 months. Receiver operating characteristic curve (ROC)-analyses were performed, and area under the curve (AUC) was calculated. Time to return of spontaneous circulation (ROSC) was correlated to suPAR levels. RESULTS: Fifty-five patients (40 male, median 65 years) were included, and 33 (60%) were alive after 6 months. The suPAR levels were significantly higher in nonsurviving patients compared with survivors at 6 and 36 hours (p=0.006 and 0.034 respectively), but not at 72 hours. The suPAR levels increased from 6 to 72 hours (p<0.0001). Time to ROSC correlated positively with suPAR levels at 6 hours (p=0.003) but not at 36 and 72 hours. ROC analysis shoved an AUC of 0.76 at 6 hours. In the subgroup of CA of cardiac cause, the AUC was 0.84. CONCLUSION: suPAR levels at 6 and 36 hours after CA were significantly higher in nonsurviving patients compared with survivors; however, the overlap in suPAR levels between the outcome groups was substantial, reducing the prognostic value. There was a significant increase in suPAR levels during the first 72 hours after CA.

Symptomatic venous thromboembolism following fractures distal to the knee: a nationwide Danish cohort study.

BACKGROUND: Our aims were to determine the incidence of symptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) that required inpatient or outpatient treatment, and to identify specific risk factors associated with DVT/PE in patients who had undergone surgery for a fracture distal to the knee. METHODS: Using individual linkage of nationwide registries, we included all Danish patients who had undergone surgery for a fracture distal to the knee between 1999 and 2011. Patients were followed for 180 days from discharge. Event rates of DVT/PE were calculated, and significant risk factors were identified with use of multivariable Cox regression analyses. Routine postdischarge antithrombotic chemoprophylaxis was not given to these patients. RESULTS: The study included 57,619 patients, 594 of whom had a venous thromboembolic event during the follow-up period. Thirty-nine (6.6%) of the 594 events were death due to PE. The overall event rate during the 180-day study period was 1.0%. The incidence rate was 7.28 events per 100 person-years before discharge, decreasing to a stable level below one event per 100 person-years in week 13 to 14 after discharge. Use of oral contraception by patients eighteen to fifty years of age (hazard ratio [HR] = 5.23, 95% confidence level [CI] = 3.35 to 8.18), previous DVT (HR = 6.27, 95% CI = 4.18 to 9.40), previous PE (HR = 5.45, 95% CI = 3.05 to 9.74), coagulopathy (HR = 2.47, 95% CI = 1.07 to 5.72), and peripheral artery disease (HR = 2.34, 95% CI = 1.20 to 4.56) were the factors associated with the highest risk of postoperative DVT/PE. Also, increasing age, increasing body mass index, cancer, and treatment with nonsteroidal anti-inflammatory drugs were associated with a significantly increased risk of DVT/PE. CONCLUSIONS: The incidence of DVT/PE was low following surgery for fractures distal to the knee; however, the risk was increased in the presence of a number of risk factors. This study suggests that specific groups of patients undergoing surgery for a fracture distal to the knee might benefit from postdischarge antithrombotic treatment.

Risk stratification in stable coronary artery disease is possible at cardiac troponin levels below conventional detection and is improved by use of N-terminal pro-B-type natriuretic peptide.

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.

Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score.

BACKGROUND: The inflammatory biomarkers soluble urokinase plasminogen activator receptor (suPAR) and C-reactive protein (CRP) independently predict cardiovascular disease (CVD). The prognostic implications of suPAR and CRP combined with Framingham Risk Score (FRS) have not been determined. METHODS: From 1993 to 1994, baseline levels of suPAR and CRP were obtained from 2315 generally healthy Danish individuals (mean [SD] age: 53.9 [10.6] years) who were followed for the composite outcome of ischemic heart disease, stroke and CVD mortality. RESULTS: During a median follow-up of 12.7 years, 302 events were recorded. After adjusting for FRS, women with suPAR levels in the highest tertile had a 1.74-fold (95% confidence interval [CI]: 1.08-2.81, p=0.027) and men a 2.09-fold (95% CI: 1.37-3.18, p<0.001) increase in risk compared to the lowest tertile. Including suPAR and CRP together resulted in stronger risk prediction with a 3.30-fold (95% CI: 1.36-7.99, p<0.01) increase for women and a 3.53-fold (1.78-7.02, p<0.001) increase for men when both biomarkers were in the highest compared to the lowest tertile. The combined extreme tertiles of suPAR and CRP reallocated individuals predicted to an intermediate 10-year risk of CVD of 10-20% based on FRS, to low (<10%) or high (>20%) risk categories, respectively. This was reflected in a significant improvement of C statistics for men (p=0.034) and borderline significant for women (p=0.054), while the integrated discrimination improvement was highly significant (P≤0.001) for both genders. CONCLUSIONS: suPAR provides prognostic information of CVD risk beyond FRS and improves risk prediction substantially when combined with CRP in this setting.

CRP and suPAR are differently related to anthropometry and subclinical organ damage.

BACKGROUND: Low-grade inflammation is a marker for cardiovascular disease (CVD). The inflammatory biomarkers C-reactive protein (CRP) and soluble urokinase plasminogen activator receptor (suPAR) independently predict CVD. We tested the hypothesis that these biomarkers reflect different aspects of the inflammation associated with CVD. METHODS: We studied 2273 subjects without CVD. Log-transformed CRP and suPAR were included in general linear and logistic regression models to compare associations with measures of anthropometry and subclinical organ damage (SOD). Owing to interactions on body mass index (BMI) (P<0.0001), the population was stratified by gender and smoking concerning anthropometry. RESULTS: In both genders, independent of smoking, log-CRP was positively associated with BMI (ß: 0.28 to 0.40, P<0.001) and waist circumference (WC) (ß: 0.27 to 0.42, P<0.001). In contrast, in smoking women and men, log-suPAR was negatively associated with BMI and WC (ß: -0.09 to -0.19, P<0.05). In non-smoking women, log-suPAR was positively associated with BMI and WC (ß: 0.14 and 0.16, P<0.001), whereas no associations were found in non-smoking men. No interactions were found on SOD. Adjusted for age, sex, smoking, and physical activity, log-suPAR was associated with an increased urine albumin/creatinine ratio (standardized odds ratio (95% confidence interval (CI)) for highest vs. lower quartiles: 1.36 (1.21-1.52), whereas log-CRP was not (1.10 (0.99-1.22))), and extent of atherosclerosis (standardized proportional odds ratio (95% CI) for carotid plaques 0, 1 ≤ to ≤ 3, >3: 1.31 (1.16-1.47), whereas log-CRP was not (1.00 (0.89-1.11))). CONCLUSIONS: CRP is positively associated with anthropometric measures, whereas suPAR is linked to endothelial dysfunction and atherosclerosis.

Relation of body mass index to risk of stent thrombosis after percutaneous coronary intervention.

Stent thrombosis is a devastating complication after percutaneous coronary intervention (PCI), but the influence of obesity on risk of stent thrombosis is unclear, and it is unknown if this relation is dependent on stent type. The objective of this study was to examine the relation between body mass index (BMI) and stent thrombosis after PCI with bare-metal stent (BMS) or drug-eluting stent (DES). We followed 5,515 patients who underwent PCI with implantation of ≥1 BMS or DES at a high-volume tertiary invasive cardiology center from 2000 through 2006. Only patients with a single type of stent (BMS or DES) implanted at the index PCI were included. Median follow-up period was 26 months (interquartile range 12 to 44) and definite stent thrombosis occurred in 78 patients. Hazard ratio of definite stent thrombosis adjusted for number of stents at the index PCI was 0.92 (95% confidence interval [CI] 0.86 to 0.97) for each increase in kilograms per square meter of BMI. There was no significant interaction between stent type and BMI (p = 0.48). Hazard ratios for probable stent thrombosis and possible stent thrombosis adjusted for numbers of stents at the index PCI were 1.01 (CI 0.99 to 1.03) and 0.99 (CI 0.98 to 1.01) for each increase in kilograms per square meter of BMI, respectively. In conclusion, BMI was inversely correlated with risk of definite stent thrombosis after PCI irrespective of stent type.

Usefulness of soluble urokinase plasminogen activator receptor to predict repeat myocardial infarction and mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous intervention.

The plasma level of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is an independent predictor of cardiovascular disease and all-cause mortality in healthy subjects. The prognostic capability of suPAR, its temporal course, and its relation to plasma C-reactive protein (CRP) in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous intervention (PCI) is unknown. Therefore, the plasma suPAR and CRP levels were measured in 296 consecutive patients with ST-segment elevation myocardial infarction admitted for primary PCI at baseline and every 6 to 8 hours thereafter until the cardiac biomarker levels had peaked. The end points were all-cause mortality and fatal or nonfatal recurrent myocardial infarction (MI). During a median follow-up period of 5.75 years, 69 deaths and 48 nonfatal and 14 fatal recurrent MIs occurred. All-cause mortality increased significantly from 8.1% to 41.5% across increasing quartiles of suPAR levels at the end of follow-up (log-rank p <0.0001). After adjustment for other independent prognostic factors, a highly significant increase was seen in all-cause mortality (hazard ratio 1.45, 95% confidence interval, 1.19 to 1.76; p <0.001) and recurrent MI (hazard ratio 1.53, 95% confidence interval 1.16 to 2.01; p <0.01) for each standard deviation increment of suPAR levels). In contrast to plasma CRP, the suPAR levels remained stable after primary PCI. Furthermore, CRP did not predict mortality or reinfarction after adjustment for age and gender (p = 0.34). In conclusion, suPAR is a stable plasma biomarker after ST-segment elevation myocardial infarction treated with primary PCI that predicts all-cause mortality and recurrent MI.

Cell-specific detection of microRNA expression during cardiomyogenesis by combined in situ hybridization and immunohistochemistry.

MicroRNAs (miRNAs) regulate gene expression by mediating translational repression or mRNA degradation of their targets, and several miRNAs control developmental decisions through embryogenesis. In the developing heart, miRNA targets comprise key players mediating cardiac lineage determination. However, although several miRNAs have been identified as differentially regulated during cardiac development and disease, their distinct cell-specific localization remains largely undetermined, likely owing to a lack of adequate methods. We therefore report the development of a markedly improved approach combining fluorescence-based miRNA-in situ hybridization (miRNA-ISH) with immunohistochemistry (IHC). We have applied this protocol to differentiating embryoid bodies (EBs) as well as embryonic and adult mouse hearts, to detect miRNAs that were upregulated during EB cardiomyogenesis, as determined by array-based miRNA expression profiling. In this manner, we found specific co-localization of miR-1 to myosin positive cells (cardiomyocytes) of EBs, developing and mature hearts. In contrast, miR-125b and -199a did not localize to cardiomyocytes, as previously suggested for miR-199a, but were rather expressed in connective tissue cells of the heart. More specifically, by co-staining with α-smooth muscle actin (α-SMA) and collagen-I, we found that miR-125b and -199a localize to perivascular α-SMA(-) stromal cells. Our approach thus proved valid for determining cell-specific localization of miRNAs, and the findings we present highlight the importance of determining exact cell-specific localization of miRNAs by sequential miRNA-ISH and IHC in studies aiming at understanding the role of miRNAs and their targets. This approach will hopefully aid in identifying relevant miRNA targets of both the heart and other organs.

Serial in vivo imaging of the porcine heart after percutaneous, intramyocardially injected 111In-labeled human mesenchymal stromal cells.

This pilot trial aimed to investigate the utilization of (111)In-labeling of mesenchymal stromal cells (MSC) for in vivo tracking after intramyocardial transplantation in a xenotransplantation model with gender mismatched cells. Human male MSC were expanded ex vivo and labeled with (111)In-tropolone. Ten female pigs were included. The labeled cells were transplanted intramyocardially using a percutaneous injection system. The (111)In activity was determined using gamma camera imaging. Excised hearts were analyzed by fluorescence in situ hybridization (FISH) and microscopy. Gamma camera imaging revealed focal cardiac (111)In accumulations up to 6 days after injection (N = 4). No MSC could be identified with FISH, and microscopy identified widespread acute inflammation. Focal (111)In accumulation, inflammation but no human MSC were similarly seen in pigs (N = 2) after immunosuppression. A comparable retention of (111)In activity was observed after intramyocardial injection of (111)In-tropolone (without cells) (N = 2), but without sign of myocardial inflammation. Injection of labeled non-viable cells (N = 1) also led to high focal (111)In activity up to 6 days after intramyocardial injection. As a positive control of the FISH method, we identified labeled cells both in culture and immediately after cell injection in one pig. This pilot trial suggests that after intramyocardial injection (111)In stays in the myocardium despite possible disappearance of labeled cells. This questions the clinical use of (111)In-labeled cells for tracking. The results further suggest that xenografting of human MSC into porcine hearts leads to inflammation contradicting previous studies implying a special immunoprivileged status for MSC.

Urine albumin/creatinine ratio, high sensitivity C-reactive protein and N-terminal pro brain natriuretic peptide--three new cardiovascular risk markers--do they improve risk prediction and influence treatment?

In order to prioritize limited health resources in a time of increasing demands optimal cardiovascular risk stratification is essential. We tested the additive prognostic value of 3 relatively new, but established cardiovascular risk markers: N-terminal pro brain natriuretic peptide (Nt-proBNP), related to hemodynamic cardiovascular risk factors, high sensitivity C-reactive protein (hsCRP), related to metabolic cardiovascular risk factors and urine albumin/creatinine ratio (UACR), related to hemodynamic as well as metabolic risk factors. In healthy subjects with a 10-year risk of cardiovascular death lower than 5% based on HeartScore and therefore not eligible for primary prevention, the actual 10-year risk of cardiovascular death exceeded 5% in a small subgroup of subjects with UACR higher than the 95-percentile of approximately 1.6 mg/mmol. Combined use of high UACR or high hsCRP identified a larger subgroup of 16% with high cardiovascular risk in which primary prevention may be advised despite low-moderate cardiovascular risk based on HeartScore. Furthermore, combined use of high UACR or high Nt-proBNP in subjects with known cardiovascular disease or diabetes identified a large subgroup of 48% with extremely high cardiovascular risk who should be referred for specialist care to optimize treatment.

Cardiac regeneration by resident stem and progenitor cells in the adult heart.

Two main pieces of data have created a new field in cardiac research. First, the traditional view on the heart as a postmitotic organ has been challenged by the finding of small dividing cells in the heart expressing cardiac contractile proteins with stem cell properties and, second, cellular therapy of the diseased heart using a variety of different cells has shown encouraging effects on cardiac function. These findings immediately raise questions like "what is the identity and origin of the cardiac progenitor cells?","which molecular factors are involved in their mobilization and differentiation?", and "can these cells repair the damaged heart?" This review will address the state of current answers to these questions. Emerging evidence suggests that several subpopulations of cardiac stem or progenitor cells (CPCs) reside within the adult heart. CPCs with the ability to differentiate into all the constituent cells in the adult heart including cardiac myocytes, vascular smooth muscle and endothelial cells have been identified. Valuable knowledge has been obtained from the large number of animal studies and a number of small clinical trials that have utilized a variety of adult stem cells for regenerating infarcted hearts. However, contradictory reports on the regenerative potential of the CPCs exist, and the mechanisms behind the reported hemodynamic effects are intensely debated. Besides directly replenishing cardiac tissue, CPCs could also function by stimulating angiogenesis and improving survival of existing cells by secretion of paracrine factors. With this review we suggest that a better understanding of CPC biology will be pivotal for progressing therapeutic cardiac regeneration. This includes an extended knowledge of the molecular mechanisms behind their mobilization, differentiation, survival and integration in the myocardium.