Weight reduction and aortic stiffness in obese children and adolescents: a 1-year follow-up study.

Little is known about the effect of weight reduction on aortic stiffness and especially so in the young. The present study investigates whether weight reduction influences aortic stiffness in obese children and adolescents. Carotid-femoral pulse wave velocity (cfPWV) and augmentation index at heart rate 75 (AIx@HR75) were measured in 72 obese patients aged 10-18 years at baseline and after 1-year of lifestyle intervention (follow-up). We found that although the degree of obesity decreased (Δbody mass index z-score: -0.24±0.45, P<0.0001), cfPWV was higher at follow-up (ΔcfPWV: 0.27±0.47 m s(-1), P<0.0001), which was explained by the increase in age (ß=0.12 ms(-1) per year, 95% confidence interval (CI) 0.07-0.17, P<0.0001) and partly by changes in mean arterial pressure and heart rate. Changes in cfPWV were not related to changes in obesity measures. No significant change was found in AIx@HR75 (ΔAIx@HR75: 2.10±9.73%, P=0.072), but changes in AIx@HR75 were related to changes in abdominal fat (Δwaist/height ratio: ß=50.3, 95% CI 6.7-94.0, P=0.02) and changes in total body fat percent by dual energy X-ray absorptiometry scan (Δtotal body fat (%): ß=0.7, 95% CI 0.1-1.3, P=0.02) when adjusted for gender and relevant baseline confounders. In conclusion, no clear effect of weight reduction was found on aortic stiffness, although changes in AIx@HR75 were associated with changes in both abdominal fat and total body fat percent. The higher cfPWV at follow-up was related to the older age.

A prediction of the renal and cardiovascular efficacy of aliskiren in ALTITUDE using short-term changes in multiple risk markers.

INTRODUCTION: We recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted. METHODS: We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change. RESULTS: Based on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of -7.9% (95% CI -2.5 to -13.4) for the cardio-renal endpoint, a risk change of -5.1% (-1.2 to -9.0) for the CV endpoint and a non-significant risk change of -19.9% (-42.1 to +2.1) for the renal endpoint. CONCLUSIONS: PRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.

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.

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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The antihypertensive effect of fermented milk in individuals with prehypertension or borderline hypertension.

Fermented milk (FM) with putative antihypertensive effect in humans could be an easy applicable lifestyle intervention against hypertension. The mode of action is supposed to be through active milk peptides, shown to possess in vitro ACE-inhibitory effect. Blood pressure (BP) reductions upto 23 mm Hg have been reported in spontaneously hypertensive rats fed FM. Results from human studies of the antihypertensive effect are inconsistent. However, many studies suffer from methodological weaknesses, as insufficient blinding and the use of office BP measurements. We conducted a randomised, double-blind placebo-controlled study of the antihypertensive effect of Lactobacillus helveticus FM in 94 prehypertensive and borderline hypertensive subjects. The participants were randomised into three treatment groups with a daily intake of 150 ml of FM, 300 ml of FM or placebo (chemically acidified milk). The primary outcome was repeated 24-h ambulatory BP measurements. There were no statistically significant differences in the outcome between the groups (systolic BP (SBP), P=0.9; diastolic BP (DBP), P=0.2). However, the group receiving 300 ml FM had reduced BP across the 8-week period in several readings, which could be compatible with a minor antihypertensive effect. Heart rate and lipids remained unchanged between groups. Hence, our study does not support earlier studies measuring office BP-measurements, reporting antihypertensive effect of FM. Based on straight performed 24-h ambulatory BP measurements, milk fermented with Lactobacillus helveticus does not posses significant antihypertensive effect.

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.

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.

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.

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.

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.

24-h Ambulatory blood pressure in patients with ECG-determined left ventricular hypertrophy: left ventricular geometry and urinary albumin excretion-a LIFE substudy.

This study was undertaken to evaluate the relationships among left ventricular (LV) geometric patterns and urinary albumin excretion in patients with hypertension and electrocardiographic (ECG) LV hypertrophy. In 143 patients with stage II-III hypertension, 24-h ambulatory blood pressure (BP) monitoring, single urine albumin determination, and echocardiography were performed after 14 days of placebo treatment. Mean age was 68+/-7 years, 35% were women, body mass index was 28+/-5 kg/m(2), LV mass index (LVMI) was 125+/-26 g/m(2), and 24% had microalbuminuria. The mean office BP was 176+/-15/99+/-8 mmHg and the mean daytime ambulatory BP was 161+/-18/92+/-12 mmHg. Ambulatory BP, but not office BP, was higher among albuminuric compared to normoalbuminuric patients. In patients with established hypertension, daytime pulse pressure and office BP were different in the four patterns of LV geometry, with the highest pressure in those with abnormal geometry. Furthermore, microalbuminuria was more frequent in hypertensive patients with LV hypertrophy than in those with either normal geometry or concentric remodelling. White coat hypertensives (10%) showed lower LVMI and no microalbuminuria compared to patients with established hypertension. There were no differences in the prevalence of nondippers (26%) among the four LV geometric patterns or in microalbuminuria. In conclusion, increased daytime pulse pressure and office BP were associated with increased prevalence of abnormal LV geometry. Microalbuminuria was more frequent in groups with concentric and eccentric LV hypertrophy. Ambulatory BP, but not office BP, was higher in albuminuric than normoalbuminuric patients. With regard to the relationship among BP, LV geometric patterns, and urine albumin excretion in this population, 24-h ambulatory BP did not provide additional information beyond the office BP.

Albuminuria predicts cardiovascular events independently of left ventricular mass in hypertension: a LIFE substudy.

We wanted to investigate whether urine albumin/creatinine ratio (UACR) and left ventricular (LV) mass, both being associated with diabetes and increased blood pressure, predicted cardiovascular events in patients with hypertension independently. After 2 weeks of placebo treatment, clinical, laboratory and echocardiographic variables were assessed in 960 hypertensive patients from the LIFE Echo substudy with electrocardiographic LV hypertrophy. Morning urine albumin and creatinine were measured to calculate UACR. The patients were followed for 60+/-4 months and the composite end point (CEP) of cardiovascular (CV) death, nonfatal stroke or nonfatal myocardial infarction was recorded. The incidence of CEP increased with increasing LV mass (below the lower quartile of 194 g to above the upper quartile of 263 g) in patients with UACR below (6.7, 5.0, 9.1%) and above the median value of 1.406 mg/mmol (9.7, 17.0, 19.0%(***)). Also the incidence of CV death increased with LV mass in patients with UACR below (0, 1.4, 1.3%) and above 1.406 mg/mmol (2.2, 6.4, 8.0%(**)). The incidence of CEP was predicted by logUACR (hazard ratio (HR)=1.44(**) for every 10-fold increase in UACR) after adjustment for Framingham risk score (HR=1.05(***)), history of peripheral vascular disease (HR=2.3(*)) and cerebrovascular disease (HR=2.1(*)). LV mass did not enter the model. LogUACR predicted CV death (HR=2.4(**)) independently of LV mass (HR=1.01(*) per gram) after adjustment for Framingham risk score (HR=1.05(*)), history of diabetes mellitus (HR=2.4(*)) and cerebrovascular disease (HR=3.2(*)). (*)P<0.05, (**)P<0.01, (***)P<0.001. In conclusion, UACR predicted CEP and CV death independently of LV mass. CV death was predicted by UACR and LV mass in an additive manner after adjustment for Framingham risk score and history of CV disease.

Alcohol consumption and cardiovascular risk in hypertensives with left ventricular hypertrophy: the LIFE study.

The Losartan Intervention For End point reduction in hypertension (LIFE) study showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke, and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios (HR) in 4287 and 685 participants who reported intakes of 1-7 and >8 drinks/week at baseline, respectively, with those in 4216 abstainers, adjusting for gender, age, smoking, exercise, and race. Within categories, clinical baseline characteristics, numbers randomized to losartan and atenolol, and blood pressure (BP) lowering were similar on the drug regimens. Overall BP control (<140/90 mmHg) at end of follow-up was similar in the categories. Composite end point rate was lower with 1-7 (24/1000 years; HR 0.87, P<0.05) and >8 drinks/week (26/1000 years; HR 0.80, NS) than in abstainers (27/1000 years). Myocardial infarction risk was reduced in both drinking categories (HR 0.76, P<0.05 and HR 0.29, P<0.001, respectively), while stroke risk tended to increase with >8 drinks/week (HR 1.21, NS). Composite risk was significantly reduced with losartan compared to atenolol only in abstainers (HR 0.81 95% confidence interval, CI (0.68, 0.96), P<0.05), while benefits for stroke risk reduction were similar among participants consuming 1-7 drinks/week (HR 0.73, P<0.05) and abstainers (HR 0.72, P<0.01). Despite different treatment benefits, alcohol-treatment interactions were nonsignificant. In conclusion, moderate alcohol consumption does not change the marked stroke risk reduction with losartan compared to atenolol in high-risk hypertensives. Alcohol reduces the risk of myocardial infarction, while the risk of stroke tends to increase with high intake.

Is inappropriate left ventricular mass related to neurohormonal factors and/or arterial changes in hypertension? A LIFE substudy.

We investigated whether inappropriately high left ventricular (LV) mass, defined as observed LV mass exceeding the level of individual LV mass predicted from gender, height, and stroke work, may be associated with an imbalance between growth-promoting and growth-inhibitory factors and/or structural vascular changes. In 53 patients with hypertension and electrocardiographic LV hypertrophy, 24-h ambulatory blood pressure (BP); echocardiographic LV mass, stroke volume and stroke work; minimal forearm vascular resistance (MFVR); and intima-media cross-sectional area in common carotid arteries (IMA) were evaluated after 2 weeks of placebo treatment. Serum insulin, plasma epinephrine, norepinephrine, endothelin, angiotensin II, aldosterone, and brain natriuretic peptide (BNP) were also measured. High observed LV mass was related to high IMA (r=0.46, P<0.001), MFVR (in men: r=0.36, P<0.05), 24-h ambulatory systolic BP (r=0.30, P=0.06), and lower plasma angiotensin II (r=-0.33, P<0.05), but not to other circulating growth factors. Stroke work was similarly related to IMA (r=0.42, P<0.01), MFVR (in men: r=0.41, P<0.05), and plasma angiotensin II (r=-0.32, P<0.05). Inappropriate LV mass, identified by the ratio between observed LV mass and the value predicted for gender, height, and stroke work, was not significantly related to any of the arterial or neurohormonal variables. In this small series of older hypertensive patients, inappropriate LV mass was not significantly related to arterial changes or to measured circulating growth factors, although weak relations cannot be excluded. Alternatively, inappropriately high LV mass might be related to unmeasured factors such as local myocardial alterations in growth factors and/or genetic predisposition to develop excessive LV hypertrophy.

Association between vascular dysfunction and reduced myocardial flow reserve in patients with hypertension: a LIFE substudy.

Impaired myocardial flow reserve (MFR) has been demonstrated in hypertension, and has been associated with peripheral vascular changes. We investigated whether MFR was impaired and associated with structural and/or functional vascular changes in hypertensive patients without evidence of coronary artery disease (CAD). We measured left ventricular (LV) mass index by echocardiography and MFR by positron emission tomography in 33 unmedicated, hypertensive patients with electrocardiographic LV hypertrophy without CAD, and 15 age- and gender-matched normotensive subjects. We also measured 24-h ambulatory blood pressure, minimal forearm vascular resistance (MFVR) by plethysmography, media:lumen ratio in isolated, subcutaneous resistance arteries by myography, intima-media cross-sectional area of the common carotid artery, and flow-mediated (FMD) and nitroglycerin-induced dilatation (NID) of the brachial artery by ultrasound. Compared to the controls, the patients had impaired MFR (2.4 (95% CI 1.95-2.8) vs 3.4 (2.7-4.2), P<0.01) due to increased resting myocardial blood flow (MBF) (0.82 (0.73-0.91) vs 0.65 (0.56-0.75) ml/g min), and decreased dipyridamole-stimulated MBF (1.80 (1.55-2.1) vs 2.3 (1.80-2.8) ml/g min, both P<0.05). The difference in resting MBF disappeared (80 (74-87) vs 86 (74-97) microl/kg mmHg, NS) when normalized for blood pressure and heart rate. MFR correlated negatively to median 24-h systolic blood pressure (r=-0.50, P<0.01) as well as to LV mass index (r=-0.45, P<0.05) and MFVR in men (r=-0.47, P<0.05), and positively to FMD (r=0.44, P<0.05) and NID (r=0.40, P<0.05). Hypertensive patients with electrocardiographic LV hypertrophy without CAD had impaired MFR associated with cardiovascular hypertrophy and vasodilatory dysfunction. This suggests that MFR is impaired by LV hypertrophy and structural/functional vascular damage in the coronary and noncoronary circulation.