Jens Tank

Carotid Baroreceptor Stimulation, Sympathetic Activity, Baroreflex Function, and Blood Pressure in Hypertensive Patients

In animals, electric field stimulation of carotid baroreceptors elicits a depressor response through sympathetic inhibition. We tested the hypothesis that the stimulation acutely reduces sympathetic vasomotor tone and blood pressure in patients with drug treatment–resistant arterial hypertension. Furthermore, we tested whether the stimulation impairs the physiological baroreflex regulation. We studied 7 men and 5 women (ages 43 to 69 years) with treatment-resistant arterial hypertension. A bilateral electric baroreflex stimulator at the level of the carotid sinus (Rheos) was implanted ≥1 month before the study. We measured intra-arterial blood pressure, heart rate, muscle sympathetic nerve activity (microneurography), cardiac baroreflex sensitivity (cross-spectral analysis and sequence method), sympathetic baroreflex sensitivity (threshold technique), plasma renin, and norepinephrine concentrations. Measurements were performed under resting conditions, with and without electric baroreflex stimulation, for ≥6 minutes during the same experiment. Intra-arterial blood pressure was 193±9/94±5 mm Hg on medications. Acute electric baroreflex stimulation decreased systolic blood pressure by 32±10 mm Hg (range: +7 to −108 mm Hg; P=0.01). The depressor response was correlated with a muscle sympathetic nerve activity reduction (r2=0.42; P<0.05). In responders, muscle sympathetic nerve activity decreased sharply when electric stimulation started. Then, muscle sympathetic nerve activity increased but remained below the baseline level throughout the stimulation period. Heart rate decreased 4.5±1.5 bpm with stimulation (P<0.05). Plasma renin concentration decreased 20±8% (P<0.05). Electric field stimulation of carotid sinus baroreflex afferents acutely decreased arterial blood pressure in hypertensive patients, without negative effects on physiological baroreflex regulation. The depressor response was mediated through sympathetic inhibition.

The Elusive Pathophysiology of Neurally Mediated Syncope

Syncope is defined as a sudden transient loss of consciousness and postural tone due to cerebral hypoperfusion. Although no permanent medical sequelae should result from syncope itself, isolated or recurrent events are often dramatic and disrupt the lifestyle of affected individuals. Syncope is a common clinical problem that affects up to 3.5% of the general population.1 Strikingly, in close to 40% of cases, the exact cause of syncope remains elusive, and ≈30% of affected patients will experience recurrent episodes.1 Neurally mediated syncope (NMS) is a common type of syncope (Figure 1⇓); clinical descriptions of it have been present in the medical literature for >100 years. Despite its prevalence, significant gaps in our understanding of its pathophysiology and treatment remain. The purpose of this review is to critically evaluate proposed theories that attempt to explain the pathophysiological mechanisms of NMS. Figure 1. Causes of syncope. NMS and orthostatic intolerance (OI) are the most frequent causes of unexplained syncope. Other causes may be hypoadrenergic (HypoAdr), cardiac (Card), neurological (Neurol), psychiatric (Psych), and/or idiopathic (Idiop). The development of arterial vasodilation in the setting of relative or absolute bradycardia characterizes NMS. This syndrome has also been known as vasovagal reaction, neurocardiogenic syncope, emotional fainting, or reflex syncope. Related processes include situational fainting (ie, shaving syncope), hyperadrenergic and hypoadrenergic conditions, and hypotensive reactions resulting from drug administration. We have classified NMS into several categories. These include central (for example, occurring in response to strong emotional stimulation), postural (associated with the upright position), and situational (after the specific stimulation of sensory or visceral afferents). Another classification considers the final hemodynamic characteristics of the patient and includes categories such as vasodepressor, bradycardic, or mixed NMS.2 One other classification relates to the clinical characteristics of the syncope and its response to treatment. This categorization includes malignant …

Oscillatory Patterns in Sympathetic Neural Discharge and Cardiovascular Variables During Orthostatic Stimulus

BACKGROUND We tested the hypothesis that a common oscillatory pattern might characterize the rhythmic discharge of muscle sympathetic nerve activity (MSNA) and the spontaneous variability of heart rate and systolic arterial pressure (SAP) during a physiological increase of sympathetic activity induced by the head-up tilt maneuver. METHODS AND RESULTS Ten healthy subjects underwent continuous recordings of ECG, intra-arterial pressure, respiratory activity, central venous pressure, and MSNA, both in the recumbent position and during 75 degrees head-up tilt. Venous samplings for catecholamine assessment were obtained at rest and during the fifth minute of tilt. Spectrum and cross-spectrum analyses of R-R interval, SAP, and MSNA variabilities and of respiratory activity provided the low (LF, 0.1 Hz) and high frequency (HF, 0.27 Hz) rhythmic components of each signal and assessed their linear relationships. Compared with the recumbent position, tilt reduced central venous pressure, but blood pressure was unchanged. Heart rate, MSNA, and plasma epinephrine and norepinephrine levels increased, suggesting a marked enhancement of overall sympathetic activity. During tilt, LF(MSNA) increased compared with the level in the supine position; this mirrored similar changes observed in the LF components of R-R interval and SAP variabilities. The increase of LF(MSNA) was proportional to the amount of the sympathetic discharge. The coupling between LF components of MSNA and R-R interval and SAP variabilities was enhanced during tilt compared with rest. CONCLUSIONS During the sympathetic activation induced by tilt, a similar oscillatory pattern based on an increased LF rhythmicity characterized the spontaneous variability of neural sympathetic discharge, R-R interval, and arterial pressure.

Catheter-Based Renal Nerve Ablation and Centrally Generated Sympathetic Activity in Difficult-to-Control Hypertensive Patients Prospective Case Series

Endovascular renal nerve ablation has been developed to treat resistant hypertension. In addition to lowering efferent renal sympathetic activation, the intervention may attenuate central sympathetic outflow through decreased renal afferent nerve traffic, as evidenced by a recent case report. We tested the hypothesis in 12 nonpreselected patients with difficult-to-control hypertension (aged 45–74 years) admitted for renal nerve ablation. All patients received ≥3 antihypertensive medications at full doses, including a diuretic. Electrocardiogram, respiration, brachial and finger arterial blood pressure, and muscle sympathetic nerve activity were recorded before and 3 to 6 months after renal nerve ablation. Heart rate and blood pressure variability were analyzed in the time and frequency domain. Pharmacological baroreflex slopes were determined using the modified Oxford bolus technique. Resting heart rate was 61±3 bpm before and 58±2 bpm after ablation (P=0.4). Supine blood pressure was 157±7/85±4 mm Hg before and 157±6/85±4 mm Hg after ablation (P=1.0). Renal nerve ablation did not change resting muscle sympathetic nerve activity (before, 34±2 bursts per minute; after, 32±3 bursts per minute P=0.6), heart rate variability, or blood pressure variability. Pharmacological baroreflex control of heart rate and muscle sympathetic nerve activity did not change. We conclude that reduced central sympathetic inhibition may be the exception rather than the rule after renal nerve ablation in unselected patients with difficult-to-control arterial hypertension.

Water Drinking Acutely Improves Orthostatic Tolerance in Healthy Subjects

Background—Orthostatic symptoms and syncope are common, even in apparently healthy subjects. In patients with severe autonomic dysfunction, water drinking elicits an acute pressor response and improves orthostatic hypotension. We tested the hypothesis that water drinking also improves orthostatic tolerance in healthy subjects. Methods and Results—In a randomized, controlled, crossover fashion, 13 healthy subjects (9 men, 4 women, 31±2 years) ingested 500 mL and 50 mL of mineral water 15 minutes before head-up tilt on two separate days. Finger blood pressure, brachial blood pressure, heart rate, thoracic impedance, and blood flow velocity in the brachial artery and the middle cerebral artery were measured. Orthostatic tolerance was determined as the time to presyncope during a combined protocol of 20 minutes of 60° head-up tilt alone, followed by additional increasing steps of lower body negative pressure (−20, −40, and −60 mm Hg for 10 minutes each or until presyncope). Drinking 500 mL of water improved orthostatic tolerance by 5±1 minute (range, −1 to +11 minutes, P <0.001). After drinking 500 mL of water, supine mean blood pressure increased slightly (P <0.01) as the result of increased peripheral resistance (P <0.01). It also blunted both the increase in heart rate and the decrease in stroke volume with head-up tilt. Cerebral blood flow regulation improved after water drinking. Conclusions—Water drinking elicits an acute hemodynamic response and changes in cerebrovascular regulation in healthy subjects. These effects are associated with a marked improvement in orthostatic tolerance.

Water drinking as a treatment for orthostatic syndromes

PURPOSE Water drinking increases blood pressure in a substantial proportion of patients who have severe orthostatic hypotension due to autonomic failure. We tested the hypothesis that water drinking can be used as a practical treatment for patients with orthostatic and postprandial hypotension, as well as those with orthostatic tachycardia. SUBJECTS AND METHODS We studied the effect of drinking water on seated and standing blood pressure and heart rate in 11 patients who had severe orthostatic hypotension due to autonomic failure and in 9 patients who had orthostatic tachycardia due to idiopathic orthostatic intolerance. We also tested the effect of water drinking on postprandial hypotension in 7 patients who had autonomic failure. Patients drank 480 mL of tap water at room temperature in less than 5 minutes. RESULTS In patients with autonomic failure, mean (+/- SD) blood pressure after 1 minute of standing was 83 +/- 6/53 +/- 3.4 mm Hg at baseline, which increased to 114 +/- 30/66 +/- 18 mm Hg (P <0.01) 35 minutes after drinking. After a meal, blood pressure decreased by 43 +/- 36/20 +/- 13 mm Hg without water drinking, compared with 22 +/- 10/12 +/- 5 mm Hg with drinking (P <0.001). In patients with idiopathic orthostatic intolerance, water drinking attenuated orthostatic tachycardia (123 +/- 23 beats per minute) at baseline to 108 +/- 21 beats per minute after water drinking ( P <0.001). CONCLUSION Water drinking elicits a rapid pressor response in patients with autonomic failure and can be used to treat orthostatic and postprandial hypotension. Water drinking moderately reduces orthostatic tachycardia in patients with idiopathic orthostatic intolerance. Thus, water drinking may serve as an adjunctive treatment in patients with impaired orthostatic tolerance.

Ballistocardiography and Seismocardiography: A Review of Recent Advances

In the past decade, there has been a resurgence in the field of unobtrusive cardiomechanical assessment, through advancing methods for measuring and interpreting ballistocardiogram (BCG) and seismocardiogram (SCG) signals. Novel instrumentation solutions have enabled BCG and SCG measurement outside of clinical settings, in the home, in the field, and even in microgravity. Customized signal processing algorithms have led to reduced measurement noise, clinically relevant feature extraction, and signal modeling. Finally, human subjects physiology studies have been conducted using these novel instruments and signal processing tools with promising results. This paper reviews the recent advances in these areas of modern BCG and SCG research.

Reference values of indices of spontaneous baroreceptor reflex sensitivity

Spontaneous baroreceptor reflex sensitivity (BRS) is a well established method for determining baroreflex function, which can be used to assess the potential impact on survival after myocardial infarction, to detect autonomic dysfunction in diabetic patients and in human essential hypertension. The assessment of impaired spontaneous baroreflex function in individual patients contains important clinical information, but age-dependent reference values are still lacking. In the present study we evaluated spontaneous BRS in healthy human controls to determine reference values as a function of age. Two hundred and sixty-two healthy volunteers divided into six age groups (I: <20 years, f = 11, m = 9, II: 20-29 years, f = 42, m = 37, III: 30-39 years, f = 23, m = 37, IV: 40-49 years, f = 27, m = 22, V: 50-59 years, f = 19, m = 17, VI: 60-69 years, f = 5, m = 13). Electrocardiograms (ECG) and finger arterial BP were measured with each subject in the supine position (sup, 7 min) and during deep breathing (dB, 6/min, 15 cycles). BRS was assessed using the sequence technique and the alpha coefficients as obtained from a power spectrum density estimate. Due to the normal logarithmic distribution of the BRS, the limits for impaired baroreflex function at rest were defined from logarithmic data. The limits for the BRS at rest (P = .025) were calculated as (-0.0283 x age) + 2.5198 for the sequence technique. We did not find significant differences in BRS among the female and male healthy volunteers. Our analysis of the six age groups showed the expected significant decrease in BRS, which was most prominent at the transition from group III (<40 years) to group IV (<50 years). BRS at rest and during deep breathing as well as sequential and spectral BRS indices did differ significantly. The results underline the necessity of reference values to evaluate impaired baroreflex function in individual patients.

Genetic Influences on Baroreflex Function in Normal Twins

Blood pressure and heart rate are strongly influenced by genetic factors; however, despite the pivotal role of genetics in short-term cardiovascular regulation, little is known about the genetic contribution to baroreflex function. We assessed genetic influence on baroreflex sensitivity (BRS) in 149 twin pairs (88 monozygotic of age 33±13 years and BMI 23±4 kg/m2 and 61 dizygotic of age 33±11 years and BMI 24±4 kg/m2). ECG and finger arterial blood pressures were measured continuously under resting conditions. BRS values were calculated by use of cross-spectral analysis (baroreflex slope calculated as mean value of transfer function between systolic blood pressure and the R-R interval in the low-frequency band [BRSLF] and baroreflex slope calculated as the mean value of transfer function between systolic blood pressure and R-R interval in the respiratory frequency band [BRSHF]) and the sequence technique (BRS+, BRS-). Heritability (h2) was estimated with a path-modeling approach. BRS values did not differ significantly between groups (monozygotic, BRSLF, 17±13; BRSHF, 21±18; BRS+, 19±16; and BRS-, 21±15, and dizygotic, BRSLF, 16±9; BRSHF, 20±14; BRS+, 18±10; and BRS-, 20±11 ms/mm Hg), and were significantly correlated (P <0.001). When variances and covariances for monozygotic and dizygotic twins were compared, significant correlations were found for BRS in monozygotic (range, r =0.38 to 0.48) but not in dizygotic twin pairs (r =-0.03 to 0.09). Thus, BRS is heritable; the variability can be explained by genetic influences (P <0.01;h2 range, 0.36 to 0.44). The genetic influence on BRS remained strong after correction for BMI and blood pressure. Therefore, BRS is strongly genetically determined, probably by different genes than are resting blood pressure and BMI.

Paradoxical Effect of Sibutramine on Autonomic Cardiovascular Regulation

Background—Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease. Methods and Results—In 11 healthy subjects (7 men, age 27±2 years, body mass index 23.1±0.7 kg/m2), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine systolic blood pressure was 113±3 mm Hg with placebo, 121±3 mm Hg with sibutramine (P <0.001 versus placebo), and 111±2 mm Hg with the combination of sibutramine and metoprolol. Similarly, sibutramine increased upright blood pressure. Sibutramine substantially increased upright heart rate. This effect was abolished with metoprolol. The blood pressure response to cold pressor and handgrip testing was attenuated with sibutramine compared with placebo. Furthermore, sibutramine decreased low-frequency oscillations of blood pressure and plasma norepinephrine concentrations in the supine position. Conclusions—The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects. The inhibitory clonidine-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reconsidered.