Losartan Intervention For Endpoint Reduction Research Articles

Impact of overweight and obesity on cardiac benefit of antihypertensive treatment

Background and aimsIncreased body mass index (BMI) has been associated with increased cardiovascular morbidity and mortality in hypertension. Less is known about the impact of BMI on improvement in left ventricular (LV) structure and function during antihypertensive treatment. Methods and resultsAnnual BMI, echocardiograms and cardiovascular events were recorded in 875 hypertensive patients with LV hypertrophy during 4.8 years randomized treatment in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy. Patients were grouped by baseline BMI into normal (n = 282), overweight (n = 405), obese (n = 150) and severely obese groups (n = 38) (BMI ≤24.9, 25.0–29.9, 30.0–34.9, and ≥35.0 kg/m2, respectively). At study end, residual LV hypertrophy was present in 54% of obese and 79% of severely obese patients compared to 31% of normal weight patients (both p < 0.01). In regression analyses, adjusting for initial LV mass/height2.7, higher BMI predicted less LV hypertrophy reduction and more reduction in LV ejection fraction (both p < 0.05), independent of blood pressure reduction, diabetes and in-study weight change. During follow-up, 91 patients suffered cardiovascular death, myocardial infarction or stroke. In Cox regression analysis 1 kg/m2 higher baseline BMI predicted a 5% higher rate of cardiovascular events and 10% higher cardiovascular mortality over 4.8 years (both p < 0.05). ConclusionsIn hypertensive patients in the LIFE study, increased BMI was associated with less reduction of LV hypertrophy and less improvement in LV systolic function which may contribute to the observed higher cardiovascular event rate of treated hypertensive patients.

The vanishing story of angiotensin II receptor blockers in the treatment of atrial fibrillation

This editorial refers to ‘Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study)’ by T. Yamashita et al. , on page 473. Pharmacological inhibition of the renin–angiotensin system (RAS) is a safe and beneficial intervention in patients with structural heart disease. Furthermore, there is good experimental evidence that AT-1 receptor blocker (ARB) therapy can prevent atrial structural remodelling in atrial fibrillation (AF).1–4 Experiments have proved that by angiotensin-converting enzyme (ACE) inhibitors and ARBs, the degree of atrial fibrosis and thereby the inducibility of AF can be reduced.2–4 In these settings, ACE inhibitors and ARBs were similarly effective. Of note, antiarrhythmic effects of ACE inhibitors and ARBs to prevent AF are supported by retrospective analyses of clinical trials including TRACE (Trandolapril Cardiac Evaluation), ValHeFT (Valsartan Heart Failure Trial), SOLVD (Studies of Left Ventricular Dysfunction), CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), and LIFE (Losartan Intervention For Endpoint reduction in hypertension).1,5 Given the observation that AF induces atrial fibrosis and contributes to electrophysiological changes, ARBs appear as a reasonable and safe additive antiarrhythmic therapy in AF, which is supported by recent meta-analyses.1,5 Yamashita et al .6 present the important data of J-RHYTHM II (Japanese Rhythm Management Trial II for Atrial …

Haemochromatosis genotype and iron overload: association with hypertension and left ventricular hypertrophy

We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH). We analysed data from a cross-sectional study of the general population including 8992 individuals from the Copenhagen City Heart Study (CCHS), a follow-up study of 36,480 individuals from the Copenhagen General Population Study (CGPS), and a case-only study of 3815 Scandinavians from the Losartan Intervention For End-point Reduction in Hypertension Genetic Substudy (LIFEGEN) with LVH and hypertension. In the CCHS, individuals with C282Y/C282Y versus wild type/wild type had an odds ratio for antihypertensive medication use of 4.8 (1.8-13; P = 0.003). In the CGPS, the corresponding hazard ratio was 1.7 (1.0-2.3; P = 0.003). Also, hazard ratios for antihypertensive medication use in the CGPS were 1.6 (1.0-2.6; P = 0.05) for transferrin saturation > or =80% vs. <50%, and 2.3 (1.3-4.2; P = 0.005) for C282Y/C282Y + transferrin saturation > or =80% vs. wild type/wild type + transferrin saturation <50%. These results were most pronounced in men above 55 years of age. We did not find any association between C282Y/C282Y or iron overload and LVH or hypertension (measured as blood pressure at a single occasion or continuous blood pressure), or LVH with hypertension in the CCHS or with severity of LVH in LIFEGEN. We found that haemochromatosis genotype C282Y/C282Y and extremely elevated transferrin saturation either separately or combined were associated with increased risk of antihypertensive medication use. Therefore, testing for haemochromatosis genotype C282Y/C282Y and extreme transferrin saturation could be considered in patients with essential hypertension.

Relationship of left atrial enlargement to persistence or development of ECG left ventricular hypertrophy in hypertensive patients: implications for the development of new atrial fibrillation

Persistence and development of ECG left ventricular hypertrophy (LVH) by Cornell product criteria are associated with an increased risk of atrial fibrillation compared with regression or continued absence of LVH. We postulated that this association might be in part mediated via greater left atrial enlargement (LAE) in patients with new and persistent ECG LVH. Baseline and third year ECG LVH and left atrial systolic diameter were examined in 663 patients in the Losartan Intervention For Endpoint reduction in hypertension echocardiographic substudy who were in sinus rhythm at baseline and had no history of atrial fibrillation. Left atrial systolic diameter was measured and considered enlarged if more than 3.8 cm in women or more than 4.2 cm in men. Cornell product LVH above 2440 mm-ms was considered consistent with LVH. After 3 years follow-up, 238 patients (35.9%) had continued absence of Cornell product LVH, 156 (23.5%) had regression of LVH, 236 (35.6%) had persistent LVH and 33 patients (5.0%) developed new ECG LVH. Compared with third year mean left atrial systolic dimension and prevalence of LAE in patients with continued absence of LVH (3.62+/-0.52 cm, 12.6%), there were step-wise increases in patients with regression of LVH (3.71+/-0.49 cm, 20.5%), persistence of LVH (3.82+/-0.57 cm, 32.2%) and development of new ECG LVH (3.91+/-0.42 cm, 36.4%, both P<0.001). After controlling for differences in age, sex, baseline SBP, BMI and Sokolow-Lyon voltage, randomized treatment allocation, change in DBP and SBP between baseline and third year and for isovolumic relaxation time and presence of an abnormal mitral E/A ratio at baseline and third year, the odds of having LAE were significantly increased in patients with persistent LVH (odds ratio 1.8, 95% confidence interval 1.1-3.2, P=0.043) or new LVH (odds ratio 3.1, 95% confidence interval 1.3-7.7, P=0.016), but not in patients with regression of Cornell product LVH (odds ratio 1.1, 95% confidence interval 0.6-2.0, P=0.860). Persistence or development of new ECG LVH during antihypertensive therapy are associated with an increased risk of LAE after 3-year follow-up, whereas regression of ECG LVH is not associated with an increased risk of LAE. These findings provide insight into a possible mechanism by which changes in ECG LVH are associated with changing risk of developing atrial fibrillation.

Are coronary revascularization and myocardial infarction a homogeneous combined endpoint in hypertension trials? The Losartan Intervention For Endpoint reduction in hypertension study

Construction of prognostically relevant endpoints for clinical trials in hypertension has increasingly included coronary revascularization with myocardial infarction (MI) as manifestations of coronary artery disease. However, whether coronary revascularization and MI predict other cardiovascular events similarly is unknown. We examined risks of cardiovascular death, all-cause death, and stroke following MI or coronary revascularization in hypertensive patients with left ventricular hypertrophy (LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE). We studied 9113 patients after excluding those who died within 7 days after MI or underwent coronary revascularization within 24 h after MI. In multivariate Cox regression adjusting for participating countries, time-varying systolic blood pressure, and Framingham risk score, hazard ratios for cardiovascular death, all-cause death, and stroke were, respectively, 4.5 (P<0.0001), 2.9 (P<0.0001), and 1.9 (P=0.003) in 321 patients with MI as first event. In similar models, coronary revascularization as first event (n=202) was not associated with increased risks of cardiovascular death, all-cause death, and stroke (P=0.06-0.86). During follow-up of hypertensive patients with LVH, occurrence of MI but not coronary revascularization as first cardiovascular event significantly increased risk of subsequent cardiovascular death, all-cause death, and stroke. In view of differences in prognostic implications, when the goal is to have a prognostically relevant composite endpoint for trials in hypertensive patients, caution should be used in combining coronary revascularization with MI.

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 160-200 mm Hg, diastolic BP <90 mm Hg 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 1050 mm × ms (1 s.d.) lower Cornell product; and HR 0.75, 95% CI: 0.65-0.87, P<0.001 per 10.5 mm (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.

Inclusion of Stroke as an Outcome and Risk Equivalent in Risk Scores for Primary and Secondary Prevention of Vascular Disease

Current guideline statements for primary and secondary prevention of cardiovascular disease (CVD) rely on estimates of absolute risk of coronary events. For example, the American Heart Association guidelines on primary prevention state that persons with ≥10% risk over 10 years of myocardial infarction (MI) or coronary death should be considered for antiplatelet therapy with aspirin.1 Similarly, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines2 state that target low-density lipoprotein level should be based on projected absolute risk of future coronary events rather than on presence or absence of specific risk factors. These guidelines state that patients at high risk of MI and coronary death, defined as an absolute 10-year risk of ≥20%, should have a target low-density lipoprotein level <100 mg/dL and should receive statin therapy if needed to achieve this goal. Stroke, however, is not included as one of the outcomes contributing to these absolute risk levels. Included in the group of patients with elevated risk, moreover, are those who already have ischemic heart disease, as well as patients deemed to be “coronary heart disease (CHD) risk equivalents,” indicating those at the same elevated risk as patients with ischemic heart disease. CHD risk equivalents include patients with diabetes mellitus, those with multiple risk factors that put them at elevated risk based on calculation of their Framingham Score, and patients with “other forms of symptomatic atherosclerotic disease.” The latter group is further defined to include those with peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), and carotid artery disease. The category of “risk equivalents” in the ATP III guidelines, however, does not include the vast majority (≈80%3) of ischemic stroke patients without carotid artery disease as cause of their stroke. Ischemic stroke is therefore notably excluded from the list of outcomes contributing to …

Serum Uric Acid Is Associated With New-Onset Diabetes in Hypertensive Patients With Left Ventricular Hypertrophy: The LIFE Study

It is unclear whether serum uric acid (SUA) is associated with development of new-onset diabetes (NOD) in patients with hypertension and left ventricular hypertrophy (LVH). The aim of the present investigation was to test the hypothesis that SUA predicts development of NOD in these patients. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, a double-masked, parallel-group design, 9,193 patients with hypertension and electrocardiographic LVH were randomized to losartan- or atenolol-based antihypertensive treatment and followed for a mean of 4.9 years. At baseline, 7,489 patients with available SUA measurements did not have diabetes mellitus and were thus at risk of its development during the study. We used Cox regression analyses to investigate whether SUA predicted development of NOD. NOD developed in 522 of 7,489 patients. The association between baseline SUA and development of NOD was significant (hazard ratio (HR) 1.29 per s.d. (1.3 mg/dl), 95% confidence interval (CI) 1.18-1.42, P < 0.001) after adjustment for treatment with losartan vs. atenolol, baseline serum glucose, urinary albumin/creatinine ratio, estimated glomerular filtration rate and Framingham risk score, time-varying systolic and diastolic blood pressure, and time-varying LVH by Cornell voltage-duration product and Sokolow-Lyon voltage. In parallel analyses, baseline quartiles of SUA were significantly associated with increasing NOD (HR 1.28, 95% CI 1.18-1.40, P < 0.001). Time-varying SUA was also associated with NOD (HR 1.10 per s.d. [1.3 mg/dl], 95% CI 1.02-1.19, P = 0.015). Our analysis suggests that SUA is an independent risk marker for NOD in hypertensive patients with LVH.

Greater Regression of Electrocardiographic Left Ventricular Hypertrophy During Hydrochlorothiazide Therapy in Hypertensive Patients

Treatment of hypertensive patients with a losartan-based regimen was associated with greater regression of electrocardiographic (ECG) left ventricular hypertrophy (LVH) than atenolol-based therapy in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, independent of blood pressure (BP) changes. However, whether concomitant hydrochlorothiazide (HCTZ) therapy in >70% of LIFE patients was associated with greater regression of LVH independent of BP changes and whether this effect differed between treatment arms has not been examined. Changes in Cornell product and Sokolow-Lyon voltage LVH were assessed in 9,193 hypertensive patients randomly assigned to treatment with losartan or atenolol, with additional HCTZ therapy added as necessary to achieve target BP goal per study protocol. After controlling for baseline and change in systolic and diastolic pressure, age, sex, race, prior antihypertensive treatment, baseline and year-4 body mass index and baseline LVH by either Cornell product or Sokolow-Lyon voltage, at year-4 follow-up HCTZ therapy was associated with greater regression of Cornell product LVH (-244 +/- 788 vs. -172 +/- 771 mm.msec, P < 0.05) and Sokolow-Lyon voltage (-4.2 +/- 6.7 vs. -3.0 +/- 7.0 mm, P < 0.001) and this effect was significantly greater in patients on losartan (-341 +/- 743 vs. -189 +/- 775 mm.msec and -5.2 +/- 6.6 vs. -3.3 +/- 6.6 mm) than in patients on atenolol (-142 +/- 822 vs. -158 +/- 765 mm.msec and -3.1 +/- 6.6 vs. -2.7 +/- 7.4 mm; both P < 0.001 for interaction of HCTZ with losartan vs. atenolol therapy). HCTZ use was associated with greater regression of ECG LVH and this effect was greater in patients on losartan- than atenolol-based therapy, independent of baseline severity of ECG LVH and hypertension and changes in BP.

Effect of ACE insertion/deletion and 12 other polymorphisms on clinical outcomes and response to treatment in the life study

This pharmacogenetics substudy from the Losartan Intervention for Endpoint reduction in Hypertension study in patients with hypertension and left ventricular hypertrophy (LVH) treated with the angiotensin receptor blocker losartan versus the beta-blocker atenolol for 4.8 years tested whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and 12 other previously well-characterized polymorphisms of hypertension susceptibility genes affected blood pressure reduction, heart rate reduction, cardiovascular events, and/or response to treatment. These polymorphisms were chosen because they could affect blood pressure control or the pharmacological action of losartan or atenolol. We genotyped 3503 patients, 1774 on losartan and 1729 on atenolol. ACE and the 12 other genotypes did not affect the reduction in systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, or heart rate, or treatment differences between losartan and atenolol on these endpoints, as assessed by general linear models. Also, ACE and the 12 other genotypes did not affect risk of the primary composite endpoint or its components stroke, myocardial infarction, and cardiovascular death, or treatment differences between losartan and atenolol on these endpoints, as assessed by Cox proportional hazards models including baseline Framingham risk score and LVH. ACE insertion/deletion and 12 other polymorphisms of hypertension susceptibility genes did not affect blood pressure reduction, heart rate reduction, or cardiovascular events in patients with hypertension and LVH, or treatment differences between losartan and atenolol on these endpoints. These results suggest that the observed effects of losartan versus atenolol in the Losartan Intervention for Endpoint reduction in hypertension study do not depend on ACE and 12 other polymorphisms of hypertension susceptibility genes.

Lack of regression of left ventricular hypertrophy is associated with higher incidence of revascularization in hypertension: The LIFE Study

Objective. Regression of left ventricular (LV) hypertrophy and albuminuria in hypertension has previously been shown to reduce clinical cardiovascular events and death. We aimed to investigate the associations of regression of electrocardiographic (ECG) LV hypertrophy and albuminuria with the incidence of revascularization. Methods. In 9193 hypertensive patients included in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, we measured urine albumin/creatinine ratio (UACR), LV hypertrophy by electrocardiography, serum high-density lipoprotein (HDL) cholesterol, and blood pressure after 2 weeks of placebo treatment and yearly during 5 years of anti-hypertensive treatment with either an atenolol- or a losartan-based regimen. The incidence of coronary and peripheral revascularization was recorded. Results. In Cox regression analyses adjusted for treatment allocation and continent, high time-varying Sokolow–Lyon voltage (hazard ratio [HR]=1.01 [1.00–1.02], p=0.01), but not time-varying Cornell product or UACR, predicted coronary revascularization together with low time-varying HDL-cholesterol, low time-varying pulse pressure, high Framingham risk score and history of angina pectoris. Adjusted for treatment allocation and continent, high time-varying Sokolow–Lyon voltage (HR=1.01 [1.00–1.03], p=0.02), but not time-varying Cornell product or UACR, predicted peripheral revascularization together with high time-varying pulse pressure, high Framingham risk score, history of peripheral vascular disease and prior myocardial infarction. Conclusion. Higher Sokolow–Lyon voltage during antihypertensive treatment, but not UACR or the Cornell voltage–duration product, was independently associated with higher incidence of coronary as well as peripheral revascularization.

Are Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Especially Useful for Cardiovascular Protection?

This article seeks to objectively review the clinical trial evidence to determine whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) have special cardiovascular protective effects. An objective review of the clinical trial evidence. Clinical trials in hypertensive patients comparing ACEI and ARB with other drugs generally showed no difference in the primary cardiovascular outcome (United Kingdom Prospective Diabetes Study Group, Captopril Prevention Project, Swedish Trial in Old Patients with Hypertension 2, Japan Multicenter Investigation for Cardiovascular Diseases-B Randomized Trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, Second Australian National Blood Pressure Study Group, Valsartan Antihypertensive Long-Term Use Evaluation). Where the primary, or major secondary, cardiovascular end-point favors one of the treatment arms, it was always the arm with the lower achieved blood pressure that saw the better clinical result as in Losartan Intervention For Endpoint Reduction in Hypertension Study, Captopril Prevention Project, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Valsartan Antihypertensive Long-Term Use Evaluation. Trials comparing ACEI or ARB against placebo in patients at high risk of cardiovascular events have not showed a consistent result; cardiovascular outcomes were reduced in Heart Outcomes Prevention Evaluation, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease, and the Jikei Heart Study, but were not significantly reduced in Perindopril Protection Against Recurrent Stroke Study, Comparison of Arnlodipine vs Enalapril to Limit Occurrences of Thrombosis Trial, Prevention of Events with ACEIs Trial, Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease Trial, and Prevention Regimen for Effectively Avoiding Second Strokes Trial. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, combining ACEIs with ARBs in high-risk patients did not reduce cardiovascular or renal outcomes compared with ACEI monotherapy alone. This absence of a reduction in cardiovascular outcome from the ACEI and ARB combination arm is further evidence suggesting that these drugs do not have any special cardiovascular protective effect. This objective review thus shows that the rennin-angiotensin antagonists do not have special cardiovascular protective properties. The key to reducing cardiovascular outcome is to appropriately control blood pressure as well as to treat all other coronary risk factors.

Mitral E Wave Deceleration Time to Peak E Velocity Ratio and Cardiovascular Outcome in Hypertensive Patients During Antihypertensive Treatment (from the LIFE Echo-Substudy)

The early mitral flow deceleration time (DTE) is a prognostically validated marker of left ventricular diastolic dysfunction. It has been reported that the DTE is influenced by the loading conditions, which can vary during antihypertensive treatment. We hypothesized that normalization of the DTE for mitral peak E-velocity (mitral deceleration index [MDI]) might better predict incident cardiovascular (CV) events in hypertensive patients during treatment compared to DTE alone or other traditional indexes of diastolic function, such as the mitral E/A ratio. We evaluated 770 hypertensive patients with electrocardiogram findings of left ventricular hypertrophy (age 66 +/- 7 years; 42% women) enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiographic substudy. Echocardiographic examinations were performed annually for 5 years during intensive antihypertensive treatment. We examined the utility of the MDI at baseline and as a time-varying predictor of incident CV events. Of the 770 patients, 70 (9%) had CV events. The baseline MDI was positively associated with age and relative wall thickness and negatively associated with gender and heart rate (all p <0.01). Unadjusted Cox regression analysis showed a positive association between the baseline MDI and CV events (hazard ratio 1.21, 95% confidence interval 1.07 to 1.37, p = 0.002). In the time-varied Cox models, a greater in-treatment MDI was associated with a greater rate of CV events (hazard ratio 1.43, 95% confidence interval 1.05 to 1.93, p = 0.022), independently of the covariates. No significant association was found for in-treatment DTE or any of the prognostically validated indexes of diastolic function. In conclusion, in our population of patients with treated hypertension with electrocardiographic findings of left ventricular hypertrophy, the MDI independently predicted future CV events. Normalization of DTE for E velocity might be preferred to other traditional diastolic function indexes in evaluating diastolic function during antihypertensive treatment.

Serial evaluation of electrocardiographic left ventricular hypertrophy for prediction of risk in hypertensive patients

Background Although the presence and severity of electrocardiographic (ECG) left ventricular hypertrophy (LVH) have been associated with an increased risk of cardiovascular (CV) morbidity and mortality, the relationship of regression of ECG LVH during antihypertensive therapy to CV risk has only recently been examined. Methods Electrocardiographic LVH was evaluated over time in 9193 hypertensive patients enrolled in the Losartan Intervention for Endpoint Reduction in Hypertension study. Patients were treated with losartan- or atenolol-based regimens and followed with serial ECGs at 6 months and then yearly until death or study end. Electrocardiographic LVH was measured using gender-adjusted Cornell product (RaVL + SV3 [+6 mm in women]) ⁎ QRS duration) and Sokolow-Lyon voltage (SV1 + RV5/6). Results After mean (SD) follow-up of 4.8 (0.9) years, the Losartan Intervention for Endpoint Reduction in Hypertension study composite end point of CV death, nonfatal myocardial infarction, or stroke occurred in 1096 patients. In Cox regression models controlling for treatment type, baseline Framingham risk score, baseline, and in-treatment blood pressure and for severity of baseline ECG LVH by Cornell product and Sokolow-Lyon voltage, lower in-treatment ECG 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 ratios (HRs) of 0.86 (95% confidence interval [CI], 0.82-0.90; P < .001) for every 1050 mm · ms (1 SD) decrease in Cornell product and 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; HR, 0.80; 95% CI, 0.73-0.87; P < .001), of myocardial infarction (HR, 0.90; 95% CI, 0.82-0.98; P = .011; HR, 0.90; 95% CI, 0.81-1.00; P = .043), and of stroke (HR, 0.90; 95% CI, 0.84-0.96; P = .002; HR, 0.81; 95% CI, 0.75-0.89; P < .001). Regression of ECG LVH was also associated with significantly reduced risks of sudden cardiac death, new-onset atrial fibrillation, hospitalization for heart failure, and new-onset diabetes mellitus. Conclusions Regression of ECG LVH by Cornell product and/or Sokolow-Lyon voltage criteria during antihypertensive therapy is associated with lower likelihoods of CV morbidity and mortality, all-cause mortality, and new-onset diabetes, independent of blood pressure lowering and treatment modality in essential hypertension. These findings suggest that antihypertensive therapy targeted at regression or prevention of ECG LVH may improve prognosis.

Exercise and cardiovascular outcomes in hypertensive patients in relation to structure and function of left ventricular hypertrophy: the LIFE study

Exercise lowers blood pressure and improves cardiovascular function, but little is known about whether exercise impacts cardiovascular morbidity and mortality independent of left ventricular hypertrophy (LVH) and LV geometry. Observational analysis of prospectively obtained echocardiographic data within the context of a randomized trial of antihypertensive treatment. A total of 937 hypertensive patients with ECG LVH were studied by echocardiography in the Losartan Intervention For Endpoint reduction in hypertension study. Baseline exercise status was categorized as sedentary (never exercise), intermediate (<or=30 min twice/week), or physically active (>30 min twice/week). During 4.8-year follow-up, 105 patients suffered the primary composite endpoint of myocardial infarction (MI), stroke, or cardiovascular death. MI occurred in 39, stroke in 60, and cardiovascular death in 33 patients. Sedentary individuals (n = 212) had, compared with those physically active (n = 511), higher heart rate (P<0.001), weight (P<0.001), body surface area (P = 0.02), body mass index (P<0.001), LV mass (LVM, P = 0.04), LVM indexed for height or body surface area (P = 0.004); thicker ventricular septum (P = 0.012) and posterior wall (P = 0.016); and larger left atrium (P = 0.006). Systolic variables did not differ. In Cox regression analysis, physically active compared with sedentary patients had lower risk of primary composite endpoint [odds ratio (OR): 0.42, 95% confidence interval (CI): 0.26-0.68, P < 0.001], cardiovascular death (OR: 0.50, 95% CI: 0.22-0.1.10, NS), and stroke (OR: 0.26, 95% CI: 0.13-0.49, P < 0.001) without significant difference for MI (OR: 0.79, 95% CI: 0.35-1.75, NS) independent of systolic blood pressure, LVM index, or treatment. In hypertensive patients with LVH, physically active patients had improved prognosis for cardiovascular endpoints, mortality, and stroke that was independent of LVM.

Prognostic Value of Changes in the Electrocardiographic Strain Pattern During Antihypertensive Treatment

The presence of the ECG strain pattern of lateral ST depression and T-wave inversion at baseline has been associated with an increased risk of cardiovascular morbidity and mortality; however, the independent predictive value for cardiovascular outcomes of regression versus persistence versus development of new ECG strain during antihypertensive therapy is unclear. ECG strain was evaluated at baseline and after 1 year of therapy in 7409 hypertensive patients in the LIFE study (Losartan Intervention For End-point reduction in hypertension) treated in a blinded manner with atenolol- or losartan-based regimens. During 3.8+/-0.8 years of follow-up after the year 1 ECG, cardiovascular death occurred in 236 patients (3.2%), myocardial infarction in 198 (2.7%), stroke in 313 (4.2%), the LIFE composite end point of these 3 events in 600 (8.1%), sudden death in 92 (1.2%), and death due to any cause in 486 (6.6%). Strain was absent on both baseline and year 1 ECGs in 6323 patients (85.3%), regressed from baseline to year 1 in 245 (3.3%), persisted on both ECGs in 549 (7.4%), and was absent at baseline but developed by year 1 in 292 patients (3.9%). Compared with absence of strain on both ECGs, development of new ECG strain was associated with 2.8- to 4.7-fold higher event rates; patients with regression or persistence of strain had intermediate event rates. In Cox multivariable analyses with adjustment for the known predictive value of in-treatment ECG left ventricular hypertrophy by Cornell product and Sokolow-Lyon voltage, in-treatment systolic and diastolic pressure, randomized treatment, and standard cardiovascular risk factors, development of new ECG strain was independently associated with increased risks of cardiovascular death (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.56 to 3.76), myocardial infarction (HR 1.95, 95% CI 1.11 to 3.44), stroke (HR 1.98, 95% CI 1.30 to 3.01), the LIFE composite end point (HR 2.05, 95% CI 1.51 to 2.78), sudden cardiac death (HR 2.19, 95% CI 1.06 to 4.53), and all-cause mortality (HR 1.92, 95% CI 1.37 to 2.69), whereas the risk associated with regression or persistence of strain was attenuated. Development of new ECG strain is associated with an increased risk of cardiovascular morbidity and mortality and of all-cause mortality in the setting of antihypertensive therapy and regression of ECG left ventricular hypertrophy.

Impact of diabetes on treatment-induced changes in left ventricular structure and function in hypertensive patients with left ventricular hypertrophy. The LIFE study

Background and aim Diabetes is associated with left ventricular hypertrophy (LVH) and impaired systolic function in hypertensive patients, but less is known about its impact on LVH regression and functional improvement during antihypertensive treatment. Methods and results We performed annual echocardiography in 730 non-diabetic and 93 diabetic patients (aged 55–80 years) with hypertension and electrocardiographic LVH during 4.8-year losartan- or atenolol-based treatment in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Baseline mean blood pressure (BP) and LV mass did not differ between groups. Diabetic patients had higher body mass index and pulse pressure, and lower LV ejection fraction, midwall shortening, stress-corrected midwall shortening, and estimated glomerular filtration rate (all p < 0.05), and were more likely to have albuminuria. Despite comparable BP reduction in diabetic and non-diabetic groups during treatment (33/18 vs. 28/16 mm Hg (ns)), diabetes was associated with higher prevalence of persistent LVH (47 vs. 39%, p < 0.05). In multivariate analyses, diabetes independently predicted less LV mass reduction and less improvement in stress-corrected LV midwall shortening (both p < 0.01). Conclusion Among hypertensive patients with LVH, diabetes is associated with more residual LVH and less improvement in systolic LV function by echocardiography over 4.8 years of antihypertensive treatment.

Effects of losartan compared with atenolol on lipids in patients with hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension study

Beta-blockers and angiotensin II receptor blockers have different effects on lipids. We examined lipid levels in the Losartan Intervention For Endpoint reduction in hypertension study and their impact on the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke. We measured total and high-density lipoprotein cholesterol at baseline and annually during 4.8 years of losartan-based compared with atenolol-based treatment in 8611 patients with hypertension and left ventricular hypertrophy. Patients randomized to losartan-based or atenolol-based treatment had similar baseline total (6.04 +/- 1.12 vs. 6.05 +/- 1.13 mmol/l, NS) and high-density lipoprotein (HDL) cholesterol (1.50 +/- 0.44 vs. 1.49 +/- 0.44 mmol/l, NS). Total cholesterol decreased significantly but equally (-0.37 +/- 1.05 vs. -0.34 +/- 1.09 mmol/l, NS), whereas HDL cholesterol decreased less during the first 2 years in patients randomized to losartan compared with atenolol (-0.13 +/- 0.24 vs. -0.19 +/- 0.25 mmol/l) and remained higher each year (1.38, 1.37, 1.42, 1.47, and 1.48 mmol/l vs. 1.32, 1.30, 1.36, 1.40, and 1.42 mmol/l, all P < 0.001) independent of hydrochlorothiazide or statin treatment. In Cox regression analysis, baseline total cholesterol [hazard ratio (HR) = 1.08 (1.02-1.14) per mmol/l, P < 0.01], HDL cholesterol [HR = 0.56 (0.48-0.66) per mmol/l, P < 0.001], and treatment allocation [HR = 0.86 (0.76-0.98), P < 0.05] predicted composite endpoint independently. Using time-varying analyses, the predictive strength of HDL cholesterol was increased [HR = 0.36 (0.30-0.44) per mmol/l, P < 0.001], whereas that of total cholesterol [HR = 1.03 (0.97-1.09) per mmol/l, NS] and treatment allocation [HR = 0.91 (0.80-1.03), NS] were reduced. Losartan blunted the decrease in HDL cholesterol during antihypertensive treatment in the LIFE study. Higher intreatment HDL cholesterol was associated with fewer composite endpoints and may partly explain the better outcome of losartan-based treatment.

The emerging role of high-density lipoprotein cholesterol in hypertension trials

Population Health Research Institute,McMaster University, Hamilton Health Sciences, Hamilton, CanadaCorrespondence to Fabio Angeli, MD, Department of Cardiology, ClinicalResearch Unit ‘Preventive Cardiology’, Hospital Santa Maria della Misericordia,06156 Perugia, ItalyTel: +39 075 5782213; fax: +39 075 5782214; e-mail: fangeli@cardionet.it

Predictors of cardiovascular events in patients with hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension study

Objective. We assessed readily available patient characteristics, including albuminuria (not included in traditional cardiovascular risk scores), as predictors of cardiovascular events in hypertension with left ventricular hypertrophy (LVH) and developed risk algorithms/scores for outcomes. Methods. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared effects of losartan-based versus atenolol-based therapy on cardiovascular events in 9193 patients with hypertension and LVH. Univariate and multivariate analyses identified baseline variables with significant impact on development of the primary composite endpoint (cardiovascular death, stroke and myocardial infarction) and its components. Multivariate analysis used a Cox regression model with stepwise selection process. Risk scores were developed from coefficients of risk factors from the multivariate analysis, validated internally using naïve and jack-knife procedures, checked for discrimination and calibration, and compared with Framingham coronary heart disease and other risk scores. Results. LIFE risk scores showed increasing endpoint rates with increasing quintile (first to fifth quintile, composite endpoint 2.8–26.7%, cardiovascular death 0.5–14.4%, stroke 1.2–11.3%, myocardial infarction 1.4–8.1%) and were confirmed with a jack-knife approach that adjusts for potentially optimistic bias. The Framingham coronary heart disease and other risk scores overestimated risk in lower risk patients and underestimated risk in higher risk patients, except for myocardial infarction. Conclusion. A number of patient characteristics predicted cardiovascular events in patients with hypertension and LVH. Risk scores developed from these patient characteristics, including albuminuria, strongly predicted outcomes and may improve risk assessment of patients with hypertension and LVH and planning of clinical trials.