B Dahlöf

Albuminuria and Cardiovascular Risk in Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE Study

Context Microalbuminuria is a known risk factor for cardiovascular disease. Contribution In this large prospective study of hypertensive patients with left ventricular hypertrophy, increasing microalbuminuria was associated with increasing risks for cardiovascular disease. Risks continuously increased without evidence of a threshold or plateau level. Implications Microalbuminuria assessment in hypertensive patients may improve cardiovascular risk stratification. Cautions The study was based on data collected during a randomized, controlled trial of antihypertensive therapy. Albuminuria was measured as the albumincreatinine ratio in a single spot urine collection. Other than for the study drug received, the authors did not adjust for treatments received during the trial. The Editors Microalbuminuria was first associated with essential hypertension in nondiabetic individuals by Parving and colleagues (1), and subsequent studies (2, 3) confirmed the association. Albuminuria is an independent risk factor for cardiovascular disease and increased all-cause mortality in relatively unselected (4, 5) or general (6-8) populations, postmenopausal women (9), older people (10, 11), diabetic patients (12, 13), hypertensive patients with or without concomitant diabetes (8, 14, 15), and people with known high risk for cardiovascular disease (16). Left ventricular hypertrophy is an independent predictor of adverse prognosis (17-19) and is related to albumin excretion independent of age, blood pressure, diabetes, race, serum creatinine level, or smoking; these associations suggest parallel cardiac damage and increased renal albumin excretion rate (20). Other studies suggest that albuminuria at levels well below traditional partition values is a risk factor for coronary vascular disease in patients with and without diabetes (16, 21), indicating that the relation between albuminuria and cardiovascular risk from other populations cannot be directly applied to nondiabetic hypertensive patients. More precise information about the relation between albuminuria and cardiovascular risk would not only help clinicians better estimate the patients absolute risk but also strengthen the decision to initiate antihypertensive treatment, since current guidelines consider not only blood pressure but also target organ damage (for example, albuminuria) (22). We conducted a prospective study to determine the albuminuria level at which cardiovascular morbidity and mortality are increased in a large group of hypertensive patients with left ventricular hypertrophy. In a predefined protocol, we hypothesized that no unique albuminuria threshold predicts increased cardiovascular risk but rather that increasing albuminuria is associated with a graded increase in risk. We anticipated that in hypertensive patients with left ventricular hypertrophy, any threshold identified would be much lower than the threshold traditionally defined in diabetic populations. Methods Patients Participants in our study were outpatients between 55 and 80 years of age. They were recruited from a mix of general and hospital practices and had previously untreated or treated stage II or III hypertension with electrocardiographically confirmed left ventricular hypertrophy (measured according to the product of QRS duration multiplied by Cornell voltage or according to SokolowLyon voltage). The patients were randomly assigned to receive double-blind therapy with losartan or atenolol in the Losartan Intervention For Endpoint reduction (LIFE) study (23, 24). Study Design The hypotheses of the current study were prespecified as part of the LIFE protocol. Inclusion criteria were a mean trough sitting systolic blood pressure of 160 to 200 mm Hg or a diastolic blood pressure of 95 to 115 mm Hg after 1 and 2 weeks of single-blind placebo treatment and no other antihypertensive medication at the time of randomization. Exclusion criteria were myocardial infarction or stroke within 6 months, current congestive heart failure or previously known left ventricular ejection fraction less than 0.40, and renal insufficiency (serum creatinine level >160 mmol/L [>1.8 mg/dL]). We excluded patients who had a condition that the treating physician believed required treatment with losartan or another angiotensin II-receptor blocker, atenolol or another -blocker, hydrochlorothiazide, or angiotensin-converting enzyme inhibitors. Patients gave informed consent under protocols approved by the ethics committees of the participating institutions. End Points and Adjudication This study of the 8206 LIFE participants who had baseline albuminuria determinations (>90% of the entire sample) is based on analysis of a primary composite end point (n = 971): the first occurrence of cardiovascular death, fatal or nonfatal stroke, and fatal or nonfatal myocardial infarction. Additional end points were all-cause mortality (n = 703) and the first occurrence of each component of the composite end point, regardless of whether it was preceded by another component of the primary end point: 383 cardiovascular deaths, 479 strokes, and 344 myocardial infarctions. In the nondiabetic subgroup there were 755 composite end points, including 292 cardiovascular deaths, 379 fatal and nonfatal strokes, 261 fatal and nonfatal myocardial infarctions, and 554 all-cause deaths. Investigators reported all end points; source data were verified by independent monitors and were adjudicated by an independent committee on the basis of definitions provided in a predefined end point manual (24). Patients and the investigators reported the prevalences of coronary, cerebral, or peripheral vascular disease and smoking habits. Diabetes was defined according to investigator report and plasma glucose level. The Framingham risk score (25) was estimated from baseline blood pressure, total cholesterol level, high-density lipoprotein cholesterol level, smoking status, glucose level, and level of left ventricular hypertrophy on electrocardiography (ECG). Renal Evaluation On the same day, a spot urine sample was collected as the first morning voiding and the serum creatinine level was measured. Urine albumin concentration was determined by standard methods (26) using a turbidometric method (Hitachi 717 analyzer, Hoffmann-La Roche Ltd., Basel, Switzerland) (27) on a single urine specimen. Both serum and urine levels of creatinine were analyzed by using the Jaff reaction without deproteinizing and then quantified by a photometric method using the same analyzer. The ratio of urine albumin (in mg/L) to creatinine concentration (UACR) (in mmol/L) provided a composite measure (in mg/mmol) of renal glomerular capillary permeability that adjusted for urine dilution (28). To derive U.S. measures of UACR (mg/g), UACR in mg/mmoL is multiplied by 8.84. Statistical Analysis We used SPSS software, version 11.0.1 (SPSS, Inc., Chicago, Illinois), for statistical analyses. The study sample as a whole and the nondiabetic patients were divided into UACR deciles; diabetic patients were divided into UACR quintiles. We used Cox proportional-hazards models to compare hazard ratios among groups and to evaluate the contributions of differences in the degree of left ventricular hypertrophy (both Cornell voltage duration product and SokolowLyon voltage as continuous variables), the Framingham risk score (25), and treatment allocation (losartan or atenolol) as covariates. To express the increase in risk per increase in UACR as a continuous variable, we log-transformed UACR. We used a Cox model in the test for trend and used the decile group as a continuous variable. Hazard ratios from the decile groups were then used to estimate the best-fitting curve (SPSS curve estimation function). Two-tailed P values less than 0.05 were considered statistically significant. Role of the Funding Source The funding source had no role in the design, analysis, and reporting of the study or in the decision to submit the manuscript for publication. Results Patient Characteristics Descriptive data for the LIFE study sample (23) and relations of microalbuminuria and macroalbuminuria to cardiovascular risk factors have been reported elsewhere (20). Of the 9193 patients participating in the LIFE study, 8206 had the baseline UACR measurements necessary for inclusion in the present study. The mean age (SD) was 66 7 years; 54% of patients were women, and 92% were white. Thirteen percent had diabetes, 13.5% had coronary heart disease, and 7.7% had had a stroke. The mean arterial blood pressure (SD) was 174 14/98 9 mm Hg, the mean serum creatinine level (SD) was 87 20 mmol/L, and the median UACR was 1.28 mg/mmol. Additional baseline characteristics of patients with albuminuria are described elsewhere (20). To stratify risk in hypertensive patients with albuminuria and left ventricular hypertrophy, patients were divided into UACR deciles, with 814 to 821 patients in each group. Patients were followed for a median of 4.8 years and a total of 39 122 patient-years. End point rates were 24.8 per 1000 patient-years of follow-up for the composite endpoint, 9.4 for cardiovascular mortality, 17.6 for all-cause mortality, 11.9 for stroke, and 8.5 for myocardial infarction. Age; sex; race; body mass index; blood pressure; level of left ventricular hypertrophy on ECG; Framingham risk score; prevalence of known diabetes, coronary heart disease, or peripheral vascular disease; and smoking habits did not differ between the patients who provided a urine sample and the 987 patients who did not. The prevalence of history of cerebral vascular disease (13.2% vs. 10.5%; P = 0.029) and mean serum creatinine level (90.0 vs. 86.7 mmol/L; P = 0.001) were higher in patients who did not provide a urine sample than in those who did. When we considered differences in left ventricular mass on ECG, Framingham risk score, and study treatment, patients without a urine sample had a 52% higher all-cause mortality rate (95% CI, 23% to 87%); the rates of t

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 194 g to above the upper quartile of 263 g) in patients with UACR below (6.7, 5.0, 9.1%) and above the median value of 1.406 mg/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 1.406 mg/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.

Clusters of metabolic risk factors predict cardiovascular events in hypertension with target-organ damage: the LIFE study

The relation of metabolic syndrome (MetS) with cardiovascular outcome may be less evident when preclinical cardiovascular disease is present. We explored, in a post hoc analysis, whether MetS predicts cardiovascular events in hypertensive patients with electrocardiographic left ventricular hypertrophy (ECG-LVH) in the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study. MetS was defined by ⩾2 risk factors plus hypertension: body mass index ⩾30 kg/m2, high-density lipoprotein (HDL)-cholesterol <1.0/1.3 mmol/l (<40/50 mg/dl) (men/women), glucose ⩾6.1 mmol/l (⩾110 mg/dl) fasting or ⩾7.8 mmol/l (⩾140 mg/dl) nonfasting or diabetes. Cardiovascular death and the primary composite end point (CEP) of cardiovascular death, stroke and myocardial infarction were examined. In MetS (1591 (19.3%) of 8243 eligible patients), low HDL-cholesterol (72%), obesity (77%) and impaired glucose (73%) were similarly prevalent, with higher blood pressure, serum creatinine and Cornell product, but lower Sokolow–Lyon voltage (all P<0.001). After adjusting for baseline covariates, hazard ratios for CEPs and cardiovascular death (4.8±1.1 years follow-up) were 1.47 (95% confidence interval (CI), 1.27–1.71)- and 1.73 (95% CI, 1.38–2.17)-fold higher with MetS (both P<0.0001), and were only marginally reduced when further adjusted for diabetes, obesity, low HDL-cholesterol, non-HDL-cholesterol, pulse pressure and in-treatment systolic blood pressure and heart rate. Thus, MetS is associated with increased cardiovascular events in hypertensive patients with ECG-LVH, independently of single cardiovascular risk factors.

Telomere length and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study

Short telomeres are associated with aging and age-related diseases. Our aim was to determine whether short leukocyte telomere length is associated with risk factors and cardiovascular diseases in a high-risk hypertensive population. We measured leukocyte telomere lengths at recruitment in 1271 subjects with hypertension and left ventricular hypertrophy (LVH) participating in the Lifestyle Interventions and Independence for Elders (LIFE) study. At baseline, short mean telomere length was associated with coronary artery disease in males (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.39–0.95), and transient ischemic attack in females (OR 0.62 95% CI 0.39–0.99). Proportion of short telomeres (shorter than 5 kb) was associated with Framingham risk score (r=0.07, P<0.05), cerebrovascular disease (OR 1.18, 95% CI 1.01–1.15) and type 2 diabetes in men (OR 1.07, 95% CI 1.02–1.11). During follow-up, proportion of short telomeres was associated with combined cardiovascular mortality, stroke or angina pectoris (hazard ratio 1.04, 95% CI 1.01–1.07). Telomere length was not associated with smoking, body mass index, pulse pressure or self-reported use of alcohol. Our data suggest that reduced leukocyte telomere length is associated with cardiovascular risk factors and diseases as well as type 2 diabetes, and is a predictor of cardiovascular disease in elderly patients with hypertension and LVH.

Regression of electrocardiographic left ventricular hypertrophy predicts regression of echocardiographic left ventricular mass: the LIFE study

The electrocardiogram (ECG) is widely used for detection of left ventricular hypertrophy (LVH). However, whether changes in ECG LVH during antihypertensive therapy predict changes in LV mass remains unclear. Baseline and year-1 ECGs and echocardiograms were assessed in 584 hypertensive patients with ECG LVH by Sokolow–Lyon or Cornell voltage–duration product criteria at entry into the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiographic substudy. A ⩾25% decrease in Cornell product defined regression of ECG LVH; a <25% decrease defined no significant regression; and an increase defined progression of ECG LVH. Regression of echocardiographic LVH was defined by a ⩾20% reduction in LV mass. After 1 year of therapy, 155 patients (27%) had regression of ECG LVH, 286 (49%) had no significant change, and 143 (25%) had progression of ECG LVH. Compared with patients with progression of ECG LVH, patients with no significant decrease and patients with regression of ECG LVH had stepwise greater absolute decreases in LV mass (−16±33 vs −29±37 vs −32±41 g, P<0.001), greater percent reductions in LV mass (−5.7±14.6 vs −11.3±13.6 vs −12.3±15.6%, P<0.001), and were more likely to decrease LV mass by ⩾20% (11.2 vs 24.8 vs 36.1%, P<0.001), even after adjusting for possible effects of baseline and change in systolic and diastolic pressures. Compared with progression of ECG LVH, regression of the Cornell product ECG LVH is associated with greater reduction in LV mass and a greater likelihood of regression of anatomic LVH.

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.

Influence of age, sex and blood pressure on the principal endpoints of the Nordic Diltiazem (NORDIL) Study

Background The aim of the Nordic Diltiazem (NORDIL) Study was to compare patients with essential hypertension receiving calcium-antagonist-based treatment with diltiazem and similar patients receiving conventional diuretic/β-blocker-based treatment, with respect to cardiovascular morbidity and mortality. Objective To assess the influence of age, sex, severity of hypertension and heart rate on treatment effects, in a sub-analysis. Methods The NORDIL study was prospective, randomized, open and endpoint-blinded. It enrolled, at health centres in Norway and Sweden, 10 881 patients aged 50–74 years who had diastolic blood pressure (DBP) of 100 mmHg or more. Systolic blood pressure (SBP) and DBP were decreased by 20.3/18.7 mmHg in the diltiazem group and by 23.3/18.7 mmHg in the diuretic/β-blocker group – a significant difference in SBP (P < 0.001). Results The incidence of the primary endpoint – a composite of cardiovascular death, cerebral stroke and myocardial infarction – was similar for the two treatments. Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 patients in the conventional treatment group [relative risk (RR) 0.80, 95% confidence interval (CI) 0.65 to 0.99;P = 0.040], whereas there was a non-significant inverse tendency with respect to all myocardial infarction. There were significantly fewer cerebral strokes in patients receiving diltiazem in the subgroups with baseline SBP > 170 mmHg (n = 5420, RR 0.75, 95% CI 0.58 to 0.98;P = 0.032), DBP ⩾ 105 mmHg (n = 5881, RR 0.74, 95% CI 0.57 to 0.97;P = 0.030) and pulse pressure ⩾ 66 mmHg (n = 5461, RR 0.76, 95% CI 0.58 to 0.99, P = 0.041), and more myocardial infarctions in those with heart rate less than 74 beats/min (n = 5303, RR 1.13, 95% CI 1.01 to 1.87;P = 0.040). However, the tendencies for fewer strokes and greater incidence of myocardial infarction were present across subgroups when results were analysed for age, sex, severity of hypertension and heart rate, and treatment–subgroup interaction analyses were not statistically significant. Conclusions Compared with a conventional diuretic/β-blocker-based antihypertensive regimen, there were additional 25% reductions in stroke in the diltiazem-treated patients with blood pressure or pulse pressure greater than the medians, and an increase in myocardial infarction in those with heart rate less than the median. Such findings may be attributable to chance, but the consistency of, in particular, the stroke findings may also suggest an ability of diltiazem, beyond conventional treatment, to prevent cerebral stroke in hypertensive patients with the greatest cardiovascular risk.

Clustered metabolic abnormalities blunt regression of hypertensive left ventricular hypertrophy: the LIFE study

BACKGROUND AND AIMS Clusters of metabolic abnormalities resembling phenotypes of metabolic syndrome predicted outcome in the LIFE study, independently of single risk markers, including obesity, diabetes and baseline ECG left ventricular hypertrophy (LVH). We examined whether clusters of two or more metabolic abnormalities (MetAb, including obesity, high plasma glucose without diabetes, low HDL-cholesterol) in addition to hypertension were associated to levels of ECG LVH reduction comparable to that obtained in hypertensive subjects without or with only one additional metabolic abnormality (no-MetAb). METHODS AND RESULTS We studied 5558 non-diabetic participants without MetAb (2920 women) and 1235 with MetAb (751 women) from the LIFE-study cohort. MetAb was defined by reported LIFE criteria, using partition values from the ATPIII recommendations. Time-trends of Cornell voltage-duration product (CP) over 5 years was assessed using a quadratic polynomial contrast, adjusting for age, sex, prevalent cardiovascular disease and treatment arm (losartan or atenolol). At baseline, despite similar blood pressures, CP was greater in the presence than in the absence of MetAb (p<0.0001). During follow-up, despite similar reduction of blood pressure, CP decreased less in patients with than in those without MetAb, even after adjustment for the respective baseline values (both p<0.002). Losartan was more effective than atenolol in reducing CP independently of MetAb. CONCLUSIONS Clusters of metabolic abnormalities resembling phenotypes of metabolic syndrome are related to greater initial ECG LVH in hypertensive patients with value of blood pressure similar to individuals without metabolic abnormalities, and are associated with less reduction of ECG LVH during antihypertensive therapy, potentially contributing to the reported adverse prognosis of metabolic syndrome.

Renal function and risk for cardiovascular events in type 2 diabetic patients with hypertension : the RENAAL and LIFE studies.

Objective To investigate whether a threshold exists for cardiovascular risk in type 2 diabetic patients with hypertension, the association between renal function and cardiovascular risk was examined across the entire physiological range of serum creatinine. Design and methods The RENAAL and LIFE studies enrolled 1513 and 1195 patients with type 2 diabetes and hypertension, respectively. The relationship between baseline serum creatinine and the risk for a composite outcome of myocardial infarction, stroke or cardiovascular death was examined using Cox regression models. To adjust for heterogeneity between studies and treatment groups, these factors were included as strata when applicable. The analyses were conducted with adjustment for age, gender, smoking, alcohol use, blood pressure, heart rate, total and high-density lipoprotein (HDL) cholesterol, hemoglobin, albuminuria and prior cardiovascular disease. Results The hazard ratios across the baseline serum creatinine categories < 0.9 mg/dl, 0.9–1.2 mg/dl, 1.2–1.6 mg/dl, 1.6–2.8 mg/dl and ≥ 2.8 mg/dl were 0.51 (95% confidence interval 0.34, 0.74), 0.74 (0.55, 1.00), 1.00 (reference), 1.24 (0.96, 1.59) and 1.67 (1.17, 2.91), respectively. Baseline serum creatinine (per mg/dl) strongly predicted the composite cardiovascular endpoint in LIFE [2.82(1.74,4.56), P < 0.001], RENAAL [1.41(1.12,1.79), P < 0.001], as well as the combined studies [1.51(1.21,1.87), P < 0.001]. Conclusion A progressively higher risk for the composite cardiovascular endpoint was observed with incremental baseline serum creatinine in type 2 diabetic patients with hypertension, even within the normal range. Thus, there appears to be no serum creatinine threshold level for an increased cardiovascular risk. Baseline serum creatinine was a major independent risk factor for cardiovascular disease (www.ClinicalTrials.gov number NCT00308347).

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 (<140/90 mmHg) 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.