Thomas Sehestedt

Risk prediction is improved by adding markers of subclinical organ damage to SCORE

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 > or = 90th percentile [HR 3.3 (1.8-5.9)], PWV > 12 m/s [HR 1.9 (1.1-3.3) for SCORE > or = 5% and 7.3 (3.2-16.1) for SCORE < 5%]. Restricting primary prevention to subjects with SCORE > or = 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 > or = 5% to include subjects with 1% < or = 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.

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.

Soluble urokinase plasminogen activator receptor is associated with subclinical organ damage and cardiovascular events

OBJECTIVE The soluble urokinase plasminogen activator receptor (suPAR) is a plasma marker of low grade inflammation and has been associated with cardiovascular risk. We wanted to investigate whether suPAR was associated with markers of subclinical organ damage. METHODS In a population sample of 2038 individuals, aged 41, 51, 61 and 71 years, without diabetes, prior stroke or myocardial infarction, not receiving any cardiovascular, anti-diabetic or lipid-lowering medications, we measured urine albumin/creatinine ratio (UACR), carotid atherosclerotic plaques and carotid/femoral pulse wave-velocity (PWV) together with traditional cardiovascular risk factors and high sensitivity C-reactive protein (hsCRP). RESULTS suPAR was significantly associated with the presence of plaques (P = 0.003) and UACR (P < 0.001), but not PWV (P = 0.17) when adjusting for age, gender, systolic blood pressure, cholesterol, plasma glucose, waist/hip ratio, smoking and hsCRP. However, suPAR explained only a small part of the variation in the markers of subclinical organ damage (R(2) 0.02-0.04). During a median follow-up of 12.7 years (5th-95th percentile 5.1-13.4 years) a total of 174 composite endpoints (CEP) of cardiovascular death, non-fatal myocardial infarction and stroke occurred. suPAR was associated with CEP independent of plaques, PWV, UACR, and hsCRP as well as age, gender, systolic blood pressure, cholesterol, plasma glucose, waist/hip ratio and smoking with a standardized hazard ratio of 1.16 (95% confidence interval 1.04-1.28, P = 0.006). CONCLUSION suPAR was associated with subclinical organ damage, but predicted cardiovascular events independent of subclinical organ damage, traditional risk factors and hsCRP. Further studies must investigate whether suPAR plays an independent role in the pathogenesis of cardiovascular disease.

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 (β: 0.28 to 0.40, P<0.001) and waist circumference (WC) (β: 0.27 to 0.42, P<0.001). In contrast, in smoking women and men, log-suPAR was negatively associated with BMI and WC (β: -0.09 to -0.19, P<0.05). In non-smoking women, log-suPAR was positively associated with BMI and WC (β: 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.

Thresholds for pulse wave velocity, urine albumin creatinine ratio and left ventricular mass index using SCORE, Framingham and ESH/ESC risk charts.

Aims: Markers of subclinical target organ damage (TOD) increase cardiovascular (CV) risk prediction beyond traditional risk factors. We wanted to establish thresholds for three markers of TOD based on absolute CV risk in different risk chart categories. Methods and results: In a cohort of 1968 healthy patients, we measured urine albumin creatine ratio (UACR), pulse wave velocity (PWV), left ventricular mass index (LVMI) and traditional risk factors. Patients were categorized according to Systemic Coronary Evaluation (SCORE), European Society of Hypertension/European Society of Cardiology (ESH/ESC) risk chart and Framingham risk score (FRS) and three corresponding endpoints were recorded: CV death (SCORE-endpoint), a composite of CV death and nonfatal myocardial infarction and stroke (ESH/ESC-endpoint), and a composite that also included hospital admissions for ischemic heart disease, heart failure, peripheral arterial disease and transient cerebral ischemic attack (FRS-endpoint). During a median follow of 12.8 years events totaled 81 SCORE-, 153 ESH/ESC-endpoints and 280 FRS-endpoints. Thresholds for UACR, PWV and LVMI are presented using 10-year risk threshold of more than 5% (SCORE-endpoint), more than 10%(ESH/ESC-endpoint) and more than 20%(FRS-endpoint), which indicated high risk and eligibility for primary prevention. As an example, the threshold was 0.83 mg/mmol, 13.7 m/s and 119 g/m2 for UACR, PWV and LVMI, respectively, for patients at moderate added risk according to ESH/ESC risk chart. Conclusion: Thresholds for UACR, PVW and LVMI based on absolute risk have primarily impact on risk stratification in patients with intermediate risk. The thresholds for PWV and LVMI in patients with moderate risk according to the ESH/ESC risk chart were similar to currently applied thresholds whereas the threshold for UACR was considerable lower than the threshold for microalbuminuria.

Which markers of subclinical organ damage to measure in individuals with high normal blood pressure

Objective Medical treatment of healthy individuals with high normal blood pressure (BP) is recommended if there is subclinical organ damage (SOD). We examined which markers of SOD to use based on their supplementary prognostic value. Methods In a population sample of 1968 individuals, aged 41, 51, 61 and 71 years, without diabetes, prior stroke or myocardial infarction, not receiving any cardiovascular, antidiabetic or lipid-lowering medications, we measured urine albumin/creatinine ratio, carotid atherosclerotic plaques, carotid/femoral pulse wave velocity and left ventricular mass index. Results During a median follow-up of 12.8 years, the composite endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction and stroke occurred in 153 individuals, of whom 32 had high normal BP. Presence of high normal BP was associated with increased risk of CEP [hazard ratio, 1.8 (95% confidence interval, 1.0–3.1; P = 0.046), optimal BP as reference group, adjusted for age and sex]. In the 337 individuals with high normal BP, using all four markers of SOD increased the sensitivity (number of CEPs in the group in which antihypertensive treatment was indicated divided by total number of CEPs) of the European Society of Hypertension risk classification chart significantly from 47 to 88% (P = 0.001) and the proportion of individuals in whom antihypertensive drug treatment was indicated from 22 to 57% (P < 0.001). Using two of pulse wave velocities of more than 12 m/s, atherosclerotic plaques or urine albumin/creatinine ratio of at least the 90th percentile did not produce significantly worse results. Seventy-five percent of individuals with three or more traditional risk factors had SOD. Conclusion In healthy individuals with high normal BP, measuring two of pulse wave velocities, atherosclerotic plaques or urine albumin/creatinine ratio was sufficient to significantly improve risk prediction.

Risk stratification with the risk chart from the European Society of Hypertension compared with SCORE in the general population.

Objective The risk chart from the European Society of Hypertension (ESH) and Systemic Coronary Risk Evaluation (SCORE) from the European Society of Cardiology (ESC) are equally recommended tools for risk stratification. However, ESH risk chart recommends measuring subclinical organ damage, whereas SCORE is based on traditional risk factors. We wanted to compare the predictive performance of the two charts. Methods In a Danish population sample of 1344 individuals aged 41, 51, 61 and 71 years without known diabetes, prior stroke or myocardial infarction, not receiving cardiovascular, antidiabetic or lipid-lowering medications and with higher than optimal blood pressure (≥120/80 mmHg), we measured traditional risk factors and subclinical organ damage. The endpoints were cardiovascular death and a composite of cardiovascular death, nonfatal myocardial infarction and stroke (CEP). Results During the following 12.8 years cardiovascular death and CEP occurred in 71 and 132 patients, respectively. Forty-two percent had unrecognized hypertension. The sizes and characteristics of the populations in the different risk categories of the charts varied considerably as ESH risk chart allocated 368 patients to higher-risk categories than SCORE (P < 0.001). These patients were younger, with higher blood pressure and less frequently male smokers. However, ESH risk chart agreed with ESC guidelines for antihypertensive treatment using SCORE in 89% (634/713) of the patients recommended treatment and produced similar sensitivities (79 vs. 79%), specificities (46 vs. 50%), positive (14 vs. 15%) and negative (95 vs. 96%) predictive values for CEP. Conclusion Although SCORE did not use subclinical organ damage, the guidelines by ESH and ESC using SCORE recommended antihypertensive treatment in almost the same patients.

Are blood pressure and diabetes additive or synergistic risk factors? Outcome in 8494 subjects randomly recruited from 10 populations

It remains unknown whether diabetes and high blood pressure (BP) are simply additive risk factors for cardiovascular outcome or whether they act synergistically and potentiate one another. We performed 24-h ambulatory BP monitoring in 8494 subjects (mean age, 54.6 years; 47.0% women; 6.9% diabetic patients) enrolled in prospective population studies in 10 countries. In multivariable-adjusted Cox regression, we assessed the additive as opposed to the synergistic effects of BP and diabetes in relation to a composite cardiovascular endpoint by testing the significance of appropriate interaction terms. During 10.6 years (median follow-up), 1066 participants had a cardiovascular complication. Diabetes mellitus as well as the 24-h ambulatory BP were independent and powerful predictors of the composite cardiovascular endpoint. However, there was no synergistic interaction between diabetes and 24-h, daytime, or nighttime, systolic or diastolic ambulatory BP (P for interaction, 0.07⩽P⩽0.97). The only exception was a borderline synergistic effect between diabetes and daytime diastolic BP in relation to the composite cardiovascular endpoint (P=0.04). In diabetic patients, with normotension as the reference group, the adjusted hazard ratios for the cardiovascular endpoint were 1.35 (95% confidence interval (CI), 0.87–2.11) for white-coat hypertension, 1.78 (95% CI, 1.22–2.60) for masked hypertension and 2.44 (95% CI, 1.92–3.11) for sustained hypertension. The hazard ratios for non-diabetic subjects were not different from those of diabetic patients (P-values for interaction, 0.09⩽P⩽0.72). In conclusion, in a large international population-based database, both diabetes mellitus and BP contributed equally to the risk of cardiovascular complications without evidence for a synergistic effect.

Worsening diastolic function is associated with elevated fasting plasma glucose and increased left ventricular mass in a supra-additive fashion in an elderly, healthy, Swedish population

AIMS To examine whether increasing fasting plasma glucose (FPG) levels were associated with worsening left ventricular (LV) diastolic function, independently of LV mass index (LVMI) in elderly, otherwise healthy subjects. METHODS AND RESULTS We tested cross-sectional associations between echocardiographically determined averaged E/é ratio/diastolic function, LVMI, cardiovascular risk factors, and FPG categorized as normal (NFG), impaired (IFG), and new-onset diabetes mellitus (DM), in 483 men and 208 women aged 56-79 years without overt cardiovascular disease, who received no cardiovascular, anti-diabetic, or lipid-lowering drugs and had a preserved LV ejection fraction >50%. Median E/é was significantly higher among subjects with diabetes than those without (8 vs. 7; p = 0.03), as was the prevalence of grade 2 or 3 diastolic dysfunction (25% vs. 16%; p = 0.02). E/é and diastolic function were significantly associated with LVMI (p ≤ 0.002), but not FPG category, on multivariable analysis. However, interaction analyses revealed that increasing LVMI was primarily associated with worsening diastolic function (higher E/é) in subjects with FPG > 6 mmol/L (β=0.005 for IFG and DM vs. 0.001 for NFG; p = 0.02), whereas increasing systolic blood pressure was primarily associated with worsening diastolic function (higher E/é) in subjects with FPG ≤ 6.9 mmol/L (β = 0.005 for NFG and 0.003 for IFG vs. -0.001 for DM; p=0.001). CONCLUSION Diastolic dysfunction was significantly more prevalent among patients with DM than those without. The importance of LVMI increased, but the importance of systolic blood pressure decreased with higher FPG category.

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.