H. Ibsen

Albuminuria predicts cardiovascular events independently of left ventricular mass in hypertension: a LIFE substudy

We wanted to investigate whether urine albumin/creatinine ratio (UACR) and left ventricular (LV) mass, both being associated with diabetes and increased blood pressure, predicted cardiovascular events in patients with hypertension independently. After 2 weeks of placebo treatment, clinical, laboratory and echocardiographic variables were assessed in 960 hypertensive patients from the LIFE Echo substudy with electrocardiographic LV hypertrophy. Morning urine albumin and creatinine were measured to calculate UACR. The patients were followed for 60±4 months and the composite end point (CEP) of cardiovascular (CV) death, nonfatal stroke or nonfatal myocardial infarction was recorded. The incidence of CEP increased with increasing LV mass (below the lower quartile of 194u2009g to above the upper quartile of 263u2009g) in patients with UACR below (6.7, 5.0, 9.1%) and above the median value of 1.406u2009mg/mmol (9.7, 17.0, 19.0%***). Also the incidence of CV death increased with LV mass in patients with UACR below (0, 1.4, 1.3%) and above 1.406u2009mg/mmol (2.2, 6.4, 8.0%**). The incidence of CEP was predicted by logUACR (hazard ratio (HR)=1.44** for every 10-fold increase in UACR) after adjustment for Framingham risk score (HR=1.05***), history of peripheral vascular disease (HR=2.3*) and cerebrovascular disease (HR=2.1*). LV mass did not enter the model. LogUACR predicted CV death (HR=2.4**) independently of LV mass (HR=1.01* per gram) after adjustment for Framingham risk score (HR=1.05*), history of diabetes mellitus (HR=2.4*) and cerebrovascular disease (HR=3.2*). *P<0.05, **P<0.01, ***P<0.001. In conclusion, UACR predicted CEP and CV death independently of LV mass. CV death was predicted by UACR and LV mass in an additive manner after adjustment for Framingham risk score and history of CV disease.

Markers of collagen synthesis is related to blood pressure and vascular hypertrophy: a LIFE substudy.

Cardiac fibrosis and high levels of circulating collagen markers has been associated with left ventricular (LV) hypertrophy. However, the relationship to vascular hypertrophy and blood pressure (BP) load is unclear. In 204 patients with essential hypertension and electrocardiographic LV hypertrophy, we measured sitting BP, serum collagen type I carboxy-terminal telopeptide (ICTP) reflecting degradation, procollagen type I carboxy-terminal propeptide (PICP) reflecting synthesis and LV mass by echocardiography after 2 weeks of placebo treatment and after 1 year of antihypertensive treatment with a losartan- or an atenolol-based regimen. Furthermore, we measured intima–media thickness of the common carotid arteries (IMT), minimal forearm vascular resistance (MFVR) by plethysmography and ambulatory 24-h BP in around half of the patients. At baseline, PICP/ICTP was positively related to IMT (r=0.24, P<0.05), MFVRmen (r=0.35, P<0.01), 24-h systolic BP (r=0.24, P<0.05) and 24-h diastolic BP (r=0.22, P<0.05), but not to LV mass. After 1 year of treatment with reduction in systolic BP (175±15 vs 151±17 mmHg, P<0.001) and diastolic BP (99±8 vs 88±9 mmHg, P<0.001), ICTP was unchanged (3.7±1.4 vs 3.8±1.4 μg/l, NS) while PICP (121±39 vs 102±29 μg/l, P<0.001) decreased. The reduction in PICP/ICTP was related to the reduction in sitting diastolic BP (r=0.31, P<0.01) and regression of IMT (r=0.37, P<0.05) in patients receiving atenolol and to reduction in heart rate in patients receiving losartan (r=0.30, P<0.01). In conclusion, collagen markers reflecting net synthesis of type I collagen were positively related to vascular hypertrophy and BP load, suggesting that collagen synthesis in the vascular wall is increased in relation to high haemodynamic load in a reversible manner.

A blood pressure independent association between glomerular albumin leakage and electrocardiographic left ventricular hypertrophy. The LIFE Study

In the Losartan Intervention For Endpoint reduction (LIFE) study left ventricular (LV) hypertrophy was associated with increased urine albumin/creatinine ratio (UACR) at baseline. To evaluate whether this association was due only to parallel blood pressure (BP)-induced changes we re-examined the patients after 1 year of antihypertensive treatment to investigate whether changes in LV hypertrophy and UACR were related independently of changes in BP. In 7142 hypertensive patients included in the LIFE study, we measured UACR, LV hypertrophy by electrocardiography, plasma glucose and BP after 2 weeks of placebo treatment and again after 1 year of antihypertensive treatment with either an atenolol or a losartan based regime. At baseline and still after 1 year of treatment logUACR (R = 0.28, P < 0.001) was still correlated to LV hypertrophy (β = 0.05) assessed by ECG independently of systolic BP (β = 0.16), plasma glucose (β = 0.19) and age (β = 0.08). Change in logUACR (R = 0.19, P < 0.001) during treatment was correlated to change in LV hypertrophy (β = 0.10) independently of reduction in systolic BP (β = 0.13) and change in plasma glucose (β = 0.06). After 1 year of antihypertensive treatment UACR was still related to LV hypertrophy independently of systolic BP, and the reduction in UACR during that first year of treatment was related to regression of LV hypertrophy independently of reduction in systolic BP. This suggests that the relationship between LV hypertrophy and glomerular albumin leakage is not just due to parallel BP-induced changes. As glomerular albumin leakage may represent generalised vascular damage we hypothesise a vascular relationship between cardiac and glomerular damage.

Association between vascular dysfunction and reduced myocardial flow reserve in patients with hypertension: a LIFE substudy.

Impaired myocardial flow reserve (MFR) has been demonstrated in hypertension, and has been associated with peripheral vascular changes. We investigated whether MFR was impaired and associated with structural and/or functional vascular changes in hypertensive patients without evidence of coronary artery disease (CAD). We measured left ventricular (LV) mass index by echocardiography and MFR by positron emission tomography in 33 unmedicated, hypertensive patients with electrocardiographic LV hypertrophy without CAD, and 15 age- and gender-matched normotensive subjects. We also measured 24-h ambulatory blood pressure, minimal forearm vascular resistance (MFVR) by plethysmography, media:lumen ratio in isolated, subcutaneous resistance arteries by myography, intima–media cross-sectional area of the common carotid artery, and flow-mediated (FMD) and nitroglycerin-induced dilatation (NID) of the brachial artery by ultrasound. Compared to the controls, the patients had impaired MFR (2.4 (95% CI 1.95–2.8) vs 3.4 (2.7–4.2), P<0.01) due to increased resting myocardial blood flow (MBF) (0.82 (0.73–0.91) vs 0.65 (0.56–0.75)u2009ml/gu2009min), and decreased dipyridamole-stimulated MBF (1.80 (1.55–2.1) vs 2.3 (1.80–2.8) ml/gu2009min, both P<0.05). The difference in resting MBF disappeared (80 (74–87) vs 86 (74–97)u2009μl/kgu2009mmHg, NS) when normalized for blood pressure and heart rate. MFR correlated negatively to median 24-h systolic blood pressure (r=−0.50, P<0.01) as well as to LV mass index (r=−0.45, P<0.05) and MFVR in men (r=−0.47, P<0.05), and positively to FMD (r=0.44, P<0.05) and NID (r=0.40, P<0.05). Hypertensive patients with electrocardiographic LV hypertrophy without CAD had impaired MFR associated with cardiovascular hypertrophy and vasodilatory dysfunction. This suggests that MFR is impaired by LV hypertrophy and structural/functional vascular damage in the coronary and noncoronary circulation.

Changes in plasma volume and extracellular fluid volume after addition of prazosin to propranolol treatment in patients with hypertension.

In fifteen patients with hypertension, inadequately controlled during treatment with propranolol alone (mean dosage 333 mg/day), plasma volume (PV) and extracellular fluid volume (ECV) were determined. After addition of prazosin for 3 months (mean dosage 9 mg/day) there was a significant increase in PV and ECV, on average 8 and 5%, respectively. The decrease in supine blood pressure, systolic as well as diastolic, was very modest, on average 11 mmHg (SD +/- 12) and 4 mmHg (SD +/- 7), respectively. The changes in standing blood pressure were more pronounced. It is assumed that the expansion of PV and ECV contributes to the inadequate blood pressure response found in the present study.

Alcohol consumption and cardiovascular risk in hypertensives with left ventricular hypertrophy: the LIFE study.

The Losartan Intervention For End point reduction in hypertension (LIFE) study showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke, and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios (HR) in 4287 and 685 participants who reported intakes of 1–7 and >8 drinks/week at baseline, respectively, with those in 4216 abstainers, adjusting for gender, age, smoking, exercise, and race. Within categories, clinical baseline characteristics, numbers randomized to losartan and atenolol, and blood pressure (BP) lowering were similar on the drug regimens. Overall BP control (<140/90u2009mmHg) at end of follow-up was similar in the categories. Composite end point rate was lower with 1–7 (24/1000 years; HR 0.87, P<0.05) and >8 drinks/week (26/1000 years; HR 0.80, NS) than in abstainers (27/1000 years). Myocardial infarction risk was reduced in both drinking categories (HR 0.76, P<0.05 and HR 0.29, P<0.001, respectively), while stroke risk tended to increase with >8 drinks/week (HR 1.21, NS). Composite risk was significantly reduced with losartan compared to atenolol only in abstainers (HR 0.81 95% confidence interval, CI (0.68, 0.96), P<0.05), while benefits for stroke risk reduction were similar among participants consuming 1–7 drinks/week (HR 0.73, P<0.05) and abstainers (HR 0.72, P<0.01). Despite different treatment benefits, alcohol-treatment interactions were nonsignificant. In conclusion, moderate alcohol consumption does not change the marked stroke risk reduction with losartan compared to atenolol in high-risk hypertensives. Alcohol reduces the risk of myocardial infarction, while the risk of stroke tends to increase with high intake.

Plasma noradrenaline concentration in hypertensive and normotensive forty-year-old individuals: Relationship to plasma renin concentration

Forty-year-old individuals with labile and with mild sustained essential hypertension, identified during a survey of a population born in 1936, were investigated. None had ever received antihypertensive treatment. In thirty-three individuals (26 M, 7F) with diastolic blood pressure (DBP) greater than or equal to 95 mmHg at the very first examination and in thirty-one (14 M, 17 F) randomly selected normotensive controls plasma noradrenaline concentration (PNAC) was measured at rest supine. In twenty-two patients (16 M, 6 F), with sustained diastolic hypertension (diastolic blood pressure greater than or equal to 95 mmHg on at least three different occasions) and in twenty-four (14 M, 10 F) normotensive controls PNAC and plasma renin concentration (PRC) were measured supine at rest and again 2 h after furosemide and ambulation. Basal and acutely stimulated values for PNAC and PRC were identical in hypertensive and normotensive individuals. A close correlation between PNAC and PRC after acute stimulation (r = 0.77, P < 0.001) as well as between the absolute changes from resting to acutely stimulated values (r = 0.72, P < 0.001) were found in the hypertensive individuals. It is concluded that sympathetic nerve activity, as defined from measurements of plasma noradrenaline concentration, is similar in young patients with mild hypertension and in normotensive controls. We propose that the discrepancies found in the literature might be related to a lack of comparability between hypertensive and normotensive individuals studied, as far as the source of study populations is concerned.

Changes in electrocardiographic left ventricular hypertrophy and risk of major cardiovascular events in isolated systolic hypertension: The LIFE study

The predictive value of changes in the severity of electrocardiographic left ventricular hypertrophy (ECG-LVH) during antihypertensive therapy remains unclear in isolated systolic hypertension (ISH). In a Losartan Intervention For Endpoint reduction in hypertension substudy, we included 1320 patients aged 54–83 years with systolic blood pressure (BP) of 160–200u2009mmu2009Hg, diastolic BP <90u2009mmu2009Hg and ECG-LVH by Cornell voltage-duration product and/or Sokolow–Lyon voltage criteria, randomized to losartan- or atenolol-based treatment with a mean follow-up of 4.8 years. The composite end point of cardiovascular death, non-fatal myocardial infarction (MI) or stroke occurred in 179 (13.6%) patients. In Cox regression models controlling for treatment, Framingham risk score, as well as baseline and in-treatment BP, less severe in-treatment ECG-LVH by Cornell product and Sokolow–Lyon voltage was associated with 17 and 25% risk reduction for the composite end point (adjusted hazard ratio (HR) 0.83, 95% confidence interval (95% CI:) 0.75–0.92, P=0.001 per 1050u2009mm × ms (1 s.d.) lower Cornell product; and HR 0.75, 95% CI: 0.65–0.87, P<0.001 per 10.5u2009mm (1 s.d.) lower Sokolow–Lyon voltage). In parallel analyses, lower Cornell product and Sokolow–Lyon voltage were associated with lower risks of cardiovascular mortality and MI, and lower Sokolow–Lyon voltage with lower risk of stroke. Lower Cornell product and Sokolow–Lyon voltage during antihypertensive therapy are associated with lower likelihoods of cardiovascular events in patients with ISH.

A prediction of the renal and cardiovascular efficacy of aliskiren in ALTITUDE using short-term changes in multiple risk markers

Introduction We recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted. Methods We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change. Results Based on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of −7.9% (95% CI −2.5 to −13.4) for the cardio-renal endpoint, a risk change of −5.1% (−1.2 to −9.0) for the CV endpoint and a non-significant risk change of −19.9% (−42.1 to +2.1) for the renal endpoint. Conclusions PRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.

New risk markers may change the HeartScore risk classification significantly in one-fifth of the population

The study aim was to determine whether urine albumin/creatinine ratio (UACR), high-sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (Nt-proBNP) added to risk prediction based on HeartScore and history of diabetes or cardiovascular disease. A Danish population sample of 2460 individuals was divided in three groups: 472 subjects receiving cardiovascular medication or having history of diabetes, prior myocardial infarction or stroke, 559 high-risk subjects with a 10-year risk of cardiovascular death above 5% as estimated by HeartScore, and 1429 low-moderate risk subjects with estimated risk below 5%. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (CEP) occurred in 204 subjects. CEP was predicted in all three groups by UACR (HRs: 2.1, 2.1 and 2.3 per 10-fold increase, all P<0.001) or by hsCRP (HRs: 1.9, 1.9 and 1.7 per 10-fold increase, all P<0.05), but not by Nt-proBNP (HRs: 1.1, 2.6 and 3.7 per 10-fold increase, last two P<0.001) (P<0.05 for interaction). In the low-moderate risk group, pre-specified gender adjusted (men/women) cutoff values of UACR⩾0.73/1.06u2009mgu2009mmol−1 or hsCRP⩾6.0/7.3u2009mgu2009l−1 identified a subgroup of 16% who experienced one-third of the CEPs. In the patient group, combined absence of high UACR and high Nt-proBNP⩾110/164u2009pgu2009ml−1 (men/women) identified a subgroup of 52% who experienced only 15% of the CEPs. Additional use of UACR and hsCRP in subjects with low-moderate risk and UACR and Nt-proBNP in subjects with known diabetes of cardiovascular disease changed HeartScore risk classification significantly in 19% of the population.