Siegfried Eckert

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.

Novel Baroreflex Activation Therapy in Resistant Hypertension Results of a European Multi-Center Feasibility Study

OBJECTIVES This study assessed the safety and efficacy of a novel implantable device therapy in resistant hypertension patients. BACKGROUND Despite the availability of potent antihypertensive drugs, a substantial proportion of patients remain hypertensive. A new implantable device (Rheos system, CVRx, Inc., Minneapolis, Minnesota) that activates the carotid baroreflex may help these patients. METHODS Forty-five subjects with systolic blood pressure ≥160 mm Hg or diastolic ≥90 mm Hg despite at least 3 antihypertensive drugs were enrolled in a prospective, nonrandomized feasibility study to assess whether Rheos therapy could safely lower blood pressure. Subjects were followed up for as long as 2 years. An external programmer was used to optimize and individualize efficacy. RESULTS Baseline mean blood pressure was 179/105 mm Hg and heart rate was 80 beats/min, with a median of 5 antihypertensive drugs. After 3 months of device therapy, mean blood pressure was reduced by 21/12 mm Hg. This result was sustained in 17 subjects who completed 2 years of follow-up, with a mean reduction of 33/22 mm Hg. The device exhibited a favorable safety profile. CONCLUSIONS The Rheos device sustainably reduces blood pressure in resistant hypertensive subjects with multiple comorbidities receiving numerous medications. This unique therapy offers a safe individualized treatment option for these high-risk subjects. This novel approach holds promise for patients with resistant hypertension and is currently under evaluation in a prospective, placebo-controlled clinical trial.

Comparison of Portapres non-invasive blood pressure measurement in the finger with intra-aortic pressure measurement during incremental bicycle exercise.

Background and designIn order to evaluate the accuracy of continuous, non-invasive blood pressure measurements in the finger during stress, blood pressure was measured in six patients with a Portapres Model 2 during increasing levels of bicycle exercise, using simultaneously registered intra-aortic (aortic arch) pressure as a reference. MethodsBlood pressure was measured continuously and non-invasively in the left middle finger using the Portapres Model 2 device, at the same time invasively using a pigtail catheter situated in the aortic arch at rest and during and after standardized bicycle exercise. At the end of each stress level, in accordance with the protocol of the Association for the Advancement of Medical Intrumentation, systolic and diastolic blood pressure and pulse values were determined from the non-invasive (Portapres Model 2) and invasive measurements for 15 s each, and the mean values and standard deviations were calculated. ResultsCompared with simultaneous invasive blood pressure measurement in the aortic arch, the difference in measured blood pressure value (the value determined by the device minus the value determined invasively) at rest fell within the authorized normal range for German and European blood pressure measurement devices: systolic +1.7 ± 1.8 mmHg and diastolic –3.7 ± 6.2 mmHg. The difference in measured value increased with the stress level. ConclusionBlood pressure and pulse can be determined reliably and accurately using the Portapres Model 2, non-invasively, both at rest and at low-to-moderate levels of stress.

Limited acute influences of electrical baroreceptor activation on insulin sensitivity and glucose delivery: a randomized, double-blind, crossover clinical study.

Arterial baroreflexes may regulate resistance vessels supplying glucose to skeletal muscle by modulating efferent sympathetic nervous system activity. We hypothesized that selective manipulation of baroreflex activity through electrical carotid sinus stimulation influences insulin sensitivity by changing muscular glucose delivery. We enrolled 16 hypertensive patients who responded to treatment with an electrical carotid sinus stimulator. Patients were submitted to a frequently sampled intravenous glucose tolerance test (FSIGT) with the stimulator on and with the stimulator off on separate days in a randomized, double-blind, crossover study. We monitored interstitial glucose, lactate, and pyruvate in the vastus lateralis muscle using microdialysis. Glucose and insulin concentrations in arterialized venous blood before and during FSIGT were virtually identical with the stimulator on and with the stimulator off. Insulin sensitivity, the primary end point of this study, was 3.3 ± 1.0 (mU/L)−1 ⋅ min−1 and 4.4 ± 2.6 (mU/L)−1 ⋅ min−1 (on vs. off; P = 0.7). Interstitial glucose, lactate, and pyruvate increased similarly during FSIGT regardless of the stimulator settings. In conclusion, acute changes in baroreceptor stimulation did not elicit significant changes in muscular glucose delivery and whole-body insulin sensitivity. Baroreflex-mediated changes in sympathetic vasomotor tone may have a limited acute effect on muscle glucose metabolism in patients with treatment-resistant hypertension.

Myocardial Sympathetic Innervation in Patients with Symptomatic Coronary Artery Disease: Follow-up After 1 Year with Neurostimulation

In both diabetic and nondiabetic patients, there is a loose correlation between coronary flow reserve (CFR) and sympathetic innervation in viable myocardial segments. The loose correlation implies that sympathetic innervation may be preserved even with major impairment of myocardial blood supply. In some patients, denervation is due to repetitive episodes of ischemia in areas with severely reduced CFR. We investigated the long-term effect of reduced CFR on myocardial sympathetic innervation in diabetic and nondiabetic patients with spinal cord stimulation. Methods: We analyzed 23 patients (10 diabetic and 13 nondiabetic) with coronary artery disease and without known cardiac autonomic neuropathy. At baseline, we determined quantitative myocardial blood flow using 13N-ammonia PET, myocardial viability using 18F-FDG PET, and cardiac innervation using 11C-hydroxyephedrine (HED) PET. At the 1-y follow-up we measured CFR and 11C-HED retention. During follow-up, no cardiac intervention was performed and no myocardial infarction occurred. In all patients, spinal cord stimulation was performed for relief of angina. Results: There was no significant difference in segmental 11C-HED retention between baseline and follow-up in the whole patient group. In diabetic patients, as well as in segments with severely reduced CFR (<1.5), 11C-HED retention showed a small but significant decrease (P < 0.05). Linear regression of segmental 11C-HED retention between baseline and follow-up was high (r2 = 0.81), confirming good reproducibility of the investigation on the one hand and little change in regional sympathetic innervation on the other hand. Conclusion: In patients with stable chronic coronary artery disease, sympathetic innervation of the myocardium is almost unchanged in both diabetic and nondiabetic patients in a 1-y follow-up. In myocardial segments with severely altered blood supply, a small but significant decrease in 11C-HED retention most probably reflects ischemic neuronal damage. The prognostic relevance of sympathetic denervation in viable myocardium still has to be determined.

Myocardial perfusion after one year of spinal cord stimulation in patients with refractory angina.

AIM Spinal cord stimulation (SCS) is recommended for patients with coronary artery disease (CAD) and refractory angina. We used positron emission tomography (PET) to investigate the long-term effect of SCS on regional myocardial perfusion in patients suffering from angina pectoris refractory to medical treatment and without option for coronary intervention. PATIENTS, METHODS We analyzed data of 44 patients with stable CAD (91% three vessel disease). At baseline, we determined coronary flow reserve (CFR) using 13N-ammonia-PET and myocardial viability with 18F-FDG. SCS was performed for one year (Medtronic Itrell III or Synergy, Düsseldorf, Germany). During follow-up, no cardiac interventions were necessary and no myocardial infarctions occurred. At one year follow-up, CFR was measured again. RESULTS In the majority of patients (77%), SCS led to an improvement of clinical symptoms. CFR did not change significantly during follow-up. Subjective improvement did not correlate with an increase of CFR. CONCLUSIONS Despite its clinical effect, SCS does not have a direct impact on CFR in patients with stable CAD. According to our results, the pain relief is not due to an improvement of the myocardial blood supply.

A universal standard for the validation of blood pressure measuring devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement

In the past 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring, and the International Organization for Standardization (ISO), have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers, and manufacturers, would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by the AAMI, ESH, and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH, and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.

Meta-analysis of three observational studies of amlodipine/valsartan in hypertensive patients with additional risk factors

Abstract Objectives. In this study, the effectiveness of amlodipine/valsartan single-pill combination was assessed in hypertensive patients with diabetes, metabolic risk or overweight. Methods. Data from 12,265 patients treated with amlodipine/valsartan from three studies were analyzed in a meta-analysis. These studies focused on (i) non-diabetic hypertensive patients suffering from abdominal obesity; (ii) hypertensive patients with at least one metabolic risk factor; and (iii) hypertensive patients with type 2 diabetes mellitus. The observation periods were 16 weeks for the first two and 24 weeks for the latter cohort. Results. At start of observation, the mean blood pressure was 162.3 mmHg (systolic) and 93.5 mmHg (diastolic). A total of 7.4% of patients were aged ≥ 80 years. At end of the observation, a normalized blood pressure was present in 38.8% of patients. No appreciable differences in blood pressure reduction were evident between the study groups. In both age subgroups (< 80 years and ≥ 80 years) blood pressure reduction was comparable. Tolerability was assessed by treating physicians as “very good” (69.3%) and “good” (27.3%). Conclusions. In daily practice, treatment of hypertensive patients with additional risk factors with amlodipine/valsartan single-pill combinations is well tolerated and associated with effective reduction of blood pressure.

The German Hypertension League (Deutsche Hochdruckliga) Quality Seal Protocol for blood pressure-measuring devices: 15-year experience and results from 105 devices for home blood pressure control

ObjectiveThe German Hypertension League (Deutsche Hochdruckliga) established a program to assess the accuracy and reliability of blood pressure (BP)-measuring devices in 1999 (Quality Seal Protocol). Here, we report on the results of a testing series of 105 devices designed for BP self-measurement. MethodsThe test protocol for the validation of upper-arm, wrist, and finger devices was developed to compare device to conventional Riva-Rocci measurements based on five criteria: mean systolic and mean diastolic differences, their standard deviations, and a point score representing the correlation of systolic and diastolic errors of individual comparisons. The results of this testing are summarized. ResultsFrom 1999 to 2014, a total of 105 BP devices for self-measurement were tested according to the Quality Seal Protocol. Of these, 47.6% fulfilled all five validation criteria, 55.7% of the upper-arm devices (39 of 71) and 32.4% (11 of 34) of the wrist devices. Finger devices were not offered for testing. Forty-four devices (41.9%) failed multiple test criteria of the validation procedure. A subanalysis with 51 devices tested showed that a stricter definition of the passing point score with a limit of at least 55% would slightly increase the consistency with the conventional criteria in comparison with a point score criterion of at least 50%. It was therefore introduced in 2007. ConclusionThe results indicate the importance of a rigorous testing of a BP-measuring device used for home BP measurement to prevent patients from making erroneous treatment decisions.

A universal standard for the validation of blood pressure measuring devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement.

: In the last 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring and the International Organization for Standardization (ISO) have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers and manufacturers would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by AAMI, ESH and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.