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Resistant hypertension (RH) is defined as uncontrolled blood pressure despite treatment with three or more antihypertensive medications, including, if tolerated, a diuretic in adequate doses. It has been widely known that race is associated with blood pressure control. However, intense debate persists as to whether this is solely explained by unadjusted socioeconomical variables or genetic variation. In this scenario, the main aim was to evaluate the association between genetic ancestry and resistant hypertension in a large sample from a multicenter trial of stage II hypertension, the ReHOT study. Samples from 1,358 patients were analyzed, of which 167 were defined as resistant hypertensive. Genetic ancestry was defined using a panel of 192 polymorphic markers. The genetic ancestry was similar in resistant (52.0% European, 36.7% African and 11.3% Amerindian) and nonresistant hypertensive patients (54.0% European, 34.4% African and 11.6% Amerindian) (p > 0.05). However, we observed a statistically suggestive association of African ancestry with resistant hypertension in brown patient group. In conclusion, increased African genetic ancestry was not associated with RH in Brazilian patients from a prospective randomized hypertension clinical trial.

Formal training to prepare physicians for careers as investigators in Brazil is still incipient (). However, the learning environment is changing dramatically. The competitive arena is transforming the traditional learning environment into a collaborative and flexible learning environment (). Clinical researchers and practitioners ideally share a goal of increasing the interactions between research and routine practice in an evidence-based medicine (EBM) environment. EBM frameworks promote clinically relevant research and consequently shape the scientific nature of the trainee’s professional development. [...]

Untreated obstructive sleep apnea (OSA) is common in patients with hypertension and may impair blood pressure (BP) and target-organ damage responses to antihypertensive therapy. In this study, we recruited hypertensive patients who underwent treatment with a 30-day regimen of hydrochlorothiazide 25 mg plus enalapril (20 mg BID) or losartan (50 mg BID) and were assessed with a baseline clinical evaluation, polysomnography, 24-hour ambulatory BP monitoring, and carotid-femoral pulse wave velocity. All the examinations except for polysomnography were repeated at 6 and 18 months of follow-up. We studied 94 hypertensive patients (mean age, 55±9 years). The frequency of OSA was 55%. Compared with baseline, we did not observe significant differences between groups in 24-hour BP, daytime systolic and diastolic BPs, or night-time systolic BP at 6 and 18 months. The BP control rate at 24 hours (P =0.027). There were no differences in the number and class of antihypertensive medications prescribed during follow-up. In terms of arterial stiffness, patients with OSA had higher pulse wave velocity than did patients without OSA at baseline (10.3±1.9 versus 9.2±1.7 m/s; P =0.024), but both groups had similar decreases in pulse wave velocity during follow-up. In conclusion, with combined antihypertensive treatment aimed at controlling BP, hypertensive patients with OSA had similar 24-hour BP and arterial stiffness to those without OSA.

The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5–50 mg QD) or clonidine (0.1–0.3 mg BID). The primary end point was BP control during office (P =1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01643434.

The prevalence of resistant hypertension (ReHy) is not well established. Furthermore, diuretics, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and calcium channel blockers are largely used as the first 3-drug combinations for treating ReHy. However, the fourth drug to be added to the triple regimen is still controversial and guided by empirical choices. We sought (1) to determine the prevalence of ReHy in patients with stage II hypertension; (2) to compare the effects of spironolactone vs clonidine, when added to the triple regimen; and (3) to evaluate the role of measuring sympathetic and renin-angiotensin-aldosterone activities in predicting blood pressure response to spironolactone or clonidine. The Resistant Hypertension Optimal Treatment (ReHOT) study (ClinicalTrials.gov NCT01643434) is a prospective, multicenter, randomized trial comprising 26 sites in Brazil. In step 1, 2000 patients will be treated according to hypertension guidelines for 12 weeks, to detect the prevalence of ReHy. Medical therapy adherence will be checked by pill count monitoring. In step 2, patients with confirmed ReHy will be randomized to an open label 3-month treatment with spironolactone (titrating dose, 12.5-50 mg once daily) or clonidine (titrating dose, 0.1-0.3 mg twice daily). The primary endpoint is the effective control of blood pressure after a 12-week randomized period of treatment. The ReHOT study will disseminate results about the prevalence of ReHy in stage II hypertension and the comparison of spironolactone vs clonidine for blood pressure control in patients with ReHy under 3-drug standard regimen.

Introduction: Recurrent hypoxia (HPX), a hallmark of the obstructive sleep apnea (OSA), impairs autonomic balance, and increases arterial blood pressure (BP). Oxidative stress is one of the mechanisms involved in these alterations. The cumulative effect of acute intermittent HPX and the chronicity may determine whether the response crosses the threshold from having protective value to pathology. However, the impact of acute intermittent HPX–reoxygenation on markers of oxidative stress in healthy individuals remains to be fully understood. Objective: To analyze the effects of the acute intermittent HPX on the generation of neutrophil-derived superoxide, sympathovagal balance, and vascular function in healthy subjects. Methods: We applied six cycles of intermittent HPX (10% O2 and 90% N2) for 5 min followed by 2 min of room-air in 15 healthy volunteers (34 ± 2 years; 22.3 ± 0.46 kg/m2), without OSA (polysomnography), during wakefulness. During the experimental protocol, we recorded O2 saturation, end-tidal CO2, heart rate (HR), systolic, and diastolic BP, cardiac output (CO) and peripheral resistance (PR). Cardiac sympathovagal balance was determined by HR variability analysis (low frequency and high frequency bands, LF/HF). Superoxide generation in polymorphonuclear neutrophil cells were established using relative luminescence units (PMNs RLU) at baseline (pre-HPX) and immediately after hypoxia induction (post-HPX6). Results: The studied subjects had normal levels of BP, plasma glucose, lipid profile, and inflammatory marker (C-reactive protein). Acute intermittent HPX increased HR, systolic BP, CO, and decreased PR. Additionally, acute intermittent HPX increased PMNs RLU, measured post-HPX6 (470 ± 50 vs. 741 ± 135, P < 0.05). We found a similar increase in LF/HF post-HPX6 (0.91 ± 0.11 vs. 2.85 ± 0.40, P < 0.05). PR was diminished from pre-HPX to post-HPX6 (1.0 ± 0.03 vs. 0.85 ± 0.06, P < 0.05). Further analysis showed significant association between O2 saturation and PMNs RLU (R = −0.62, P = 0.02), and with LF/HF (R = −0.79, P = 0.02) post-HPX6. In addition, an association was found between PMNs RLU and PR post-HPX6 (R = 0.58, P = 0.04). Conclusion: Acute exposure to intermittent HPX not only increased superoxide generation in neutrophils, but also impaired cardiac sympathovagal balance in healthy subjects. These data reinforce the role of intermittent HPX in superoxide generation on neutrophils, which may lead to an impairment in peripheral vascular resistance.

BACKGROUND Spontaneous arousals are relatively common during sleep, and induce hemodynamic responses. We sought to investigate the frequency and magnitude of blood pressure (BP) increases triggered by spontaneous arousals in patients with primary hypertension. METHODS We conducted a study in which we divided 18 nonobese, sedentary adults without sleep-disordered breathing into two groups, consisting of: (i) hypertensive (HT, n = 8) patients; and (ii) normotensive (NT, n = 10) controls. The groups were matched for age and body mass index. All subjects underwent full polysomnography with simultaneous monitoring of heart rate (HR) and beat-by-beat BP. Each subject's BP and HR were analyzed immediately before BP peaks triggered by spontaneous arousals during stage 2 of nonrapid eye movement sleep. RESULTS The total sleep time, sleep efficiency, and sleep structure in the two study groups were similar. In contrast, the number of arousals was significantly higher in the HT than in the NT group, at 25 ± 5 vs. 12 ± 3 events/h, respectively (P < 0.05). The HR of the HT and NT groups was similar before arousal (65 ± 3 bpm vs. 67 ± 3 bpm, respectively, P < 0.01) and increased significantly and similarly in the two groups upon arousal (to 79 ± 6 bpm vs. 74 ± 4 bpm, respectively, P < 0.01). Systolic and diastolic BPs were significantly higher throughout sleep in the HT than in the NT group. During spontaneous arousals, BP increased in both groups (P < 0.05). However, the magnitude of the increase in systolic BP was significantly greater in the HT than in the NT group (22 ± 3 mm Hg vs. 15 ± 3 mm Hg, P < 0.05). CONCLUSIONS Patients with hypertension who do not have sleep-disordered breathing have an increased cardiovascular burden during sleep, which may be due to the greater number of arousals and exacerbated systolic BP response that they experience during sleep. These novel findings may have cardiovascular implications in patients with hypertension.

Whether sex influences the association of obstructive sleep apnea (OSA) with markers of cardiovascular risk in patients with hypertension is unknown. In this study, 95 hypertensive participants underwent carotid-femoral pulse wave velocity, 24-hour ambulatory blood pressure monitoring, echocardiogram, and polysomnography after a 30-day standardized treatment with hydrochlorothiazide plus enalapril or losartan. OSA was present in 52 patients. Compared with non-OSA patients, pulse wave velocity values were higher in the OSA group (men: 11.1±2.2 vs 12.7±2.4 m/s, P=.04; women: 11.8±2.4 vs 13.2±2.2 m/s, P=.03). The proportion of diastolic dysfunction was significant in men and women with OSA. Compared with non-OSA patients, nondipping systolic blood pressure in OSA was higher in men (14.3% vs 46.4%) and in women (41.4% vs 65.2%). OSA was independently associated with pulse wave velocity (β=1.050; P=.025) and nondipping systolic blood pressure (odds ratio, 3.03; 95% confidence interval, 1.08-8.55; P=.035) in the regression analysis. In conclusion, OSA is independently associated with arterial stiffness and nondipping blood pressure in patients with hypertension regardless of sex.

Background: The prevalence, predictors and the best anti-hypertensive regimen for resistant hypertension (RH) are not well established especially in Countries with multiethnic profile. Our main aim was to compare spironolactone versus clonidine as a fourth drug therapy for patients with RH. Methods: This is a multicentric, randomized controlled trial comprising 26 sites in Brazil that recruited outpatients from a highly admixed population with hypertension stage 2 (≥160/100mmHg) at study entry. Medical therapy adherence was checked by pill counting. Patients with confirmed RH (no office and 24hs ambulatory blood pressure monitoring - ABPM - control despite treatment with 3 drugs including a diuretic for 12 weeks) were randomized to additional 12 weeks treatment with spironolactone (12.5-50mg once daily) or clonidine (0.1-0.3mg twice daily). The primary endpoint was blood pressure (BP) control from both office ( Results: A total of 1597 patients were included in the analysis. We found that 14.9% (238 patients) fulfilled the RH criteria. Predictors of true RH include male gender (OR 1.43; CI 1.02-2.00), previous stroke (OR 2.81; CI 1.51-5.06), diabetes (OR 2.09; CI 1.48-2.94) and BP ≥180x110mmHg at study entry (OR 2.53; CI 1.88-3.43). Compared to patients randomized to spironolactone (n=119), those patients randomized to clonidine (n=119) presented similar rate of the primary endpoint (19.8 vs. 24%, respectively; p=0.59). Similarly, no differences were observed between groups in the blood pressure reduction analyzed either by office as well as by 24-h ABPM. No differences in the pill counting monitoring were observed in the groups. Conclusions: Appropriate treatment for stage 2 hypertension under the national universal health care conditions provided blood pressure control in 85% from a highly admixed population. Spironolactone or clonidine displayed comparable BP control as a fourth drug in patients with RH. Funding: Ministry of Health/H. Samaritano, National Research Council, Sao Paulo Research Foundation and Zerbini Foundation.

FUNDAMENTO: Infusão de intralipid e heparina resulta em aumento da pressão arterial e também em anormalidades autonômicas em indivíduos normais e hipertensos. OBJETIVO: Avaliar a sensibilidade a insulina e o impacto da infusão de intralipid e de heparina (ILH) sobre a resposta hemodinâmica, metabólica e autonômica em pacientes com a forma indeterminada da doença de Chagas. MÉTODOS: Doze pacientes com a forma indeterminada da doença de Chagas e 12 voluntários saudáveis foram avaliados. RESULTADOS: A pressão arterial basal e a frequência cardíaca foram semelhantes nos dois grupos. Os níveis plasmáticos de noradrenalina encontravam-se ligeiramente aumentados no grupo de pacientes chagásicos. Após o Teste de Tolerância a Insulina (TTI), houve um declínio significativo na glicose dos dois grupos. A Infusão de ILH resultou em aumento da pressão arterial em ambos os grupos, mas não houve nenhuma mudança significativa na noradrenalina plasmática. O componente de Baixa Frequência (BF) mostrou-se semelhante e aumentou de forma semelhante em ambos os grupos. O componente de Alta Frequência (AF) apresentou-se menor no grupo chagásico. CONCLUSÃO: Pacientes com forma indeterminada da doença de Chagas apresentaram aumento da atividade simpática no momento basal e uma resposta inadequada à insulina. Eles também tiveram um menor componente de alta frequência e sensibilidade barorreflexa prejudicada no momento basal e durante a infusão de intralipid e heparina.

Introduction Among patients with congestive heart failure (CHF) both obstructive and central sleep apnea (SA) are associated with increased sympathetic activity. However, the day–night pattern of cardiac autonomic nervous system modulation in CHF patients with and without sleep apnea is unknown. Material and methods Twenty-five CHF patients underwent polysomnography with simultaneous beat-to-beat blood pressure (Portapres), respiration and electrocardiogram monitoring. Patients were divided according to the presence (SA, n =17) and absence of SA (NoSA, n =8). Power spectral analyses of heart rate variability (HRV) and spontaneous baroreflex sensitivity (BRS) were determined in periods with stable breathing while awake at 6 am, 10 am, 10 pm, as well as during stage 2 sleep. In addition, muscle sympathetic nerve activity (MSNA) was evaluated at 10 am. Results RR variance, low-frequency (LF), high-frequency (HF) powers of HRV, and BRS were significantly lower in patients with SA compared with NoSA in all periods. HF power, a marker of vagal activity, increased during sleep in patients with NoSA but in contrast did not change across the 24-hour period in patients with SA. MSNA was significantly higher in patients with SA compared with NoSA. RR variance, LF and HF powers correlated inversely with simultaneous MSNA ( r =−0.64, −0.61, and −0.61 respectively; P Conclusions Patients with CHF and SA present a reduced and blunted cardiac autonomic modulation across the 24-hour period. These findings may help to explain the increased cardiovascular risk in patients with CHF and SA.

Academic Health Centers (AHC) were created in North America in the 20th century, at a time when hospitals worldwide were utilized mostly as charitable housing for aged and chronically ill people. At that time, hospitals were not engaged in treatment and were not involved in medical education or research; moreover, there was no organized teaching or training of future doctors during the undergraduate period (). The turning point in the transformation of these old health systems into modern medicine, including [...]

Arterial stiffness is an independent marker of cardiovascular events. Pulse wave velocity (PWV) is a validated method to detect arterial stiffness that can be influenced by several factors including age and blood pressure. However, it is not clear whether PWV could be influenced by circadian variations. In the present study, the authors measured blood pressure and carotid‐femoral PWV measurements in 15 young healthy volunteers in 4 distinct periods: 8 am, noon, 4 pm, and 8 pm. No significant variations of systolic (P=.92), mean (P=.77), and diastolic (P=.66) blood pressure among 8 am (113±15, 84±8, 69±6 mm Hg), noon (114±13, 83±8, 68±6 mm Hg), 4 pm (114±13, 85±8, 70±7 mm Hg), and 8 pm (113±7, 83±10, 68±7 mm Hg), respectively, were observed. Similarly, carotid‐femoral PWV did not change among the periods (8 am: 7.6±1.4 m/s, noon: 7.4±1.1 m/s, 4 pm: 7.6±1.0 m/s, 8 pm, 7.6±1.3 m/s; P=.85). Considering all measurements, mean blood pressure significantly correlated with PWV (r=.31; P=.016). In young healthy volunteers, there is no significant circadian variation of carotid‐femoral PWV. These findings support the concept that it does not appear mandatory to perform PWV measurements at exactly the same period of the day. J Clin Hypertens (Greenwich). 2011;13:19–22. ©2010 Wiley Periodicals, Inc.

Background. The incidence of unexplained sudden death (SD) and the factors involved in its occurrence in patients with chronic kidney disease are not well known.Methods. We investigated the incidence and the role of co-morbidities in unexplained SD in 1139 haemodialysis patients on the renal transplant waiting list.Results. Forty-four patients died from SD of undetermined causes (20% of all deaths; 3.9 deaths/1000 patients per year), while 178 died from other causes and 917 survived. SD patients were older and likely to have diabetes, hypertension, past/present cardiovascular disease, higher left ventricular mass index, and lower ejection fraction. Multivariate analysis showed that cardiovascular disease of any type was the only independent predictor of SD (P = 0.0001, HR = 2.13, 95% CI 1.46–3.22). Alterations closely associated with ischaemic heart disease like angina, previous myocardial infarction and altered myocardial scan were not independent predictors of SD. The incidence of unexplained SD in these haemodialysis patients is high and probably a consequence of pre-existing cardiovascular disease.Conclusions. Factors influencing SD in dialysis patients are not substantially different from factors in the general population. The role played by ischaemic heart disease in this context needs further evaluation.

De Lima JJG, Gowdak LHW, de Paula FJ, Arantes RL, Ianhez LE, Ramires JAF, Krieger EM. Influence of coronary artery disease assessment and treatment in the incidence of cardiac events in renal transplant recipients. Clin Transplant 2010: 24: 474–480. © 2009 John Wiley & Sons A/S. Abstract: Background: The best strategy for pre-transplant investigation and treatment of coronary artery disease (CAD) is controversial. Methods: We evaluated 167 renal transplant recipients before transplantation to determine the incidence of cardiac events and death. We performed clinical evaluations and myocardial scans in all patients and coronary angiography in select patients. Results: Asymptomatic patients with normal myocardial scans (n = 57) had significantly fewer cardiac events (log-rank = 0.0002) and deaths (log-rank = 0.0005) than did patients with abnormal scans but no angiographic evidence of CAD (n = 76) and individuals with CAD (n = 34) documented angiographically. CAD increased the probability of events (HR = 2.27, % CI 1.007–5.11; p = 0.04). The incidence of cardiac events (log-rank = 0.349) and deaths (log-rank = 0.588) was similar among patients treated medically (n = 23) or by intervention (n = 11). Conclusion: Asymptomatic patients with normal myocardial scans had a better cardiac prognosis than did patients with or without CAD and positive for myocardial ischemia. Patients with altered scan and CAD had the poorer outcome. Guideline-oriented medical treatment is safe and yields results comparable to coronary intervention in renal transplant patients with CAD. The data do not support pre-emptive myocardial revascularization for renal transplant candidates.

BACKGROUND We validated a strategy for diagnosis of coronary artery disease (CAD) and prediction of cardiac events in high-risk renal transplant candidates (at least one of the following: age > or =50 years, diabetes, cardiovascular disease). METHODS A diagnosis and risk assessment strategy was used in 228 renal transplant candidates to validate an algorithm. Patients underwent dipyridamole myocardial stress testing and coronary angiography and were followed up until death, renal transplantation, or cardiac events. RESULTS The prevalence of CAD was 47%. Stress testing did not detect significant CAD in 1/3 of patients. The sensitivity, specificity, and positive and negative predictive values of the stress test for detecting CAD were 70, 74, 69, and 71%, respectively. CAD, defined by angiography, was associated with increased probability of cardiac events [log-rank: 0.001; hazard ratio: 1.90, 95% confidence interval (CI): 1.29-2.92]. Diabetes (P=0.03; hazard ratio: 1.58, 95% CI: 1.06-2.45) and angiographically defined CAD (P=0.03; hazard ratio: 1.69, 95% CI: 1.08-2.78) were the independent predictors of events. CONCLUSION The results validate our observations in a smaller number of high-risk transplant candidates and indicate that stress testing is not appropriate for the diagnosis of CAD or prediction of cardiac events in this group of patients. Coronary angiography was correlated with events but, because less than 50% of patients had significant disease, it seems premature to recommend the test to all high-risk renal transplant candidates. The results suggest that angiography is necessary in many high-risk renal transplant candidates and that better noninvasive methods are still lacking to identify with precision patients who will benefit from invasive procedures.

BACKGROUND: We assessed the results of a noninvasive therapeutic strategy on the long-term occurrence of cardiac events and death in a registry of patients with chronic kidney disease (CKD) and coronary artery disease (CAD). METHODS: We analyzed 519 patients with CKD (56+/-9 years, 67% men, 67% whites) on maintenance hemodialysis with clinical or scintigraphic evidence of CAD by using coronary angiography. RESULTS: In 230 (44%) patients, coronary angiography revealed significant CAD (lumen reduction > or =70%). Subjects with significant CAD were kept on medical treatment (MT; n=184) or referred for myocardial revascularization (percutaneous transluminal coronary angioplasty/coronary artery bypass graft-intervention; n=30) according to American College of Cardiology/American Heart Association guidelines. In addition, 16 subjects refused intervention and were also followed-up. Event-free survival for patients on MT at 12, 36, and 60 months was 86%, 71%, and 57%, whereas overall survival was 89%, 71%, and 50% in the same period, respectively. Patients who refused intervention had a significantly worse prognosis compared with those who actually underwent intervention (events: hazard ratio=4.50; % confidence interval=1.48-15.10; death: hazard ratio=3.39; % confidence interval 1.41-8.45). CONCLUSIONS: In patients with CKD and significant CAD, MT promotes adequate long-term event-free survival. However, failure to perform a coronary intervention when necessary results in an accentuated increased risk of events and death.

1. Clinical and experimental evidence highlights the importance of the renin-angiotensin system in renovascular hypertension. Furthermore, genetic factors affecting angiotensin-converting enzyme (ACE) could influence the development of renovascular hypertension. 2. To test the effect of small gene perturbations on the development of renovascular hypertension, mice harbouring two or three copies of the Ace gene were submitted to 4 weeks of two-kidney, one-clip (2K1C) hypertension. Blood pressure (BP), cardiac hypertrophy, baroreflex sensitivity and blood pressure and heart rate variability were assessed and compared between the different groups. 3. The increase in BP induced by 2K1C was higher in mice with three copies of the Ace gene compared with mice with only two copies (46 vs 23 mmHg, respectively). Moreover, there was a 3.8-fold increase in the slope of the left ventricle mass/BP relationship in mice with three copies of the Ace gene. Micewith three copies of the Ace gene exhibited greater increases in cardiac and serum ACE activity than mice with only two copies of the gene. Both baroreflex bradycardia and tachycardia were significantly depressed in mice with three copies of the Ace gene after induction of 2K1C hypertension. The variance in basal systolic BP was greater in mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two copies of the gene (106 vs 54%, respectively). In addition, the low-frequency component of the pulse interval was higher mice with three copies of the Ace gene after 2K1C hypertension compared with those with only two (168 vs 86%, respectively). Finally, in mice with three copies of the Ace gene, renovascular hypertension induced a 6.1-fold increase in the sympathovagal balance compared with a 3.2-fold increase in mice with only two copies of the gene. 4. Collectively, these data provide direct evidence that small genetic disturbances in ACE levels per se have an influence on haemodynamic, cardiac mass and autonomic nervous system responses in mice under pathological perturbation.

Metabolic syndrome (MS) is associated with subclinical atherosclerosis, but the relative role of obstructive sleep apnoea (OSA) is largely unknown. The main objective of this study is to determine the impact of OSA on markers of atherosclerosis in patients with MS.Eighty-one consecutive patients with MS according to the Adult Treatment Panel III underwent a clinical evaluation, polysomnography, laboratory and vascular measurements of carotid intima media thickness (IMT), carotid-femoral pulse wave velocity (PWV) and carotid diameter (CD) in a blind fashion. OSA was defined as an apnoea-hypopnoea index (AHI)or =15 events/hour. Multiple linear regression was performed to determine the variables that were independently associated with the vascular parameters.Fifty-one patients (63%) had OSA. No significant differences existed in age, sex, MS criteria, and cholesterol levels between patients with (MS+OSA) and without OSA (MS-OSA). Compared with MS-OSA patients, MS+OSA patients had higher levels of IMT (661+/-117 vs. 767+/-140 microm), PWV (9.6+/-1.0 vs. 10.6+/-1.6m/s), and CD (6705+/-744 vs. 7811+/-862 microm) (P0.001 for each comparison). Among patients with MS+OSA, all vascular parameters were similar in patients with and without daytime sleepiness. The independent parameters associated with IMT, PWV, and CD were AHI, abdominal circumference, and systolic blood pressure (R(2)=0.42); AHI and systolic blood pressure (R(2)=0.38); and AHI, age, abdominal circumference and systolic blood pressure (R(2)=0.45), respectively. The R(2) of AHI for IMT, PWV and CD was 0.12, 0.10 and 0.20, respectively.OSA is very common and has an incremental role in atherosclerotic burden in consecutive patients with MS.

The purpose of the present study was to determine the range of the influence of the baroreflex on blood pressure in chronic renal hypertensive rats. Supramaximal electrical stimulation of the aortic depressor nerve and section of the baroreceptor nerves (sinoaortic denervation) were used to obtain a global analysis of the baroreceptor-sympathetic reflex in normotensive control and in chronic (2 months) 1-kidney, 1-clip hypertensive rats. The fall in blood pressure produced by electrical baroreceptor stimulation was greater in renal hypertensive rats than in normotensive controls (right nerve: -47 +/- 8 vs -23 +/- 4 mmHg; left nerve: -51 +/- 7 vs -30 +/- 4 mmHg; and both right and left nerves: -50 +/- 8 vs -30 +/- 4 mmHg; P0.05). Furthermore, the increase in blood pressure level produced by baroreceptor denervation in chronic renal hypertensive rats was similar to that observed in control animals 2-5 h (control: 163 +/- 5 vs 121 +/- 1 mmHg; 1K-1C: 203 +/- 7 vs 170 +/- 5 mmHg; P0.05) and 24 h (control: 149 +/- 3 vs 121 +/- 1 mmHg; 1K-1C: 198 +/- 8 vs 170 +/- 5 mmHg; P0.05) after sinoaortic denervation. Taken together, these data indicate that the central and peripheral components of the baroreflex are acting efficiently at higher arterial pressure in renal hypertensive rats when the aortic nerve is maximally stimulated or the activity is abolished.

Objectives The present study investigates the hemodynamic and autonomic regulation during sleep-awake transitions and across different sleep cycles in patients with essential hypertension. Methods Nineteen individuals free of sleep apnea (10 normotensive and nine hypertensive matched for age, sex, and body mass index) underwent a standard polysomnography, with simultaneous electrocardiography and beat-to-beat blood pressure monitoring (Portapres). All measurements were determined while awake (before and after sleep), as well as in the beginning and at end of the sleep cycle (first/last cycle of nonrapid and rapid eye movement stages). Results Systolic blood pressure was higher in hypertensives and exhibited a similar reduction to the normotensives ones in initial nonrapid eye movement sleep. This reduction was because of different mechanisms: a significant fall in cardiac output in normotensives, whereas in hypertensives was also dependent of a decrease in peripheral vascular resistance. Hypertensive patients presented lower heart rate variation and attenuated baroreflex sensitivity during sleep but not immediately before and after sleep. Spectral analysis suggested a higher sympathetic activity in the sleep stages in hypertension. Additionally, a progressive sympathetic predominance (final rapid eye movement > initial rapid eye movement and awake period postsleep > awake period presleep) was observed in both groups. Conclusion Hypertension is associated with depressed baroreflex sensitivity and increased sympathetic activation during sleep. The greater sympathetic predominance at the end of night (preceding the morning surge of sympathetic activity) could be implicated in the occurrence of cardiovascular events.

OBJECTIVES: To compare the metabolic, hemodynamic, autonomic, and endothelial responses to short-term red wine consumption in subjects with hypercholesterolemia or arterial hypertension, and healthy controls. METHODS: Subjects with hypercholesterolemia (n=10) or arterial hypertension (n=9), or healthy controls (n=7) were given red wine (250 mL/night) for 15 days. Analyses were performed before and after red wine intake. RESULTS: Red wine significantly increased the plasma levels of HDL-cholesterol in the controls, but not in the other groups. The effects on hemodynamic measurements were mild, non-significantly more prominent in healthy subjects, and exhibited high interindividual variability. Across all participants, mean blood pressure decreased 7 mmHg (p

creased forearm blood flow (P < 0.01), peak V O 2 (P < 0.01), and quality of life (P < 0.01) in all groups, independent of the presence of sleep ap- nea. Exercise training improved the apnea-hypopnea index, minimum O 2 saturation, and amount stage 3-4 sleep (P < 0.05) in patients with obstructive sleep apnea but had no significant effects in patients with central sleep apnea. conclusions. The beneficial effects of exercise training on neurovas - cular function, functional capacity, and quality of life in patients with systolic dysfunction and heart failure occurs independently of sleep dis- ordered breathing. Exercise training lessens the severity of obstructive sleep apnea but does not affect central sleep apnea in patients with heart failure and sleep disordered breathing.

Obstructive sleep apnea (OSA) has emerged as an independent risk factor for atherosclerosis. However, OSA is frequently associated with several risk factors for atherosclerosis, including hypertension (HTN). The impact of OSA and HTN alone compared with the association of both conditions on carotid atherosclerosis is not understood. We studied 94 middle-aged participants free of smoking and diabetes mellitus who were divided into 4 groups: controls (n=22), OSA (n=25), HTN (n=20), and OSA+HTN (n=27). All of the participants underwent polysomnography and carotid measurements of intima-media thickness, diameter, and distensibility with an echo-tracking device. Compared with controls, intima-media thickness and carotid diameter were similarly higher in OSA (713±117 and 7117±805 μm), and HTN groups (713±182 and 7191±818 μm), with a further significant increase in OSA+HTN patients (837±181 and 7927±821 μm, respectively; P P P P

Malignant hypertension seems to be the consequence of very high blood pressure. Furthermore, an increase in sympathetic andrenin-angiotensin system activity is considered to be the main mechanisms producing malignant hypertension. In the presentstudy, 10 offspring of malignant hypertensive (OMH) parents (age 28 ± 5 years, 7 males, 3 females, 2 white and 8 non-white) and10 offspring of normotensive (ONT) parents (age 28 ± 6 years, 2 males, 8 females, 3 white and 7 non-white) were evaluated. TheOMH group had significantly higher (P < 0.05) casual blood pressure (125 ± 10/81 ± 5 mmHg) compared with ONT (99 ± 13/67± 5 mmHg). The increase in blood pressure was greater in OMH (∆ SBP = 17 ± 2 vs ∆ SBP = 9 ± 1 mmHg in ONT) during coldpressor testing, but they had a lower increase in heart rate ( ∆ HR = 13 ± 2 vs ∆ HR = 20 ± 3 bpm in ONT) during isometric exercise(handgrip test). Sympathetic activity, measured by microneurography, was significantly higher (P < 0.05) before exercise inOMH (17 ± 6 vs 11 ± 4 burst/min in ONT) and exhibited a greater increase (∆ = 18 ± 10 vs ∆ = 8 ± 3 burst/min in ONT) duringisometric exercise. This study showed increased sympathetic activity in OMH before exercise and a greater response duringisometric exercise, suggesting an autonomic abnormality before exercise and a greater sympathetic response to physical stressin OMH compared to ONT.Key words: Malignant hypertension; Offspring of malignant hypertensive parents; Sympathetic activity; MicroneurographyPublication supported by FAPESP.Received September 17, 2007. Accepted August 19, 2008

SLEEP IS A COMPLEX AND HETEROGENEOUS STATE THAT ACCOUNTS FOR A SIGNIFICANT FRACTION OF THE BEHAVIORAL PATTERN EXHIBITED DURING A 24-hour period.1 The 2 states of natural sleep, namely slow-wave or synchronized sleep and rapid eye movement (REM) or desynchronized sleep depend on distinct neural mechanisms and affect the regulation of the cardiovascular system differently.2 Hemodynamic control during the sleep phases is remarkably different among species. In cats, the most detailed species studied, a slight decrease in blood pressure, cardiac output, and heart rate during synchronized sleep and desynchronized sleep phases has been previously described.3–8 The fall in blood pressure becomes more intense during desynchronized sleep, mainly due to a decrease in total vascular resistance (caused by renal and splanchnic vasodilatation) and an intense bradycardia (that contributes to decrease cardiac output). In rats, blood pressure remains unchanged and stable during synchronized sleep and increases during desynchronized sleep.9–11 In humans, Khatri and Freis12 described a small reduction in blood pressure and cardiac output during synchronized sleep in relation to the awake state. The decline in cardiac output was associated with a reduction in heart rate rather than in stroke volume, and total vascular resistance remains essentially unchanged. Conversely, blood pressure, cardiac output, total vascular resistance, heart rate, and respiratory rate have been found to be increased during the desynchronized sleep phase.12 These hemodynamic adjustments, which occur during synchronized and desynchronized sleep phases, could be a consequence of a baroreflex buffering the blood pressure levels. Indeed, arterial baroreflex is one of the most powerful and rapid mechanisms for blood pressure control, buffering the short-term pressure fluctuations that accompany the 24-hour period.13 Several techniques can be used to evaluate the relative role of baroreceptors on hemodynamic control.14 Sinoaortic denervation (SAD) is a well-established experimental technique,9–11,15–17 described in rats in our laboratory,18 that involves the differentiation and resection of aortic and carotid baroreceptors. During the sleep phases, we have also reported that rats that undergo SAD have a paradoxic blood pressure response, with increased blood pressure levels during synchronized sleep and marked hypotension during desynchronized sleep.9–11 However, the hemodynamic behavior during the sleep phases after baroreceptor deafferentation has not been completely explored in the rat. To our knowledge, no previous study in rats has analyzed the changes in cardiac output and vascular resistance during sleep. In the present study, our objective was to determine the relative role of arterial baroreflex on hemodynamic parameters during the synchronized and desynchronized sleep phases of natural sleep in rats, especially the changes observed in cardiac output and total and regional vascular resistance.

The effects of exercise training on baroreflex control of sympathetic nerve activity in human hypertension are unknown. We hypothesized that exercise training would improve baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate (HR) in patients with hypertension and that exercise training would reduce MSNA and blood pressure (BP) in hypertensive patients. Twenty never-treated hypertensive patients were randomly divided into 2 groups: exercise-trained (n=11; age: 46±2 years) and untrained (n=9; age: 42±2 years) patients. An age-matched normotensive exercise-trained group (n=12; age: 42±2 years) was also studied. Baroreflex control of MSNA (microneurography) and HR (ECG) was assessed by stepwise intravenous infusions of phenylephrine and sodium nitroprusside and analyzed by linear regression. BP was monitored on a beat-to-beat basis. Exercise training consisted of three 60-minute exercise sessions per week for 4 months. Under baseline conditions (before training), BP and MSNA were similar between hypertensive groups but significantly increased when compared with the normotensive group. Baroreflex control of MSNA and HR was similar between hypertensive groups but significantly decreased when compared with the normotensive group. In hypertensive patients, exercise training significantly reduced BP ( P P P P P P

Obstructive sleep apnea (OSA) and hypertension are independently associated with increased stiffness of large arteries that may contribute to left ventricular (LV) remodeling. We sought to investigate the impact of OSA, hypertension, and their association with arterial stiffness and heart structure.We studied 60 middle-aged subjects classified into four groups according to the absence or presence of severe OSA with and without hypertension. All participants were free of other comorbidities. The groups were matched for age, sex, and body mass index.Full polysomnography, pulse-wave velocity (PWV), and transthoracic echocardiography were performed in all participants. Compared with normotensive subjects without OSA, PWV, left atrial diameter, interventricular septal thickness, LV posterior wall thickness, LV mass index, and percentage of LV hypertrophy had similar increases in normotensive OSA and patients with hypertension and no OSA (p0.05 for all comparisons), with a significant further increase in PWV, LV mass index, and percentage of LV hypertrophy in subjects with OSA and hypertension. Multivariate regression analysis showed that PWV was associated with systolic BP (p0.001) and apnea-hypopnea index (p = 0.002). The only independent variable associated with LV mass index was PWV (p0.0001).Severe OSA and hypertension are associated with arterial stiffness and heart structure abnormalities of similar magnitude, with additive effects when both conditions coexist. Increased large arterial stiffness contributes to ventricular afterload and may help to explain heart remodeling in both OSA and hypertension.

Patients with end-stage renal disease (ESRD) are at high risk for cardiovascular disease (CVD) and therefore should be treated according to ACC/AHA Guidelines. Scant data are available concerning the actual use of cardioprotective drugs in this population. The use of angiotensin-converting enzyme inhibitors (ACE-I), beta-blockers, aspirin, and statins was assessed in 271 (72% males, 66% Caucasians) high-risk ESRD patients on hemodialysis. The study population comprised 27% smokers, 95% with hypertension, 38% with diabetes, and 44% with dyslipidemia; 44% of patients had overt CVD at baseline, including 9% with heart failure, 9% with prior myocardial infarction, and 3% with previous myocardial revascularization. One-third of all patients were not receiving any cardioprotective drugs; among those patients who were, 42% were on one drug, 21% were on two, 3.7% were on three, and 1.5% were on four. The most prescribed agent was ACE-I (35.8%), followed by aspirin (30.6%), and beta-blockers (28.0%). The use of statins was remarkably and significantly low (4.1%) (p < 0.001), even in the higher risk subgroups (patients with diabetes or macrovascular disease). ACE-I plus aspirin was the most prescribed combination (8.5%). Cardioprotective agents recommended for risk-factor modification by the ACC/AHA Guidelines for their well-established efficacy in the general population were underutilized in this cohort of high-risk hypertensive hemodialysis patients, despite an elevated prevalence of clinically evident CVD. Speculatively, this fact may be relevant to better understand the known increased cardiovascular morbidity-mortality associated with chronic renal disease.

Introduction: In men with hypertension, obstructive sleep apnea (OSA) is associated with increased arterial stiffness. However, it is not clear if the impact of OSA on patients with hypertension is similar in women. Methods: We recruited consecutive patients with established diagnosis of hypertension under a standardized antihypertensive treatment (hydrochlorothiazide plus enalapril or losartan). All patients were submitted to full polysomnography and carotid-femoral pulse wave velocity (PWV). We performed analysis according to the presence of OSA (defined by an apnea-hypopnea index ≥15 events/hour of sleep) and by gender (male and females). Results: Ninety-five patients were studied (14males without OSA; 28 males with OSA, 29 females without OSA and 24 females with OSA). OSA frequency was 66% in males group versus 45% in females group (p=0.02). The age of female with OSA (59±10yrs) was significantly higher than female without OSA(52±10yrs), while the age did not differ between the male with(58±10yrs) or without OSA(56±8yrs). The BMI was also significantly greater in female with OSA (32.8±5 vs. 28.7±5kg/m2), while was similar in male with(30.5±4.5) or without OSA(29.5±2.5). The blood pressure was not different in the patients with or without OSA. PWV was significantly higher in both male(12.7m/s) and female(13.2m/s) with OSA than the couterparts without OSA(male-11 m/s, female-11.7 m/s) even after adjustments by age. The multivariate linear regression showed that OSA was independently associated with PWV(p=0.008). Conclusions: In patients with hypertension, the presence of OSA is associated with higher PWV regardless of gender.

The influence of genetic factors on complex phenotypes is context dependent, posing a challenge to quantify the role of single gene variants on this process. Moreover, redundancy and reserve capacity among control systems prevent most physiological stimuli to destabilize these processes. To test whether small gene perturbation can disrupt this equilibrium under pathological conditions, mice harboring one, two, or three copies of the angiotensin converting enzyme ( Ace) gene were submitted to 3 and 6 wk of pressure overload (PO). Direct systolic blood pressure (SBP), as an index of cardiac afterload, and left ventricle mass index (LVMI) were measured. LVMI under normotension was the same regardless of the Ace genotype, but the slopes of the LVMI/SBP curves increased in the three- vs. one-copy group by ∼50% upon 3- or 6-wk PO. Angiotensin II AT1 receptor blocker treatment produced a significant pressure independent decrease in the LVMI/SBP ratio. Unlike the one-copy group, PO resulted in a significant reduction in angiotensinogen and an increase in Ace mRNA expression accompanied by an increase in cardiac angiotensin II levels in the three-copy group. Similarly, the human ACE D gene variant influenced cardiac mass, estimated by Sokolov-Lyon index, in a sample of 1,507 individuals from an urban population only in individuals in the 4th quartile of the blood pressure distribution. Collectively, these data provide direct evidence that ACE gene dosage per se does not influence cardiac mass but upon a pathological stimulus, such as elevation in blood pressure, it modulates cardiac mass in both mice and humans.

Exercise training improves arterial baroreflex control in heart failure (HF) rabbits. However, the mechanisms involved in the amelioration of baroreflex control are unknown. We tested the hypothesis that exercise training would increase the afferent aortic depressor nerve activity (AODN) sensitivity in ischemic-induced HF rats. Twenty ischemic-induced HF rats were divided into trained ( n = 11) and untrained ( n = 9) groups. Nine normal control rats were also studied. Power spectral analysis of pulse interval, systolic blood pressure, renal sympathetic nerve activity (RSNA), and AODN were analyzed by means of autoregressive parametric spectral and cross-spectral algorithms. Spontaneous baroreflex sensitivity of heart rate (HR) and RSNA were analyzed during spontaneous variation of systolic blood pressure. Left ventricular end-diastolic pressure was higher in HF rats compared with that in the normal control group ( P = 0.0001). Trained HF rats had a peak oxygen uptake higher than untrained rats and similar to normal controls ( P = 0.01). Trained HF rats had lower low-frequency [1.8 ± 0.2 vs. 14.6 ± 3 normalized units (nu), P = 0.0003] and higher high-frequency (97.9 ± 0.2 vs. 85.0 ± 3 nu, P = 0.0005) components of pulse interval than untrained rats. Trained HF rats had higher spontaneous baroreceptor sensitivity of HR (1.19 ± 0.2 vs. 0.51 ± 0.1 ms/mmHg, P = 0.003) and RSNA [2.69 ± 0.4 vs. 1.29 ± 0.3 arbitrary units (au)/mmHg, P = 0.04] than untrained rats. In HF rats, exercise training increased spontaneous AODN sensitivity toward normal levels (trained HF rats, 1,791 ± 215; untrained HF rats, 1,150 ± 158; and normal control rats, 2,064 ± 327 au/mmHg, P = 0.05). In conclusion, exercise training improves AODN sensitivity in HF rats.

SUMMARY 1 In chronic hypertension, the baroreceptors reset to hypertensive levels with a decrease in gain sensitivity, but only a few studies have evaluated baroreceptor resetting during chronic hypotension and, under these conditions, no consistent information is available concerning changes in baroreceptor gain sensitivity. Therefore, in the present study, the aortic baroreceptor function curve and the baroreflex control of heart rate (HR) were evaluated in chronic hypotension produced by myocardial infarction (MI) with no heart failure. 2 Aortic baroreceptor function curves were studied in anaesthetized three groups of rats: (i) MI-7, six rats 7 days after MI; (ii) MI-30, nine rats 30 days after MI; and (iii) five control animals (SHAM). The pressure–nerve activity relationship was measured during rapid changes in blood pressure by integrating the whole-nerve activity of the baroreceptors in a computerized beat-to-beat analysis. 3 Both long-term periods (7 or 30 days) of hypotension were accompanied by complete resetting of the baroreceptor in rats (the leftward displacement of the baroreceptor curve matched the decrease in blood pressure). Moreover, the resetting of the baroreceptor function curve was not accompanied by changes in gain sensitivity (1.47, 1.64 and 1.67%/mmHg for SHAM, MI-7 and MI-30 groups, respectively) and the baroreflex control of HR was normal comparing SHAM and MI-30 groups (bradycardic 1.62 ± 0.18 vs 1.99 ± 0.52 b.p.m./mmHg, respectively; tachycardic 3.6 ± 0.5 vs 4.1 ± 0.4 b.p.m./mmHg for, respectively). 4 The data indicate that the resetting of baroreceptors in chronic hypotension is stable and is not accompanied by changes in gain sensitivity, as observed in hypertension. This may account for the normal baroreflex control of HR observed in non-anaesthetized rats.

We used microneurography to measure muscle sympathetic nerve activity (MSNA) in 25 hypertensive subjects and correlated these results with the presence or absence of signs of neurovascular compression (NVC) at the rostral ventrolateral (RVL) medulla on MRI. Subjects were divided into 3 groups based on MRI findings: NVC − , no MRI evidence of NVC (N=9); NVC+contact, image showing artery in contact but not compressing the RVL medulla (N=8); and NVC+compression, image showing arterial compression of the RVL medulla (N=8). The MSNA measurements were performed at rest, after a hypothermic stimulus, and during isometric exercise. The MSNA during rest in the NVC+compression group was significantly higher than that in the NVC+contact and NVC − groups (30.4±3.4 versus 17.5±1.1 and 21.4±3.2 spikes per minute, respectively). However, the blood pressure in the NVC+compression group was slightly but not significantly higher than that in the other 2 groups (183±7/115±8, 174±6/108±7, and 171±5/110±5 mm Hg, respectively). The increases in MSNA, blood pressure, and heart rate during the cold pressor and isometric exercise tests were similar. Our results show that, although resting MSNA is elevated in patients with true NVC of the RVL medulla, patients without NVC or with arterial contact but not overt compression of the RVL medulla have similar MSNA. These findings are important for identifying, among hypertensive patients with NVC, individuals who may have associated physiological repercussions, such as increased sympathetic activity.

Obstructive sleep apnea (OSA) causes secondary hypertension. However, the reasons why the prevalence of hypertension among OSA patients varies widely (35-70%) are not clear. We sought to investigate the phenotypic characteristics of patients with and without hypertension among OSA patients who were matched for disease severity. We studied 152 OSA patients (76 normotensive and 76 hypertensive) diagnosed by polysomnography. Detailed phenotypic characteristics, including laboratorial analysis, were determined in all patients. Univariate analysis followed by multiple logistic regression analysis was used to identify variables that were independently associated with hypertension. The apnea-hypopnea index in normotensive and hypertensive patients was similar (48+/-26 and 48+/-26 events/h, respectively) as well as minimum arterial oxygen saturation (76+/-10 and 75+/-10%, respectively) and total sleep time with oxyhaemoglobin saturation90% (25+/-25 and 28+/-26%, respectively). Hypertensive patients were older (57+/-11 vs 47+/-12 years; P0.001), had a higher body mass index (BMI; 34+/-7 vs 30+/-5 kg/m(2); P0.001), had a higher frequency of women (37 vs 8%; P0.001), had a higher incidence of diabetes (25 vs 6%; P=0.002) and a higher family history of hypertension (75 vs 42%; P=0.01) than did the normotensive patients. Multiple logistic regression analysis indicated that age (P=0.004), familial history of hypertension (P=0.004), BMI (P=0.04) and female sex (P=0.03) were the independent variables associated with hypertension. We concluded that increasing age and BMI, familial history of hypertension as well as female gender are phenotypic characteristics associated with hypertension among OSA patients with similar disease severity.

We studied heart rate (HR) responses to vagal electrical stimulation (VES) and the expression of muscarinic acetylcholine receptors (mAChRs) in the rat atria 1 day (SADa) and 20 days (SADc) after sinoaortic denervation (SAD). Arterial blood pressure (BP) was recorded in conscious, unrestrained rats and during vagal electrical stimulation of the vagus nerve. In the acute phase, SADa rats had hypertension, tachycardia, and increased blood pressure lability. In the chronic phase, heart rate and blood pressure in SADc rats returned to normal whereas blood pressure lability remained increased. VES produced a frequency-dependent bradycardia that was higher in SADa and SADc groups. Binding experiments with [H] N-methylscopolamine showed that in the chronic phase of SAD mAChRs density (SADc = 412.2 +/- 28.64, SADa = 273.38 +/- 48.37 and CTR = 241.5 +/- 25.35 fmol/mg of protein, P < 0.05) and affinity increased in SADc rats (reduced dissociation constant: SADc = 0.45 +/- 0.05, SADa = 1.01+/-0.26, and CTR = 0.98 +/- 0.12 mM, P < 0.05). Our study provides evidence that vagal hyperresponsiveness coexists with increased sympathetic activity in SADa rats without a concomitant increase in mAChRs density or affinity, suggesting that complex mechanisms might modulate the "accentuated antagonism" observed in the acute SAD phase. However, SADc rats had increased bradycardia to VES, increased affinity, and upregulation of mAChRs in the atria. Our results show that, 20 days after SAD in the rat, functional and cellular adaptations occur in the cardiac parasympathetic efferent pathway that may contribute to other regulatory mechanisms to compensate for cardiovascular changes provoked by baroreceptor arch disruption.

Hypertension (HTN) has been controversially related to neurovascular compression (NVC) at the rostral ventrolateral (RVL) medulla in anatomical, surgical, and radiological reports. Our objective was to investigate the association between primary HTN and signs of NVC at the medulla oblongata on magnetic resonance imaging (MRI) and to explore a new classification based on image criteria. Subjects with (n=64) and without (n=29) HTN were studied. Three-millimeter slices, with 1-mm intervals in between, were performed on T2-weighted images in axial and coronal views. Attention was focused on the relationship between the upper medulla and the surrounding arteries. The findings were divided into three categories: 1) non-NVC: absence of signs of NVC, 2) NVC type I: an artery in contact with the RVL medulla but not compressing it, and 3) NVC type II: evident compression of the RVL medulla by an artery. Signs of NVC were observed in 65.7% (42/64) of the HTN group (type I: 39.1%, 25/42 patients; type II: 26.6%, 17/42 patients). Among the normotensive subjects, 27.6% (8/29) had signs of NVC; only one (3.3%) of these had NVC type II (evident compression), and the rest were NVC type I. We conclude that the presence of NVC at the RVL medulla on MRI is related to HTN. More importantly, the finding of frank compression (NVC type II) is present almost exclusively in hypertensive subjects; only one individual (3.3% of our normotensive population) had NVC type II.

The renin–angiotensin system (RAS) plays an important role in the regulation of the cardiovascular system and the kallikrein–kinin system (KKS) appears to counteract most of the RAS effects. In this study the vagal and the sympathetic influences on the heart rate and the baroreflex control of the heart rate were evaluated in transgenics rats with human tissue kallikrein gene expression [TGR(hKLK1)], and transgenics rats with tissue renin overexpression [TGR(mREN2)27]. Heart rate was similar in all groups but mean arterial pressure was higher in mREN2 rats than in kallikrein and control rats (149 ± 4 vs. 114 ± 3 vs. 113 ± 3 mm Hg, respectively). The intrinsic heart rate was lower in mREN2 rats than in kallikrein and control rats (324 ± 5 vs. 331 ± 3 vs. 343 ± 7 bpm). The HR response to atropine was similar but the response to propranolol was higher in kallikrein rats than control group (61 ± 7 vs. 60 ± 9 vs. 38 ± 7 bpm, respectively). The vagal tonus was lower in mREN2 than in SD and hKAL rats (18 ± 3 vs. 40 ± 6 vs. 35 ± 6 bpm) whereas the sympathetic tonus was higher in kallikrein rats (118 ± 7 vs. 96 ± 1 vs. 81 ± 9 bpm in the mREN2 and SD rats), respectively. Baroreflex sensitivity to bradycardic responses was attenuated in mREN2 rats (0.37 ± 0.05 vs. 1.34 ± 0.08 vs. 1.34 ± 0,13 bpm/mm Hg) while the tachycardic responses were unchanged. The bradycardic responses to electrical stimulation of the vagal nerve were depressed in both renin and kallikrein rats (129 ± 47 vs. 129 ± 22 vs. 193 ± 25 bpm in control group in response to 32 Hz). In conclusion: 1.The rats with overexpression of renin showed decreased intrinsic heart rate and impairment of vagal function, characterized by decreased vagal tonus, reduced response of HR to electrical stimulation of vagus nerve, and depressed reflex bradycardia provoked by increases of blood pressure. 2. The rats with overexpression of kallikrein showed an increase of sympathetic activity that regulates the heart rate, characterized by increased HR response to propranolol and increased sympathetic tonus, accompanied by decreased bradycardic responses to electrical vagal stimulation.

Experiments were performed to investigate the influence of exercise training on cardiovascular function in mice. Heart rate, arterial pressure, baroreflex sensitivity, and autonomic control of heart rate were measured in conscious, unrestrained male C57/6J sedentary ( n = 8) and trained mice ( n = 8). The exercise training protocol used a treadmill (1 h/day; 5 days/wk for 4 wk). Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses induced by sodium nitroprusside and phenylephrine, respectively. Autonomic control of heart rate and intrinsic heart rate were determined by use of methylatropine and propranolol. Resting bradycardia was observed in trained mice compared with sedentary animals [485 ± 9 vs. 612 ± 5 beats/min (bpm)], whereas mean arterial pressure was not different between the groups (106 ± 2 vs. 108 ± 3 mmHg). Baroreflex-mediated tachycardia was significantly enhanced in the trained group (6.97 ± 0.97 vs. 1.6 ± 0.21 bpm/mmHg, trained vs. sedentary), whereas baroreflex-mediated bradycardia was not altered by training. The tachycardia induced by methylatropine was significantly increased in trained animals (139 ± 12 vs. 40 ± 9 bpm, trained vs. sedentary), whereas the propranolol effect was significantly reduced in the trained group (49 ± 11 vs. 97 ± 11 bpm, trained vs. sedentary). Intrinsic heart rate was similar between groups. In conclusion, dynamic exercise training in mice induced a resting bradycardia and an improvement in baroreflex-mediated tachycardia. These changes are likely related to an increased vagal and decreased sympathetic tone, similar to the exercise response observed in humans.

Arterial hypertension is a public health problem and patient adherence to treatment is challenging. This study tested whether frequent nurse visits provide additional benefits to antihypertensive treatment. Every 30 days, a pharmacist visited these patients to deliver antihypertensive drugs and perform a pill count. Nurses visited group A (48 patients) every 15 days and group B (52 patients) every 90 days. Ambulatory blood pressure (BP) monitoring was performed 15 and 180 days after randomization. At randomization, groups A and B had the same clinical systolic (191 +/- 5 v 186 +/- 3 mm Hg) and diastolic BP levels (122 +/- 3 v 117 +/- 4 mm Hg), respectively. After 90 days, BP declined more in group A than in group B (35 +/- 5/19 +/- 3 v 27 +/- 5/9 +/- 3 mm Hg). At 180 days, the difference increased because the reduction persisted in group A but decreased in group B (36 +/- 6/21 +/- 4 v 17 +/- 4/10 +/- 2 mm Hg). The mean ambulatory BP monitoring values were similar in both groups at 15 and 180 days. However, the attenuation of the clinic-daytime BP difference was larger in group A than in group B (systolic, -13 +/- 4 v -3 +/- 4 mm Hg; diastolic -11 +/- 3 v -4 +/- 3 mm Hg). The patients with clinic-daytime differences decreased more in group A (systolic, 16 to 10; diastolic, 20 to 14) than in group B (systolic, 19 and 20; diastolic, 22 and 22). These data indicate that frequent nurse visits significantly attenuate the white coat effect (clinic daytime BP difference).

Endothelium may be damaged, especially at the coronary microcirculation, in animal models of Chagas' disease by several mechanisms. Endothelial dysfunction has been reported in chronic Chagas' heart disease patients with heart failure. Nevertheless, peripheral endothelial function has never been studied in patients with Chagas' heart disease without heart failure and other conditions that could per se alter the endothelial function. Endothelial function was evaluated in 9 patients with Chagas' heart disease (44.8 +/- 1.5 years, 5 females, left ventricular ejection fraction > or = 60%) and 10 healthy matched controls (38.6 +/- 5.5 years, 5 females). Extreme caution was exercised to select patients with no other conditions that could per se alter the endothelial function. Forearm blood flow was measured at baseline and during intra-brachial artery infusion of crescent doses of acetylcholine (0.75, 5, and 15 microg/100 mL tissue/min) and nitroprusside (1, 2, and 4 microg/ 100 mL tissue/min), an endothelium-dependent and an endothelium-independent vasoactive drug, respectively. At baseline, blood pressure and heart rate (continuously recorded with Finapress) and the forearm blood flow were similar in both groups. Acetylcholine (ACh) and sodium nitroprusside (SNP) caused significant and similar dose-dependent increases in forearm blood flow of all subjects: maximum ACh response of 24.8 versus 23.7, and maximum SNP response 24.4 versus 23.7 mL/100 mL tissue/min, respectively, for control and chagasic Groups. No significant systemic hemodynamic changes were observed during the intra-arterial infusion of the drugs. The authors conclude that the peripheral endothelial function is preserved in Chagas' heart disease patients without heart failure.

Objective— During hypoxia, active substances released by the endothelium play a key role in the cardiovascular and respiratory responses elicited to optimize oxygen delivery. As hypercholesterolemia is a major cause of endothelial dysfunction, it may interfere with these responses. Methods and Results— We studied cardiovascular and ventilatory responses to acute systemic hypoxia in 14 patients with hypercholesterolemia (HC) and 13 control (CO) subjects. Oxygen saturation decreased similarly in both groups. Diastolic blood pressure increased only in the HC group ( P =0.0002) and, despite systolic blood pressure increases both in the HC group, 140±4 (95% confidence interval [CI],131 to 149 mm Hg) to 154±4 mm Hg (95% CI,145 to 164 mm Hg), and in the CO group, 133±3 (95% CI,126 to 140 mm Hg) to 140±4 mm Hg (95% CI,132 to 148 mm Hg), the HC group showed an enhanced pressor response ( P =0.03, group comparison). Both groups had increased forearm blood flow, but the decrease in forearm vascular resistance in the CO group, 40±5 (95% CI, 30 to 51 UR) to 31±4 UR (95% CI,23 to 39 UR) ( P =0.0001) was not seen in the HC group, 29±3 (95% CI, 22 to 37 UR) to 26±3 UR (95% CI, 20 to 33 UR), ( P =0.03, group comparison). Conclusions— Hypercholesterolemic patients demonstrate a hyperreactive pressor response and absence of forearm vasodilation during acute systemic hypoxia.

Objectives The goal of this study was to test the hypothesis that exercise training reduces resting sympathetic neural activation in patients with chronic advanced heart failure. Background Exercise training in heart failure has been shown to be beneficial, but its mechanisms of benefit remain unknown. Methods Sixteen New York Heart Association class II to III heart failure patients, age 35 to 60 years, ejection fraction ≤40% were divided into two groups: 1) exercise-trained (n = 7), and 2) sedentary control (n = 9). A normal control exercise-trained group was also studied (n = 8). The four-month supervised exercise training program consisted of three 60 min exercise sessions per week, at heart rate levels that corresponded up to 10% below the respiratory compensation point. Muscle sympathetic nerve activity (MSNA) was recorded directly from peroneal nerve using the technique of microneurography. Forearm blood flow was measured by venous plethysmography. Results Baseline MSNA was greater in heart failure patients compared with normal controls; MSNA was uniformly decreased after exercise training in heart failure patients (60 ± 3 vs. 38 ± 3 bursts/100 heart beats), and the mean difference in the change was significantly (p Conclusions These findings demonstrate that exercise training in heart failure patients results in dramatic reductions in directly recorded resting sympathetic nerve activity. In fact, MSNA was no longer greater than in trained, healthy controls.

Background. The aim of this study was to examine prospectively the impact of renal transplantation on the morphological and functional characteristics of the carotid arteries and heart in a group of end-stage renal failure patients without overt cardiovascular disease, followed up for )3 years. Methods. Twenty-two patients were evaluated 2‐3 weeks after renal transplantation, and again 12 and 40 months post-transplant, using high resolution ultrasound imaging and echocardiography. Results. Kidney and patient survival were 100% at the end of follow-up without any major cardiovascular events. After 40"1.2 months, carotid morphological parameters were normalized: carotid intima-media thickness fell from 788"24 to 676"32 m m( P-0.01) and the carotid wallulumen ratio fell from 118"3 to 103"3 m m( P-0.01). Significant reduction of left ventricular (LV) posterior wall thickness (11.5"0.2 to 11.3"0.2 mm, P-0.05) and LV mass index (172"9 to 158" 8g um 2 , P-0.01) was already observed after 12"0.2 months. Further reduction of LV posterior wall thickness (10.4"0.3 mm, P-0.01) and of LV mass index (136" 7g um 2 , P-0.01) also occurred after 40"1.2 months. However, carotid distensibility (19.5"2.1 vs 22"2.4, not significant (NS)) and LV compliance (early to atrial flow ratio: 1.2"0.1 vs 1.3"0.1, NS) remained abnormal, and normalization of the LV mass was attained by only 25% of the patients with LV hypertrophy on baseline. Multiple stepwise regression analysis showed that the rate of change of reduction of the intima-media thickness was influenced by age (negative association, P-0.001) and was positively related to white race (P-0.05), female sex (P-0.01) and to the parallel reduction of maximum carotid diameter (P-0.001). Reduction of LV mass index over time was negatively related to the duration of dialysis treatment and to the parallel increase observed in body mass index and haematocrit, and was positively related to the simultaneous reduction of diastolic blood pressure (P-0.01 for all variables). Conclusions. Successful renal transplantation improves but does not cause complete regression of the cardiovascular alterations of end-stage renal disease. Only intima-media thickness was normalized by transplantation, whereas LVMI and carotid and ventricular distensibility remained abnormal. The results suggest that extended duration of dialysis, weight gain, high blood pressure and high haematocrit may adversely affect the rate of change of post-transplant cardiovascular hypertrophy.