Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study

This study assessed the safety and efficacy of a novel implantable device therapy in resistant hypertension patients.

Sustained acute voltage-dependent blood pressure decrease with prolonged carotid baroreflex activation in therapy-resistant hypertension

Chronic carotid baroreflex stimulation (Rheos system) has been shown to effectively reduce blood pressure in patients with resistant hypertension. Upon acute stimulation blood pressure also falls as a function of voltage. the aim of this study is to evaluate whether this voltage-dependent blood pressure decrease is preserved after long-term carotid baroreflex stimulation.

Acute device-based blood pressure reduction: electrical activation of the carotid baroreflex in patients undergoing elective carotid surgery

Carotid sinus baroreceptors are involved in controlling blood pressure (BP) by providing input to the cardiovascular regulatory centers of the medulla. The acute effect of temporarily placing an electrode on the carotid sinus wall to electrically activate the baroreflex was investigated. We studied 11 patients undergoing elective carotid surgery. Baseline BP was 146+30/66+/-17 mm Hg and heart rate (HR) 72+/-7 bpm (mean +/- standard deviation). An electrode was placed upon the carotid sinus and after obtaining a steady state baseline of BP and HR, an electric current was applied and increased in 1-volt increments. A voltage dependent and highly significant reduction in BP was observed which averaged 18+/-26* and 8.0+/-12 mm Hg for systolic BP and diastolic BP, respectively. Maximal reductions occurred at 4.4+/-1.2 V: 23+/-24 mm Hg*, 16+/-10 mm Hg* and 7+/-12 bpm* for systolic BP, diastolic BP and HR, respectively ( = p <.05). Thus, electrical stimulation of the carotid sinus activates the carotid baroreflex resulting in a reduction in BP and HR. This presents a proof of concept for device based baroreflex modulation in acute BP regulation and adds to the available data which provide a rationale for evaluating this system in the context of chronic BP reduction in hypertensive patients.

An implantable carotid sinus baroreflex activating system: surgical technique and short-term outcome from a multi-center feasibility trial for the treatment of resistant hypertension

OBJECTIVES: To assess perioperative outcomes and blood pressure (BP) responses to an implantable carotid sinus baroreflex activating system being investigated for the treatment of resistant hypertension. METHODS: We report on the first seventeen patients enrolled in a multicenter study. Bilateral perivascular carotid sinus electrodes (CSL) and a pulse generator (IPG) are permanently implanted. Optimal placement of the CSL is determined by intraoperative BP responses to test activations. Acute BP responses were tested postoperatively and during the first four months of follow-up. RESULTS: Prior to implant, BP was 189.6+/-27.5/110.7+/-15.3 mmHg despite stable therapy (5.2+/-1.8 antihypertensive drugs). The mean procedure time was 202+/-43 minutes. No perioperative strokes or deaths occurred. System tests performed 1 or up to 3 days postoperatively resulted in significant (all p < or = 0.0001) mean maximum reduction, with standard deviations and 95% confidence limits for systolic BP, diastolic BP and heart rate of 28+/-22 (17, 39) mmHg, 16+/-11 (10, 22) mmHg and 8+/-4 (6, 11) BPM, respectively. Repeated testing during 3 months of therapeutic electrical activation demonstrated a durable response. CONCLUSIONS: These preliminary data suggest an acceptable safety of the procedure with a low rate of adverse events and support further clinical development of baroreflex activation as a new concept to treat resistant hypertension.

[Drug-independent blood pressure control through the autonomous nervous system]

Arterial hypertension is a chronic disease with a therapeutical challenge for the patient and the physician involved. Patient-independent techniques with good efficacy and tolerability are wanted. The autonomous nervous system insufficiently therapeutically exploited to date, is now approachable by two types of intervention: renal nerve ablation, an endovascular approach without remaining foreign body, and BAT, baroreflex activating therapy using an implantable device stimulating the carotid sinus. The blood pressure lowering potency of BAT appears more than with renal nerve ablation and also clinical study data are more prevalent. With both treatment options the patients having the most profit are insufficiently defined. Given this knowledge, any form of secondary hypertension needs to be excluded beforehand.

Autonomic cardiovascular regulation in obesity

Obese persons suffer from an increased mortality risk supposedly due to cardiovascular disorders related to either continuously lowered parasympathetic or altered sympathetic activation. Our cross-sectional correlation study establishes the relationship between obesity and autonomic regulation as well as salivary cortisol levels. Three patient cohorts were sampled, covering ranges of body mass index (BMI) of 27-32 (n=17), 33-39 (n=13) and above 40 kg/m(2)(n=12), and stratified for age, sex and menopausal status. Autonomic cardiovascular regulation was assessed by use of heart rate variability and continuous blood pressure recordings. Spectral analytical calculation (discrete Fourier transformation) yields indices of sympathetic and parasympathetic activation and baroreflex sensitivity. Morning salivary cortisol was concurrently collected. Contrary to expectation, BMI and waist/hip ratio (WHR) were inversely correlated with sympathetic activity. This was true for resting conditions (r=-0.48, P<0.001; r=-0.33, P<0.05 for BMI and WHR respectively) and for mental challenge (r=-0.42, P<0.01 for BMI). Resting baroreflex sensitivity was strongly related to the degree of obesity at rest (BMI: r=-0.35, P<0.05) and for mental challenge (r=-0.53, P<0.001). Salivary cortisol correlated significantly with waist circumference (r=-0.34, P=0.05). With increasing weight, no overstimulation was found but a depression in sympathetic and parasympathetic activity together with a significant reduction in baroreflex functioning and in salivary cortisol levels.

Effects of chronic baroreceptor stimulation on the autonomic cardiovascular regulation in patients with drug-resistant arterial hypertension

In patients with drug-resistant hypertension, chronic electric stimulation of the carotid baroreflex is an investigational therapy for blood pressure reduction. We hypothesized that changes in cardiac autonomic regulation can be demonstrated in response to chronic baroreceptor stimulation, and we analyzed the correlation with blood pressure changes. Twenty-one patients with drug-resistant hypertension were prospectively included in a substudy of the Device Based Therapy in Hypertension Trial. Heart rate variability and heart rate turbulence were analyzed using 24-hour ECG. Recordings were obtained 1 month after device implantation with the stimulator off and after 3 months of chronic electric stimulation (stimulator on). Chronic baroreceptor stimulation decreased office blood pressure from 185+/-31/109+/-24 mm Hg to 154+/-23/95+/-16 mm Hg (P<0.0001/P=0.002). Mean heart rate decreased from 81+/-11 to 76+/-10 beats per minute(-1) (P=0.001). Heart rate variability frequency-domain parameters assessed using fast Fourier transformation (FFT; ratio of low frequency:high frequency: 2.78 versus 2.24 for off versus on; P<0.001) were significantly changed during stimulation of the carotid baroreceptor, and heart rate turbulence onset was significantly decreased (turbulence onset: -0.002 versus -0.015 for off versus on; P=0.004). In conclusion, chronic baroreceptor stimulation causes sustained changes in heart rate variability and heart rate turbulence that are consistent with inhibition of sympathetic activity and increase of parasympathetic activity in patients with drug-resistant systemic hypertension; these changes correlate with blood pressure reduction. Whether the autonomic modulation has favorable cardiovascular effects beyond blood pressure control should be investigated in further studies.

Differential effects of captopril and nitrates on muscle sympathetic nerve activity in volunteers

BACKGROUND The sympathetic nervous system (SNS) is an important regulator of cardiovascular function. Activation of SNS plays an important role in the pathophysiology and the prognosis of cardiovascular diseases such as heart failure, acute coronary syndromes, arrhythmia, and possibly hypertension. Vasodilators such as adenosine and sodium nitroprusside are known to activate SNS via baroreflex mechanisms. Because vasodilators are widely used in the treatment of patients with cardiovascular diseases, the aim of the present study was to assess the influence of clinically used dosages of isosorbide dinitrate and captopril on sympathetic nerve activity at rest and during stimulatory maneuvers. METHODS AND RESULTS Twenty-eight healthy volunteers were included in this double-blind placebo-controlled study, and muscle sympathetic nerve activity (MSA; with microelectrodes in the peroneal nerve), blood pressure, heart rate, and neurohumoral parameters were measured before and 90 minutes after the oral administration of 40 mg isosorbide dinitrate or 6.25 mg captopril. Furthermore, a 3-minute mental stress test and a cold pressor test were performed before and 90 minutes after drug administration. Resting MSA did not change after captopril and decreased compared with placebo (P < .05 versus placebo), whereas isosorbide dinitrate led to a marked increase in MSA (P < .05). Systolic blood pressure was reduced by isosorbide dinitrate (P < .05), whereas captopril decreased diastolic blood pressure (P < .05). The increases in MSA, blood pressure, and heart rate during mental stress were comparable before and after drug administration regardless of the medication. During cold pressor test, MSA and systolic and diastolic blood pressures increased to the same degree independent of treatment, but after isosorbide dinitrate, the increase in MSA seemed to be less pronounced. Heart rate did not change during cold stimulation. Plasma renin activity increased after captopril and isosorbide dinitrate (P < .05), whereas placebo had no effect. Endothelin-1 increased after placebo and isosorbide dinitrate (P < .05) but not after captopril. CONCLUSIONS Thus, captopril suppressed MSA despite lowering of diastolic blood pressure but allowed normal adaptation of the SNS during mental or physical stress. In contrast, the nitrate strongly activated the SNS under baseline conditions. These findings demonstrate that vasodilators differentially interact with the SNS, which could be of importance in therapeutic strategies for the treatment of patients with cardiovascular diseases.

Analysis of Pressure Head-Flow Loops of Pulsatile Rotodynamic Blood Pumps

The clinical importance of pulsatility is a recurring topic of debate in mechanical circulatory support. Lack of pulsatility has been identified as a possible factor responsible for adverse events and has also demonstrated a role in myocardial perfusion and cardiac recovery. A commonly used method for restoring pulsatility with rotodynamic blood pumps (RBPs) is to modulate the speed profile, synchronized to the cardiac cycle. This introduces additional parameters that influence the (un)loading of the heart, including the timing (phase shift) between the native cardiac cycle and the pump pulses, and the amplitude of speed modulation. In this study, the impact of these parameters upon the heart-RBP interaction was examined in terms of the pressure head-flow (HQ) diagram. The measurements were conducted using a rotodynamic Deltastream DP2 pump in a validated hybrid mock circulation with baroreflex function. The pump was operated with a sinusoidal speed profile, synchronized to the native cardiac cycle. The simulated ventriculo-aortic cannulation showed that the level of (un)loading and the shape of the HQ loops strongly depend on the phase shift. The HQ loops displayed characteristic shapes depending on the phase shift. Increased contribution of native contraction (increased ventricular stroke work [WS ]) resulted in a broadening of the loops. It was found that the previously described linear relationship between WS and the area of the HQ loop for constant pump speeds becomes a family of linear relationships, whose slope depends on the phase shift.

Electrical carotid baroreceptor stimulation

The Barostim neo ™ system is a novel implantable device that activates the carotid baroreflex. It decreases the sympathetic activity and inhibits the renin system, which results in reduced blood pressure and heart rate. In patients with resistant hypertension, electrically activation of the baroreflex leads to an average decrease in systolic blood pressure of 38, 36, 40 and 53 mmHg at 1, 2, 3 and 4 years, respectively. Additionally, cardiac remodelling with reduced left ventricular mass and posterior wall thickness has been observed in long-term studies. In a limited number of patients with heart failure, baroreflex activation therapy leads to a decrease in muscle sympathetic nerve activity and to improved quality of life and functional capacities. The implantation procedure is safe and associated with risks comparable with those of other active implantable devices. Barostim neo is currently available in several European countries.

Karotisstimulation. Update zum aktuellen Forschungsstand

Beim Karotisstimulator handelt es sich um ein Gerät, welches den Baroreflex-Mechanismus elektrisch aktiviert. Dies hat zur Folge, dass der Sympathikotonus abgeschwächt und das ­Renin-Angiotensin-Aldosteron-System gedämpft wird, was eine Reduktion des Blutdrucks und der Herzfrequenz bewirkt. Die Baroreflex-Aktivierungstherapie (BAT) führt im Langzeitverlauf zu einer dauerhaften durchschnittlichen Senkung des systoli­schen Blutdrucks von 40–50 mmHg nach vier Jahren. Bei den Patienten konnte ausser der blutdrucksenkenden Wirkung eine Reduktion der Herzmuskeldicke festgestellt werden. Die Wirkung bei Patienten mit Herzinsuffizienz wird zurzeit geprüft. Die Implantation des Geräts gilt als sicher. Der Karotis­stimulator ist nun in mehreren europäischen Ländern erhältlich.