Markku S. Nieminen

Echocardiographic left ventricular geometry in hypertensive patients with electrocardiographic left ventricular hypertrophy: The LIFE Study.

Aim: To assess the prevalence of echocardiographic left ventricular hypertrophy (LVH) and concentric remodeling in hypertensive patients with electrocardiographic (ECG)-LVH and to estimate the costeffectiveness of echocardiography and ECG for detection of LVH.Design: Echocardiographic LV measurements and the prevalence of abnormal LV geometric patterns were compared between 964 hypertensive patients with ECG-LVH (Cornell voltage-duration product > 2440 and/or SV1

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.

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±41u2009g, 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.

Incidence of Atrial Fibrillation in Relation to Changing Heart Rate Over Time in Hypertensive Patients The LIFE Study

Background—Onset of atrial fibrillation (AF) has been linked to changes in autonomic tone, with increasing heart rate (HR) immediately before AF onset in some patients suggesting a possible role of acute increases in sympathetic activity in AF onset. Although losartan therapy and decreasing ECG left ventricular hypertrophy are associated with decreased AF incidence, the relationship of HR changes over time to development of AF has not been examined. Methods and Results—HR was evaluated in 8828 hypertensive patients without AF by history or on baseline ECG in the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study. Patients were treated with losartan- or atenolol-based regimens and followed with serial ECGs annually which were used to determine HR and ECG left ventricular hypertrophy by Cornell product and Sokolow-Lyon voltage criteria. During mean follow-up of 4.7±1.1 years, new-onset AF occurred in 701 patients (7.9%). Patients with new AF had smaller decreases in HR to last in-treatment ECG or last ECG before AF (−2.7±13.5 versus −5.2±12.5 bpm), whether on losartan- (−0.4±13.5 versus −2.2±11.7 bpm) or atenolol-based treatment (−5.3±12.8 versus −8.3±12.6 bpm, all P<0.001). In univariate Cox analyses, higher HR on in-treatment ECGs was associated with an increased risk of new-onset AF, with a 15% greater risk of AF for every 10 bpm higher HR (95% CI 8% to 22%). In alternative analyses, persistence or development of a HR≥84 (upper quintile of baseline HR) was associated with a 46% greater risk of developing AF (95% CI 19% to 80%). After adjusting for treatment with losartan versus atenolol, baseline risk factors for AF, baseline and in-treatment systolic and diastolic pressure and the known predictive value of baseline and in-treatment ECG left ventricular hypertrophy for new AF, higher in-treatment HR remained strongly associated with new AF with a 19% higher risk for every 10 bpm higher HR (95% CI 10% to 28%) or a 61% increased rate of AF in patients with persistence or development of a HR≥84 (95% CI 27% to 104%, all P<0.001). Conclusion—Higher in-treatment HR on serial ECGs is associated with an increased likelihood of new-onset AF, independent of treatment modality, blood pressure lowering, and regression of ECG left ventricular hypertrophy in patients with essential hypertension.

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.

Impact of age on left ventricular hypertrophy regression during antihypertensive treatment with losartan or atenolol (the LIFE study)

To assess the influence of age on changes in left ventricular (LV) mass and geometry during antihypertensive treatment, we related age to clinical and echocardiographic findings before and after 4 years of antihypertensive treatment in a subset of 560 hypertensive patients without known concurrent disease in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which randomized patients to blinded losartan- or atenolol-based treatment. Patients ⩾65 years (older group) included more women and patients with isolated systolic hypertension or albuminuria (all P<0.05). Compared to patients <65 years, older patients had higher pulse pressure, LV mass, and prevalence of concentric hypertrophy at baseline (78 vs 69u2009mmHg, 234 vs 224u2009g, and 28 vs 16%, respectively, all P<0.01), while the mean blood pressure did not differ. Over 4 years, reductions in LV mass and the mean blood pressure were similar in both groups, but older patients more often had residual hypertrophy (31 vs 15%, P<0.001) with a preponderance of eccentric geometry. In multivariate analysis of 4-year change in LV mass controlling for baseline mass, larger hypertrophy reduction was associated with losartan treatment, while age, gender, body mass index, and 4-year change in pulse pressure and albuminuria did not enter (Multiple Ru20092=0.40, P<0.001). Thus, in up-to-80-year-old hypertensive patients with left ventricular hypertrophy, age did not significantly attenuate hypertrophy reduction during antihypertensive treatment, although residual hypertrophy was more prevalent in older patients as a consequence of higher initial LV mass.

Electrocardiographic strain pattern and left ventricular diastolic function in hypertensive patients with left ventricular hypertrophy: the LIFE study.

Background Whether the typical electrocardiographic (ECG) strain pattern (Strain, in leads V5 and/or V6), which is associated with left ventricular hypertrophy (LVH) and LV systolic dysfunction, is independently associated with LV diastolic dysfunction is unknown. Methods The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study enrolled hypertensive patients with ECG-LVH, of whom 10% underwent Doppler echocardiography. LV diastolic function measures included peak mitral E and A wave velocities and their ratio (E/A); E wave deceleration time (EDT); atrial filling fraction (AFF); and isovolumic relaxation time (IVRT). Normal filling pattern was defined by E/A < 1 with EDT ≥ 150 and ≤ 250 ms and IVRT ≤ 100 and ≥60 ms; abnormal relaxation by E/A < 1 with EDT > 250 ms or IVRT > 100 ms; pseudonormal filling pattern by E/A ≥ 1 associated with IVRT > 100 ms or EDT > 250 ms; restrictive pattern by E/A ≥ 1 with IVRT < 100 ms and EDT < 250 ms. A combined index of LV systolic–diastolic function was also computed (isovolumic time/ejection time, modified myocardial performance index). Of LIFE echo substudy participants with all needed ECG and Doppler data (n = 791), 110 (14%) had Strain. Results Strain was associated with male gender, African–American race, diabetes, history of coronary heart disease (CHD), higher systolic blood pressure (BP), LV mass and relative wall thickness, and higher prevalences of echo-LV hypertrophy and wall motion abnormalities, and with slower heart rate (all P < 0.05). Age, diastolic BP and LV ejection fraction were similar in patients with or without Strain. Diastolic parameters, and prevalences of different LV filling patterns, did not differ significantly between patients with versus those without Strain (all P > 0.1), but modified myocardial performance index was higher with Strain (P < 0.05). Findings were consistent in multivariate analyses. The association of Strain with higher modified myocardial performance index was no longer statistically significant after accounting for LV systolic function and wall motion abnormalities. Conclusions In hypertensive patients with ECG-LVH, the ECG Strain pattern did not identify independently those with more severe LV diastolic abnormalities.

Usefulness of the assessment of the appropriateness of left ventricular mass to detect left ventricular systolic and diastolic abnormalities in absence of echocardiographic left ventricular hypertrophy: the LIFE study

Conventional definitions of left ventricular (LV) hypertrophy do not account for interindividual differences in loading conditions. We may define LV mass as inappropriately high when exceeding 128% of theoretical values predicted by gender, height2.7, and stroke work, which explain up to 82% of the variability of LV mass in normal reference subjects. In 652 participants in the Losartan Intervention For Endpoint reduction in hypertension study without clinically overt cardiovascular disease or diabetes, we investigated whether inappropriately high LV mass is associated with relevant LV abnormalities independent of traditional definition of LV hypertrophy (ie, LV mass index >116u2009g/m2 in men and >104u2009g/m2 in women). The study sample was divided into three groups: patients with inappropriately high LV mass but without LV hypertrophy were compared to patients with LV hypertrophy and to patients with appropriate LV mass and without LV hypertrophy. Patients with inappropriately high but nonhypertrophic LV mass had higher body mass index and relative wall thickness, and lower LV myocardial systolic function, than patients with appropriate LV mass or patients with LV hypertrophy. In multivariate analyses, inappropriately high LV mass was independently associated with lower myocardial systolic function independent of LV hypertrophy and other covariates. Inappropriately high LV mass was also associated with prolonged isovolumic relaxation time and lower mitral E/A ratio independent of covariates. In conclusion, inappropriately high LV mass was associated with relevant, often preclinical, manifestations of cardiac disease in the absence of traditionally defined echocardiographic LV hypertrophy and concentric geometry.

Impact of valvular regurgitation on left ventricular geometry and function in hypertensive patients with left ventricular hypertrophy: the LIFE study

Mild-to-moderate aortic and mitral regurgitation are frequently detected by echocardiogram in asymptomatic hypertensive patients. Our goal was to assess the prevalence and impact of mild-to-moderate mitral and/or aortic regurgitation on left ventricular (LV) structure and function in patients with hypertension and LV hypertrophy (LVH). Hypertensive patients with ECG LVH enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy were evaluated. Among 939 patients with needed LV measurements and Doppler data, 242 had mild (1+) valvular regurgitation, and 51 patients had moderate (2+ or 3+) regurgitation of one or both valves. In analyses adjusting for gender, patients with mild mitral and/or aortic regurgitation had larger LV internal dimensions (5.25 vs 5.33u2009cm, P<0.05), higher LV mass indexed for body surface area (122 vs 125u2009g/m2, P<0.05) or height2.7 (55.4 vs 57.3, P<0.05), and larger left atrial diameter. Patients with moderate regurgitation of one or both valves had larger LV chambers (5.25 vs 5.9u2009cm, P<0.001), greater mean LV mass (232 vs 248u2009g, P<0.001) and LV mass indexed for body surface area or height2.7, and higher Doppler stroke volume. Patients with moderate valvular regurgitation also had a higher prevalence of LVH due to an increased prevalence of eccentric LVH. There were no differences among groups defined by the presence and severity of valvular regurgitation in cardiac output, total peripheral resistance, or pulse pressure/stroke volume, indicating that the observed inter-group differences in LV geometry were not due to differences in the haemodynamic severity of hypertension. Hypertensive patients with mild-to-moderate mitral or aortic valvular insufficiency have additional LV structural and functional changes that may affect prognosis.

The effect of losartan compared with atenolol on the incidence of revascularization in patients with hypertension and electrocardiographic left ventricular hypertrophy. The LIFE study

The effect of losartan compared with atenolol on the incidence of revascularization in patients with hypertension and electrocardiographic left ventricular hypertrophy. The LIFE study.