Enhanced left ventricular endocardial border delineation with an intravenous injection of SonoVue, a new echocardiographic contrast agent: A European multicenter study.

The safety and efficacy of SonoVue (also referred to as BR1), a new contrast agent for delineating endocardial border of the left ventricle after intravenous administration, was assessed. Two hundred and eighteen patients with suspected coronary artery disease undergoing fundamental echocardiography for the assessment of left ventricle were enrolled in a prospective multicenter, single blind, cross-over study with random sequence allocation of four different doses of SonoVue. Endocardial border definition in the apical and parasternal views was scored as 0 = not visible, 1 = barely visible, and 2 = well visualized before and after contrast enhancement. Analysis was performed by two pairs of off-site observers. Safety of SonoVue was also assessed. Results of our study indicated that the mean improvements in the endocardial border visualization score were as follows: 3.1 +/- 7.8 (95% CI, 2.5 and 3.7) for 0.5 ml, 3.4 +/- 8.0 (95% CI, 2.8 and 4.0) for 1 ml, 3.4 +/- 7.9 (95% CI, 2.8 and 4.0) for 2 ml, and 3.7 +/- 8.0 (95% CI, 3.1 and 4.3) for 4 ml (P < 0.05 for all doses from baseline). Changes from baseline in endocardial visualization scores were also seen in the apical views (P < 0.05) and they were dose-dependent (P < 0.001). Similar enhancements of endocardial visualization scores were observed in the apical views in patients with suboptimal baseline echocardiographic images. Diagnostic confidence for assigning a score and image quality also were significantly better following contrast enhancement. No significant changes in the laboratory parameters and vital signs were noted following contrast enhancement, and the side effects were minimal. It was concluded that SonoVue is safe and effective in delineating endocardial border, including in patients with suboptimal baseline images.

Effect of L-arginine infusion in normotensive subjects with and without a family history of hypertension.

BACKGROUND: Experimental studies have shown that nitric oxide (NO) generation in the kidney from L-arginine participates in the regulation of renal function. Our purpose was to study the effect of infusion of L-arginine (1, 5, and 10 mg/kg/min) on blood pressure (BP), renal hemodynamics, and urinary excretion of sodium and albumin in normotensive subjects with a family history of either severe hypertension (FHSH, N = 17) or mild hypertension (FHMH, N = 20) and in control subjects (N = 18) without a hereditary predisposition for hypertension. METHODS: The glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by renal clearances of Cr51 ethylenediaminetetraacetic acid and paramino-hippurate. Renal tubular reabsorption of sodium was estimated by lithium clearance. To evaluate the effect of L-arginine infusion on the L-arginine/NO pathway, we measured the NO-metabolite nitrate in plasma, and urinary excretion of cGMP, the second messenger of NO. The derivative at an L-arginine dose of 7.5 mg/kg/min was used as a measure of sensitivity to L-arginine. RESULTS: There was no difference in baseline systolic BP between the groups, but diastolic BP was significantly higher in FHSH compared with control subjects (P < 0.05). L-arginine caused a significant increase in urine flow, urinary excretion of albumin and sodium, and lithium clearance in all groups. FHSH showed a significantly decreased sensitivity to L-arginine with respect to urine flow rate (P = 0029) compared with FHMH and control subjects. L-arginine caused a significant decrease in the GFR in FHSH (P < 0.02) and control subjects (P < 0.001), but in FHMH, the decrease did not reach statistical significance (P = 0.097). There was no difference in sensitivity to L-arginine with respect to BP, RPF, or GFR between the three groups. In all patients, there was a significant positive relationship between Delta urine flow rate or Delta urinary sodium excretion and Delta GFR during infusion of L-arginine (P = 0.003 and P = 0.03, respectively). Plasma nitrate and urinary cGMP decreased in all groups during the L-arginine infusion. CONCLUSION: L-Arginine infusion in normotensive subjects caused an enhanced urine flow rate and urinary sodium and albumin excretion and a slight reduction in GFR. The effect of L-arginine on the urine flow rate was significantly less pronounced in subjects with a family history of severe hypertension, which may indicate a tubular disturbance in hypertension.

Antihypertensive effects of moexipril, a new ACE inhibitor, as add-on therapy to nifedipine in patients with essential hypertension.

Moexipril is a new nonpeptide angiotensin-converting enzyme (ACE) inhibitor with an intermediate duration of action. The antihypertensive efficacy and safety of moexipril as add-on therapy to nifedipine retard (20 mg b.i.d) was compared to placebo during 8 weeks in a double-blind trial with a parallel group design. A total of 203 patients with essential hypertension and a sitting diastolic blood pressure (DBP) > or = 95 mm Hg on nifedipine alone were randomly assigned to placebo or moexipril 3.75 mg o.d., 7.5 mg o.d., or 15 mg o.d.. At endpoint, the adjusted mean reductions in DBP from baseline were 6 mm Hg, 9 mm Hg (p < 0.01), and 9 mm Hg (p < 0.05) in the moexipril 3.75 mg, 7.5 mg, and 15 mg groups, respectively, compared to 5 mm Hg in the placebo group. All dosages of moexipril were well tolerated, and the overall percentages of patients who reported adverse experiences were smaller than in the placebo group. We concluded that moexipril as add-on therapy to nifedipine is well tolerated and gives additional antihypertensive effects.

Insulin sensitivity is more related to fat distribution than to heredity for hypertension in normotensive men.

The insulin-mediated glucose disposal rate was assessed during a euglycemic hyperinsulinemic clamp in 16 normotensive men (mean age, 41 +/- 5 years) with positive family histories of hypertension and mild overweight (PFHO) and in 25 men with negative family histories of hypertension (NFH). The control group was divided into one group with normal body weight ([NFHN] n = 11) and a second group with a similar degree of overweight ([NFHO] n = 14) as in the group with PFHO. Systolic and diastolic blood pressures were significantly greater in subjects with PFHO as compared with the NFHN group. Blood glucose and plasma insulin at baseline and during the insulin clamp did not differ between the three groups. Insulin sensitivity, expressed as the glucose disposal rate per total body weight, was significantly (P < .01) decreased in PFHO subjects (7.7 +/- 3.0 mg/kg/min) and in NFHO subjects (7.1 +/- 3.5 mg/kg/min) as compared with NFHN subjects (11.1 +/- 4.0 mg/kg/min). In multivariate analysis using body mass index, waist to hip ratio, and blood pressure as predictor variables, the waist to hip ratio was significantly related to both baseline plasma insulin (r = .70, P < .0001) and insulin sensitivity (r = -.71, P < .0001). In the present study, insulin sensitivity was related to body weight and fat distribution, whereas no difference was found regarding insulin sensitivity in subjects with or without positive family histories of hypertension.

Low-dose angiotensin II increases glucose disposal rate during euglycemic hyperinsulinemia.

To study the metabolic effects of angiotensin II we examined the glucose disposal rate and calf blood flow in healthy men (n = 39) during euglycemic hyperinsulinemia followed by a period with simultaneous angiotensin II infusion at a low dose (0.1 ng/kg/min). Angiotensin II infusion abruptly increased the glucose disposal rate significantly as compared with glucose disposal rate during euglycemic hyperinsulinemia only. There were no differences in blood glucose or plasma insulin between the euglycemic hyperinsulinemic and the angiotensin II infusion period. During hyperinsulinemia alone, blood pressure was unchanged while calf muscle blood flow increased significantly as compared with the baseline period, while during the angiotensin infusion the systolic blood pressure increased and calf blood flow decreased significantly as compared with the hyperinsulinemic period. We conclude that angiotensin II within physiological range stimulates insulin-mediated glucose uptake in healthy men. The mechanisms are, however, unclear, but changes in blood flow are probably not responsible for the observed effects.

Reduced left ventricular distensibility in normotensive men with a positive family history of hypertension.

Left ventricular (LV) morphology and function (echocardiography) were assessed in a population-derived sample of young normotensive men with a positive (PFH, n = 15) or negative (NFH, n = 29) family history of hypertension for at least two generations. Since subjects with PFH were overweight (mean weight, 89 kg), the control group was divided into one group with mild overweight (n = 15) and one lean control group (n = 14). Blood pressure, cardiac output, and calculated total peripheral resistance did not differ between the groups. LV mass was significantly increased (P < .05 to .01) in the two groups, with overweight, compared with the lean control group and in multivariate analysis body mass index (BMI), the primary determinant for LV mass (r = 0.63, P < .001). Neither LV contractility nor LV relaxation time index differed between the groups. Left ventricular distensibility (a/H ratio), which was moderately related to BMI, systolic blood pressure, and the renal vascular sensitivity to angiotensin II (r = 0.34, P < 0.03), was reduced compared with the control groups. This difference persisted after adjusting for BMI and blood pressure. The present study shows that in normotensive subjects with a positive family history of hypertension the increased LV mass was primarily dependent on weight, irrespective of heredity. However, the observed reduction in LV distensibility remained after adjusting for weight, suggesting that diastolic abnormalities may occur before hypertension in subjects likely to later develop the clinical condition.

Ambulatory blood pressure: a predictor of left ventricular mass and future blood pressure in subjects predisposed for hypertension.

Twenty-four-hour ambulatory blood pressure (SpaceLab 5200) and a single laboratory blood pressure were measured in a population-derived sample of normotensive men (mean age 36 years) with (n = 13) or without (n = 16) a positive family history of hypertension. The aim was to determine whether ambulatory monitoring was a better predictor than clinical measurements for echocardiographic derived indices of left ventricular mass and for future blood pressure. At the initial examination ambulatory blood pressure could discriminate between the groups, showing significant differences that were not evident from the clinical blood pressure measurement. After 5 years the blood pressure had increased in the group with a family predisposition for hypertension but only one subject had overt hypertension. The correlation between the average day-time blood pressure and the clinical blood pressure at follow-up was only marginally better than the correlation for the initial clinical blood pressure. In contrast to the clinical blood pressure, both day-time and night-time blood pressure averages were significantly correlated to left ventricular mass at the initial examination. It is concluded that in still normotensive subjects, ambulatory monitoring is a better predictor than clinical measurements for left ventricular mass but not for future blood pressure.

Increased response to physical and mental stress in men with hypertensive parents.

Blood pressure and heart rate responses to isometric handgrip exercise were studied at age 31 and after 5 years in young nonhypertensive men with positive family histories of hypertension (n = 13) and in those with negative family histories of hypertension (n = 13) for two generations to test whether subjects with positive family histories established a pattern of increased blood pressure and heart rate responses during the 5-year follow-up period. At follow-up the response to mental stress (Stroop's color word test) was also studied. Baseline blood pressure and heart rate at rest did not differ, initially or at follow-up, between the groups. At the initial examination, absolute blood pressure levels were significantly higher during isometric handgrip exercise just before exhaustion in subjects with positive family histories. At follow-up the absolute blood pressure level (p < 0.001) and the blood pressure responses (p < 0.01-0.001) were found to be significantly increased during handgrip exercise in subjects with positive family histories compared with subjects with negative family histories. In subjects with positive family histories the diastolic blood pressure response was significantly higher (p < 0.01) at follow-up than initially and was significantly related (r = 0.70, p < 0.01) to changes in baseline diastolic blood pressure during the follow-up period. In subjects with negative family histories the systolic blood pressure response was somewhat lower at follow-up than initially. During the mental stress test, the blood pressure response was significantly greater in subjects with positive than with negative family histories.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased waist/hip ratio, metabolic disturbances, and family history of hypertension.

To test whether nonhypertensive subjects with a two-generation positive family history of hypertension (PFH) are characterized by disturbed glucose metabolism, 16 men (38 +/- 6 years old) with PFH and 25 subjects matched for age and with negative family histories of hypertension (NFH) were recruited. Blood pressure; serum lipids; erythrocyte transmembrane sodium transport; and the glucose, plasma insulin, and C-peptide responses to an oral glucose tolerance test were investigated. Subjects with PFH had higher blood pressure, body weight, body mass index (BMI), waist/hip ratio (WHR), and abdominal sagittal diameter than subjects with NFH. Baseline blood glucose, plasma insulin, serum lipids, and transmembrane sodium transport did not differ between the two groups. Blood glucose levels at 90 and 120 minutes after oral glucose were significantly higher in subjects with PFH than in controls. Blood glucose adjusted for BMI and WHR at 90 minutes was significantly related to a PFH. Plasma insulin level at 90 minutes during the glucose load was significantly higher in subjects with PFH. In multivariate analysis, WHR was significantly related to baseline blood pressure, insulin, and cholesterol, whereas BMI was significantly associated with the insulin response to the oral glucose tolerance test. Transmembrane sodium transport was significantly related to blood pressure only. In conclusion, subjects with PFH are characterized by increased body weight and BMI, increased visceral fat accumulation, and an altered blood glucose response to an oral glucose load. It was also shown that WHR was related to blood pressure and that BMI was more related to cholesterol and response to glucose loading than a PFH was.

Reduced venous compliance in normotensive men with positive family histories of hypertension.

OBJECTIVE: To test the hypothesis of reduced venous compliance and increased cardiovascular responses to volume expansion and alpha-agonist stimulation. METHOD: Non-hypertensive healthy young men with positive (PFH) and negative family histories of hypertension were investigated regarding peripheral haemodynamics and changes in central venous pressure (CVP) and arterial blood pressure in response to graded doses of phenylephrine and acute i.v. fluid volume loading (1000 saline solution in 10 min). The control group was divided into one group matched for body mass index to PFH subjects (NFHO) and one lean control group (NFHN). RESULTS: Supine blood pressure was higher in PFH and NFHO subjects compared with NFHN subjects, whilst CVP was similar in the three groups at baseline. No significant differences in calf or forearm haemodynamics or blood volume were observed between the three groups. Cardiovascular responses to bolus doses of phenylephrine did not differ between the three groups. Saline infusion significantly increased CVP and systolic blood pressure, and effective vascular compliance (change in blood volume: CVP ratio) was reduced in PFH subjects. CONCLUSION: PFH subjects have decreased effective vascular compliance and altered arterial blood pressure responses to acute increases in vascular fluid volume. This may result from multiple factors such as increased venous vascular tone, structural reduction of venous distensibility and/or an altered neurohormonal response to increased CVP.

Increased systemic and renal vascular sensitivity to angiotensin II in normotensive men with positive family histories of hypertension.

Normotensive young men (mean age 36 years) with positive (PFH) (n = 13) and negative (n = 29) family histories of hypertension were investigated in order to study systemic and renal hemodynamics at baseline conditions and during infusion of low doses (0.1 and 0.5 ng/min/kg) of angiotensin II (AII). The control group with negative family histories of hypertension was subdivided into one group matched for body mass index (n = 15) to subjects with PFH, and one lean control group (n = 14). Baseline blood pressure and sodium intake, measured as urinary excretion, were higher in PFH and in matched controls than in the lean control group. At baseline, renal blood flow (para-aminohippurate clearance) did not differ significantly among the three groups, while glomerular filtration rate (inulin clearance) was higher in PFH than in matched controls. Both doses of angiotensin II infusion increased the blood pressure significantly in PFH. In matched controls a small increase in blood pressure was seen with the highest dose only, while no change in blood pressure was observed in the lean control group. In PFH both doses of AII infusion caused diminished renal blood flow (P less than .01) and increased renal vascular resistance (P less than .001). The two control groups remained unchanged with both AII doses. These results could indicate that normotensive subjects with positive family histories of hypertension are characterized by an increased sensitivity to AII in the systemic and renal circulation as compared with subjects with negative family histories of hypertension.

Blunted renal sodium excretion during acute saline loading in normotensive men with positive family histories of hypertension.

The natriuretic and intra-arterial blood pressure response to an acute saline load (1000 mL 0.9% NaCl), was studied in normotensive young men with positive (n = 11) and negative (n = 21) family histories of hypertension. The age-matched (36 +/- 5 years) control group with negative family histories of hypertension was subdivided into two groups, one matched for body mass index (BMI) to the subjects with positive family histories of hypertension (n = 10), and another lean control group (n = 11). Baseline blood pressure was significantly higher in subjects with positive family histories of hypertension and in controls matched for BMI as compared with lean controls. Sodium excretion increased in all three groups during the saline infusion, while subjects with positive family histories of hypertension disclosed a diminished natriuretic response as compared with the two control groups. Systolic blood pressure increased significantly during the saline load in subjects with positive family histories of hypertension, while in subjects with negative family histories of hypertension, no significant change in blood pressure was observed. Plasma renin activity, angiotensin II, serum aldosterone, plasma noradrenaline, blood volume, and ouabain-sensitive erythrocyte sodium efflux rate constant did not differ between the three groups at baseline. A significant negative correlation was found between baseline sodium excretion and sodium efflux rate constant in subjects with positive family histories of hypertension. We conclude that the subjects with positive family histories of hypertension exhibit a blunted natriuretic and an exaggerated blood pressure response to an acute saline load as compared with the two control groups with negative family histories of hypertension. This could be of neuronal and/or hormonal origin.

Normotensive young men with family histories of hypertension gain weight and decrease their intraerythrocyte sodium content during a 5-year follow-up.

Young normotensive men matched for age and body mass index with (n = 16) and without (n = 13) family histories of hypertension were investigated at baseline and after 5 years of follow-up with respect to blood pressure, body weight and intracellular sodium content. Subjects with positive family histories of hypertension increased significantly in body weight (from 81.9 +/- 11.5 kg to 89.5 +/- 11.4 kg, P less than 0.001) compared to subjects with negative family histories of hypertension (from 79.9 +/- 10.8 kg to 80.7 +/- 12.2 kg, NS). Their blood pressure did not differ initially (137 +/- 12/75 +/- 11 mmHg vs. 135 +/- 8/72 +/- 9 mmHg), but was reduced in subjects without family histories of hypertension (to 125 +/- 3/68 +/- 13 mmHg) in the follow-up examination. At follow-up, body mass index showed a positive correlation with blood pressure among subjects with positive family histories of hypertension (r = 0.77, P less than 0.001). At baseline, subjects with hypertensive fathers had significantly higher intraerythrocyte sodium levels than subjects with normotensive parents. At re-examination 5 years later, this difference was no longer present. We conclude that normotensive subjects with positive family histories of hypertension are predisposed to gain weight rather than to show an increase in blood pressure at this age. Normalization of intracellular sodium content, as found in the present study, could be a consequence of this weight gain and the ensuing metabolic adaption.

Resting and volume-stimulated circulating atrial natriuretic peptide in young normotensive men with positive family histories of hypertension.

Normotensive young men (36 +/- 5 years old) with positive family histories of hypertension (n = 11) and age-matched controls (n = 21) with negative family histories of hypertension were examined. The control group was divided into one group matched for body mass index with those subjects with positive family histories (n = 10) and one group with normal body mass index (n = 11). Blood pressure, central venous pressure (CVP), plasma atrial natriuretic peptide (ANP) and serum aldosterone were examined at a baseline and during an acute volume load with 1000 ml saline solution. Subjects with positive family histories and controls matched for body mass index had a higher blood pressure at baseline than controls with normal body mass index. CVP and serum aldosterone did not differ between the three groups, while sodium intake and plasma concentrations of ANP were significantly higher in subjects with positive family histories. During volume loading, CVP increased significantly more in subjects with positive family histories as compared with the two control groups. A blunted response to ANP was observed during volume loading in subjects with positive family histories, while subjects in the two control groups demonstrated comparable and significant increases in circulating ANP. Serum aldosterone, however, decreased during volume loading in all three groups, with no difference between the groups. We conclude that normotensive subjects with positive family histories are characterized by increased basal concentrations of ANP and exhibit a blunted response to an acute volume load.(ABSTRACT TRUNCATED AT 250 WORDS)

Family history and pathophysiological mechanisms of primary hypertension. Studies in non-hypertensive young men with positive and negative family histories of hypertension.

In an attempt to explore pathophysiological mechanisms relevant for the development for future primary hypertension, we investigated young normotensive men with positive family histories of hypertension (PFH) regarding blood pressure, body weight, systemic and renal haemodynamics as well as cardiovascular hormones and sodium homeostasis. Sixteen subjects with PFH and thirteen controls with negative family histories (NFH), matched for age and body weight were investigated at age 31 and after five years. Blood pressure and heart rate did not differ between the two groups at the first or follow-up examination. At follow-up body weight had increased and a positive correlation between blood pressure and body mass index was found in subjects with PFH, while subjects with NFH had unchanged blood pressure and body weight. Initially, intraerythrocyte sodium content was increased in subjects with PFH, however, at follow-up intraerythrocyte sodium content did not differ between the two groups. At follow-up systemic and renal haemodynamics and sodium homeostasis were investigated in fifteen subjects with PFH and in twenty-nine controls matched for age (36 +/- 5 year) and with NFH. The control group was divided into one group matched for body mass index (n = 15) and one group with normal body mass index (n = 14). Blood pressure and central venous pressure were measured during bolus injections of phenylephrine and during an acute saline/fluid load (1000ml 0.9% NaCl within 10 min). Renal haemodynamics and blood pressure were measured during low doses (0.1 and 0.5 ng/min/kg) continuous infusions of angiotensin II (AII). At baseline blood pressure, body weight and sodium excretion were higher in subjects with PFH and matched controls as compared with lean controls. Calf and forearm haemodynamics (pletysmography), plasma catecholamines, plasma renin activity, angiotensin II, aldosterone, blood volume and erythrocyte sodium efflux rate constant did not differ between the three groups. Circulating atrial natriuretic peptide was higher in subjects with PFH than in the two control groups. In subjects with PFH there was a negative correlation between renal sodium excretion at baseline and the ouabain-sensitive sodium efflux rate constant. During the acute saline/fluid load central venous pressure and systolic blood pressure increased more and venous vascular compliance (ml/mmHg/kg) was reduced in PFH. Atrial natriuretic peptide release and renal sodium excretion were blunted during saline/fluid load in subjects with PFH as compared with the two control groups. Renal blood flow and renal vascular resistance did not differ at baseline. Glomerular filtration rate was somewhat higher in PFH.(ABSTRACT TRUNCATED AT 400 WORDS)

Central hemodynamics and brachial artery compliance during therapy with isradipine, a new calcium antagonist.

Seventeen middle-aged males with sustained essential hypertension (WHO stage II) and diastolic blood pressures (BP) exceeding 100 mm Hg during a placebo run-in period completed a trial to assess the hemodynamic effects of isradipine, a new dihydropyridine calcium antagonist. The study was double-blind and placebo-controlled with a crossover design. Brachial artery compliance was assessed as the ratio of stroke volumes and simultaneous pulse pressure. During therapy with isradipine (all patients received 7.5 mg b.i.d.), highly significant reductions in supine systolic BP [from 184 +/- 16 to 162 +/- 20 mm Hg (mean +/- S.D.)] and diastolic BP (from 96 +/- 8 to 83 +/- 8 mm Hg) were observed. Heart rate was unchanged (69 +/- 3 vs. 73 +/- 2 beats/min) during chronic therapy. Total peripheral resistance was significantly reduced (from 24.8 +/- 9 to 17.4 +/- 5 units) while cardiac output was unchanged (6.0 +/- 1.9 vs. 7.2 +/- 1.8 L/min). Stroke volume was unchanged (92 +/- 25 vs. 100 +/- 25 ml/beat), and a significant (p less than 0.05) increase in brachial artery compliance (from 1.05 +/- 0.25 to 1.26 +/- 0.35 ml/mm Hg) was observed.