Michael H. Olsen

Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document.

Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Commit

Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study.

Few data are available to clarify whether changes in albuminuria over time translate to changes in cardiovascular risk. The aim of the present study was to examine whether changes in albuminuria during 4.8 years of antihypertensive treatment were related to changes in risk in 8206 patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Urinary albumin/creatinine ratio (UACR) was measured at baseline and annually. Time-varying albuminuria was closely related to risk for the primary composite end point (ie, when UACR decreased during treatment, risk was reduced accordingly). When the population was divided according to median baseline value (1.21 mg/mmol) and median year 1 UACR (0.67 mg/mmol), risk increased stepwise and significantly for the primary composite end point from those with low baseline/low year 1 (5.5%), to low baseline/high year 1 (8.6%), to high baseline/low year 1 (9.4%), and to high baseline/high year 1 (13.5%) values. Similar significant, stepwise increases in risk were seen for the components of the primary composite end point (cardiovascular mortality, stroke, and myocardial infarction). The observation that changes in UACR during antihypertensive treatment over time translated to changes in risk for cardiovascular morbidity and mortality was not explained by in-treatment level of blood pressure. We propose that monitoring of albuminuria should be an integrated part of the management of hypertension. If albuminuria is not decreased by the patient’s current antihypertensive and other treatment, further intervention directed toward blood pressure control and other modifiable risks should be considered.

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.

Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy.

Objective Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve insulin sensitivity through regression of peripheral vascular hypertrophy/rarefaction. Methods In 70 hypertensive patients with electrocardiographic left ventricular hypertrophy, we measured minimal forearm vascular resistance (MFVR) by plethysmography and insulin sensitivity (M/IG) by a 2-h isoglycemic hyperinsulinemic clamp at baseline and after 1, 2 and 3 years of blinded treatment with atenolol- or losartan-based regimens. Results Blood pressures were reduced similarly in the two treatment groups. After 3 years, MFVR was increased (3.7 versus 3.2 mmHg × min × 100, P < 0.05) and M/IG decreased (8.6 versus 12.1 l2/kg × mmol × min, P < 0.05) in patients treated with atenolol, whereas MFVR and M/IG were unchanged (3.5 versus 3.5 mmHg × min × 100 and 12.6 versus 11.1 l2/kg × mmol × min, both P = NS) in patients treated with losartan. As compared to atenolol, losartan treatment was associated with less increase in MFVR (4.3 versus 27%, P < 0.05) and less decrease in M/IG (24 versus −14%, P < 0.01). The relative change in M/IG was inversely associated with the relative change in MFVR (r = −0.16, P < 0.05) independently of the relative change in body mass index (r = −0.29, P < 0.001). Conclusions As compared to atenolol, losartan treatment was associated with less peripheral vascular hypertrophy/rarefaction and higher insulin sensitivity. The relative change in MFVR and M/IG were inversely related, supporting the hypothesis that peripheral vascular changes in hypertension may induce insulin resistance. The ability of losartan to preserve insulin sensitivity may explain the lower incidence of new onset diabetes in patients treated with losartan in the LIFE study.

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.

Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS, a LIFE sub study

Background Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. Methods In 88 unmedicated patients with stage II–III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima–media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. Results IMT was positively correlated to systolic blood pressure (r = 0.26, P < 0.05), whole body glucose uptake index (M/IG; r = 0.22, P < 0.05), age (r = 0.24, P < 0.05) and negatively correlated to body mass index (r = −0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r = −0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = −0.40, P < 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). Conclusions High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.

Measures of overweight and obesity and risk of cardiovascular disease: a population-based study.

Background Although overweight and obesity are associated with cardiovascular disease (CVD), it is unclear which clinical measure of overweight and obesity is the strongest predictor of CVD, and it is unclear whether the various measures of overweight and obesity are indeed independent predictors of CVD. Methods This study was a prospective population-based study of 2493 Danish men and women, age 41–72 years, without major CVD at baseline. At baseline, body mass index, waist circumference, hip circumference, waist-to-hip ratio (WHR), and traditional and new risk factors were recorded. Results Over a median follow-up of 12.6 years, the incidence of a combined CV event (CV death, nonfatal ischemic heart disease, and nonfatal stroke) amounted to 328 cases. Of the various measures of overweight and obesity, in Cox-proportional hazard models, adjusted for age, only WHR was significantly associated with incident CVD with a hazard ratio (95% confidence interval) in women of 2.22 (1.31–3.77; P = 0.0032) in the highest compared with the lowest quartile, and a hazard ratio in men of 1.73 (1.12–2.66; P = 0.014) in the highest compared with the lowest quartile. However, when adjustments were made for the presence of diabetes, dyslipidemia, hypertension, hyperinsulinemia, and inflammation, WHR was no longer significantly (P > 0.41) associated with incident CVD. Conclusion In this study, of the various measures of overweight and obesity, WHR was the only significant predictor of incident CVD, and the relationship between WHR and risk of CVD was mediated by well-known risk factors of CVD.

NT-proBNP is associated with fibulin-1 in Africans: The SAfrEIC study

OBJECTIVES The N-terminal prohormone B-type natriuretic peptide (NT-proBNP) is involved in the regulation of volume load and secreted when systemic cardiac overload occurs. Fibulin-1 on the other hand is a component of many extracellular matrix proteins including those present in atherosclerotic lesions, expressed in elastin-containing fibres of blood vessels, and also in the heart. Due to an alarming prevalence of hypertensive heart disease in black South Africans, we investigated the associations of NT-proBNP with fibulin-1 and markers of arterial stiffness in Africans and Caucasians. METHODS We included 231 Africans and 238 Caucasians from South Africa aged 22-77 years. Serum NT-proBNP and fibulin-1 levels were determined, and arterial compliance and pulse wave velocity were measured. RESULTS Africans had significantly higher blood pressure and NT-proBNP levels than Caucasians and African men had higher fibulin-1 levels than Caucasian men. In single regression analysis, NT-proBNP was significantly associated with fibulin-1 in African men and Caucasian women. NT-proBNP correlated negatively with arterial compliance in all groups except Caucasian women. After partial adjustments, the association between NT-proBNP and fibulin-1 strengthened in African men only. After full adjustment in multiple regression analysis, the association of NT-proBNP with fibulin-1 was confirmed in African men (R(2)=0.41; β=0.26; p<0.01) and also in younger women (R(2)=0.34; β=0.251; p=0.012). CONCLUSIONS Only Africans indicated a significant independent association between NT-proBNP and fibulin-1, suggesting that cardiovascular alterations are already present in this relatively young African population as opposed to Caucasians.

Are left ventricular mass, geometry and function related to vascular changes and/or insulin resistance in long-standing hypertension? ICARUS: a LIFE substudy

Vascular hypertrophy and insulin resistance have been associated with abnormal left ventricular (LV) geometry in population studies. We wanted to investigate the influence of vascular hypertrophy and insulin resistance on LV hypertrophy and its function in patients with hypertension. In 89 patients with essential hypertension and electrocardiographic LV hypertrophy, we measured blood pressure; insulin sensitivity by hyperinsulinaemic euglucaemic clamp; minimal forearm vascular resistance (MFVR) by plethysmography; intima-media cross-sectional area of the common carotid arteries (IMA) by ultrasound; and LV mass, relative wall thickness (RWT), systolic function and diastolic filling by echocardiography after two weeks of placebo treatment. LV mass index correlated to IMA/height (r=0.36, P=0.001), serum insulin (r=−0.25, P<0.05), plasma glucose (r=−0.34, P<0.01), and showed a tendency towards a correlation to insulin sensitivity (r=0.21, P=0.051), but was unrelated to MFVR. Deceleration time of early diastolic transmitral flow positively correlated to IMA/height (r=0.30, P<0.01). The ratio between early and atrial LV filling peak flow velocity negatively correlated to MFVRmen (r=−0.30, P<0.05). Endocardial and midwall systolic LV function were not related to vascular hypertrophy, plasma glucose, serum insulin or insulin sensitivity. In conclusion, insulin resistance was not related to LV hypertrophy or reduced LV function. However, high thickness of the common carotid arteries was associated with LV hypertrophy and high deceleration time of early diastolic transmitral flow. High MFVR was associated with low ratio between early and atrial LV filling peak flow velocity. This may suggest that systemic vascular hypertrophy contributes to abnormal diastolic LV relaxation in patients with hypertension and electrocardiographic LV hypertrophy.