Impact of overweight and obesity on cardiac benefit of antihypertensive treatment.

BACKGROUND AND AIMS: Increased 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 RESULTS: Annual 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/m(2), 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/height(2.7), 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/m(2) higher baseline BMI predicted a 5% higher rate of cardiovascular events and 10% higher cardiovascular mortality over 4.8 years (both p < 0.05). CONCLUSIONS: In 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.

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

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

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. 28/16mmHg (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.

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.

Impact of the metabolic syndrome on the predictive values of new risk markers in the general population.

Although the metabolic syndrome (MetS) is positively associated with high-sensitivity C-reactive protein (hsCRP), negatively associated with N-terminal pro-brain natriuretic peptide (Nt-proBNP) and inconsequently related to urine albumin/creatinine ratio (UACR) they are all associated with cardiovascular events. Therefore, we wanted to determine the influence of MetS on the predictive values of UACR, hsCRP and Nt-proBNP. On the basis of the definition of MetS by the International Diabetes Federation, a Danish population sample of 1983 apparently healthy subjects was divided into three groups: 530 subjects without any elements of MetS, 1093 subjects with some elements of MetS and 360 subjects with MetS. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (composite cardiovascular end point, CEP) occurred in 204 subjects. In Cox-regression analyses adjusting for age, gender and smoking, all three cardiovascular risk markers predicted CEP independently of MetS. Despite no significant interaction with MetS, high log(hsCRP) was associated with CEP primarily in subjects without any elements of MetS (hazard ratio (HR)=4.5 (1.5-14.0), P<0.01), log(Nt-proBNP) primarily in subjects with some elements of MetS (HR=3.0 (1.6-5.6), P<0.01), and logUACR independently of elements of MetS. Pre-specified gender-adjusted (men/women) cutoff values of hsCRP > or = 6.0/7.3 mg l(-1) predicted CEP in subjects without elements of MetS with positive and predictive values of 11.5 and 98%, respectively. UACR > or = 0.73/1.06 mg mmol(-1) predicted CEP in subjects with MetS with positive and predictive values of 23.5 and 93%, respectively. In apparently healthy subjects, high hsCRP was associated with CEP primarily in subjects without MetS, high Nt-proBNP in subjects with elements of MetS and UACR independently of MetS.

Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients with left ventricular hypertrophy and diabetes.

In type 2 diabetes the degree of albuminuria is strongly related to progression of diabetic renal disease, as well as to the risk for cardiovascular complications. If normoalbuminuria is maintained, the risk of diabetic nephropathy is very low. In individuals with microalbuminuria, the rate of decline in glomerular filtration rate is closely related to the degree of albuminuria, and regression to normoalbuminuria slows down the rate of decline in renal function. Data from the LIFE-diabetes subgroup showed that levels of albuminuria well below what is usually defined as microalbuminuria, strongly predicted risk for cardiovascular complications. This indicates that when albuminuria is used as a risk predictor for cardiovascular events, so called normal values should be redefined. Traditional values for normo-micro-macroalbuminuria are primarily defined as predictors for the risk of development of diabetic nephropathy. In the LIFE-diabetes subgroup we found that reduction in albuminuria was more pronounced in losartan-based as compared with atenolol-based treatment. The benefit in favor of losartan was partly related to its major influence on albuminuria. Individuals with the highest baseline values of albuminuria had the greatest benefit in terms of reduction in cardiovascular morbidity and mortality on losartan as compared with atenolol. The level of albuminuria during treatment was closely related to the risk for cardiovascular events. We conclude that tiny amounts of albuminuria, well below traditional levels for microalbuminuria, predict cardiovascular morbidity and mortality. Reduction in albuminuria during treatment translates to reduction in cardiovascular events. Monitoring of albuminuria should be an integrated part of management of hypertension in diabetic as well as nondiabetic patients.

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 >or=2 risk factors plus hypertension: body mass index >or=30 kg/m(2), high-density lipoprotein (HDL)-cholesterol <1.0/1.3 mmol/l (<40/50 mg/dl) (men/women), glucose >or=6.1 mmol/l (>or=110 mg/dl) fasting or >or=7.8 mmol/l (>or=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 (1,591 (19.3%) of 8,243 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.

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

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

Impact of different partition values on prevalences of left ventricular hypertrophy and concentric geometry in a large hypertensive population : the LIFE study.

Left ventricular (LV) hypertrophy and concentric remodeling have been defined by using a variety of indexation methods and partition values (PVs) for LV mass and relative wall thickness (RWT). The effects of these methods on the distribution of LV geometric patterns in hypertensive subjects remain unclear. Echocardiograms were obtained in 941 patients with stage I to III hypertension and LV hypertrophy by ECG. LV mass was calculated by using different methods of indexation for body size and different PVs to identify hypertrophy: LV mass/body surface area (g/m(2)) PV for men/women 116/104, 125/110, or 125/125; LV mass/height (g/m) PV 143/102 or 126/105; and LV mass/height(2.7) (g/m(2.7)) PV 51/51 or 49.2/46.7. RWT was calculated by either 2xend-diastolic posterior wall thickness (PWT)/end-diastolic LV internal dimension (LVID) or end-diastolic interventricular septum dimension+end-diastolic PWT/end-diastolic LVID. LV hypertrophy or remodeling was present in 63% to 86% of subjects, and LV hypertrophy was present in 42% to 77%. By any index, eccentric hypertrophy was the common LV geometric pattern. Use of interventricular septum dimension+PWT/LVID to calculate RWT slightly increased the prevalence of normal geometry and eccentric hypertrophy compared with the use of 2xPWT/LVID. Subjects with LV hypertrophy identified by only LV mass/height(2.7) PV 49.2/46.7 were more obese, whereas those identified by only LV mass/body surface area PV 116/104 were taller and thinner than those in the 2 concordant groups with or without LV hypertrophy by both criteria. By either criterion, there were no significant differences between different LV geometric patterns in clinical cardiovascular disease. Hypertensive patients with LV hypertrophy by ECG have a high prevalence of geometric abnormalities, especially eccentric hypertrophy, irrespective of method of indexation or PV. LV mass indexation by body surface area or height(2.7) identifies lean and obese subjects, respectively. We found no difference in prevalent cardiovascular disease in subjects identified by either criterion, suggesting a similar high risk.

Left ventricular wall stresses and wall stress-mass-heart rate products in hypertensive patients with electrocardiographic left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint reduction in hypertension.

OBJECTIVE: Left ventricular (LV) hypertrophy on echocardiogram (ECG) strongly predicts coronary heart disease events, but the mechanisms linking increased LV mass to ischemic vascular events is uncertain. DESIGN: Variables related to myocardial oxygen demand were compared among normotensive adults and patients with mild and more severe hypertension, and among groups of moderately hypertensive patients with target organ damage in relation to gender, LV geometry and LV systolic function. SETTING: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial, in which hypertensive patients with ECG LV hypertrophy (Cornell voltage-duration product, > 2440 mm x ms and/or SV1 + RV(5-6) > 38 mm) were randomized to > or = 4 years double-blinded treatment with losartan or atenolol. PATIENTS/PARTICIPANTS: A total of 964 LIFE participants enrolled in an echocardiographic substudy, and groups of 282 employed hypertensive and 366 apparently normal adults. INTERVENTIONS: None. MAIN OUTCOME MEASURES: ECG LV parameters contributing to myocardial oxygen demand (wall stresses, LV mass, heart rate and wall stress-mass-heart rate products). RESULTS: In both women and men, stepwise increases from reference subjects to employed hypertensives to LIFE patients were observed for LV wall stresses, mass and stress-mass-heart rate products. LIFE men patients had slightly higher wall stresses and significantly higher triple products than women. Wall stresses were increased in patients with normal LV geometry, eccentric or concentric hypertrophy; triple products were about three and two times normal with eccentric and concentric hypertrophy, with smaller increases in other geometric groups. Patients with decreased LV fractional shortening had two times normal end-systolic stresses and three or four times normal triple products; smaller increases in stresses and triple products occurred with decreased LV midwall function. CONCLUSIONS: Hypertensive patients with ECG LV hypertrophy have increased LV wall stresses and stress-mass-heart rate products, suggesting a contribution of high myocardial oxygen demand to increased risk in such patients. Particularly high stresses and triple products were associated with echocardiographic LV hypertrophy, and subnormal LV chamber and midwall function.

Relation of QT interval and QT dispersion to echocardiographic left ventricular hypertrophy and geometric pattern in hypertensive patients. The LIFE study. The Losartan Intervention For Endpoint Reduction.

OBJECTIVE: In hypertensive patients, left ventricular hypertrophy (LVH) predicts increased mortality, in part due to an increased incidence of sudden death. Repolarization-related arrhythmogenesis may be an important mechanism of sudden death in hypertensive patients with LVH. Increased QT interval and QT dispersion are electrocardiographic (ECG) measures of ventricular repolarization, and also risk markers for ventricular tachyarrhythmias. We assessed the relation of QT intervals and QT dispersion to echocardiographically determined left ventricular (LV) mass and geometry in a large population of hypertensive patients with ECG evidence of LVH. METHODS: QT intervals and QT dispersion were determined from baseline 12-lead ECGs in 577 (57% male; mean age 65 +/- 7 years) participants in the LIFE study. LV mass index (LVMI) and geometric pattern were determined by echocardiography and QT interval duration and QT dispersion were assessed in relation to gender-specific LVMI quartiles. RESULTS: In both genders, increasing LVMI was associated with longer rate-adjusted QT intervals. QT dispersion measures showed a weaker association with LVMI quartiles. Both concentric and eccentric LVH were associated with increased QT interval duration and QT dispersion. These relations remained significant after controlling for relevant clinical variables. CONCLUSIONS: In hypertensive patients with ECG evidence of LVH, increased LVMI and LVH are associated with a prolonged QT interval and increased QT dispersion. These findings suggest that an increased vulnerability to repolarization-related ventricular arrhythmias might in part explain the increased risk of sudden death in hypertensive patients with increased LV mass.

Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS, a LIFE sub study. Insulin Carotids US Scandinavia.

BACKGROUND: Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. METHODS: In 88 unmedicated patients with stage II-III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima-media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. RESULTS: IMT was positively correlated to systolic blood pressure (r= 0.26, P < 0.05), whole body glucose uptake index (M/IG; r= 0.22, P< 0.05), age (r= 0.24, P< 0.05) and negatively correlated to body mass index (r= -0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r= -0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = -0.40, P< 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). CONCLUSIONS: High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.

Relation of left ventricular geometry and function to systemic hemodynamics in hypertension: the LIFE Study. Losartan Intervention For Endpoint Reduction in Hypertension Study.

OBJECTIVES: To clarify the relations of systemic hemodynamics to left ventricular (LV) geometric patterns in patients with moderate hypertension and target organ damage. BACKGROUND: LV geometry stratifies risk in hypertension, but relations of LV geometry to systemic hemodynamic patterns in moderately severe hypertension have not been fully elucidated. DESIGN: Cross-sectional case-control study. SETTING: Baseline findings in the echocardiographic substudy of the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE) and in a normotensive reference group. PATIENTS/PARTICIPANTS: Nine hundred and sixty-four patients with Stage I-II hypertension and LV hypertrophy by Cornell voltage duration criteria ((SV3 + RaVL [+ 6 mm in women]) x QRS > 2440 mm x ms) or modified Sokolow- Lyon voltage criteria (SV1 + RV5/RV6 > 38 mm), and 366 apparently normal adults. INTERVENTIONS: None. METHODS: Two-dimensional and Doppler echocardiograms were used to classify hypertensive patients into groups with normal geometry, concentric remodelling and concentric and eccentric hypertrophy, and to measure stroke volume (SV), cardiac output, peripheral resistance and pulse pressure/SV as a measure of arterial stiffness. Comparisons were adjusted for covariates by general linear model with the Sidak post-hoc test RESULTS: Mean SV was higher in patients with eccentric hypertrophy (83 ml/beat) and lower with concentric remodeling (68 ml/beat) than in normal adults (73 ml/ beat). Cardiac output was highest in patients with eccentric LV hypertrophy and lower with concentric remodeling than eccentric hypertrophy; mean pressure and peripheral resistance were equally high in all hypertensive subgroups, whereas pulse pressure/SV was most elevated (by a mean of 47% versus reference subjects) with concentric remodeling and least so (mean + 15%) with eccentric hypertrophy. In multivariate analysis (Multiple R + 0.68), LV mass was independently related to higher systolic pressure, older age, SV, male gender and body mass index (all P< 0.001). Relative wall thickness was independently related (Multiple R + 0.50) to older age, higher systolic pressure, lower SV (all P< 0.001) and higher body mass index (P + 0.007). SV and cardiac output were lower in patients with low stress-corrected midwall shortening. CONCLUSION: In patients with moderate hypertension and ECG LV hypertrophy, the levels of SV and pulse pressure/ SV, are associated with, and may be stimuli to different LV geometric phenotypes.

Left ventricular filling patterns in patients with systemic hypertension and left ventricular hypertrophy (the LIFE study). Losartan Intervention For Endpoint.

Abnormal left ventricular (LV) filling may exist in early stages of hypertension. Whether this finding is related to LV hypertrophy is currently controversial. This study was undertaken to assess relations between abnormal diastolic LV filling and LV geometry in a large series of hypertensive patients with electrocardiographic LV hypertrophy. M-mode, 2-dimensional, and pulsed Doppler echocardiographic recordings of mitral inflow velocity and isovolumetric relaxation time (IVRT) were obtained in 750 patients with stage I to III hypertension and LV hypertrophy determined by electrocardiography (sex-adjusted Cornell voltage duration criteria or Sokolow-Lyon voltage criteria) after 14 days of placebo treatment. The patients' mean age was 67+/-7 years and 44% were women. One hundred forty patients (19%) had normal LV geometric pattern, 79 (11%) had concentric remodeling, 342 (45%) had eccentric LV hypertrophy, and 189 (25%) had concentric LV hypertrophy. A normal LV filling pattern was found in 116 patients (16%), abnormal relaxation in 519 (69%), "pseudonormal" filling was found in 83 (11%), and a restrictive filling pattern in 32 (4%). Prolonged IVRT was associated with LV hypertrophy (p<0.01) as well as elevated relative wall thickness (p<0.05). A stronger difference (p<0.01) in IVRT was found between groups with and without LV hypertrophy. Multiple regression analysis revealed that increased LV mass correlated with prolonged IVRT, whereas LV mass and geometry were not associated with peak early LV filling velocity (E), peak atrial filling velocity (A) ratio or mitral valve E-peak deceleration time, although IVRT was found to be an independent correlate of E/A ratio and deceleration time. Thus, abnormal IVRT was highly prevalent in all LV geometric subgroups among hypertensive patients with electrocardiographic LV hypertrophy, even in those with normal LV geometry determined by echocardiography. We found that IVRT differed significantly among patient groups with different LV geometric patterns, primarily because of the association of IVRT to LV mass.

Effect of electrocardiographic left ventricular hypertrophy on left ventricular systolic function in systemic hypertension (The LIFE Study). Losartan Intervention For Endpoint.

Left ventricular (LV) ejection fraction is normal in most patients with uncomplicated hypertension, but the prevalence and correlates of decreased LV systolic chamber and myocardial function, as assessed by midwall mechanics, in hypertensive patients identified as being at high risk by the presence of LV hypertrophy on the electrocardiogram has not been established. Therefore echocardiograms were obtained in 913 patients with stage I to III hypertension and LV hypertrophy determined by electrocardiographic (Cornell voltage duration or Sokolow-Lyon voltage) criteria after 14 days' placebo treatment. The 913 patients' mean age was 66 years, and 42% were women. Fourteen percent had subnormal LV endocardial shortening, 24% had subnormal midwall shortening, and 13% had reduced stress-corrected midwall shortening. Nineteen percent had normal LV geometry, 11% had concentric remodeling, 47% had eccentric hypertrophy, and 23% had concentric hypertrophy. LV systolic performance evaluated by LV endocardial shortening and midwall shortening was impaired in 10% of patients with normal geometry, 20% with concentric remodeling, 27% with eccentric hypertrophy, and 42% with concentric hypertrophy. Relative wall thickness, an important independent correlate of LV chamber function, was related directly to endocardial shortening and negatively to midwall shortening and stress-corrected midwall shortening. LV mass was the strongest independent correlate of impaired endocardial shortening, midwall shortening, or both. In hypertensive patients with electrocardiographic LV hypertrophy, indexes of systolic performance are subnormal in 10% to 42% with different LV geometric patterns. Depressed endocardial shortening is most common in patients with eccentric LV hypertrophy, whereas impaired midwall shortening is most prevalent in patients with concentric remodeling or hypertrophy. Thus, in hypertensive patients with electrocardiographic LV hypertrophy, impaired LV performance occurs most often, and is associated with greater LV mass and relative wall thickness and may contribute to the high rate of cardiovascular events.

Endothelial dysfunction in resistance arteries is related to high blood pressure and circulating low density lipoproteins in previously treated hypertension.

BACKGROUND: Peripheral endothelial dysfunction has been demonstrated in hypertension. However, its relationship to blood pressure (BP) load, vascular structure, and metabolic disturbances in patients with long-standing, previously treated hypertension is unclear. METHODS: A total of 41 patients with stage I to III essential hypertension and electrocardiographic left ventricular hypertrophy were studied. After 2 to 3 weeks of placebo treatment we measured nitroprusside-induced relaxation (NIR), acetylcholine-induced relaxation (AIR), and media:lumen ratio in isolated, subcutaneous resistance arteries by myography, as well as 24-h ambulatory BP, and serum lipids. RESULTS: Maximal AIR correlated negatively with median 24-h diastolic BP (r=-0.42, P=.01), and sensitivity to AIR correlated negatively with serum low density lipoprotein (LDL) (r =-0.36, P < .05). In multiple regression analyses, sensitivity to AIR correlated negatively with serum LDL (beta=-0.33) independently of maximal NIR (beta=0.41) (adjusted R2 =0.26, P < .01). Maximal acetylcholine-induced relaxation correlated negatively with median 24-h diastolic BP (beta=-0.38) independently of maximal NIR (beta=0.45) (adjusted R2= 0.32, P < .001). Acetylcholine-induced relaxation was not significantly related to diabetes or to media:lumen ratio (r = -0.26, NS). CONCLUSIONS: High diastolic BP and high serum LDL were associated with impaired maximal AIR and reduced sensitivity to AIR, respectively, independently of smooth muscle cell responsiveness to nitroprusside. This indicated decreasing endothelial function in small resistance arteries with increasing BP and increasing LDL in hypertension. Endothelial function was not significantly related to vascular structure of the resistance arteries or to diabetes in these patients with long-standing hypertension.

Similar effects of isolated systolic and combined hypertension on left ventricular geometry and function: the LIFE Study.

Echocardiograms of 143 patients with isolated systolic hypertension were compared to 808 patients with combined (systolic and diastolic) hypertension. All patients met electrocardiographic criteria for left ventricular hypertrophy and were evaluated off medication. Patients with isolated systolic hypertension were older, shorter, weighed less, and were mostly women, but body mass index (BMI) was similar in both groups. Systolic blood pressure (SBP) was 172 mm Hg in isolated systolic hypertension, 174 mm Hg in combined (P = not significant). Diastolic blood pressure was 83 and 101 mm Hg, respectively (P < .001). Despite having mean arterial pressure 12 mm Hg lower than patients with combined hypertension, the group with isolated systolic hypertension had equally severe abnormalities of left ventricular mass, left ventricular geometric patterns, and measures of systolic and diastolic function. Peripheral resistance was lower and pulse pressure/stroke volume ratio (arterial stiffness index) was higher and the isovolumic relaxation time shorter in isolated systolic hypertension. Multiple regression analyses identified age, height, BMI, stress-corrected mid wall shortening, stroke volume, male gender, and systolic or mean blood pressure (but not isolated systolic hypertension) as independent correlates of left ventricular mass. Relative wall thickness was independently associated with isolated systolic hypertension (P = .001) in addition to mean pressure and other covariates. The present results add support to the concept that systolic blood pressure (SBP) is a stronger determinant than diastolic pressure of cardiac target organ damage in hypertension.

Maximal exercise capacity is related to cardiovascular structure in patients with longstanding hypertension. A LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension.

BACKGROUND: Cardiovascular hypertrophy and remodeling in patients with never-treated hypertension has been associated with impaired exercise capacity, but whether this relationship remains in patients with longstanding hypertension and target organ damage is less elucidated. METHODS: In 43 unmedicated patients with essential hypertension and electrocardiographic left ventricular (LV) hypertrophy, we measured maximal workload and oxygen reserve by bicycle test, 24-h ambulatory blood pressure (BP), LV mass index by magnetic resonance imaging (LVMI(MRI), n = 31), LVMI(echo) and systemic vascular compliance by echocardiography, minimal forearm vascular resistance (MFVR) by plethysmography, and intima media thickness and distensibility in the common carotid arteries by ultrasound. RESULTS: The patients did not achieve the maximal workload as predicted by age, gender and body composition (146[129-163] v 162[146-179] Watt, P = .01). This impaired exercise capacity, calculated as the ratio between achieved and predicted maximal workload, was in simple regression analyses related to lower distensibility of the common carotid artery (r = 0.38, P = .01) and lower oxygen reserve (r = 0.68, P < .001). In multiple regression analyses, lower oxygen reserve was related to higher LVMI(MRI) (beta = -0.44), lower systemic vascular compliance (beta = -0.36), and higher MFVR (beta = -0.52) (adjusted R2 = 0.53, P < .001). CONCLUSIONS: Patients with longstanding hypertension and target organ damage cannot achieve the predicted maximal workload. This impaired exercise capacity was associated with lower common carotid distensibility and lower oxygen reserve. The latter was independently related to LV hypertrophy, low systemic vascular compliance and peripheral vascular remodeling, suggesting that cardiovascular hypertrophy and remodeling may reduce exercise capacity by itself.

Long-term plasma catecholamines in patients with hypertension and left ventricular hypertrophy treated with losartan or atenolol: ICARUS, a LIFE substudy.

Hypertension is a major risk factor for morbidity and mortality. Plasma catecholamines are linked to the pathogenesis of hypertension. Pharmacological intervention, including treatment with beta-blockers, reduces cardiovascular mortality and morbidity. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, the angiotensin receptor blocker losartan significantly reduced cardiovascular end points compared to the beta-blocker atenolol. Thus, for the first time, one drug was shown to be superior to another in hypertension. The present substudy examined the effects of atenolol vs losartan treatment on plasma catecholamines at rest and during hyperinsulinaemia in a cohort of 86 LIFE patients. Plasma adrenaline increased significantly from placebo treatment at baseline to year 1 of treatment (P<0.0001), and also during hyperinsulinaemia (P<0.0001). Plasma noradrenaline did not change significantly from placebo treatment at baseline to year 1, but increased significantly during hyperinsulinaemia both at baseline and at year 1 (P<0.0001 for both). There were no differences in plasma catecholamines or the relative changes between the two treatment arms at any stage. In a subset of 42 patients examined also at years 2 and 3, these findings were confirmed during long-term treatment. Thus, losartan had an effect on plasma catecholamines comparable to that with the beta-blocker atenolol in patients with hypertension and left ventricular hypertrophy at rest and during hyperinsulinaemia. We find it unlikely that a difference in sympathetic activity explains the outcome benefits of losartan over atenolol in the LIFE study.

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.