Intensive Blood Pressure Management Preserves Functional Connectivity in Patients with Hypertension from the Systolic Blood Pressure Intervention Randomized Trial.

BACKGROUND AND PURPOSE: The Systolic Blood Pressure Intervention (SPRINT) randomized trial demonstrated that intensive blood pressure management resulted in slower progression of cerebral white matter hyperintensities, compared with standard therapy. We assessed longitudinal changes in brain functional connectivity to determine whether intensive treatment results in less decline in functional connectivity and how changes in brain functional connectivity relate to changes in brain structure. MATERIALS AND METHODS: Five hundred forty-eight participants completed longitudinal brain MR imaging, including resting-state fMRI, during a median follow-up of 3.84 years. Functional brain networks were identified using independent component analysis, and a mean connectivity score was calculated for each network. Longitudinal changes in mean connectivity score were compared between treatment groups using a 2-sample t test, followed by a voxelwise t test. In the full cohort, adjusted linear regression analysis was performed between changes in the mean connectivity score and changes in structural MR imaging metrics. RESULTS: Four hundred six participants had longitudinal imaging that passed quality control. The auditory-salience-language network demonstrated a significantly larger decline in the mean connectivity score in the standard treatment group relative to the intensive treatment group (P = .014), with regions of significant difference between treatment groups in the cingulate and right temporal/insular regions. There was no treatment group difference in other networks. Longitudinal changes in mean connectivity score of the default mode network but not the auditory-salience-language network demonstrated a significant correlation with longitudinal changes in white matter hyperintensities (P = .013). CONCLUSIONS: Intensive treatment was associated with preservation of functional connectivity of the auditory-salience-language network, while mean network connectivity in other networks was not significantly different between intensive and standard therapy. A longitudinal increase in the white matter hyperintensity burden is associated with a decline in mean connectivity of the default mode network.

Decrease in peripheral sympathetic nervous system activity following renal denervation or unclipping in the one-kidney one-clip Goldblatt hypertensive rat.

Increased sympathetic nervous system activity has been demonstrated in established one-kidney one-clip hypertension in the rat. We have found that renal denervation in this model results in an attenuation of hypertension, unassociated with alterations in sodium or water balance or renin activity. To determine whether the depressor effect of renal denervation is associated with changes in peripheral sympathetic nervous system activity, sham operation (n = 12), renal denervation (n = 13), or unclipping (n = 13) was carried out 2 wk after the onset of one-kidney one-clip hypertension. Normotensive unine-phrectomized age- and sex-matched rats were used as controls (n = 14). Renal denervation resulted in a significant decrease in systolic blood pressure (201+/-7 to 151+/-6 mm Hg), while unclipping lowered systolic blood pressure to normotensive levels (130+/-6 mm Hg). 8 d after operation plasma norepinephrine and mean arterial pressure before and after ganglionic blockade with 30 mg/kg hexamethonium bromide were measured in conscious, unrestrained, resting animals, as indices of peripheral sympathetic nervous system activity. Plasma norepinephrine was significantly higher in hypertensive sham-operated rats (422+/-42 pg/ml) compared with normotensive controls (282+/-25 pg/ml) (P < 0.01). Both renal denervation and unclipping restored plasma norepinephrine to normal levels (273+/-22 and 294+/-24 pg/ml, respectively). Ganglionic blockade in hypertensive sham-operated animals resulted in a significantly greater decrease in mean arterial pressure than occurred in renal denervated, unclipped, or control rats. The data suggest that the depressor effect of renal denervation or unclipping in the one-kidney one-clip hypertensive rat is associated with a decrease in peripheral sympathetic nervous system activity.

Role of the renal sympathetic nerves in the development and maintenance of hypertension in the spontaneously hypertensive rat.

Neurogenic factors and, in particular, enhanced renal sympathetic tone, have been implicated in the pathogenesis of hypertension in the spontaneously hypertensive rat of the Okamoto strain. To examine the hypothesis that the renal sympathetic nerves contribute to the development and maintenance of hypertension by causing urinary sodium retention, 7-wk-old (early hypertensive) and 18-wk-old (established hypertensive) male spontaneously hypertensive rats were subjected to bilateral renal denervation and compared with sham-operated controls. In 7-wk-old animals renal denervation delayed the onset and slowed the rate of development of hypertension. These alterations were associated with a significantly greater fractional excretion of sodium (percentage of sodium intake excreted) during the first 3 wk after denervation. Blood pressure 2 wk after surgery was 169+/-3.5 (sham) vs. 150+/-2.4 mm Hg (denervated) (P < 0.001), corresponding to fractional sodium excretions of 65+/-1.3% (sham) vs. 80+/-2.3% (denervated) (P < 0.001). By the 5th wk after surgery, at which time an increase in renal norepinephrine content of denervated animals suggested reinnervation, blood pressures in the two groups converged (sham, 199+/-6.5 mm Hg vs. denervated 180+/-3.5 mm Hg, NS) and there was no difference in sodium excretion (sham, 77+/-2.5% vs. denervated 79+/-2.3%). Plasma and kidney renin activity of denervated animals did not differ significantly from that of sham-operated controls. In 18-wk-old rats renal denervation did not alter blood pressure or urinary sodium excretion. These data indicate that the renal sympathetic nerves contribute to the development of hypertension in the spontaneously hypertensive rat in part by causing enhanced sodium retention. Once hypertension is established the renal nerves do not play a significant role in the maintenance of increased blood pressure.

Atrial natriuretic peptide attenuates the development of pulmonary hypertension in rats adapted to chronic hypoxia.

To test the hypothesis that chronic infusion of atrial natriuretic peptide (ANP) instituted before hypoxic exposure attenuates the development of pulmonary hypertension in hypoxia adapted rats, ANP (0.2 and 1.0 microgram/h) or vehicle was administered intravenously via osmotic minipump for 4 wk beginning before exposure to 10% O2 or to room air. Low dose ANP increased plasma ANP levels by only 60% of vehicle controls after 4 wk and significantly decreased mean pulmonary arterial pressure (MPAP) (P less than 0.01), the ratio of right ventricular weight to body weight (RV/BW) (P less than 0.01), and the wall thickness of small (50-100 microns) pulmonary arteries (P = 0.01) in hypoxia-adapted rats. ANP did not alter any of these parameters in air-control rats. High dose ANP increased plasma ANP levels by 230% of control and produced greater reductions in MPAP (P less than 0.001) and RV/BW) (P less than 0.05), but not in pulmonary arterial wall thickness, than the low dose. Neither dose of ANP altered mean systemic arterial pressure in either hypoxic or normoxic rats. The data demonstrate that chronic infusion of exogenous ANP at a dose that does not affect MPAP or RV weight in air-control rats attenuates the development of pulmonary hypertension and RV enlargement in rats adapted to chronic hypoxia.

Atrial natriuretic peptide regulation of noradrenaline release in the anterior hypothalamic area of spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHR), high NaCl diets increase arterial pressure and sympathetic nervous system activity by decreasing noradrenaline release in the anterior hypothalamic area (AHA), thereby reducing the activation of sympathoinhibitory neurons in AHA. Atrial natriuretic peptide (ANP) can inhibit the release of noradrenaline, and ANP concentration is elevated in the AHA of SHR. The present study tests the hypothesis that in SHR, local ANP inhibits noradrenaline release from nerve terminals in AHA. Male SHR fed a basal or high NaCl diet for 2 wk and normotensive Wistar Kyoto rats (WKY) fed a basal NaCl diet were studied. In SHR on the basal diet, microperfusion of exogenous ANP into the AHA elicited a dose-related decrease in the concentration of the major noradrenaline metabolite 3-methoxy-4-hydroxy-phenylglycol (MOPEG) in the AHA; this effect was attenuated in the other two groups. In a subsequent study, the ANP-C (clearance) receptor agonist c-ANP was microperfused into the AHA to increase extracellular concentration of endogenous ANP in AHA. c-ANP reduced AHA MOPEG concentration in SHR on the basal NaCl diet but not in the other two groups. These data support the hypothesis that local ANP inhibits noradrenaline release in the AHA and thereby contributes to NaCl-sensitive hypertension in SHR.

Mechanism of postarrhythmic renal vasoconstriction in the anesthetized dog.

The mechanism of postarrhythmic renal vasoconstriction was studied in 28 dogs anesthetized with pentobarbital sodium (30 mg/kg i.v.). Rapid atrial or ventricular pacing or induction of atrial fibrilation were used to produce at least 20% prompt decrease in cardiac output and mean arterial blood pressure. Return to control cardiac output and blood pressure occurred within 3 minutes after cessation of the arrhythmia, but renal blood flow remained significantly decreased (26%) with gradual recovery by 17.7 +/- 6.6 min. Infusion of phentolamine (0.25 mg/min) into the renal artery, intravenous hexamethonium (l mg/kg), adrenal demedullation, or cooling the cervical vagi prevented postarrhythmic renal vasoconstriction. In contrast, renal denervation, intravenous bretylium (10 mg/kg), intravenous atropine (0.5 mg/kg) or intrarenal SQ 20881 (0.20 mg/min) has no effect on postarrhythmic renal vasoconstriction. Intravenous propranolol (0.5 mg/kg) intensified postarrhythmic renal vasoconstriction. These data suggested that the postarrhythmic renal vasoconstrictive response required intact vagi and was due to alpha adrenergic stimulation by adrenal catecholamines. However, femoral arterial catecholamine levels were not elevated above control during postarrhythmic renal vasoconstriction. We therefore sought local vascular pathways by which catecholamines might reach the kidneys. An adrenorenal vascular network was found in each dog. Collection of catecholamines from these vessels during postarrhythmic renal vasoconstriction in six dogs revealed catecholamine concentrations threefold higher than simultaneously collected femoral arterial catecholamines levels. Because ligation of these vessels abolished postarrhythmic renal vasoconstriction in each dog, we conclude that postarrhythmic renal vasconstriction is due to adrenal catecholamines reaching the kidneys through an adreno-renal vascular network and that the response requires intact vagi.

Blockade of endogenous anterior hypothalamic atrial natriuretic peptide with monoclonal antibody lowers blood pressure in spontaneously hypertensive rats.

We have previously shown that the atrial natriuretic peptide (ANP) content of the anterior hypothalamic region of NaCl-sensitive spontaneously hypertensive rats (SHR-S) is higher than that of Wistar-Kyoto (WKY) rats. ANP has been shown to inhibit neuronal norepinephrine release and to reduce the excitability of hypothalamic neurons. This study tested the hypothesis that blockade of endogenous ANP in the anterior hypothalamus by local microinjection of a monoclonal antibody to ANP (MAb KY-ANP-II) lowers blood pressure in SHR-S. Purified MAb KY-ANP-II (0.055 and 0.55 micrograms) or control mouse IgG in 200 nl saline was microinjected into the anterior hypothalamic area (AHA) of conscious SHR-S and control WKY rats. As a further control, Mab KY-ANP-II (0.55 microgram) was microinjected into the posterior hypothalamic area (PHA) of SHR-S. Anterior hypothalamic microinjection of MAb KY-ANP-II caused significant dose-related decreases in mean arterial pressure (MAP) and heart rate (HR) in SHR-S but not in WKY rats. Control injections of equal volumes of IgG had no effect on MAP or HR. Microinjection of Mab KY-ANP-II into PHA produced no significant alteration in MAP or HR in SHR-S. These data provide the first demonstration that endogenous ANP in a region of brain known to influence cardiovascular function mediates BP and HR control in the rat. These findings suggest that the increased endogenous ANP in the anterior hypothalamus of SHR-S may be involved in the central regulation of BP in the model.

Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces.

Angiotensin-converting enzyme inhibitors have beneficial effects that are presumably mediated by decreased angiotensin II (ANG II) production. In this study, we measure for the first time ANG I and ANG II levels in the interstitial fluid (ISF) space of the heart. ISF and aortic plasma ANG I and II levels were obtained at baseline, during intravenous infusion of ANG I (5 microM, 0.1 ml/min, 60 min), and during ANG I + the angiotensin-converting enzyme inhibitor captopril (cap) (2.5 mM, 0.1 ml/min, 60 min) in six anesthetized open-chested dogs. ISF samples were obtained using microdialysis probes inserted into the left ventricular myocardium (3-4 probes/dog). ANG I increased mean arterial pressure from 102+/-3 (SEM) to 124+/-3 mmHg (P < 0.01); addition of cap decreased MAP to 95+/-3 mmHg (P < 0.01). ANG I infusion increased aortic plasma ANG I and ANG II (pg/ml) (ANG I = 101+/-129 to 370+/-158 pg/ml, P < 0.01; and ANG II = 22+/-40 to 466+/-49, P < 0.01); addition of cap further increased ANG I (1,790+/-158, P < 0.01) and decreased ANG II (33+/-49, P < 0.01). ISF ANG I and ANG II levels (pg/ml) were > 100-fold higher than plasma levels, and did not change from baseline (8,122+/-528 and 6,333+/-677), during ANG I (8,269+/-502 and 6, 139+/-695) or ANG I + cap (8,753+/-502 and 5,884+/-695). The finding of very high ANG I and ANG II levels in the ISF vs. intravascular space that are not affected by IV ANG I or cap suggests that ANG II production and/or degradation in the heart is compartmentalized and mediated by different enzymatic mechanisms in the interstitial and intravascular spaces.

Estrogen-induced vasoprotection is independent of inducible nitric oxide synthase expression: evidence from the mouse carotid artery ligation model.

BACKGROUND: Estrogen is vasoprotective in animal models of vascular injury, yet the mechanisms involved are incompletely understood. The role of inducible nitric oxide synthase (iNOS) in vascular repair is controversial, but many lines of evidence indicate that it plays a role in neointima formation after arterial injury and that 17beta-estradiol (E(2)) modulates iNOS expression. This study tested the hypothesis that E(2) reduces neointima formation after vascular injury via a mechanism that is dependent on modulation of iNOS expression. METHODS AND RESULTS: Male and female wild-type (iNOS(+/+)) mice and mice with homozygous deletion of the iNOS gene (iNOS(-/-)) were studied intact (INT) or after ovariectomy (OVX) and implantation of E(2) or vehicle (V) pellets. Mice were randomized to 8 groups based on sex, iNOS status, OVX, and treatment with E(2) or V. Twenty-eight days after carotid artery ligation, mice were euthanized, and occluded vessels were evaluated for neointima formation by morphometric analysis. There was a marked sexual dimorphism in neointima formation in both the iNOS(+/+) mice and the iNOS(-/-) mice. iNOS(+/+) INT females had a >90% reduction in neointima formation compared with iNOS(+/+) males, and iNOS(-/-) INT females had a 65% reduction in neointima formation compared with iNOS(-/-) males. The sexually dimorphic response was attenuated by OVX and restored by E(2) replacement in both iNOS(+/+) and iNOS(-/-) mice. CONCLUSIONS: These results demonstrate that the vasoprotective effects of E(2) after ligation vascular injury are, at least in part, independent of iNOS expression.

Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries.

BACKGROUND: Clinical and experimental evidence suggest that the adventitia participates in the response to endoluminal vascular injury. The current study used a direct approach to test the hypothesis that, after balloon injury of the rat carotid artery, adventitial fibroblasts migrate in a luminal direction and contribute to neointima formation. METHODS AND RESULTS: Primary syngeneic adventitial fibroblasts were stably transduced with retroviral particles coordinating expression of beta-galactosidase (LacZ) and introduced into the adventitia of right carotid arteries of rats immediately after balloon injury. At defined times after injury and fibroblast implantation, rats were euthanized, and arterial tissue was examined for detection of LacZ mRNA (reverse transcription polymerase chain reaction), DNA (polymerase chain reaction), and in situ enzymatic activity. LacZ expression was detected in the media 5 days postinjury and in both media and neointima at 7, 10, and 14 days postinjury. LacZ was undetectable in injured vessels that had not been seeded with transduced fibroblasts and was restricted to the adventitia in seeded vessels that were not injured. CONCLUSIONS: These observations provide direct demonstration of adventitial fibroblast migration into neointima of arteries after endoluminal injury.

Estrogen-induced vasoprotection is estrogen receptor dependent: evidence from the balloon-injured rat carotid artery model.

BACKGROUND: Previous studies have shown that estrogen (E2) is vasoprotective in multiple animal models of vascular injury, including mice with homologous disruptions of either the alpha or beta isoforms of the estrogen receptor (ER) gene, calling into question the ER dependency of the vasoprotective effect. This study used ICI 182,780, a nonselective ER antagonist, to test the hypothesis that the vasoprotective effect of E2 in the rat carotid injury model is ER mediated. METHODS AND RESULTS: Intact female Sprague-Dawley rats were divided into 4 groups and treated with the nonselective ER antagonist ICI 182,780 (ICI; 0.5, 1.5, or 5 mg. kg(-1). d(-1), subcutaneously [S.C.]) or vehicle, beginning before balloon injury of the right common carotid artery and continuing for 14 days afterward. Four groups of ovariectomized rats (OVX) were treated with 17beta estradiol (E2) (20 microgram. kg(-1). d(-1), S.C.) alone or combined with ICI 5 mg. kg(-1). d(-1), S.C.; with ICI 5 mg. kg(-1). d(-1) alone; or with vehicle according to a similar protocol. Two weeks after injury, rats were killed, and the carotid arteries were evaluated for neointima formation using morphometric analysis. ICI 182,780 blunted the E2-related protective effect and increased neointima formation in injured carotid arteries of intact female rats in a dose-dependent fashion. ICI had no effect on neointima formation in OVX, but addition of ICI to E2 in OVX blocked the inhibitory effect of exogenous E2 on neointima formation. CONCLUSIONS: These results indicate that the vasoprotective effect of E2 in the balloon-injured rat carotid artery model is mediated by ER.

Estrogen attenuates integrin-beta(3)-dependent adventitial fibroblast migration after inhibition of osteopontin production in vascular smooth muscle cells.

BACKGROUND: Previous in vitro studies have suggested that estrogen attenuates the vascular injury response by modulating vascular smooth muscle cell (VSMC) expression of soluble factor(s) directing migration of adventitial fibroblasts. Previous in vivo studies have established a role for osteopontin (OPN) and its integrin receptors after vascular injury. In this study, we examined OPN expression in activated VSMCs, its modulation by estrogen, and its effects on adventitial fibroblast migration. In addition, the relative functional roles of beta(1)- and beta(3)-integrin-matrix interactions were examined. METHODS AND RESULTS: Primary cultures of VSMCs and adventitial fibroblasts were derived from female Sprague-Dawley rats. Serum-activated VSMCs expressed high levels of OPN mRNA and secreted protein that was effectively inhibited by estrogen treatment (10(-7) mol/L). Compared with VSMCs, fibroblasts expressed similar levels of integrins alphanu and beta(1) and higher levels of integrin-beta(3). Exogenous OPN (5.0 to 40 microg/mL) directed fibroblast migration in a dose-dependent fashion. Anti-beta(3)-integrin antibody (F11) pretreatment markedly inhibited adventitial fibroblast migration directed by exogenous OPN or VSMC-conditioned medium in a dose-dependent manner. In contrast, anti-beta(1)-integrin antibody (Ha2/5) did not affect fibroblast migration. Similarly, pretreatment with either linear or cyclic RGD peptides (10 to 1000 micromol/L) inhibited fibroblast migration directed by OPN or VSMC-conditioned medium in a dose-dependent manner. CONCLUSIONS: These observations suggest that estrogen indirectly attenuates integrin-beta(3)-dependent adventitial fibroblast migration after inhibition of OPN expression in VSMCs.

Estrogen inhibits vascular smooth muscle cell-dependent adventitial fibroblast migration in vitro.

BACKGROUND: Mounting experimental evidence suggests that estrogen treatment protects against neointima formation in response to vascular injury in vivo. Previous studies have suggested that this process includes the activation and migration of adventitial fibroblasts. The present in vitro study was designed to establish a mechanism whereby estrogen attenuates migration of adventitial fibroblasts. METHDS AND RESULTS: Primary cultures of vascular smooth muscle cells (VSMCs) and adventitial fibroblasts were derived from female Sprague-Dawley rats. Reverse transcriptase-polymerase chain reaction and Western blotting were used to determine that expression of the estrogen receptor (ER) was restricted to early-passage VSMCs. Migration of transduced (retrovirally mediated) fibroblasts was determined by counting the number of blue lacZ-expressing cells attached to Boyden-type chambers preconditioned under defined experimental conditions. Compared with growth medium alone, chambers treated with medium conditioned by VSMCs demonstrated a 2-fold increase in fibroblast migration, suggesting that VSMCs release soluble factor(s) competent to bind the Transwell membrane and promote fibroblast migration. In contrast, treatment of VSMCs with 17beta-estradiol (10(-9) to 10(-7) mol/L) before preconditioning of the chamber induced a dose-dependent inhibition of fibroblast migration. Cotreatment of VSMCs with 17beta-estradiol and the ER antagonist ICI-182780 (10(-7) mol/L) blocked the inhibitory effect of estrogen on fibroblast migration. CONCLUSIONS: These observations suggest a novel mechanism of hormonal vasoprotection by which estrogen directly modulates VSMC expression of factor(s) controlling migration of adventitial fibroblasts via an ER-dependent mechanism.

Genetic variation in angiotensin-converting enzyme does not prevent development of cardiac hypertrophy or upregulation of angiotensin II in response to aortocaval fistula.

BACKGROUND: Experimental and clinical evidence suggests that angiotensin II may be an important mediator of cardiac hypertrophy in response to hemodynamic stress. We investigated the effect of genetic variation in angiotensin-converting enzyme (ACE) on the development of cardiac hypertrophy and left ventricular (LV) dysfunction in response to volume overload. METHODS AND RESULTS: Male heterozygous ACE knockout (1/0) and wild-type (1/1) mice were studied 4 weeks after the creation of an aortocaval fistula (ACF). The LV weight/body weight ratio increased 74% in ACF versus sham-operated control mice but did not differ between genotypes. Echocardiographic circumferential stress versus rate-corrected velocity of circumferential shortening curves demonstrated depressed LV function in ACF versus sham-operated mice but no difference between genotypes. LV ACE activity was higher in 1/1 versus 1/0 mice and in ACF versus sham-operated mice, and it increased significantly more in the 1/1 versus the 1/0 mice after ACF (P<0.001 for effect of genotype, ACF/sham operation, and interaction term). LV angiotensin II was higher in ACF versus sham-operated mice but did not differ between genotypes, despite 3-fold higher LV ACE activity in ACF 1/1 versus ACF 1/0 mice. CONCLUSIONS: ACE underexpression does not prevent cardiac hypertrophy or LV dysfunction in response to volume overload. LV angiotensin II is unaffected by ACE genotype, both at baseline and after volume overload, indicating that the heart can maintain angiotensin II levels across a broad range of genetic ACE variation under both physiological and pathophysiological conditions.

Pathogenesis of ventricular hypertrophy.

Growth of the vertebrate heart during embryonic and fetal life is characterized by hyperplasia of myocardial cells. Shortly after birth, myocardial cells lose the capability of dividing, and further growth of the heart is due to myocardial cell hypertrophy and nonmuscle cell hyperplasia. This process results in a 30- to 40-fold increase in volume of individual myocardial cells during normal postnatal growth and maturation. The transition from hyperplastic to hypertrophic growth is related to formation of binucleated myocardial cells as a result of karyokinesis without cytokinesis. The molecular mechanism of this transition is uncertain. The response of the heart to increased metabolic demands or an increased work load depends on the age of the animal at the time when the stress is imposed. Increased myocardial work loads in fetal or early neonatal life lead to cardiac enlargement by causing an increased rate of hyperplasia of myocardial cells or continuation of hyperplasia beyond the normal period of hyperplastic growth. In contrast, imposition of increased loads on the hearts of older animals results in cardiac hypertrophy due to enlargement of myocardial cells and hyperplasia of nonmuscular components. In addition to cellular enlargement, structural remodeling of the myocardial cells and of the chambers of the heart occurs during the development of hypertrophy. Important stimuli of cardiac hypertrophy include increased systolic force or tension generated by the myocardial fibers (pressure overload), increased end-diastolic wall stress (volume overload) and neurohumoral factors such as increased circulating catecholamines or discharge of cardiac sympathetic nerves, or both, activation of the renin-angiotensin system and increased levels of thyroxine and growth hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral-contraceptive-induced hypertension after adrenalectomy and hypophysectomy.

The cause of oral-contraceptive-induced hypertension in certain susceptible subjects is obscure. We describe a woman who was receiving replacement doses of fludrocortisone acetate after adrenalectomy and hypophysectomy who developed high blood pressure while ingesting an estrogen-containing oral contraceptive. Renin substrate level was increased, but renin activity was suppressed and unresponsive to tilting. The patient developed a markedly exaggerated natriuresis when infused with saline. Both blood pressure and her responses to infused sodium and tilting normalized after discontinuance of the oral contraceptive medication. In this adrenalectomized patient, the estrogenic component of the pill acting synergistically with a fixed ("nonsuppressible") replacement dose of mineralocorticoid seems to have caused a volume-related hypertension.

A randomized trial of improved weight loss with a prepared meal plan in overweight and obese patients: impact on cardiovascular risk reduction.

OBJECTIVE: To assess the long-term effects of a prepackaged, nutritionally complete, prepared meal plan compared with a usual-care diet (UCD) on weight loss and cardiovascular risk factors in overweight and obese persons. DESIGN: In this randomized multicenter study, 302 persons with hypertension and dyslipidemia (n = 183) or with type 2 diabetes mellitus (n = 119) were randomized to the nutrient-fortified prepared meal plan (approximately 22% energy from fat, 58% from carbohydrate, and 20% from protein) or to a macronutrient-equivalent UCD. MAIN OUTCOME MEASURES: The primary outcome measure was weight change. Secondary measures were changes in blood pressure or plasma lipid, lipoprotein, glucose, or glycosylated hemoglobin levels; quality of life; nutrient intake; and dietary compliance. RESULTS: After 1 year, weight change in the hypertension/dyslipidemia group was -5.8+/-6.8 kg with the prepared meal plan vs -1.7+/-6.5 kg with the UCD plan (P<.001); for the type 2 diabetes mellitus group, the change was -3.0+/-5.4 kg with the prepared meal plan vs -1.0+/-3.8 kg with the UCD plan (P<.001) (data given as mean +/- SD). In both groups, both interventions improved blood pressure, total and low-density lipoprotein cholesterol levels, glycosylated hemoglobin level, and quality of life (P<.02); in the diabetic group, the glucose level was reduced (P<.001). Compared with those in the UCD group, participants with hypertension/dyslipidemia in the prepared meal plan group showed greater improvements in total (P<.01) and high-density lipoprotein (P<.03) cholesterol levels, systolic blood pressure (P<.03), and glucose level (P<.03); in participants with type 2 diabetes mellitus, there were greater improvements in glucose (P =.046) and glycosylated hemoglobin (P<.02) levels. The prepared meal plan group also showed greater improvements in quality of life (P<.05) and compliance (P<.001) than the UCD group. CONCLUSIONS: Long-term dietary interventions induced significant weight loss and improved cardiovascular risk in high-risk patients. The prepared meal plan simultaneously provided the simplicity and nutrient composition necessary to maintain long-term compliance and to reduce cardiovascular risk.

Nutritional management of cardiovascular risk factors. A randomized clinical trial.

BACKGROUND: Adherence to dietary recommendations for disease management is often hindered by the complexity of incorporating them into the daily diet. Nutrition and cardiovascular scientists and food technologists collaborated to develop a prepared meal plan that meets national dietary guidelines for cardiovascular risk reduction. OBJECTIVE: To assess the clinical effects of this plan, which incorporates all National Academy of Sciences National Research Council recommended dietary allowances for vitamins, minerals, and macronutrients, compared with a patient-selected American Heart Association Step I and Step II diet plan. METHODS: This multicenter, randomized, parallel-intervention trial was conducted at 10 medical centers in the United States and Canada and involved 560 men and women with hypertension, dyslipidemia, or diabetes. Following calculation of prescriptions to meet individual nutritional requirements based on the Harris-Benedict equation, participants were randomized to the Campbell's Center for Nutrition and Wellness (CCNW) plan, which is composed of prepackaged breakfast, lunch, and dinner meals provided to participants, or a nutritionist-guided American Heart Association Step I and Step II diet, in which participants self-selected foods to meet their nutrition prescription for 10 weeks. MAIN OUTCOME MEASURES: Blood pressure (BP); lipid, glucose, glycosylated hemoglobin (HbA1c), and insulin levels; body weight; dietary intake; and quality of life. RESULTS: Patients' BP, lipid levels, carbohydrate metabolism, weight, and quality of life (P < or = .001 for all findings except low-density lipoprotein-high-density lipoprotein ratio, P = .25) all improved on both nutrition plans. Mean differences (+/-SD) between baseline and treatment clinical values for the CCNW and the self-selected diet groups (between-group P values), respectively, were as follows: systolic BP, -6.4 +/- 9.2 mm Hg and -4.6 +/- 9.0 mm Hg (P = .02); diastolic BP, -4.2 +/- 5.7 mm Hg and -3.0 +/- 5.1 mm Hg (P = .006); cholesterol, -0.32 +/- 0.58 mmol/L and -0.27 +/- 0.56 mmol/L (-12.4 +/- 22.5 mg/dL and -10.4 +/- 21.9 mg/dL) (P = .30); glucose, -0.65 +/- 1.88 mmol/L and -0.75 +/- 2.03 mmol/L (-11.7 +/- 34.0 mg/dL and -13.5 +/- 36.6 mg/dL) (P = .10); and HbA1c, -0.4% +/- 0.8% and -0.3% +/- 0.7% (P = .66). Weight loss with the CCNW and self-selected plans, respectively, was as follows: men, -4.5 +/- 3.6 kg and -3.5 +/- 3.3 kg; and women, -4.8 +/- 3.0 kg and -2.8 +/- 2.8 kg. Quality of life was significantly improved for daily and work activities (P < .05) and nutritional health perceptions (P < .05) with the CCNW plan relative to the self-selected group. Overall nutrient intake and compliance were both significantly (P < .001) better with the CCNW plan. CONCLUSIONS: Nutritionally balanced meals that meet the recommendations of national health organizations improved multiple risk factors for patients with cardiovascular disease. The CCNW plan resulted in greater clinical benefits, nutritional completeness, and compliance than the self-selected diet. The CCNW is a comprehensive nutrition plan, convenient for both prescription and practice, and appears viable for effecting favorable dietary changes in patients at high risk for cardiovascular disease.

Gender and cardiovascular disease recent insights.

Cardiovascular disease is rare in premenopausal women compared with men in similar age groups. After menopause, however, the gender difference in cardiovascular disease diminishes, and there is an increased incidence of coronary risk and events in women. Although a number of factors contribute to the development of atherosclerotic disease in women, estrogen replacement therapy reduces cardiovascular risk. Potential molecular mechanisms for the antiatherosclerotic effects of estrogen are discussed here. It is proposed that lipid-lowering and antioxidant properties of estrogen synergize to elicit the observed vasoprotective effects. These processes are discussed in the context of balloon-injury models and hypercholesterolemia. (Trends Cardiovasc Med 1997;7:94-100). © 1997, Elsevier Science Inc.

Multicenter randomized trial of a comprehensive prepared meal program in type 2 diabetes.

OBJECTIVE: To evaluate the clinical effects of a comprehensive prepackaged meal plan, incorporating the overall dietary guidelines of the American Diabetes Association and other national health organizations, relative to those of a self-selected diet based on exchange lists in free-living individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 202 women and men (BMI < or = 42 kg/m2) whose diabetes was treated with diet alone or an oral hypoglycemic agent were enrolled at 10 medical centers. After a 4-week baseline period, participants were randomized to a nutrient-fortified prepared meal plan or a self-selected exchange-list diet for 10 weeks. On a caloric basis, both interventions were designed to provide 55-60% carbohydrate, 20-30% fat, and 15-20% protein. At intervals, 3-day food records were completed, and body weight, glycemic control, plasma lipids, and blood pressure were assessed. RESULTS: Food records showed that multiple nutritional improvements were achieved with both diet plans. There were significant overall reductions in body weight and BMI, fasting plasma glucose and serum insulin, fructosamine, HbA1c, total and LDL cholesterol, and blood pressure (P < 0.001 or better for all). In general, differences in major end points between the diet plans were not statistically significant. CONCLUSIONS: Glycemic control and cardiovascular risk factors improve in individuals with type 2 diabetes who consume diets in accordance with the American Diabetes Association guidelines. The prepared meal program was as clinically effective as the exchange-list diet. The prepared meal plan has the additional advantages of being easily prescribed and eliminating the complexities of meeting the multiple dietary recommendations for type 2 diabetes management.