Increased baseline left ventricular (LV) mass predicts cardiovascular (CV) complications of hypertension, but the relation between lower LV mass and outcome during treatment for hypertension is ...uncertain.
To determine whether reduction of LV mass during antihypertensive treatment modifies risk of major CV events independent of blood pressure change.
Prospective cohort substudy of the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) randomized clinical trial, conducted from 1995 to 2001. A total of 941 prospectively identified patients aged 55 to 80 years with essential hypertension and electrocardiographic LV hypertrophy had LV mass measured by echocardiography at enrollment in the LIFE trial and thereafter were followed up annually for a mean (SD) of 4.8 (1.0) years for CV events.
Composite end point of CV death, fatal or nonfatal myocardial infarction, and fatal or nonfatal stroke.
The composite end point occurred in 104 patients (11%). The multivariable Cox regression model showed a strong association between lower in-treatment LV mass index and reduced rate of the composite CV end point (hazard ratio HR, 0.78 per 1-SD (25.3) decrease in LV mass index; 95% confidence interval CI, 0.65-0.94; P = .009) over and above that predicted by reduction in blood pressure. There were parallel associations between lower in-treatment LV mass index and lower CV mortality (HR, 0.62; 95% CI, 0.47-0.82; P = .001), stroke (HR, 0.76; 95% CI, 0.60-0.96; P = .02), myocardial infarction (HR, 0.85; 95% CI, 0.62-1.17, P = .33), and all-cause mortality (HR, 0.72; 95% CI, 0.59-0.88, P = .002), independent of systolic blood pressure and assigned treatment. Results were confirmed in analyses adjusting for additional CV risk factors, electrocardiographic changes, or when only considering events after the first year of study treatment.
In patients with essential hypertension and baseline electrocardiographic LV hypertrophy, lower LV mass during antihypertensive treatment is associated with lower rates of clinical end points, additional to effects of blood pressure lowering and treatment modality.
The associations of low (<0.90) and high (>1.40) ankle brachial index (ABI) with risk of all-cause and cardiovascular disease (CVD) mortality have not been examined in a population-based setting.
We ...examined all-cause and CVD mortality in relation to low and high ABI in 4393 American Indians in the Strong Heart Study. Participants had bilateral ABI measurements at baseline and were followed up for 8.3+/-2.2 years (36 589 person-years). Cox regression was used to quantify mortality rates among participants with high and low ABI relative to those with normal ABI (0.90 < or =ABI < or =1.40). Death from all causes occurred in 1022 participants (23.3%; 27.9 deaths per 1000 person-years), and of these, 272 (26.6%; 7.4 deaths per 1000 person-years) were attributable to CVD. Low ABI was present in 216 participants (4.9%), and high ABI occurred in 404 (9.2%). Diabetes, albuminuria, and hypertension occurred with greater frequency among persons with low (60.2%, 44.4%, and 50.1%) and high (67.8%, 49.9%, and 45.1%) ABI compared with those with normal ABI (44.4%, 26.9%, and 36.5%), respectively (P<0.0001). Adjusted risk estimates for all-cause mortality were 1.69 (1.34 to 2.14) for low and 1.77 (1.48 to 2.13) for high ABI, and estimates for CVD mortality were 2.52 (1.74 to 3.64) for low and 2.09 (1.49 to 2.94) for high ABI.
The association between high ABI and mortality was similar to that of low ABI and mortality, highlighting a U-shaped association between this noninvasive measure of peripheral arterial disease and mortality risk. Our data suggest that the upper limit of normal ABI should not exceed 1.40.
Whether diabetes mellitus (DM) adversely affects left ventricular (LV) structure and function independently of increases in body mass index (BMI) and blood pressure is controversial.
Echocardiography ...was used in the Strong Heart Study, a study of cardiovascular disease in American Indians, to compare LV measurements between 1810 participants with DM and 944 with normal glucose tolerance. Participants with DM were older (mean age, 60 versus 59 years), had higher BMI (32.4 versus 28.9 kg/m(2)) and systolic blood pressure (133 versus 124 mm Hg), and were more likely to be female, to be on antihypertensive treatment, and to live in Arizona (all P<0.001). In analyses adjusted for covariates, women and men with DM had higher LV mass and wall thicknesses and lower LV fractional shortening, midwall shortening, and stress-corrected midwall shortening (all P<0.002). Pulse pressure/stroke volume, a measure of arterial stiffness, was higher in participants with DM (P<0.001 independent of confounders).
Non-insulin-dependent DM has independent adverse cardiac effects, including increased LV mass and wall thicknesses, reduced LV systolic chamber and myocardial function, and increased arterial stiffness. These findings identify adverse cardiovascular effects of DM, independent of associated increases in BMI and arterial pressure, that may contribute to cardiovascular events in diabetic individuals.
Although systemic lupus erythematosus is associated with premature myocardial infarction, the prevalence of underlying atherosclerosis and its relation to traditional risk factors for cardiovascular ...disease and lupus-related factors have not been examined in a case-control study.
In 197 patients with lupus and 197 matched controls, we performed carotid ultrasonography, echocardiography, and an assessment for risk factors for cardiovascular disease. The patients were also evaluated with respect to their clinical and serologic features, inflammatory mediators, and disease treatment.
The risk factors for cardiovascular disease were similar among patients and controls. Atherosclerosis (carotid plaque) was more prevalent among patients than the controls (37.1 percent vs. 15.2 percent, P<0.001). In multivariate analysis, only older age, the presence of systemic lupus erythematosus (odds ratio, 4.8; 95 percent confidence interval, 2.6 to 8.7), and a higher serum cholesterol level were independently related to the presence of plaque. As compared with patients without plaque, patients with plaque were older, had a longer duration of disease and more disease-related damage, and were less likely to have multiple autoantibodies or to have been treated with prednisone, cyclophosphamide, or hydroxychloroquine. In multivariate analyses including patients with lupus, independent predictors of plaque were a longer duration of disease, a higher damage-index score, a lower incidence of the use of cyclophosphamide, and the absence of anti-Smith antibodies.
Atherosclerosis occurs prematurely in patients with systemic lupus erythematosus and is independent of traditional risk factors for cardiovascular disease. The clinical profile of patients with lupus and atherosclerosis suggests a role for disease-related factors in atherogenesis and underscores the need for trials of more focused and effective antiinflammatory therapy.
This study was designed to evaluate whether different antihypertensive treatment regimens with similar blood pressure reduction have different effects on new-onset atrial fibrillation (AF).
It is ...unknown whether angiotensin II receptor blockade is better than beta-blockade in preventing new-onset AF.
In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study 9,193 hypertensive patients and patients with electrocardiogram-documented left ventricular hypertrophy were randomized to once-daily losartan- or atenolol-based antihypertensive therapy. Electrocardiograms were Minnesota coded centrally, and 8,851 patients without AF by electrocardiogram or history, who were thus at risk of developing AF, were followed for 4.8 +/- 1.0 years.
New-onset AF occurred in 150 patients randomized to losartan versus 221 to atenolol (6.8 vs. 10.1 per 1,000 person-years; relative risk 0.67, 95% confidence interval CI 0.55 to 0.83, p < 0.001) despite similar blood pressure reduction. Patients receiving losartan tended to stay in sinus rhythm longer (1,809 +/- 225 vs. 1,709 +/- 254 days from baseline, p = 0.057) than those receiving atenolol. Moreover, patients with new-onset AF had two-, three- and fivefold increased rates, respectively, of cardiovascular events, stroke, and hospitalization for heart failure. There were fewer composite end points (n = 31 vs. 51, hazard ratio = 0.60, 95% CI 0.38 to 0.94, p = 0.03) and strokes (n = 19 vs. 38, hazard ratio = 0.49, 95% CI 0.29 to 0.86, p = 0.01) in patients who developed new-onset AF in the losartan compared to the atenolol treatment arm of the study. Furthermore, Cox regression analysis showed that losartan (21% risk reduction) and new-onset AF both independently predicted stroke even when adjusting for traditional risk factors.
Our novel finding is that new-onset AF and associated stroke were significantly reduced by losartan- compared to atenolol-based antihypertensive treatment with similar blood pressure reduction.
Background To date there has been no comprehensive review of the association between left ventricular hypertrophy (LVH) at baseline and subsequent adverse clinical events. Methods A total of 20 ...studies (with 48,545 participants) published between January 1960 and January 2000, identified through MEDLINE and other sources, related baseline electrocardiographic (ECG) or echocardiographic data on LVH to subsequent cardiovascular morbidity and all-cause mortality. Results The prevalence of baseline LVH was higher in echocardiographic studies than in ECG studies (16%-74% vs 1%-44%, respectively). The adjusted risk of future cardiovascular morbidity associated with baseline LVH ranged from 1.5 to 3.5, with a weighted mean risk ratio of 2.3 for all studies combined. The adjusted risk of all-cause mortality associated with baseline LVH ranged from 1.5 to 8.0, with a weighted mean risk ratio of 2.5 for all studies combined. There was a trend toward a worse prognosis among women with baseline LVH compared with men. These findings persisted in the various population and ethnic groups studied. Conclusion With the exception of one study in dialysis patients, LVH consistently predicted high risk, independently of examined covariates, with no clear difference in relation to race, presence or absence of hypertension or coronary disease, or between clinical and epidemiologic samples. These results clarify the strong relation between LVH and adverse outcome and emphasize the clinical importance of its detection. (Am Heart J 2001;141:334-41.)
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.
An echocardiographic substudy of the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial was designed to test the ability of losartan to reduce left ventricular (LV) mass more ...than atenolol.
A total of 960 patients with essential hypertension and LV hypertrophy (LVH) on screening ECG were enrolled at centers in 7 countries and studied by echocardiography at baseline and after 1, 2, 3, 4, and 5 years' randomized therapy. Clinical examination and blinded readings of echocardiograms in 457 losartan-treated and 459 atenolol-treated participants with > or =1 follow-up measurement of LV mass index (LVMI) were used in an intention-to-treat analysis. Losartan-based therapy induced greater reduction in LVMI from baseline to the last available study than atenolol with adjustment for baseline LVMI and blood pressure and in-treatment pressure (-21.7+/-21.8 versus -17.7+/-19.6 g/m2; P=0.021). Greater LVMI reduction with losartan was observed in women and men, participants >65 or <65 years of age, and with mild or more severe baseline hypertrophy. The difference between treatment arms in LVH regression was due mainly to reduced concentricity of LV geometry in both groups and lesser increase in LV internal diameter in losartan-treated patients.
Antihypertensive treatment with losartan, plus hydrochlorothiazide and other medications when needed for pressure control, resulted in greater LVH regression in patients with ECG LVH than conventional atenolol-based treatment. Thus, angiotensin receptor antagonism by losartan has superior efficacy for reversing LVH, a cardinal manifestation of hypertensive target organ damage.
Electrocardiographic left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular (CV) morbidity and mortality. However, the predictive value of changes in the magnitude of ...electrocardiographic LVH criteria during antihypertensive therapy remains unclear.
To test the hypothesis that lesser severity of electrocardiographic LVH during antihypertensive treatment is associated with decreased CV morbidity and mortality, independent of blood pressure levels and reduction and treatment modality.
Double-blind, randomized, parallel-group study conducted in 1995-2001 among 9193 men and women with hypertension aged 55 through 80 years (mean, 67 years), with electrocardiographic LVH by Cornell voltage-duration product or Sokolow-Lyon voltage criteria and enrolled in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study.
Losartan- or atenolol-based treatment regimens, with follow-up assessments for at least 4 (mean, 4.8 SD, 0.9) years.
Composite end point of CV death, myocardial infarction (MI), or stroke in relation to severity of electrocardiographic LVH determined at baseline and on subsequent electrocardiograms obtained at 1 or more annual revisits.
Cardiovascular death, nonfatal MI, or stroke occurred in 1096 patients (11.9%). In Cox regression models controlling for treatment type, baseline Framingham risk score, baseline and in-treatment blood pressure, and severity of baseline electrocardiographic LVH by Cornell product and Sokolow-Lyon voltage, less-severe in-treatment LVH by Cornell product and Sokolow-Lyon voltage were associated with 14% and 17% lower rates, respectively, of the composite CV end point (adjusted hazard ratio HR, 0.86; 95% confidence interval CI, 0.82-0.90; P<.001 for every 1050-mm x ms 1-SD decrease in Cornell product; and HR, 0.83; 95% CI, 0.78-0.88; P<.001 for every 10.5-mm 1-SD decrease in Sokolow-Lyon voltage). In parallel analyses, lower Cornell product and Sokolow-Lyon voltage were each independently associated with lower risks of CV mortality (HR, 0.78; 95% CI, 0.73-0.83; P<.001; and HR, 0.80; 95% CI, 0.73-0.87; P<.001, respectively), MI (HR, 0.90; 95% CI, 0.82-0.98; P=.01; and HR, 0.90; 95% CI, 0.81-1.00; P = .04), and stroke (HR, 0.90; 95% CI, 0.84-0.96; P=.002; and HR, 0.81; 95% CI, 0.75-0.89; P<.001).
Less-severe electrocardiographic LVH by Cornell product and Sokolow-Lyon voltage criteria during antihypertensive therapy is associated with lower likelihoods of CV morbidity and mortality, independent of blood pressure lowering and treatment modality in persons with essential hypertension. Antihypertensive therapy targeted at regression or prevention of electrocardiographic LVH may improve prognosis.
The impact of serum uric acid on cardiovascular outcomes in the LIFE study.
The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study demonstrated the superiority of a ...losartan-based regimen over atenolol-based regimen for reduction of cardiovascular (CV) morbidity and mortality. It has been suggested that the LIFE study results may be related to the effects of losartan on serum uric acid (SUA). SUA has been proposed as an independent risk factor for CV morbidity and death.
Cox regression analysis was used to assess relationship of SUA and treatment regimens with the LIFE primary composite outcome (CV death, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke).
Baseline SUA was significantly associated with increased CV events hazard ratio (HR) 1.024 (95% CI 1.017–1.032) per 10 μmol/L, P < 0.0001 in the entire study population. The association was significant in women HR = 1.025 (1.013–1.037), P < 0.0001, but not in men HR = 1.009 (0.998–1.019), P = 0.108. After adjustment for Framingham risk score (FRS), SUA was no longer significant in the entire study population HR = 1.006 (0.998–1.014), P = 0.122 or in men HR = 1.006 (0.995–1.017), P = 0.291, but was significant in women HR = 1.013 (1–1.025), P = 0.0457. The baseline-to-end-of-study increase in SUA (standard deviation, SD) was greater (P < 0.0001) in atenolol-treated subjects (44.4 ± 72.5 μmol/L) than in losartan-treated subjects (17.0 ± 69.8 μmol/L). SUA as a time-varying covariate was strongly associated with events (P < 0.0001) in the entire population. The contribution of SUA to the treatment effect of losartan on the primary composite end point was 29% (14%-107%), P = 0.004. The association between time-varying SUA and increased CV risk tended to be stronger in women (P < 0.0001) than in men (P = 0.0658), although the gender-outcome interaction was not significant (P = 0.079).
The increase in SUA over 4.8years in the LIFE study was attenuated by losartan compared with atenolol treatment, appearing to explain 29% of the treatment effect on the primary composite end point. The association between SUA and events was stronger in women than in men with or without adjustment of FRS.
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