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Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High-Fidelity Cardiovascular Phenotyping.
Heusser, K, Tank, J, Brinkmann, J, Schroeder, C, May, M, Großhennig, A, Wenzel, D, Diedrich, A, Sweep, FC, Mehling, H, et al
Journal of the American Heart Association. 2016;(1)
Abstract
BACKGROUND Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization-activated cyclic nucleotide-gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. METHODS AND RESULTS We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading. CONCLUSIONS HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.
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The osmopressor response is linked to upregulation of aquaporin-1 tyrosine phosphorylation on red blood cell membranes.
Chu, YH, Hsu, YJ, Lee, HS, Ho, ST, Tung, CS, Tseng, CJ, Li, MH, Lin, TC, Lu, CC
Hypertension (Dallas, Tex. : 1979). 2013;(1):197-202
Abstract
Studies in patients with an impaired efferent baroreflex led us to discover that ingesting water induces a robust increase in blood pressure and vascular resistance. This response was also present in healthy subjects with intact baroreflexes, described as osmopressor response. This study was to discover the physiology of the osmopressor response by determining functional activation of the aquaporin-1 water channel receptor on red blood cell membranes in young healthy subjects. In a randomized, controlled, crossover fashion, 22 young healthy subjects (age, 19-27 years) ingested either 500 or 50 mL of water. Heart rate, blood pressure, cardiac index, and total peripheral vascular resistance were measured using a Finometer hemodynamic monitor. Blood sampling was performed at 5 minutes before and at 25 and 50 minutes after either the water ingestion or control session. Immunoblotting for aquaporin-1 tyrosine phosphorylation was performed before and after subjects ingested either 500 or 50 mL of water. At 25 minutes after the ingestion of 500 mL of water, total peripheral resistance increased significantly, and plasma osmolality decreased. Functional expression of aquaporin-1 tyrosine phosphorylation on red blood cell membranes increased significantly at 25 and 50 minutes after subjects ingested 500 mL of water compared with that before water ingestion. This study concludes that water ingestion produces upregulation of aquaporin-1 tyrosine phosphorylation on red blood cell, which presents as a novel biological marker that occurs simultaneously with the osmopressor response.
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Behavioural modification of the cholinergic anti-inflammatory response to C-reactive protein in patients with hypertension.
Nolan, RP, Floras, JS, Ahmed, L, Harvey, PJ, Hiscock, N, Hendrickx, H, Talbot, D
Journal of internal medicine. 2012;(2):161-9
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Abstract
OBJECTIVES A central hypothesis of the cholinergic anti-inflammatory reflex model is that innate immune activity is inhibited by the efferent vagus. We evaluated whether changes in markers of tonic or reflex vagal heart rate modulation following behavioural intervention were associated inversely with changes in high-sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6). DESIGN Subjects diagnosed with hypertension (n = 45, age 35-64 years, 53% women) were randomized to an 8-week protocol of behavioural neurocardiac training (with heart rate variability biofeedback) or autogenic relaxation. Assessments before and after intervention included pro-inflammatory factors (hsCRP, IL-6), markers of vagal heart rate modulation [RR high-frequency (HF) power within 0.15-0.40 Hz, baroreflex sensitivity and RR interval], conventional measures of lipoprotein cholesterol and 24-h ambulatory systolic and diastolic blood pressure. RESULTS Changes in hsCRP and IL-6 were not associated with changes in lipoprotein cholesterol or blood pressure. After adjusting for anti-inflammatory drugs and confounding factors, changes in hsCRP related inversely to changes in HF power (β = -0.25±0.1, P = 0.02), baroreflex sensitivity (β = -0.33±0.7, P = 0.04) and RR interval (β = -0.001 ± 0.0004, P = 0.02). Statistically significant relationships were not observed for IL-6. CONCLUSIONS Changes in hsCRP were consistent with the inhibitory effect of increased vagal efferent activity on pro-inflammatory factors predicted by the cholinergic anti-inflammatory reflex model. Clinical trials for patients with cardiovascular dysfunction are warranted to assess whether behavioural interventions can contribute independently to the chronic regulation of inflammatory activity and to improved clinical outcomes.
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Altered systemic hemodynamic and baroreflex response to angiotensin II in postural tachycardia syndrome.
Mustafa, HI, Raj, SR, Diedrich, A, Black, BK, Paranjape, SY, Dupont, WD, Williams, GH, Biaggioni, I, Robertson, D
Circulation. Arrhythmia and electrophysiology. 2012;(1):173-80
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BACKGROUND Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that patients with POTS have increases in plasma angiotensin II (Ang II) that are twice as high as healthy subjects despite normal blood pressures (BPs). In this study, we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls. METHODS AND RESULTS Following a 3-day sodium-controlled diet, we infused Ang II (3 ng/kg per minute) for 1 hour in patients with POTS (n=15) and healthy controls (n=13) in the supine position. All study subjects were women with normal BP. Ages were similar for patients with POTS and controls (mean±SEM, 30±2 versus 26±1 years; P=0.11). We measured the changes from baseline mean arterial pressure, renal plasma flow, plasma renin activity, aldosterone, urine sodium, and baroreflex sensitivity in both groups. In response to Ang II infusion, patients with POTS had a blunted increase compared with controls in mean arterial pressure (10±1 versus 14±1 mm Hg, P=0.01) and diastolic BP (9±1 versus 13±1 mm Hg, P=0.01) but not systolic BP (13±2 versus 15±2 mm Hg, P=0.40). Renal plasma flow decreased similarly with Ang II infusion in patients with POTS versus controls (-166±20 versus -181±17 mL/min per 1.73 kg/m(2), P=0.58). Postinfusion, the decrease in plasma renin activity (-0.9±0.2 versus -0.6±0.2 ng/mL per hour, P=0.43) and the increase in aldosterone (17±1 versus 15±2 pg/mL, P=0.34) were similar in both groups. The decrease in urine sodium excretion was similar in patients with POTS and controls (-49±12 versus -60±16 mEq/g creatinine, P=0.55). The spontaneous baroreflex sensitivity at baseline was significantly lower in patients with POTS compared with controls (10.1±1.2 versus 16.8±1.5 ms/mm Hg, P=0.003), and it was further reduced with Ang II infusion. CONCLUSIONS Patients with POTS have blunted vasopressor response to Ang II and impaired baroreflex function. This impaired vasoconstrictive response might be exaggerated with upright posture and may contribute to the subsequent orthostatic tachycardia that is the hallmark of this disorder. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00962949.
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Aerobic training restores arterial baroreflex sensitivity in older adults with type 2 diabetes, hypertension, and hypercholesterolemia.
Madden, KM, Lockhart, C, Potter, TF, Cuff, D
Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine. 2010;(4):312-7
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OBJECTIVE Lowered baroreflex sensitivity (BRS) predicts mortality and occurs with increasing age and diabetes. We examined whether aerobic exercise could restore arterial BRS in adults at high cardiovascular risk (diabetes, geriatric age group, hypercholesterolemia, and hypertension). DESIGN Randomized, controlled, single-blind study. SETTING VITALiTY (Vancouver Initiative to Add Life to Years) Research Laboratory. PARTICIPANTS Thirty-nine older adults (mean age, 71.5 +/- 0.7 years) with diet-controlled or oral hypoglycemic-controlled type 2 diabetes, hypertension, and hypercholesterolemia. INTERVENTIONS Subjects were recruited to each of 2 groups: an aerobic group (3 months of vigorous aerobic exercise as defined by 80% to 85% of maximal heart rate), and a nonaerobic (no aerobic exercise) group. Exercise sessions were supervised by a certified exercise trainer 3 times per week. MAIN OUTCOME MEASURES : Baroreflex function was assessed using the spontaneous baroreflex method. Main outcome measures included BRS, BRS(up), BRS(down), and [latin capital V with dot above]o(2)max. RESULTS The aerobic group demonstrated an increase in BRS that was not demonstrated in the nonaerobic group (+60.9 +/- 23.5 vs +2.2 +/- 7.9%; P = 0.010). CONCLUSIONS Our findings indicate that a relatively short aerobic exercise intervention can reverse functional impairments of the arterial baroreflex function in older adults at high cardiovascular risk.
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Acute autonomic effects of vitamins and fats in male smokers.
Wright, CI, Ruediger, H, Kroner, CI, Janssen, BJ, Draijer, R
European journal of clinical nutrition. 2009;(2):246-52
Abstract
BACKGROUND/OBJECTIVES Vitamins can help improve cardiovascular control. In contrast, smoking works in the opposite fashion, reducing the baroreflex control of heart rate (HR) possibly via oxidative stress. High-fat challenges also impair cardiovascular regulation. Whether vitamins have acute beneficial effects on the baroreflex control of HR in smokers is unclear. SUBJECTS/METHODS A randomized, placebo-controlled crossover study in 30 male smokers (34.2+/-6.9 years). Interventions were: (1) moderate (vitamin C (300 mg) and E (75 IU) and folic acid (1 mg)); (2) high doses of vitamins (vitamin C (2 g) and E (800 IU), and folic acid (5 mg)); or, (3) placebo. Vitamins were ingested with cream (a high-fat challenge) or milk (low-fat control). Four hours later, blood was withdrawn and radial pulse wave forms recorded via tonometry. Spontaneous beat-to-beat variations in HR and systolic blood pressure (SBP) were analysed by spectral analysis techniques and sympathovagal control of HR and baroreflex sensitivity (BRS) were assessed. RESULTS High doses of vitamins increased plasma vitamin C, E and folic acid levels (P<0.05) with no change in SBP, HR or BRS (P>0.05, analysis of variance). Plasma vitamin levels did not correlate with any cardiovascular parameters. Moderate vitamins increased the vagal control of HR (+23%; P<0.05) and cream led to small increases (P<0.05) in SBP (+2 mm Hg) and HR (+2 beats min(-1)) with no change in BRS. CONCLUSIONS In male smokers, circulating antioxidants had no effect on BRS and minor effects on the cardiovascular system were seen following acute fat and vitamin ingestion.
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Exercise training restores baroreflex sensitivity in never-treated hypertensive patients.
Laterza, MC, de Matos, LD, Trombetta, IC, Braga, AM, Roveda, F, Alves, MJ, Krieger, EM, Negrão, CE, Rondon, MU
Hypertension (Dallas, Tex. : 1979). 2007;(6):1298-306
Abstract
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<0.01) and MSNA (P<0.01) levels and significantly increased baroreflex control of MSNA and HR during increases (P<0.01 and P<0.03, respectively) and decreases (P<0.01 and P<0.03, respectively) in BP. The baseline (preintervention) difference in baroreflex sensitivity between hypertensive patients and normotensive individuals was no longer observed after exercise training. No significant changes were found in untrained hypertensive patients. In conclusion, exercise training restores the baroreflex control of MSNA and HR in hypertensive patients. In addition, exercise training normalizes MSNA and decreases BP levels in these patients.
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Effects of new calcium channel blocker, azelnidipine, and amlodipine on baroreflex sensitivity and ambulatory blood pressure.
Eguchi, K, Tomizawa, H, Ishikawa, J, Hoshide, S, Fukuda, T, Numao, T, Shimada, K, Kario, K
Journal of cardiovascular pharmacology. 2007;(6):394-400
Abstract
The effect of dihydropyridine calcium channel blocker (CCB) on baroreflex sensitivity (BRS) is not well described. We studied the effect of a new CCB, azelnidipine, compared with amlodipine, on BRS and ambulatory blood pressure (BP) in newly diagnosed untreated hypertension. This study was a prospective, randomized, and open-label study. We randomized patients to either azelnidipine or amlodipine treatment. Azelnidipine 8 to 16 mg (average 14.5 mg) and amlodipine 2.5 to 7.5 mg (average 4.9 mg) were used to lower the clinical BP <140/90 mm Hg. BRS, evaluated by the spontaneous and the Valsalva methods, and clinical and ambulatory BP were evaluated at baseline and after 13 weeks of each treatment. A total of 47 patients (age 53.1 +/- 10.8 years, 51% male), 26 in the azelnidipine group and 21 in the amlodipine group, completed the study. For baseline and after therapy respectively, both Valsalva-BRS (4.8 +/- 1.7 vs. 8.4 +/- 3.1 msec/mm Hg, P = 0.001) and spontaneous-BRS (5.5 +/- 2.5 vs. 8.2 +/- 5.6 msec/mm Hg, P = 0.019) were increased by azelnidipine, but amlodipine did not change them. Clinical and awake BPs were similarly reduced by each drug therapy. In conclusion, BRS was increased by azelnidipine therapy, but not by amlodipine therapy. This differential effect may be important in cardiovascular risk reduction.
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The effects of exercise training on arterial baroreflex sensitivity in neurally mediated syncope patients.
Gardenghi, G, Rondon, MU, Braga, AM, Scanavacca, MI, Negrão, CE, Sosa, E, Hachul, DT
European heart journal. 2007;(22):2749-55
Abstract
AIMS: The clinical effects of different modalities of treatment for neurally mediated syncope have been studied for years; however, their influences on its pathophysiological mechanisms still have not been determined. This research aimed to observe the effects of physical training, tilt training, and pharmacological therapy on the arterial baroreflex sensitivity and muscle sympathetic nerve activity in neurally mediated syncope patients. METHODS AND RESULTS Seventy patients with recurrent neurally mediated syncope were included in this study. Patients were divided into the following four groups, depending on the treatment proposed: (i) physical training, (ii) tilt training, (iii) pharmacological therapy, and (iv) control group. All patients underwent an autonomic evaluation with microneurography, when the vagal and sympathetic arterial baroreflex gain were tested, using graded infusions of phenylephrine or sodium nitroprusside, before and 4 months after the interventions. The vagal and sympathetic arterial baroreflex gain significantly increased after a 4-month protocol of physical training. Tilt training, pharmacological therapy, and the control group had no significant change in the arterial baroreceptor responses. CONCLUSION Physical training improves arterial baroreflex sensitivity in neurally mediated syncope patients and could be applied as a non-pharmacological therapeutic alternative for these patients.
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Exercise training improves baroreflex sensitivity in type 2 diabetes.
Loimaala, A, Huikuri, HV, Kööbi, T, Rinne, M, Nenonen, A, Vuori, I
Diabetes. 2003;(7):1837-42
Abstract
Type 2 diabetes is a strong risk factor for coronary heart disease and sudden cardiac death. It is associated with reduced baroreflex sensitivity (BRS) and heart rate variability (HRV), which are indicators of increased risk for mortality and morbidity in various patient populations. This study was designed to assess the effects of exercise training on BRS, HRV, and hemodynamics in patients with type 2 diabetes. Subjects (50 men, mean age 53.3 +/- 5.1 years) with type 2 diabetes were randomized into either a control group, in which they received conventional treatment only, or an exercise group, in which they received conventional treatment together with heart rate-controlled endurance training twice a week and supervised muscle strength training twice a week for 12 months. Measurements taken at baseline and follow-up included VO(2max), standard time and frequency domain measures of HRV during 24-h recording, and BRS by the phenylephrine method. Cardiac index, systemic vascular resistance index, stroke index, and pulse wave velocity were measured by whole-body impedance cardiography. Significant improvements in VO(2max) (exercise group: +2.3 ml x kg(-1) x min(-1); P < 0.005 vs. control group), muscle strength, and glycemic control (exercise group: HbA(1c) -0.9%; P < 0.001 vs. control group) were observed in the exercise group. BRS increased in the exercise group, from 6.8 to 8.6 ms/mmHg, and decreased in the control group, from 7.5 to 6.4 ms/mmHg (95% CI for the difference between 0.05 and 4.36 ms/mmHg; P < 0.05). No significant changes in the time or frequency domain measures of HRV or in systemic hemodynamics were observed. We concluded that exercise training improves BRS sensitivity in type 2 diabetes subjects in addition to increasing the exercise capacity and muscle strength and improving glucose control. These beneficial effects in reflectory autonomic regulation and glucose control caused by exercise may be associated with improved prognosis of type 2 diabetes patients.