Julia Brinkmann

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.

Acute Response to Unilateral Unipolar Electrical Carotid Sinus Stimulation in Patients With Resistant Arterial Hypertension

Bilateral bipolar electric carotid sinus stimulation acutely reduced muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant arterial hypertension but is no longer available. The second-generation device uses a smaller unilateral unipolar disk electrode to reduce invasiveness while saving battery life. We hypothesized that the second-generation device acutely lowers BP and MSNA in treatment-resistant hypertensive patients. Eighteen treatment-resistant hypertensive patients (9 women/9 men; 53±11 years; 33±5 kg/m2) on stable medications have been included in the study. We monitored finger and brachial BP, heart rate, and MSNA. Without stimulation, BP was 165±31/91±18 mm Hg, heart rate was 75±17 bpm, and MSNA was 48±14 bursts per minute. Acute stimulation with intensities producing side effects that were tolerable in the short term elicited interindividually variable changes in systolic BP (–16.9±15.0 mm Hg; range, 0.0 to −40.8 mm Hg; P=0.002), heart rate (−3.6±3.6 bpm; P=0.004), and MSNA (−2.0±5.8 bursts per minute; P=0.375). Stimulation intensities had to be lowered in 12 patients to avoid side effects at the expense of efficacy (systolic BP, −6.3±7.0 mm Hg; range, 2.8 to −14.5 mm Hg; P=0.028 and heart rate, −1.5±2.3 bpm; P=0.078; comparison against responses with side effects). Reductions in diastolic BP and MSNA (total activity) were correlated (r2=0.329; P=0.025). In our patient cohort, unilateral unipolar electric baroreflex stimulation acutely lowered BP. However, side effects may limit efficacy. The approach should be tested in a controlled comparative study.

Patients With Continuous-Flow Left Ventricular Assist Devices Provide Insight in Human Baroreflex Physiology

The superior clinical outcome of new continuous-flow left ventricular assist devices (LVADs) challenges the physiological dogma that cardiovascular autonomic homeostasis requires pulsatile blood flow and pressure. We tested the hypothesis that continuous-flow LVADs impair baroreflex control of sympathetic nerve traffic, thus further exacerbating sympathetic excitation. We included 9 male heart failure patients (26–61 years; 18.9–28.3 kg/m2) implanted with a continuous-flow LVAD. We recorded ECG, respiration, finger blood pressure, brachial blood pressure, and muscle sympathetic nerve activity. After baseline measurements had been taken, patients underwent autonomic function testing including deep breathing, a Valsalva maneuver, and 15° head-up tilt. Finally, we increased the LVAD speed in 7 patients. Spontaneous sympathetic baroreflex sensitivity was analyzed. Brachial blood pressure was 99±4 mm Hg with 14±2 mm Hg finger pulse pressure. Muscle sympathetic nerve activity bursts showed a normal morphology, were linked to the cardiac cycle, and were suppressed during blood pressure increases. Mean burst frequency was lower compared with age- and body mass index–matched controls in 2 patients, slightly increased in 4 patients, and increased in 2 patients (P=0.11). Muscle sympathetic nerve activity burst latency and the median values of the burst amplitude distribution were similar between groups. Muscle sympathetic nerve activity increased 4±1 bursts per minute with head-up tilt (P<0.0003) and decreased 3±4 bursts per minute (P<0.031) when LVAD speed was raised. The mean sympathetic baroreflex slope was −3.75±0.79%/mm Hg in patients and −3.80±0.55%/mm Hg in controls. We conclude that low pulse pressure levels are sufficient to restrain sympathetic nervous system activity through baroreflex mechanisms.

Electrical carotid sinus stimulation in treatment resistant arterial hypertension.

Treatment resistant arterial hypertension is commonly defined as blood pressure that remains above goal in spite of the concurrent use of three antihypertensive agents of different classes. The sympathetic nervous system promotes arterial hypertension and cardiovascular as well as renal damage, thus, providing a logical treatment target in these patients. Recent physiological studies suggest that baroreflex mechanisms contribute to long-term control of sympathetic activity and blood pressure providing an impetus for the development of electrical carotid sinus stimulators. The concept behind electrical stimulation of baroreceptors or baroreflex afferent nerves is that the stimulus is sensed by the brain as blood pressure increase. Then, baroreflex efferent structures are adjusted to counteract the perceived blood pressure increase. Electrical stimulators directly activating afferent baroreflex nerves were developed years earlier but failed for technical reasons. Recently, a novel implantable device was developed that produces an electrical field stimulation of the carotid sinus wall. Carefully conducted experiments in dogs provided important insight in mechanisms mediating the depressor response to electrical carotid sinus stimulation. Moreover, these studies showed that the treatment success may depend on the underlying pathophysiology of the hypertension. Clinical studies suggest that electrical carotid sinus stimulation attenuates sympathetic activation of vasculature, heart, and kidney while augmenting cardiac vagal regulation, thus lowering blood pressure. Yet, not all patients respond to treatment. Additional clinical trials are required. Patients equipped with an electrical carotid sinus stimulator provide a unique opportunity gaining insight in human baroreflex physiology.

Truly Refractory Hypertension

What really is refractory or resistant hypertension? Twenty years ago, Setaro and Black defined the condition as blood pressure >140/90 mm Hg, no evidence of secondary hypertension, maximal doses of at least 2 appropriate antihypertensive agents, and sufficient treatment duration to allow the treatments to be effective.1 Today, we would probably expand the definition to at least 3 agents2 or patients who do not respond to 3 agents, including a thiazide diuretic plus mineralocorticoid-receptor inhibition. Thirty years ago, Swales et al performed a trial of regimens for such patients.3 One of the following 4 regimens was used: oral diazoxide, minoxidil, captopril, or quadruple therapy (diuretic+β-adrenoceptor blocker+hydralazine+prazosin). Despite the severity of hypertension, blood pressure could be controlled in almost all these patients. Since then, sleep apnea has come under scrutiny as a common unappreciated cause. Ruttanaumpawan et al found that about half of their 42 therapy-resistant patients with hypertension were suffering from obstructive sleep apnea.4 Of course, there is always the lingering possibility that the patients are just not ingesting their medicines, and novel strategies have been developed to deal with that issue.5 The advent of device-related treatments has pretty well laid the issue of refractory hypertension to rest. Typing the condition into search engines invariably leads the searcher to articles on catheter-based renal denervation.6 We present a case that we believe is an example for truly resistant hypertension, and we like to coin in the term device-resistant hypertension into the debate about uncontrollable hypertension. Our patient, who kindly provided written consent for this report, is a slender (body mass index, 17.4 kg/m2) 51-year-old woman, who was normotensive until age 36 years. By that time, she had had 4 uneventful pregnancies without complications. Her mother was hypertensive, and her father also had elevated blood pressure …

Spike rate of multi-unit muscle sympathetic nerve fibers after catheter-based renal nerve ablation

Patients with treatment-resistant arterial hypertension exhibited profound reductions in single sympathetic vasoconstrictor fiber firing rates after renal nerve ablation. In contrast, integrated multi-unit muscle sympathetic nerve activity (MSNA) changed little or not at all. We hypothesized that conventional MSNA analysis may have missed single fiber discharges, thus, obscuring sympathetic inhibition after renal denervation. We studied patients with difficult-to-control arterial hypertension (age 45-74 years) before, 6 (n = 11), and 12 months (n = 8) after renal nerve ablation. Electrocardiogram, respiration, brachial, and finger arterial blood pressure (BP), as well as the MSNA and raw MSNA signals were analyzed. We detected MSNA action-potential spikes using 2 stage kurtosis wavelet denoising techniques to assess mean, median, and maximum spike rates for each beat-to-beat interval. Supine heart rate and systolic BP did not change at 6 (ΔHR: -2 ± 3 bpm; ΔSBP: 2 ± 9 mm Hg) or at 12 months (ΔHR: -1 ± 3 mm Hg, ΔSBP: -1 ± 9 mm Hg) after renal nerve ablation. Mean burst frequency and mean spike frequency at baseline were 34 ± 3 bursts per minute and 8 ± 1 spikes per second. Both measurements did not change at 6 months (-1.4 ± 3.6 bursts/minute; -0.6 ± 1.4 spikes/second) or at 12 months (-2.5 ± 4.0 bursts/minute; -2.0 ± 1.6 spikes/second) after renal nerve ablation. After renal nerve ablation, BP decreased in 3 of 11 patients. BP and MSNA spike frequency changes were not correlated (slope = -0.06; P = .369). Spike rate analysis of multi-unit MSNA neurograms further suggests that profound sympathetic inhibition is not a consistent finding after renal nerve ablation.

Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High‐Fidelity Cardiovascular Phenotyping

Background Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization‐activated cyclic nucleotide–gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. Methods and Results We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading. Conclusions HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.

Physiology Unmasks Hypertension

When giving classes on diagnosis and treatment of hypertension to medical students or doctors in training, we receive the impression from their glassy-eyed looks that this important entity no longer has luster. Apparently, hypertension is considered an easy fix, both in terms of diagnosis and clinical management. Why even bother to think about human cardiovascular physiology when the disease mechanisms are largely unknown? Have the nurse measure brachial blood pressure (BP), prescribe a guideline-recommended drug, and add drugs as needed to attain target BP. The patient minority refusing to respond to such treatment undergoes standardized test batteries according to the diagnostic algorithm of choice to rule out secondary hypertension. Indeed, hypertension management has made great strides in the past decades such that in many patients BP can be controlled with effective, safe, and well-tolerated drugs or combinations. Whether or not device-based treatments will have a role in tougher cases remains to be shown.1,2 Suffice it to say that on the population level, poor BP control rates largely result from failure to measure BP, to initiate proper treatment, or to convince the patient that BP control is beneficial. Yet, there is a smaller population of patients in whom BP is particularly difficult to control. In this population, unusual disease mechanisms are enriched that are not uncovered by routine diagnostic testing. Textbooks and clinical guidelines are little help. Instead, perseverance and physiological reasoning are required. Hypertension that occurs at home but not at the office is said to increase cardiovascular risk and is termed masked hypertension. We have borrowed the term to describe a patient with swinging hypertensive episodes at the office that made little sense. We used cardiovascular physiology to unmask the matter. The Institutional Ethics Commission of the …

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

Drs Vink and Blankestijn1 suggest that patients before and after renal nerve ablation should have been investigated off antihypertensive medications or on a standardized treatment regimen. For studies on human physiology, highly standardized conditions are desirable. However, our goal was studying influences of renal nerve ablation on sympathetic nervous system regulation in a clinical setting. Indeed, patients in previous renal nerve ablation trials were on multiple medications. Drug withdrawal is difficult to justify in these …

Response to Blood Pressure and Sympathetic Nervous System Response to Renal Denervation

Dr Schlaich et al1 suggest that differences in blood pressure and muscle sympathetic nerve responses to renal nerve ablation between studies could be explained by differences in patient characteristics. All of our patients fulfilled diagnostic criteria for treatment-resistant arterial hypertension and had office blood pressure measurements in the hypertensive range, despite treatment with multiple antihypertensive drugs. Yet, we assessed blood pressure after an almost 60-minute resting period in the supine position. In the SYMPLICITY trials, office blood pressure measurements were taken in the seated position. Thus, baseline blood pressure is difficult to compare between studies. Even if blood pressure readings were somewhat lower …