Catheter-based renal denervation in the treatment of resistant hypertension.

Clinical trials have shown that catheter-based renal denervation (RD), i.e. interruption of afferent and efferent sympathetic nerves supplying the kidney, can reduce systolic blood pressure (BP) by approximately 30 mm Hg. This technology is currently being tested as a therapeutic option for patients with resistant hypertension, a condition in which BP remains elevated despite adherence to a rational medication regimen. This novel treatment approach was developed on the basis of a wealth of animal and human research demonstrating the importance of the sympathorenal axis in the pathogenesis of hypertension. Sympathetic efferent signals to the kidneys raise BP by stimulating sodium retention and renin release, and the kidneys influence central sympathetic drive via afferent nerves. But as is true with many therapeutic advances, RD has shown benefit in clinical studies long before the mechanisms are fully understood. Additional research is needed to understand the contribution of afferent sympathetic nerve interruption to BP reductions observed with RD; to examine the degree and significance of re-innervation following RD; to elucidate factors that may lead to a lack of response to RD in some patients; to determine whether the modulation of the sympathetic nervous system via RD can have beneficial effects independent of BP reduction; and to develop methods to measure the effectiveness of RD in real time.

Acute effects of monounsaturated fatty acids with and without omega-3 fatty acids on vascular reactivity in individuals with type 2 diabetes.

AIMS/HYPOTHESIS: We examined the acute postprandial effects of meals containing unsaturated fatty acids on flow-mediated dilation (FMD) of the brachial artery and triacylglycerols in individuals with type 2 diabetes. We hypothesised that consumption of omega-3 fatty acids would enhance vascular function. Saturated fat reduces FMD for several hours, but there is inconsistent evidence about whether foods containing unsaturated fats impair FMD acutely. Little is known about the acute effects of omega-3 fatty acids on vascular reactivity. METHODS: We measured FMD before and 4 h after 3 test meals (50 g fat, 2,615 kJ) in 18 healthy adults with type 2 diabetes. The monounsaturated fatty acids (MUFA) meal contained 50 g fat from high oleic safflower and canola oils. Two additional meals were prepared by replacing 7% to 8% of MUFA with docosahexaenoic acid and eicosapentaenoic acid from sardine oil or alpha-linolenic acid from canola oil. RESULTS: In the sample as a whole, FMD was increased 17% at 4 h vs. the fasting baseline. After the MUFA meal, subjects with the largest increases in triacylglycerols had the largest FMD decreases. The opposite pattern was observed after meals containing docosahexaenoic acid and eicosapentaenoic acid or alpha-linolenic acid. In subjects with high fasting triacylglycerols, meals containing 3 to 5 g of omega-3 fatty acids increased FMD by 50% to 80% and MUFA alone had no significant effects on FMD. CONCLUSIONS/INTERPRETATION: Endothelium-dependent vasodilation was not impaired 4 h after meals containing predominantly unsaturated fatty acids. The fatty acid composition of the meal and the metabolic status of the individual determine the vascular effects of a high-fat meal.

Biological correlates of day-to-day variation in flow-mediated dilation in individuals with Type 2 diabetes: a study of test-retest reliability.

AIMS/HYPOTHESIS: Dysfunction of the vascular endothelium is commonly observed in Type 2 diabetes, and endothelial function may be an important outcome for clinical trials in diabetic samples. However, the most commonly used non-invasive test of endothelial function (flow-mediated dilation [FMD]) is technically challenging to perform, and no previous studies have carefully examined the reproducibility of FMD measurements in individuals with Type 2 diabetes. In this study, we tested the hypothesis that larger day-to-day changes in insulin and glucose are associated with larger fluctuations in FMD. METHODS: Ultrasound was used to measure the FMD (% change from baseline diameter) of the brachial artery in 18 healthy adults with Type 2 diabetes on three separate occasions, in the absence of changes to diet, activity level or medications. The CV and mean deviations between pairs of FMD scores in the same individual were used as the primary outcome variables. RESULTS: The CV for FMD (29.7%) was higher than the level traditionally accepted for biochemical assays. However, this CV estimate is within the low range of published values for FMD in healthy individuals. FMD scores were not significantly correlated with glucose or insulin levels. However, subjects with the largest variability in FMD also showed the largest fluctuations in glucose ( r=0.52), insulin ( r=0.47) and heart rate ( r=0.48) ( p

Blunted nighttime blood pressure dipping in postmenopausal women.

Blunting of the normal drop in blood pressure (BP) from day to night is emerging as a strong prognostic indicator of cardiovascular morbidity and mortality. This study evaluated the effects of natural menopause on BP dipping in African American and white women. A total of 112 women (62 premenopausal and 50 postmenopausal) took part in the study. Pre- and postmenopausal groups were comparable in terms of clinic BP, body mass index, and ethnic composition. Ambulatory BP was recorded over 24 h during a typical workday, with measurements programmed to be taken every 15 min during waking hours and every 30-minutes during sleeping hours. Nocturnal BP dipping was defined as the difference between waking and sleep BP. Waking BP did not differ by menopausal status. However, nocturnal systolic BP (SBP) and diastolic BP (DBP) dipping were attenuated in postmenopausal women, with both SBP (P < .05) and DBP (P < .05) higher during nighttime sleep in postmenopausal than in premenopausal women. Ethnicity was also related to BP dipping, with African American women tending to show blunted SBP dipping (P = .055) compared with white women; BP dipping was most blunted in postmenopausal African American women. These observations suggest that blunted nighttime BP dipping may contribute to increased cardiovascular disease risk in postmenopausal women.

Religious coping, ethnicity, and ambulatory blood pressure.

OBJECTIVE: To investigate the relationship between religious coping, ethnicity, and ambulatory blood pressure (ABP) measured during daily life. METHODS: A 24-hour ABP was obtained from 155 men and women (78 African American and 77 white) on a typical workday. ABP was averaged over awake and sleep periods, and clinic BP was also assessed. Psychosocial measures of coping style, negative affect, social support, stress, and health behaviors were completed before ABP measurement. RESULTS: Multiple regression analyses, controlling for demographic variables, revealed a significant religious coping by ethnicity interaction for ABP (p < .01) and clinic BP (p < .05). Religious coping was not related to BP among whites. Among African Americans, however, higher levels of religious coping were associated with lower awake (p < .05) and sleep (p < .01) ABP. Social support satisfaction also was related to lower awake ABP among African Americans, but it did not mediate the relationship between religious coping and ABP. CONCLUSIONS: The results of this study extend previous findings by showing that, among African Americans, religious coping and BP are related during daily activities as well as in the clinic. Lower 24-hour BP load may be a pathway through which religiosity and cardiovascular health are related.

Transdermal estrogen reduces vascular resistance and serum cholesterol in postmenopausal women.

OBJECTIVE: Our aim was to compare the effects of transdermal versus oral estrogens on vascular resistance index, mean arterial pressure, serum lipid concentrations, norepinephrine, and left ventricular structure. STUDY DESIGN: Ten postmenopausal women received transdermal estradiol (0.05 mg/d) plus cyclic oral progesterone for 6 months. Responses were compared with those of 23 women receiving oral conjugated estrogens (0.625 mg/d) plus cyclic progesterone and with those of 9 subjects receiving placebo in a concurrent randomized trial. We assessed the vascular resistance index and the mean arterial pressure at rest and during behavioral stressors. RESULTS: Oral and transdermal estrogen significantly decreased the vascular resistance index, mean arterial pressure, norepinephrine, and total and low-density lipoprotein cholesterol to a similar extent. Changes in the vascular resistance index and mean arterial pressure were equally evident at rest and during stress. Although both treatments reduced left ventricular mass (-4% to -6%) and relative wall thickness (-3% to -5%), these changes were not statistically significant. CONCLUSIONS: Equivalent reductions in vascular resistance index, norepinephrine, mean arterial pressure, and cholesterol were observed with transdermal and oral estrogens. Future studies comparing novel hormone regimens with oral hormone replacement therapy should include multiple risk markers to allow better assessment of their potential impact on coronary artery health.

Hormone replacement improves hemodynamic profile and left ventricular geometry in hypertensive and normotensive postmenopausal women.

BACKGROUND: Postmenopausal estrogen replacement, with or without progestins, has been related to lower cardiovascular risks. OBJECTIVE: We investigated whether the actions of estrogen on vascular resistance contribute to this cardioprotective effect. DESIGN AND METHODS: In a 6-month double-blind study, pre- and post-treatment blood pressure, cardiac index, total vascular resistance index and plasma catecholamine responses during baseline and mental stressors were compared in 69 women (including 19 with mild hypertension but no history of heart disease). Women were randomized to receive either conjugated estrogens alone, estrogens plus medroxyprogesterone, or placebo. RESULTS: Both groups on active hormone replacement showed similar decreases in vascular resistance and modest blood pressure reductions, which differed from the unchanged responses of those on placebo (P< 0.05) after 3 and 6 months of treatment. Hypertensive women showed greater reductions in vascular resistance than normotensives (P< 0.05) and their blood pressure reductions tended to be larger. Women receiving hormone replacement showed increased stroke volume and cardiac index at 6 months, particularly among hypertensives and those receiving medroxyprogesterone (P < 0.05). Hormone replacement was also related to decreases in plasma norepinephrine. Finally, in 33 women receiving hormone replacement, significant 5 and 3% decreases in echocardiographic measures of left ventricular mass index and relative wall thickness were evident at 6 months (P < 0.05), while 20 placebo-treated women showed no reliable echocardiographic improvements (P= NS). CONCLUSIONS: These findings suggest that estrogen-mediated reductions in hemodynamic load on the heart may contribute to the reduced risk of cardiovascular events in relatively healthy postmenopausal women who use hormone replacement.

Postmenopausal smokers show reduced hemodynamic benefit from oral hormone replacement.

With use of a randomized, placebo-controlled trial, 62 healthy, postmenopausal smokers and nonsmokers were tested for resting and stress-induced hemodynamic variables before and after 6 months of treatment with either oral hormone replacement therapy or placebo. Smokers had significantly less reduction in both resting and stress-induced vascular resistance and blood pressure after treatment with oral hormone replacement therapy than nonsmokers.

Frequency and prognostic significance of pericardial effusion in primary pulmonary hypertension. PPH Study Group. Primary pulmonary hypertension.

Pericardial effusion was noted in 43 of 79 patients (54%) with severe primary pulmonary hypertension. Larger effusion was associated with hemodynamic and echocardiographic evidence of right heart failure, impaired exercise tolerance, and a poor 1-year prognosis.

High stress responsivity predicts later blood pressure only in combination with positive family history and high life stress.

High cardiovascular responsivity to stressors has not consistently improved prediction of later blood pressure increases beyond the predictive effects of baseline pressure. Animal models suggest that genetic susceptibility to hypertension and frequent stress exposure are important modulating factors in stress-related hypertension. Thus in 103 men originally tested at age 18 to 22 years and reassessed 10 years later, interactive effects of genetic susceptibility (defined as 1 or more hypertensive parents) with high stress responsivity (defined as top 25% on the basis of blood pressure and cardiac responses during both reaction time and cold pressor tasks) were examined in relation to follow-up systolic and diastolic levels and to change in blood pressure status from normal (diastolic<80 mm Hg) to marginally elevated (diastolic 85 to 95 mm Hg). Men with the combination of high stress response and hypertensive parents demonstrated higher systolic (P<0.05) and diastolic levels (P<0.05) at follow-up, and they showed a 7-fold increase (7.5, 95% confidence intervals 2.3, 24.3; P<0.001) in relative risk of change in blood pressure status versus men with no family history and a 3-fold increase (3.8, confidence intervals 1.5, 9.6; P<0.004) versus less stress-responsive men who also had hypertensive parents. In 65 men who also provided ratings of daily stress, family historyxstress responsivityxdaily stress interactions were significant in predicting follow-up systolic and diastolic levels (P<0.006 and 0.03, respectively), with highest pressure levels seen when high life stress was reported by high stress responders and/or men with hypertensive parents. In conclusion, results suggest that stress responsivity as a long-term predictor is modulated by both genetic and environmental factors.

Endothelial function and hemodynamic responses during mental stress.

OBJECTIVE: The hemodynamic basis of blood pressure responses during psychological stress shows striking individual differences that share an interesting similarity with risk for cardiovascular disease. Factors accounting for these individual differences are poorly understood. The present study examined the relationship of vascular endothelial function to stress-induced hemodynamic responses. METHODS: Subjects were 40 healthy men and women, aged 25 to 44 years. Hemodynamic responses were assessed during exposure to a battery of four diverse laboratory stressors. Endothelium-dependent arterial dilation (EDAD) was measured by ultrasound imaging of the brachial artery in response to reactive hyperemia. RESULTS: High EDAD response was associated with lower resting systolic (p < .01) and diastolic blood pressure (p < .05). EDAD response was unrelated to blood pressure responses during stress. However, systemic vascular resistance responses during laboratory stress were significantly greater (p < .02) for individuals with low EDAD responses. CONCLUSIONS: Exaggerated systemic vascular resistance responses during stress may reflect endothelial dysfunction. This association may help explain the growing evidence of a relationship between stress hemodynamics and cardiovascular disease risk. The nature of this association is discussed in terms of a possible interplay between the sympathetic nervous system and the endothelium in regulation of vascular tone.

Potassium supplementation induces beneficial cardiovascular changes during rest and stress in salt sensitive individuals.

The typical American diet includes high salt and low potassium, a pattern linked to elevated blood pressure (BP) in cross-cultural studies. This study compared resting and stress cardiovascular responses on a high salt, low potassium diet to those observed during 2 interventions: salt restriction and potassium supplementation. Forty-seven percent of the primarily normotensive sample (n = 67 adults) were salt sensitive, showing a decrease in mean arterial pressure > or = 5 mmHg during low salt and equivalent reductions during high potassium. The equivalent benefits of the interventions were maintained, but not enhanced, during exposure to behavioral stress (i.e., no effect on reactivity). Salt resistants (SRs) exhibited no change in resting or stress BP across the diets. High salt increased cardiac index in both groups, whereas vascular tone was decreased only in the SR group. High potassium produced hemodynamic benefits similar to low salt, even with continued high salt intake.

The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers.

Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady-state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open-label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that fluvastatin did not significantly change the steady-state AUC0-24 or half-life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.

Hostility and adrenergic receptor responsiveness: evidence of reduced beta-receptor responsiveness in high hostile men.

We examined the relation of Cook and Medley Hostility (Ho) scores to alpha- and beta-adrenergic receptor responsiveness to pharmacological agonists in 22 normotensive and 14 hypertensives (aged 18-34) white males, matched for age and body mass. alpha-Adrenergic receptor responsiveness was measured by the phenylephrine dose required to increase mean blood pressure by 25 mmHg (PD25). beta-Adrenergic responsiveness was measured by the isoproterenol dose needed to increase heart rate by 25 bpm (CD25), and to lower systemic vascular resistance by 40% (VD40). Relative to men with low Ho scores (< or = 21), men with high Ho scores (> or = 21) showed significantly reduced vascular beta 2-adrenergic receptor responsiveness (VD40). Moreover, the decreased vascular responsiveness was more pronounced in borderline hypertensive men with high Ho scores. Ho scores were also marginally significant in predicting cardiac beta 1- and beta 2-adrenergic receptor responsiveness, such that men with high Ho scores showed decreased responsiveness as indexed by a larger CD25. Vascular alpha 1-adrenergic responsiveness was not associated with hostility. These observations suggest that hostility, alone or in conjunction with BP status, is associated with reduced cardiovascular beta-adrenergic receptor responsiveness.

Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group.

BACKGROUND: Right heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationship of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy. METHODS AND RESULTS: The 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n = 41) or conventional therapy alone (n = 40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricular dilatation and dysfunction, abnormal septal curvature, and significant tricuspid regurgitation with a high regurgitant velocity. Pericardial effusions were common. More pronounced abnormalities in right heart structure and function were associated with higher pulmonary arterial and mean right atrial pressures, lower cardiac index, and impaired exercise capacity but had no predictable relationship to quality-of-life indicators. The 12-week infusion of prostacyclin had beneficial effects on right ventricular size, curvature of the interventricular septum, and maximal tricuspid regurgitant jet velocity. CONCLUSIONS: The echocardiographic manifestations of severe primary pulmonary hypertension reflect abnormalities in hemodynamics and exercise capacity. Prostacyclin has beneficial effects on right heart structure and function that may contribute to the clinical improvement and prolonged survival observed with this drug.

Ten-year stability of cardiovascular responses to laboratory stressors.

In this study, we examined test-retest stability of cardiovascular stress responses over a decade of the life span. Participants were 55 male college undergraduates, 19 years of age at initial testing, and 29 years of age at follow-up testing. Stressors were a foot cold pressor and an aversive reaction time task. Cardiovascular measures included systolic and diastolic blood pressure, heart rate, and preejection period. For cold pressor, the magnitude and pattern of cardiovascular responses remained unchanged at the 10-year follow-up. For the reaction time task, the characteristic cardiovascular response patterns was preserved but with significant attenuation of magnitude. The present findings are consistent with previous observations of temporal stability but over a substantially longer test-retest interval. The long-term stability of stress responses is discussed in the context of stress test methodology, behavioral response demands, and maturation of the physiological systems involved in cardiovascular response expression.

Atrial anastomotic thrombus causes neurologic deficits in a lung transplant recipient.

Pulmonary thrombus formation in the region of atrial anastomosis following lung transplantation has been reported by several authors. Such patients typically present immediately after surgery with significant hemodynamic compromise causing pulmonary edema and hypoxemia. We describe a patient who presented with bilateral neurologic deficits 4 and 6 weeks after lung transplantation. Despite a normal transthoracic echocardiogram, transesophageal echocardiography (TEE) detected a large left atrial thrombus adherent to the atrial anastomosis. This thrombus was treated with intravenous heparin and subsequently warfarin. After 3 weeks, a repeat TEE demonstrated complete resolution of the lesion. This case demonstrates that postoperative left atrial and pulmonary venous thrombi may provide the basis for serious patient morbidity without hemodynamic or radiographic clues to their presence, that TEE is superior to transthoracic echocardiography for detecting left atrial thrombi, and that such lesions can respond to medical management alone.

Ethnic differences in forearm vasodilator capacity.

Previous studies have demonstrated significant ethnic differences in left ventricular structure in both normotensive and hypertensive subjects. To determine if these differences in ventricular geometry are associated with differences in vascular structure, we measured the minimum forearm vascular resistance in 30 healthy young African-American adults and in 30 whites matched for age, gender, and blood pressure. Average daytime blood pressure was determined by ambulatory monitoring during a typical work day. Minimum forearm vascular resistance was measured by plethysmography after 10 minutes of forearm ischemia. Indexed left ventricular mass and relative wall thickness were measured by 2-dimensional-directed M-mode echocardiography. The mean (+/-SD) ambulatory pressure was 126 +/- 11/79 +/- 8 mm Hg in African-Americans and 126 +/- 11/79 +/- 7 mm Hg in whites. The 2 groups were similar in body mass index and in family history of hypertension. African-Americans had a higher minimum forearm vascular resistance than did whites (2.39 +/- 0.75 vs 2.03 +/- 0.55 mm Hg, p <0.05). There was a trend toward a greater left ventricular relative wall thickness in African-Americans (0.38 +/- 0.07 vs 0.35 +/- 0.06, p=0.09). These results suggest that early vascular remodeling is present in African-Americans who do not have established hypertension, and that this ethnic difference in vascular structure is associated with a difference in ventricular geometry.

Acute aerobic exercise reduces ambulatory blood pressure in borderline hypertensive men and women.

Ambulatory blood pressure (BP) monitoring was undertaken on two days in 31 men and women (11 with elevated resting and ambulatory BP and 20 who were normotensive), once following each of these treatment conditions: 20 min of moderate aerobic bicycle ergometry, and an equivalent control rest period. The two monitoring days were conducted within a 72 h period with the order of treatments counterbalanced across subjects. Mean BP and heart rate (HR) levels were calculated for each individual on an hourly basis and for work, home, and sleep periods, In the elevated BP group, the exercise day compared to the control day was associated with lower BP at work. Hour-by-hour analyses confirmed that the BP-lowering effect of exercise was significant for 5 h and diminished in magnitude between hours 6 and 9. These effects were not attributable to any marked differences in mood, total daily stress, posture, or activities between test days. Exercise was not associated with any appreciable differences in sleep BP or in the 24-h HR profile No differences in BP or HR as a function of exercise were seen in the normotensive group; however, the exercise-induced reduction in mean arterial BP (MAP) for hours 2 through 5 was significantly positively correlated with control day MAP levels at work in the total sample. Thus, moderate aerobic exercise, when engaged in prior to the stresses of daily living, seems to confer a protective reduction in ambulatory BP, particularly in individuals with elevated BP.