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Papers by Jens Tank

Research paper thumbnail of Conditional symbolic analysis detects nonlinear influences of respiration on cardiovascular control in humans

Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Jan 13, 2015

We propose a symbolic analysis framework for the quantitative characterization of complex dynamic... more We propose a symbolic analysis framework for the quantitative characterization of complex dynamical systems. It allows the description of the time course of a single variable, the assessment of joint interactions and an analysis triggered by a conditioning input. The framework was applied to spontaneous variability of heart period (HP), systolic arterial pressure (SAP) and integrated muscle sympathetic nerve activity (MSNA) with the aim of characterizing cardiovascular control and nonlinear influences of respiration at rest in supine position, during orthostatic challenge induced by 80° head-up tilt (TILT) and about 3 min before evoked pre-syncope signs (PRESY). The approach detected (i) the exaggerated sympathetic modulation and vagal withdrawal from HP variability and the increased presence of fast MSNA variability components during PRESY compared with TILT; (ii) the increase of the SAP-HP coordination occurring at slow temporal scales and a decrease of that occurring at faster ti...

Research paper thumbnail of Oscillatory Patterns in Sympathetic Neural Discharge and Cardiovascular Variables During Orthostatic Stimulus

Circulation, 2000

Background-We tested the hypothesis that a common oscillatory pattern might characterize the rhyt... more 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°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. (Circulation. 2000;101:886-892.)

Research paper thumbnail of Sympathetic nerve traffic and circulating norepinephrine levels in RGS2-deficient mice

Autonomic Neuroscience-basic & Clinical, 2007

Regulator of G protein signaling 2 (RGS2−/−) deficient mice feature an increased resting blood pr... more Regulator of G protein signaling 2 (RGS2−/−) deficient mice feature an increased resting blood pressure and an excessive pressor response to stress. We measured renal sympathetic nerve activity (RSNA) directly to test the hypothesis that RSNA is increased in RGS2−/− mice, compared to RGS2+/+ mice. Seventeen mice (RGS2−/−, n=9; RGS2+/+, n=8) were anesthetized with isoflurane. We cannulated the left jugular

Research paper thumbnail of Sympathetic Vasomotor Tone Determines Blood Pressure Response to Long-Term Sibutramine Treatment

The Journal of Clinical Endocrinology & Metabolism, 2007

The serotonin and norepinephrine transporter inhibitor sibutramine is a widely used antiobesity d... more The serotonin and norepinephrine transporter inhibitor sibutramine is a widely used antiobesity drug. In acute studies, the peripheral sympathomimetic effect of sibutramine was counteracted by a central sympatholytic action. The objective was to test the hypothesis that blood pressure responses to long-term sibutramine therapy may be related to sympathetic nerve traffic before treatment in a prospective open-label study in an academic clinical research center. This study comprised 20 obese subjects (body mass index, 30-40 kg/m2; age, 30-57 yr) receiving 5 d of placebo treatment followed by open-label 15 mg/d sibutramine and hypocaloric diet over 12 wk. Body weight, blood pressure, heart rate, muscle sympathetic nerve activity (MSNA) (microneurography), plasma catecholamines, and adipose tissue gene expression were measured. Open-label sibutramine treatment decreased body weight 4.1 kg (P<0.01) and MSNA 17 bursts per minute (P=0.001), and increased diastolic blood pressure 3 mm Hg (P<0.05) and heart rate 8 bpm (P<0.01). The change in blood pressure with sibutramine treatment was inversely correlated with initial MSNA (r2=0.34; P<0.01). Chronic sibutramine treatment increased adrenoreceptor gene expression and plasma catecholamines. The blood pressure response to sibutramine treatment is related to initial MSNA so that subjects with higher MSNA exhibit a smaller increase or even a decrease in blood pressure. The phenomenon might be explained by a sustained reduction in central sympathetic activity with sibutramine treatment.

Research paper thumbnail of PDE3A mutations cause autosomal dominant hypertension with brachydactyly

Nature Genetics, 2015

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major... more Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor 1 . Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB) 2 . The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated 3, 4

Research paper thumbnail of A pilot study comparison of a new method for aortic pulse wave velocity measurements using transthoracic bioimpedance and thigh cuff oscillometry with the standard tonometric method

Journal of the American Society of Hypertension : JASH, Jan 14, 2015

Aortic pulse wave velocity (aPWV) can be measured with different methodologies, including applana... more Aortic pulse wave velocity (aPWV) can be measured with different methodologies, including applanation tonometry. These pilot study findings suggest that impedance cardiography combined with thigh oscillometry provides comparable results. Intra- and inter-observer variability was tested by two observers in two subjects. We instrumented 41 patients and 12 healthy normotensive controls for impedance cardiography and consecutive applanation tonometry and compared methods using the Bland-Altman method. Observer variability for the impedance-thigh cuff method (range, 3.61%-7.77%) was comparable with the tonometric method (range, 2.93%-7.37%). Comparison of the two methods based on the Bland-Altman plot revealed a good agreement between methods. The bias between impedance and tonometric measurements was -0.28 ± 0.37 m/s. Both measurements were significantly correlated (r(2) = 0.94; P < .0001; slope = 1.038).Impedance cardiography combined with thigh oscillometry is an easy to use approa...

Research paper thumbnail of A Novel Pharmacological Approach to Determining Parasympathetic Heart Rate Reserve in Human Subjects

Severe cardiac parasympathetic dysfunction can be diagnosed using bedside tests, such as a Valsal... more Severe cardiac parasympathetic dysfunction can be diagnosed using bedside tests, such as a Valsalva maneuver. However, the tests that are in use are of limited value in detecting and quantifying an early impairment in cardiac parasympathetic function. We showed that α-2-adrenoreceptor stimulation with clonidine combined with pharmacological baroreceptor loading unmasks impaired parasympathetic heart rate reserve before overt changes in heart rate regulation occur. The methodology could be utilized to monitor the progression of autonomic nervous system disease in studies carried out to test neuroprotective strategies.

Research paper thumbnail of Norepinephrine transporter function and tolerance to hypergravitational stress: A pilot study

Pharmacological norepinephrine transporter (NET) inhibition improves orthostatic tolerance on a t... more Pharmacological norepinephrine transporter (NET) inhibition improves orthostatic tolerance on a tilt table while increasing heart rate. We tested the cardiovascular response to NET inhibition during a graded human centrifuge run in seven healthy men. g-Load was increased in 0.5 g steps with 3 g maximal g-load. On two separate days, patients were tested after selective NET inhibition with reboxetine or with placebo in a double-blind, randomized, crossover fashion. Resting diastolic blood pressure increased moderately with NET inhibition. Resting heart rate was profoundly increased by NET inhibition. NET inhibition augmented the heart rate response while attenuating the increase in blood pressure during hypergravitation. NET inhibition could be tested for its potential to improve cardiovascular g-tolerance.

Research paper thumbnail of Alpha-2 adrenergic transmission and human baroreflex regulation

Hypertension, 2004

We observed earlier that central alpha-2 adrenoceptor stimulation in mice greatly augments parasy... more We observed earlier that central alpha-2 adrenoceptor stimulation in mice greatly augments parasympathetic tone. To test the effects in humans, we assessed autonomic vasomotor tone and baroreflex regulation in 9 normal young adults on 2 occasions, once with and once without clonidine. We determined heart rate (HR), beat-by-beat blood pressure (BP), and muscle sympathetic nerve activity. HR variability was analyzed in the time and frequency domain. Pharmacological baroreflex slopes were determined using incremental phenylephrine and nitroprusside infusions. Clonidine lowered resting BP (122+/-4/73+/-3 versus 100+/-7/55+/-3 mm Hg, P<0.01), muscle sympathetic nerve activity (18+/-3 versus 4+/-2 bursts/min, P<0.01), and HR (62+/-3 versus 56+/-3 bpm, P<0.05). The baroreflex heart rate curve was reset to much lower HR values and showed no saturation at low HR. HR variability profoundly increased during clonidine plus phenylephrine (total power: 3224+/-843 versus 8943+/-2329 ms2, ...

Research paper thumbnail of Baroreflex regulation of heart rate and sympathetic vasomotor tone in women and men

Hypertension, 2005

Gender has been reported to influence baroreflex heart rate regulation and baroreflex blood press... more Gender has been reported to influence baroreflex heart rate regulation and baroreflex blood pressure buffering. We tested the hypothesis that gender influences baroreflex regulation of heart rate and sympathetic vasomotor tone. We recruited 32 normal-weight healthy subjects (17 men and 15 women). ECGs for heart rate, brachial and finger blood pressure, and muscle sympathetic nerve activity (MSNA) were measured. Baroreflex heart rate and MSNA regulation were assessed using incremental phenylephrine and nitroprusside infusions. Baseline blood pressure was similar in men and women. MSNA was 21+/-2.5 bursts/min in women and 19+/-2.8 bursts/min in men (NS). The gain of the baroreflex MSNA curves was similar in women and men (-1.9+/-0.2 bursts/min per mm Hg in men and -2.0+/-0.3 bursts/min per mm Hg in women). Baroreflex gain for heart rate regulation was 17+/-3.2 ms/mm Hg in women and 19+/-1.9 ms/mm Hg in men (NS). We conclude that baroreflex gains for heart rate and sympathetic MSNA reg...

Research paper thumbnail of Complexity of impaired parasympathetic heart rate regulation in diabetes

Research paper thumbnail of Preserved functional autonomic phenotype in adult mice overexpressing moderate levels of human alpha-synuclein in oligodendrocytes

Physiological reports, 2014

Mice overexpressing human alpha-synuclein in oligodendrocytes (MBP1-α-syn) recapitulate some key ... more Mice overexpressing human alpha-synuclein in oligodendrocytes (MBP1-α-syn) recapitulate some key functional and neuropathological features of multiple system atrophy (MSA). Whether or not these mice develop severe autonomic failure, which is a key feature of human MSA, remains unknown. We explored cardiovascular autonomic regulation using long-term blood pressure (BP) radiotelemetry and pharmacological testing. We instrumented 12 MBP1-α-syn mice and 11 wild-type mice aged 9 months for radiotelemetry. Animals were tested with atropine, metoprolol, clonidine, and trimethaphan at 9 and 12 months age. We applied spectral and cross-spectral analysis to assess heart rate (HR) and BP variability. At 9 months of age daytime BP (transgenic: 101 ± 2 vs. wild type: 99 ± 2 mmHg) and HR (497 ± 11 vs. 505 ± 16 beats/min) were similar. Circadian BP and HR rhythms were maintained. Nighttime BP (109 ± 2 vs. 108 ± 2 mmHg) and HR (575 ± 15 vs. 569 ± 14 beats/min), mean arterial BP responses to trimeth...

Research paper thumbnail of Conditional symbolic analysis detects nonlinear influences of respiration on cardiovascular control in humans

Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Jan 13, 2015

We propose a symbolic analysis framework for the quantitative characterization of complex dynamic... more We propose a symbolic analysis framework for the quantitative characterization of complex dynamical systems. It allows the description of the time course of a single variable, the assessment of joint interactions and an analysis triggered by a conditioning input. The framework was applied to spontaneous variability of heart period (HP), systolic arterial pressure (SAP) and integrated muscle sympathetic nerve activity (MSNA) with the aim of characterizing cardiovascular control and nonlinear influences of respiration at rest in supine position, during orthostatic challenge induced by 80° head-up tilt (TILT) and about 3 min before evoked pre-syncope signs (PRESY). The approach detected (i) the exaggerated sympathetic modulation and vagal withdrawal from HP variability and the increased presence of fast MSNA variability components during PRESY compared with TILT; (ii) the increase of the SAP-HP coordination occurring at slow temporal scales and a decrease of that occurring at faster ti...

Research paper thumbnail of Adrenergic and Atrial Natriuretic Peptide Interactions on Human Cardiovascular and Metabolic Regulation

Context: Atrial natriuretic peptide (ANP) has well-known cardiovascular effects and modifies lipi... more Context: Atrial natriuretic peptide (ANP) has well-known cardiovascular effects and modifies lipid and carbohydrate metabolism in humans.

Research paper thumbnail of Water Drinking Acutely Improves Orthostatic Tolerance in Healthy Subjects

Background—Orthostatic symptoms and syncope are common, even in apparently healthy subjects. In p... more 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, 312 years) ingested

Research paper thumbnail of Interaction between b-Adrenergic Receptor Stimulation and Nitric Oxide Release on Tissue Perfusion and Metabolism

Nitric oxide (NO) may be an important modulator of sympathetic tone. We used im and sc microdialy... more Nitric oxide (NO) may be an important modulator of sympathetic tone. We used im and sc microdialysis in humans to characterize the interaction of NO synthase inhibition and adrenoreceptor stimulation on tissue perfusion, metabolism, and norepinephrine release. Micro- dialysis probes were perfused with L -o rD-nitro-L-arginine-methyl- ester (100 mmol/L) followed by incremental doses of isoproterenol, epinephrine, or nitroprusside. Blood flow

Research paper thumbnail of Beta-Adrenergic and Atrial Natriuretic Peptide Interactions on Human Cardiovascular and Metabolic Regulation Short title: ANP and beta-adrenergic receptors

et al.. Beta-adrenergic and atrial natriuretic peptide interactions on human cardiovascular and m... more et al.. Beta-adrenergic and atrial natriuretic peptide interactions on human cardiovascular and metabolic regulation.

Research paper thumbnail of Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects

Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity tr... more Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment. Studies in healthy subjects suggested that sibutramine might have opposing effects on peripheral and central sympathetic activity; an increase in blood pressure has been claimed. Direct measurements of muscle sympathetic nerve activity (MSNA) in sibutramine-treated patients have not been conducted. Twenty nondiabetic obese men and women completed the study (mean body mass index, 35 +/- 3 kg/m2; mean age, 42 +/- 8 years). They were treated for 5 days with 15 mg sibutramine per day or matching placebo in a randomized, double-blind, crossover fashion. At the end of each intervention, heart rate, blood pressure, and MSNA were recorded. Patients underwent cold pressor testing and phenylephrine and nitroprusside infusions. The mean blood pressure (systolic/diastolic) was 118 +/- 13 mm Hg/70 +/- 9 mm Hg with placebo and 120 +/- 13 mm Hg/69 +/- 8 mm Hg with sibutramine (P = .29). The mean resting MSNA was 28 +/- 14 bursts/min with placebo and 12 +/- 10 bursts/min with sibutramine (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .0001). Sibutramine attenuated the rise in blood pressure (25 +/- 9 mm Hg/9 +/- 9 mm Hg versus 31 +/- 12 mm Hg/14 +/- 9 mm Hg, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01) and MSNA (0.3 +/- 0.5 arbitrary units/min versus 1.0 +/- 1.1 arbitrary units/min, P = .01) in response to cold pressor testing. Baroreflex heart rate control was similar with sibutramine and with placebo. The sympathetic baroreflex was shifted such that at a given blood pressure, MSNA was substantially decreased (top, 44 +/- 1.23 bursts/min versus 58 +/- 2.99 bursts/min [P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001]; center point, 65 +/- 0.32 mm Hg versus 67 +/- 0.81 mm Hg [P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05]). Sibutramine treatment profoundly and selectively reduces sympathetic nerve traffic at rest and attenuates the responsiveness to sympathetic stimuli. Our data support the idea that sibutramine&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s peripheral sympathomimetic effect is counteracted by a central sympatholytic mechanism.

Research paper thumbnail of Severely Impaired Baroreflex-Buffering in Patients With Monogenic Hypertension and Neurovascular Contact

Background—We identified a family with a monogenic syndrome of hypertension, brachydactyly, and n... more Background—We identified a family with a monogenic syndrome of hypertension, brachydactyly, and neurovascular contact of the brain stem. Neurovascular contact of the ventrolateral medulla may lead to arterial hypertension by interfering with baroreflex function. Methods and Results—In 5 patients with monogenic hypertension (18 to 34 years old), we conducted detailed autonomic function tests. Blood pressure during complete ganglionic blockade was

Research paper thumbnail of Baroreflex Buffering and Susceptibility to Vasoactive Drugs

Background—The overall effect of vasoactive drugs on blood pressure is determined by a combinatio... more Background—The overall effect of vasoactive drugs on blood pressure is determined by a combination of the direct effect on vascular tone and an indirect baroreflex-mediated effect, a baroreflex buffering of blood pressure. Differences in baroreflex function affect the responsiveness to vasoactive medications, particularly baroreflex buffering of blood pressure; however, the magnitude is not known. Methods and Results—We characterized baroreflex function

Research paper thumbnail of Conditional symbolic analysis detects nonlinear influences of respiration on cardiovascular control in humans

Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Jan 13, 2015

We propose a symbolic analysis framework for the quantitative characterization of complex dynamic... more We propose a symbolic analysis framework for the quantitative characterization of complex dynamical systems. It allows the description of the time course of a single variable, the assessment of joint interactions and an analysis triggered by a conditioning input. The framework was applied to spontaneous variability of heart period (HP), systolic arterial pressure (SAP) and integrated muscle sympathetic nerve activity (MSNA) with the aim of characterizing cardiovascular control and nonlinear influences of respiration at rest in supine position, during orthostatic challenge induced by 80° head-up tilt (TILT) and about 3 min before evoked pre-syncope signs (PRESY). The approach detected (i) the exaggerated sympathetic modulation and vagal withdrawal from HP variability and the increased presence of fast MSNA variability components during PRESY compared with TILT; (ii) the increase of the SAP-HP coordination occurring at slow temporal scales and a decrease of that occurring at faster ti...

Research paper thumbnail of Oscillatory Patterns in Sympathetic Neural Discharge and Cardiovascular Variables During Orthostatic Stimulus

Circulation, 2000

Background-We tested the hypothesis that a common oscillatory pattern might characterize the rhyt... more 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°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. (Circulation. 2000;101:886-892.)

Research paper thumbnail of Sympathetic nerve traffic and circulating norepinephrine levels in RGS2-deficient mice

Autonomic Neuroscience-basic & Clinical, 2007

Regulator of G protein signaling 2 (RGS2−/−) deficient mice feature an increased resting blood pr... more Regulator of G protein signaling 2 (RGS2−/−) deficient mice feature an increased resting blood pressure and an excessive pressor response to stress. We measured renal sympathetic nerve activity (RSNA) directly to test the hypothesis that RSNA is increased in RGS2−/− mice, compared to RGS2+/+ mice. Seventeen mice (RGS2−/−, n=9; RGS2+/+, n=8) were anesthetized with isoflurane. We cannulated the left jugular

Research paper thumbnail of Sympathetic Vasomotor Tone Determines Blood Pressure Response to Long-Term Sibutramine Treatment

The Journal of Clinical Endocrinology & Metabolism, 2007

The serotonin and norepinephrine transporter inhibitor sibutramine is a widely used antiobesity d... more The serotonin and norepinephrine transporter inhibitor sibutramine is a widely used antiobesity drug. In acute studies, the peripheral sympathomimetic effect of sibutramine was counteracted by a central sympatholytic action. The objective was to test the hypothesis that blood pressure responses to long-term sibutramine therapy may be related to sympathetic nerve traffic before treatment in a prospective open-label study in an academic clinical research center. This study comprised 20 obese subjects (body mass index, 30-40 kg/m2; age, 30-57 yr) receiving 5 d of placebo treatment followed by open-label 15 mg/d sibutramine and hypocaloric diet over 12 wk. Body weight, blood pressure, heart rate, muscle sympathetic nerve activity (MSNA) (microneurography), plasma catecholamines, and adipose tissue gene expression were measured. Open-label sibutramine treatment decreased body weight 4.1 kg (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01) and MSNA 17 bursts per minute (P=0.001), and increased diastolic blood pressure 3 mm Hg (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) and heart rate 8 bpm (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). The change in blood pressure with sibutramine treatment was inversely correlated with initial MSNA (r2=0.34; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). Chronic sibutramine treatment increased adrenoreceptor gene expression and plasma catecholamines. The blood pressure response to sibutramine treatment is related to initial MSNA so that subjects with higher MSNA exhibit a smaller increase or even a decrease in blood pressure. The phenomenon might be explained by a sustained reduction in central sympathetic activity with sibutramine treatment.

Research paper thumbnail of PDE3A mutations cause autosomal dominant hypertension with brachydactyly

Nature Genetics, 2015

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major... more Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor 1 . Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB) 2 . The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated 3, 4

Research paper thumbnail of A pilot study comparison of a new method for aortic pulse wave velocity measurements using transthoracic bioimpedance and thigh cuff oscillometry with the standard tonometric method

Journal of the American Society of Hypertension : JASH, Jan 14, 2015

Aortic pulse wave velocity (aPWV) can be measured with different methodologies, including applana... more Aortic pulse wave velocity (aPWV) can be measured with different methodologies, including applanation tonometry. These pilot study findings suggest that impedance cardiography combined with thigh oscillometry provides comparable results. Intra- and inter-observer variability was tested by two observers in two subjects. We instrumented 41 patients and 12 healthy normotensive controls for impedance cardiography and consecutive applanation tonometry and compared methods using the Bland-Altman method. Observer variability for the impedance-thigh cuff method (range, 3.61%-7.77%) was comparable with the tonometric method (range, 2.93%-7.37%). Comparison of the two methods based on the Bland-Altman plot revealed a good agreement between methods. The bias between impedance and tonometric measurements was -0.28 ± 0.37 m/s. Both measurements were significantly correlated (r(2) = 0.94; P < .0001; slope = 1.038).Impedance cardiography combined with thigh oscillometry is an easy to use approa...

Research paper thumbnail of A Novel Pharmacological Approach to Determining Parasympathetic Heart Rate Reserve in Human Subjects

Severe cardiac parasympathetic dysfunction can be diagnosed using bedside tests, such as a Valsal... more Severe cardiac parasympathetic dysfunction can be diagnosed using bedside tests, such as a Valsalva maneuver. However, the tests that are in use are of limited value in detecting and quantifying an early impairment in cardiac parasympathetic function. We showed that α-2-adrenoreceptor stimulation with clonidine combined with pharmacological baroreceptor loading unmasks impaired parasympathetic heart rate reserve before overt changes in heart rate regulation occur. The methodology could be utilized to monitor the progression of autonomic nervous system disease in studies carried out to test neuroprotective strategies.

Research paper thumbnail of Norepinephrine transporter function and tolerance to hypergravitational stress: A pilot study

Pharmacological norepinephrine transporter (NET) inhibition improves orthostatic tolerance on a t... more Pharmacological norepinephrine transporter (NET) inhibition improves orthostatic tolerance on a tilt table while increasing heart rate. We tested the cardiovascular response to NET inhibition during a graded human centrifuge run in seven healthy men. g-Load was increased in 0.5 g steps with 3 g maximal g-load. On two separate days, patients were tested after selective NET inhibition with reboxetine or with placebo in a double-blind, randomized, crossover fashion. Resting diastolic blood pressure increased moderately with NET inhibition. Resting heart rate was profoundly increased by NET inhibition. NET inhibition augmented the heart rate response while attenuating the increase in blood pressure during hypergravitation. NET inhibition could be tested for its potential to improve cardiovascular g-tolerance.

Research paper thumbnail of Alpha-2 adrenergic transmission and human baroreflex regulation

Hypertension, 2004

We observed earlier that central alpha-2 adrenoceptor stimulation in mice greatly augments parasy... more We observed earlier that central alpha-2 adrenoceptor stimulation in mice greatly augments parasympathetic tone. To test the effects in humans, we assessed autonomic vasomotor tone and baroreflex regulation in 9 normal young adults on 2 occasions, once with and once without clonidine. We determined heart rate (HR), beat-by-beat blood pressure (BP), and muscle sympathetic nerve activity. HR variability was analyzed in the time and frequency domain. Pharmacological baroreflex slopes were determined using incremental phenylephrine and nitroprusside infusions. Clonidine lowered resting BP (122+/-4/73+/-3 versus 100+/-7/55+/-3 mm Hg, P<0.01), muscle sympathetic nerve activity (18+/-3 versus 4+/-2 bursts/min, P<0.01), and HR (62+/-3 versus 56+/-3 bpm, P<0.05). The baroreflex heart rate curve was reset to much lower HR values and showed no saturation at low HR. HR variability profoundly increased during clonidine plus phenylephrine (total power: 3224+/-843 versus 8943+/-2329 ms2, ...

Research paper thumbnail of Baroreflex regulation of heart rate and sympathetic vasomotor tone in women and men

Hypertension, 2005

Gender has been reported to influence baroreflex heart rate regulation and baroreflex blood press... more Gender has been reported to influence baroreflex heart rate regulation and baroreflex blood pressure buffering. We tested the hypothesis that gender influences baroreflex regulation of heart rate and sympathetic vasomotor tone. We recruited 32 normal-weight healthy subjects (17 men and 15 women). ECGs for heart rate, brachial and finger blood pressure, and muscle sympathetic nerve activity (MSNA) were measured. Baroreflex heart rate and MSNA regulation were assessed using incremental phenylephrine and nitroprusside infusions. Baseline blood pressure was similar in men and women. MSNA was 21+/-2.5 bursts/min in women and 19+/-2.8 bursts/min in men (NS). The gain of the baroreflex MSNA curves was similar in women and men (-1.9+/-0.2 bursts/min per mm Hg in men and -2.0+/-0.3 bursts/min per mm Hg in women). Baroreflex gain for heart rate regulation was 17+/-3.2 ms/mm Hg in women and 19+/-1.9 ms/mm Hg in men (NS). We conclude that baroreflex gains for heart rate and sympathetic MSNA reg...

Research paper thumbnail of Complexity of impaired parasympathetic heart rate regulation in diabetes

Research paper thumbnail of Preserved functional autonomic phenotype in adult mice overexpressing moderate levels of human alpha-synuclein in oligodendrocytes

Physiological reports, 2014

Mice overexpressing human alpha-synuclein in oligodendrocytes (MBP1-α-syn) recapitulate some key ... more Mice overexpressing human alpha-synuclein in oligodendrocytes (MBP1-α-syn) recapitulate some key functional and neuropathological features of multiple system atrophy (MSA). Whether or not these mice develop severe autonomic failure, which is a key feature of human MSA, remains unknown. We explored cardiovascular autonomic regulation using long-term blood pressure (BP) radiotelemetry and pharmacological testing. We instrumented 12 MBP1-α-syn mice and 11 wild-type mice aged 9 months for radiotelemetry. Animals were tested with atropine, metoprolol, clonidine, and trimethaphan at 9 and 12 months age. We applied spectral and cross-spectral analysis to assess heart rate (HR) and BP variability. At 9 months of age daytime BP (transgenic: 101 ± 2 vs. wild type: 99 ± 2 mmHg) and HR (497 ± 11 vs. 505 ± 16 beats/min) were similar. Circadian BP and HR rhythms were maintained. Nighttime BP (109 ± 2 vs. 108 ± 2 mmHg) and HR (575 ± 15 vs. 569 ± 14 beats/min), mean arterial BP responses to trimeth...

Research paper thumbnail of Conditional symbolic analysis detects nonlinear influences of respiration on cardiovascular control in humans

Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Jan 13, 2015

We propose a symbolic analysis framework for the quantitative characterization of complex dynamic... more We propose a symbolic analysis framework for the quantitative characterization of complex dynamical systems. It allows the description of the time course of a single variable, the assessment of joint interactions and an analysis triggered by a conditioning input. The framework was applied to spontaneous variability of heart period (HP), systolic arterial pressure (SAP) and integrated muscle sympathetic nerve activity (MSNA) with the aim of characterizing cardiovascular control and nonlinear influences of respiration at rest in supine position, during orthostatic challenge induced by 80° head-up tilt (TILT) and about 3 min before evoked pre-syncope signs (PRESY). The approach detected (i) the exaggerated sympathetic modulation and vagal withdrawal from HP variability and the increased presence of fast MSNA variability components during PRESY compared with TILT; (ii) the increase of the SAP-HP coordination occurring at slow temporal scales and a decrease of that occurring at faster ti...

Research paper thumbnail of Adrenergic and Atrial Natriuretic Peptide Interactions on Human Cardiovascular and Metabolic Regulation

Context: Atrial natriuretic peptide (ANP) has well-known cardiovascular effects and modifies lipi... more Context: Atrial natriuretic peptide (ANP) has well-known cardiovascular effects and modifies lipid and carbohydrate metabolism in humans.

Research paper thumbnail of Water Drinking Acutely Improves Orthostatic Tolerance in Healthy Subjects

Background—Orthostatic symptoms and syncope are common, even in apparently healthy subjects. In p... more 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, 312 years) ingested

Research paper thumbnail of Interaction between b-Adrenergic Receptor Stimulation and Nitric Oxide Release on Tissue Perfusion and Metabolism

Nitric oxide (NO) may be an important modulator of sympathetic tone. We used im and sc microdialy... more Nitric oxide (NO) may be an important modulator of sympathetic tone. We used im and sc microdialysis in humans to characterize the interaction of NO synthase inhibition and adrenoreceptor stimulation on tissue perfusion, metabolism, and norepinephrine release. Micro- dialysis probes were perfused with L -o rD-nitro-L-arginine-methyl- ester (100 mmol/L) followed by incremental doses of isoproterenol, epinephrine, or nitroprusside. Blood flow

Research paper thumbnail of Beta-Adrenergic and Atrial Natriuretic Peptide Interactions on Human Cardiovascular and Metabolic Regulation Short title: ANP and beta-adrenergic receptors

et al.. Beta-adrenergic and atrial natriuretic peptide interactions on human cardiovascular and m... more et al.. Beta-adrenergic and atrial natriuretic peptide interactions on human cardiovascular and metabolic regulation.

Research paper thumbnail of Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects

Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity tr... more Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment. Studies in healthy subjects suggested that sibutramine might have opposing effects on peripheral and central sympathetic activity; an increase in blood pressure has been claimed. Direct measurements of muscle sympathetic nerve activity (MSNA) in sibutramine-treated patients have not been conducted. Twenty nondiabetic obese men and women completed the study (mean body mass index, 35 +/- 3 kg/m2; mean age, 42 +/- 8 years). They were treated for 5 days with 15 mg sibutramine per day or matching placebo in a randomized, double-blind, crossover fashion. At the end of each intervention, heart rate, blood pressure, and MSNA were recorded. Patients underwent cold pressor testing and phenylephrine and nitroprusside infusions. The mean blood pressure (systolic/diastolic) was 118 +/- 13 mm Hg/70 +/- 9 mm Hg with placebo and 120 +/- 13 mm Hg/69 +/- 8 mm Hg with sibutramine (P = .29). The mean resting MSNA was 28 +/- 14 bursts/min with placebo and 12 +/- 10 bursts/min with sibutramine (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .0001). Sibutramine attenuated the rise in blood pressure (25 +/- 9 mm Hg/9 +/- 9 mm Hg versus 31 +/- 12 mm Hg/14 +/- 9 mm Hg, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01) and MSNA (0.3 +/- 0.5 arbitrary units/min versus 1.0 +/- 1.1 arbitrary units/min, P = .01) in response to cold pressor testing. Baroreflex heart rate control was similar with sibutramine and with placebo. The sympathetic baroreflex was shifted such that at a given blood pressure, MSNA was substantially decreased (top, 44 +/- 1.23 bursts/min versus 58 +/- 2.99 bursts/min [P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001]; center point, 65 +/- 0.32 mm Hg versus 67 +/- 0.81 mm Hg [P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05]). Sibutramine treatment profoundly and selectively reduces sympathetic nerve traffic at rest and attenuates the responsiveness to sympathetic stimuli. Our data support the idea that sibutramine&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s peripheral sympathomimetic effect is counteracted by a central sympatholytic mechanism.

Research paper thumbnail of Severely Impaired Baroreflex-Buffering in Patients With Monogenic Hypertension and Neurovascular Contact

Background—We identified a family with a monogenic syndrome of hypertension, brachydactyly, and n... more Background—We identified a family with a monogenic syndrome of hypertension, brachydactyly, and neurovascular contact of the brain stem. Neurovascular contact of the ventrolateral medulla may lead to arterial hypertension by interfering with baroreflex function. Methods and Results—In 5 patients with monogenic hypertension (18 to 34 years old), we conducted detailed autonomic function tests. Blood pressure during complete ganglionic blockade was

Research paper thumbnail of Baroreflex Buffering and Susceptibility to Vasoactive Drugs

Background—The overall effect of vasoactive drugs on blood pressure is determined by a combinatio... more Background—The overall effect of vasoactive drugs on blood pressure is determined by a combination of the direct effect on vascular tone and an indirect baroreflex-mediated effect, a baroreflex buffering of blood pressure. Differences in baroreflex function affect the responsiveness to vasoactive medications, particularly baroreflex buffering of blood pressure; however, the magnitude is not known. Methods and Results—We characterized baroreflex function