Abstract
Previously, we reported that magnetic stimulation of carotid sinus (MSCS) could lower arterial pressure in rabbits. In this randomized, sham‐controlled pilot study, we evaluated the effects of MSCS on blood pressure in pre‐hypertensive and hypertensive subjects. A total of 15 subjects with blood pressure higher than 130/80 mm Hg were randomized to receive sham or 1Hz MSCS. The changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MAP) during treatment were compared between groups. The heart rate variability (HRV) and baroreflex sensitivity (BRS) before, during, and after treatments were analyzed. Reduction of SBP was significantly greater in subjects with MSCS than those with sham stimulation (6.6 ± 0.4 vs −2.5 ± 0.4 mm Hg, P < 0.001). Reduction of DBP was significantly greater in subjects with MSCS than those with sham stimulation (1.2 ± 0.2 vs −2.8 ± 0.2 mm Hg, P < 0.001). Reduction of MAP was significantly greater in subjects with MSCS than those with sham stimulation (1.4 ± 0.3 mm Hg vs −4.0 ± 0.3 mm Hg, P < 0.001). Reduction of HR was significantly greater in subjects with MSCS than those with sham stimulation (0.5 ± 0.5 vs −1.9 ± 0.3 beats/min, P = 0.002). BRS increased from 6.85 ± 0.77 to 8.79 ± 0.95 ms/mm Hg after MSCS compared with that at baseline (P = 0.027). Thus, MSCS can lower blood pressure and heart rate in pre‐hypertensive and hypertensive subject, warranting further study for establishing MSCS as a treatment for hypertension.
Keywords: arterial pressure, carotid baroreflex, hypertension, repetitive magnetic stimulation
1. INTRODUCTION
Hypertension is a major risk for cardiovascular diseases and death. Although novel antihypertensive drugs keep emerging, the control rates of hypertension seem to have been maximized in recent years.1 More than one‐third of hypertensive patients cannot have their blood pressures under control even with multi‐drug therapy.2 On the other hand, a sizeable proportion of patients cannot tolerant antihypertensive drugs. Recently, the American Heart Association lowered the criteria of hypertension, which dramatically increased the number of hypertensives and emphasized the importance of behavioral and biofeedback therapies.3
Electrical stimulation of carotid sinus has been confirmed with substantive antihypertensive effects, but the obvious invasiveness limited its clinical application. According to Faraday electromagnetic induction theory, fluctuating magnetic fields can induce electric currents.4 Repetitive transcranial magnetic stimulation (rTMS) uses this principle to stimulate the central nervous system.5 Our previous study observed that magnetic stimulation of carotid sinus (MSCS) could lower blood pressure of normotensive rabbits.6 The noninvasiveness makes MSCS a more favorable choice in treating hypertension than electrical stimulation. In this randomized controlled cross‐over pilot study, we investigated the effects of MSCS on blood pressure in newly discovered prehypertensive and hypertensive patients for the first time.
2. METHODS
2.1. Participants
Subjects were recruited from the outpatient department of Jinling Hospital. Subjects were included if they: (a) aged 20‐70 years old and (b) had a systolic blood pressure (SBP) higher than 130 mm Hg. The estimates of blood pressure (BP) were based on two readings at separate visits. In each evaluation, blood pressure was measured three times at an interval of 10 minutes, using the automated Omron 705IT device (Omron, UK). Subjects were excluded if they: (a) had a history of neck surgery or radiation therapy; (b) had stent or other metal materials implanted in body; (c) had atrial fibrillation; (d) had structural heart diseases; (e) had psychiatric disorders; (f) was in pregnancy; (g) had stroke or myocardial infarction in 6 months; and (h) on antihypertensive drugs. Written informed consent was obtained from all included subjects. The study protocol was approved by the Internal Review Board of Jinling Hospital, and written informed consents were obtained from all patients.
2.2. Study design
This is a randomized, controlled, cross‐over pilot study. A total of 15 subjects underwent randomization into group A and group B. In group A, participants were then assigned to start with sham stimulation first. In group B, participants were started with 1 Hz stimulation. Within 4 hours before rTMS treatment, subjects were asked to avoid caffeine‐containing foods or medications, which may affect autonomic functions. Blood pressure before, during, and after stimulation was conducted with the participant lying supine on a massage table, with their arm relaxed by their side. During stimulation, eyes were covered with a piece of opaque sheet to reduce tension. The treatment was initiated with the baseline recording for 1 minutes and then 5 minutes sham stimulation, followed by 1 Hz, 300 pulses stimulation for 5 minutes or vice versa, the intervention periods were separated by a 30 minutes washout period to eliminate possible after effects. One subject who received 1 Hz stimulation first reported pain, and his test was stopped. All subjects were blinded to the order and type of treatments. The same technician performed all magnetic stimulations. A flow chart for patient intervention is shown in Figure 1.
Figure 1.
Participants’ flow diagram of the study progress
2.3. Magnetic stimulation protocol
The Optimum Magnetic stimulator (MagPro X 100; Tonica, DK, Farum, Denmark) with a C‐100 circular coil was used for magnetic stimulation. The maximum stimulation output (MSO) of the C‐100 coil was 1.9 T. The diameter of the coil disk is 11 cm with an inner hole of 20 mm in diameter. The subjects were instructed to bend their necks backward slightly with face turn left for better exposing the right carotid sinus. The center of the coil disk was pointed to the right carotid sinus. The carotid sinus is anatomically located below angulus mandibulae and is of the same height of the upper margin of the thyroid cartilage. The carotid sinus can be determined by palpating the strongest beating point of the carotid artery. A probe with type‐B ultrasound later confirmed the location. The coil disk is linked to the stimulator to generate alternative magnetic field near the coil disk. Stimulation scheme is shown in Figure 2. The stimulus transmitted a biphasic waveform with a pulse width of 280 μs. The position and angle of stimulation coil was minimally adjusted according to hemodynamic responses to find the most optimal position. The intensity was set at 20% MSO, with 300 pulses, 1 Hz rTMS which was adapted from our previous study in normotensive rabbits.6 Since the magnetic stimulator has an effective range of 5 cm, in the sham stimulation, subjects were treated with the coil placed 20 cm above the carotid sinus spot to avoid real stimulation and achieve similar stimulation sound.
Figure 2.
Schematic of magnetic stimulation of carotid sinus in patients. The carotid sinus is anatomically located below angulus mandibulae and is of the same height of the upper margin of the thyroid cartilage, determined by palpating the strongest beating point of the carotid artery. The coil disk is linked to the stimulator to generate alternative magnetic field near the coil disk. The magnetic field can converge beneath the center hole of the coil disk and reach about 5 cm into the tissue. Due to Faraday's law of induction, the time‐varying magnetic field can induce electrical currents in electrically conductive material within its range. These currents are called eddy currents (or Foucault currents), for they flow in closed loops, like the water eddy, within the conductors, in planes perpendicular to the magnetic field
2.4. Hemodynamic assessment
Hemodynamic parameters were measured with a Finometer Pro monitor (Finapres Medical Systems BV, Netherlands). After determining the carotid sinus location and optimum stimulation position, subjects rested in supine position for 10 minutes. The SBP, diastolic blood pressure (DBP), mean blood pressure (MAP), and heart rate (HR) were recorded continuously. The 1‐minute averaged hemodynamic parameters before MSCS were used as baseline reference. The magnetic stimulation process continued for 5 minutes in all subjects, their BP was monitored continuously until 5 minutes after stimulation. Power spectral density of HR variability (HRV) was estimated from 5‐minute recordings of R wave‐to‐R wave (RR) intervals during spontaneous breathing using Labchart 8 (AD Instruments, Australia). Total power (TP), power in low‐frequency range (low frequency: 0.05 to <0.15 Hz), high‐frequency range (high frequency: 0.15 to <2 Hz), and low‐frequency‐to‐high‐frequency ratio (low frequency/high frequency) were calculated. Baroreflex sensitivity (BRS) was also recorded.
2.5. Statistical analysis
Parameters were expressed as mean ± standard error or as median with interquartile ranges. The reductions of SBP, MAP, DBP, and HR were calculated as the value at the end of treatment subtracted from the value at the baseline. The efficacy of MSCS on SBP, MAP, HR, and DBP was analyzed using a linear mixed‐effects model with terms for treatment and stage as fixed effects, and subject as a random effect. If differences of treatment were detected, paired sample t test was performed to compare differences between groups. A two‐tailed α value of 0.05 was deemed as statistically significant. Statistical analysis was performed using SPSS 22.0 (IBM, Armonk, NY).
3. RESULTS
The characteristics of the enrolled subjects in baseline and during stimulations were shown (Table 1). Of the 15 subjects being recruited to the study, 14 (nine women and five men) completed the study. One subject reported intolerable pain during treatment so that the stimulation was stopped. No other side effects were reported. The volunteers were aged 51.5 ± 3.8 years and had a mean BMI (in kg/m2) of 24.3 ± 0.7. No subject had history of diabetic mellitus or cardiovascular diseases.
Table 1.
Baseline characteristics of subjects
| Participants (n = 14) | |
|---|---|
| Age (years) | 51.5 ± 3.8 |
| Weight | 65.8 ± 2.9 |
| BMI | 24.3 ± 0.7 |
| SBP | 141.6 ± 2.7 |
| DBP | 74.5 ± 2.11 |
| MAP | 101.2 ± 2.3 |
| HR | 67.7 ± 1.5 |
BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; SBP, systolic blood pressure.
There was no interaction between the order of stimulation and changes of SBP, MAP, DBP, and HR MSCS treatment reduced MAP (F = 37.4, P < 0.001), SBP (F = 50.7, P < 0.001), HR (F = 7.7, P = 0.017), and DBP (F = 33.8, P < 0.001) significantly. Reduction of SBP was significantly greater during MSCS than during sham stimulation (6.6 ± 0.4 vs −2.5 ± 0.4 mm Hg, P < 0.0001). Reduction of DBP was significantly greater in subjects with MSCS than those with sham stimulation (1.2 ± 0.2 vs −2.8 ± 0.2 mm Hg, P < 0.0001). Reduction of MAP was significantly greater in subjects with MSCS than those with sham stimulation (1.4 ± 0.3 mm Hg vs −4.0 ± 0.3 mm Hg, P < 0.0001). Reduction of HR was significantly greater in subjects with MSCS than those with sham stimulation (0.5 ± 0.5 vs −1.9 ± 0.3 beats/min, P = 0.002). Heart rate decreased from 67.0 ± 1.10 to 65.1 ± 1.3 mm Hg in MSCS (P = 0.051)‐treated subjects, while increased from 67.7 ± 1.5 mm Hg to 68.3 ± 1.5 mm Hg (P = 0.2) in sham stimulation subjects. SBP decreased from 145.0 ± 2.3 to 138.5 ± 2.4 mm Hg in MSCS‐treated subjects (P = 0.00011), while increased from 141.6 ± 2.7 mm Hg to 144.1 ± 3.0 mm Hg (P = 0.012) in sham stimulation‐treated subjects. DBP decreased from 78.9 ± 1.9 mm Hg to 76.2 ± 1.9 mm Hg (P = 0.000122) in MSCS‐treated subjects, while increased from 74.5 ± 2.1 mm Hg to 75.6 ± 2.2 mm Hg (P = 0.012) in sham stimulation‐treated subjects. MAP decreased from 105.7 ± 2.0 mm Hg to 101.8 ± 2.1 mm Hg in MSCS‐treated subjects (P = 0.000029), while increased from 101.2 ± 2.3 mm Hg to 102.6 ± 2.5 mm Hg (P = 0.038) in sham stimulation treated (Table 2). HR, SBP, DBP, and MAP decreased simultaneously during stimulation (Figure 3).
Table 2.
Responses of blood pressure and heart to magnetic stimulation of carotid sinus
| Variable | Control | 1 Hz rTMS | P Value | ||
|---|---|---|---|---|---|
| Before | During | Before | During | ||
| SBP | 141.6 ± 2.7 | 144.1 ± 3.0 | 145.0 ± 2.3 | 138.5 ± 2.4a | |
| Changes | −2.5 ± 0.4 | 6.6 ± 0.4 | <0.001 | ||
| DBP | 74.5 ± 2.1 | 75.6 ± 2.2 | 78.9 ± 1.9 | 76.2 ± 1.9 a | |
| Changes | 1.2 ± 0.2 | −2.8 ± 0.2 | <0.001 | ||
| MAP | 101.2 ± 2.3 | 102.6 ± 2.5 | 105.7 ± 2.0 | 101.8 ± 2.1 a | |
| Changes | 1.4 ± 0.3 | −4.0 ± 0.3 | <0.001 | ||
| HR | 67.7 ± 1.5 | 68.3 ± 1.5 | 67.0 ± 1.1 | 65.1 ± 1.3 | |
| Changes | 0.5 ± 0.5 | −1.9 ± 0.3 | 0.002 | ||
Parameters were expressed as mean ± standard error.
DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; rTMS, repetitive transcranial magnetic stimulation; SBP, systolic blood pressure.
P <0.05 compared with before MSCS.
Figure 3.
Reactions of SBP, DAP, MAP, HR to magnetic stimulation of carotid sinus in stimulation and sham group, respectively (n = 14). Stimulation pattern was set at 1 Hz, 20%MSO. DAP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.
In the HRV comparison, there were no obvious changes in terms of TP, low‐frequency power, high‐frequency power, and low‐frequency/high‐frequency power ratio between different treatments. In addition, there was a significant increase of BRS after stimulation compared with that at baseline (6.85 ± 0.77 vs 8.79 ± 0.95 ms/mm Hg, P = 0.027, Table 3).
Table 3.
Heart rate variability and baroreflex sensitivity measures before, during, and after magnetic stimulation of carotid sinus
| Parameter | Group | Before MSCS | During MSCS | After MSCS |
|---|---|---|---|---|
| TP (ms2) | Control | 1.66 ± 0.36 | 1.84 ± 0.43 | 1.97 ± 0.40 |
| 1 Hz | 2.12 ± 0.38 | 2.19 ± 0.49 | 2.57 ± 0.45 | |
| LF (ms2) | Control | 0.44 ± 0.15 | 0.32 ± 0.06 | 0.38 ± 0.07 |
| 1 Hz | 0.47 ± 0.78 | 0.53 ± 0.12 | 0.72 ± 0.18 | |
| HF (ms2) | Control | 0.38 ± 0.09 | 0.41 ± 0.10 | 0.47 ± 0.15 |
| 1 Hz | 0.38 ± 0.05 | 0.47 ± 0.07 | 0.48 ± 0.07 | |
| LF:HF ratio | Control | 1.35 ± 0.29 | 1.20 ± 0.31 | 0.96 ± 0.17 |
| 1 Hz | 1.64 ± 0.38 | 1.03 ± 0.15 | 1.63 ± 0.35 | |
| BRS (ms/mm Hg) | Control | 7.52 ± 1.13 | 7.73 ± 0.96 | 7.64 ± 0.95 |
| 1 Hz | 6.85 ± 0.77 | 8.55 ± 0.94 | 8.79 ± 0.95a |
Parameters were expressed as mean ± standard error.
BRS, baroreflex sensitivity; HF, high frequency; LF, low frequency; MSCS, magnetic stimulation of carotid sinus; TP, total power of heart rate variability.
P <0.05 compared with before MSCS.
4. DISCUSSION
This study found that 1 Hz MSCS with the intensity of 20% MSO can lower SBP (6.6 ± 0.4 vs −2.5 ± 0.4 mm Hg, P < 0.0001) and HR (0.5 ± 0.5 vs −1.9 ± 0.3 beats/min, P = 0.002) than sham stimulation. No significant side effects were observed during or after MSCS.
Magnetic stimulation uses Faraday's law of induction to convert a time‐varying magnetic field into induced electrical currents in tissues within its reach.7 The nerve fibers with low resistant inside carotid sinus are conductors which can be stimulated by the stimulation. Therefore, the BP‐lowering effects of MSCS observed in this study were supposed to be the activation of carotid baroreflex. MSCS was proved to rapidly decrease blood pressure and heart rate, a similar response was observed previously in electrical carotid sinus stimulation. Electrical carotid sinus stimulation was first experimented in dogs in 1965,8 later come into a halt for the development of hypotensive drugs.9 In electrical stimulation, baroreflex afferent nerves were directly stimulated.10 The stimulus can be transmitted to the brainstem and interpreted as an elevated blood pressure, triggering central nervous system modulation of sympathetic and vagal outflows, resulting in lowered blood pressure and heart rate.11, 12 Normally, blood pressure reduction elicits a baroreflex‐mediated increase in heart rate. In this study, we observed that heart rate and blood pressure reduced simultaneously after stimulation. This result suggested that electric field stimulation of carotid baroreceptors acutely attenuates sympathetic activation of vasculature and heart. In addition, after the reduction of BP of rabbit MSCS in our previous study,6 plasma epinephrine and norepinephrine levels were increased during and shortly after MSCS, indicating that the sympathetic nerves were activated by hypotension, decreasing the hypotensive effect of MSCS. On the other hand, for the negative feedback regulation of carotid baroreflex, when the arterial pressure goes down, less activating the unstimulated left baroreceptor, resulting in increased sympathetic tone, further reduced the hypotensive effect. Simultaneously after discontinuation of MSCS, both MAP and heart rate increased immediately to baseline level, suggesting that the mechanism is mainly regulated by neurons rather than hormones.
The reduction of BP in MSCS observed in this study was lower than direct electrical stimulation in previous studies (ranging from 15 to 30 mm Hg).10, 13 On the Rheos Baroreflex Hypertension Therapy System which measured acute electrical carotid stimulation in 9 minutes stimulation, SBP decreased 32 ± 10 mm Hg, heart rate was lowered by 4.5 ± 1.5 bpm.14 In this study, the average systolic BP reduction was 6.59 ± 0.43 mm Hg. The heart rate trended down by 0.23 ± 0.36 beats/min. Compared with direct electrical stimulation, the induced current in the carotid sinus was not measured, but in rTMS of the brain which has better conductivity, the induced current was usually around 5.13 × 10−8 A,2, 15 much smaller than the electrical stimulation intensity (10 mA).16 In our previous experiment in MSCS of anesthetized normotensive rabbits, a blood pressure reduction of 10.4 ± 2.3 mm Hg was achieved.6 In the rabbit MSCS, stimulation intensity was set at 200% motor threshold, usually 60% MSO, much higher than this study. In this human MSCS, for safety concern, stimulation intensity was just 20% MSO to minimize the comfortless of stimulation. MSCS of different stimulation need to be investigated.
In the Barostim neo trial test, which used chronic stimulation, the long‐term stimulation achieved a stable systolic BP reduction of 26.0 ± 4.4 mm Hg at 6 months. The heart rates were trended down by 5.0 ± 2.6 beats/min.10 In a follow‐up of 6 years, resistant hypertension patients in DEBuT‐HT and Rheos Trial showed persistent reduction of office blood pressure (systolic pressure decreased 23 ± 7 mm Hg).16 Baroreflex electrical stimulation showed better hypotensive effect than our study may result in its ability to reset the BRS of hypertensive patients in chronic stimulation. The resetting of the baroreflex resulted in lower set point of the blood pressure. About 60% of patients exhibit some degree of true baroreceptor resetting after baroreflex activation treatment, their hypertension becomes less severe or more receptive to pharmacological treatment.16 Another analysis of data from 34 patients pooled from different studies that used BAT for 6 months demonstrated improvement in left atrial and ventricular structure and function (assessed by echocardiography).17 This further proved the remodeling effect of electrical stimulation. In human electrical carotid stimulation, when the stimulator was switched off, blood pressure also immediately returned to the baseline level.18
The maximum output (MSO) of our device is 1.9 T with a round coil that is 10 cm in diameter, designed to penetrate the skull for post‐stroke patients with neuron damage. In carotid simulation, the sinus is closer and weaker stimulation amplitude can achieve same stimulation depth portable device of smaller MSO like 0.7, 0.8 T with a diameter of 2 or 3 cm will make the stimulation more localized. Smaller coils of 50 mm diameters have been used in rats for research. Portable, wearable, or wireless devices for magnetic brain stimulation are under‐developing.19 The results of the current study provided proof for a new treatment which hold a promise for magnetic carotid stimulation for further investigation. For patients with resistant hypertension, blood pressure could be lowered with portable, wearable, or wireless focal magnetic stimulation devices. If feasible device for MSCS can be invented, it will be of great clinic value.
Several new treatment strategies are under‐developing for resistant hypertension. BAT is now near clinical use. Arteriovenous (AV) coupler creates a central iliac AV shunt, leading to reduction in systemic resistance, lower BP, and heart failure prevention. In an open‐label multicenter prospective randomized trial, blood pressures in patients with resistant hypertension were significantly lowered with AV coupler.20 Carotid artery stenting has promising antihypertensive effects, but only studied in occluded patients. In a pilot study without randomization and control, seventeen (80.95%) of the 21 subjects with chronically occluded internal carotid artery with ischemic symptoms refractory to medical therapy showed hypotensive effect.21 Large numbered, randomized, prospective study is still vacant in this area. In electrical stimulation of carotid sinus, for its invasive nature, have inevitable complications like self‐inflicted wound complication, pulse generator pocket hematoma, discomfort in the pulse generator pocket, and intermittent pain near the pulse generator were the most common complications. Besides, the battery of the stimulator had limited life span, averaging 2.8 ± 1.4 years, replacing the battery bring more suffering to the patients.1 All the procedures are invasive, we hope the noninvasive MSCS can be a supplement in the future.
In MSCS, only one patient reported pain during stimulation and the stimulation can be stopped at any time without irreversible damage and invasiveness, further proved its excellence.
In this study, considering chemoreceptor is adjacent to baroreceptor, during stimulation, chemoreceptor might be activated spontaneously which can be evidenced by changed respiratory rate. But in the previous rabbit study, no obvious changes of respiratory rate were observed during MSCS,6 eliminating the possible stimulation effect.
4.1. Limitations
There are several limitations in our study. First, we tested the effect of magnetic stimulation in pre‐hypertensive and hypertensive patients, not the typical resistant hypertensive patients. The response to carotid baroreflex activation was reported to be different in long‐term poorly controlled hypertensive patients.1 Older adults had been proved to display reduced carotid strain and increased carotid stiffness which would reduce the stimulation effect.22 Secondly, for the self‐limit of current stimulus device, only short time stimulation can be achieved, the response of arterial pressure of long‐term, multi‐trial stimulations remained unclear. Thirdly, the sample size is small. In the previous study, we observed that magnetic carotid sinus stimulation could lower blood pressure in rabbits.6 In this preliminary study, we aimed to evaluate this possibility in human. If feasible, a large randomized control trial with portable or wearable device may be followed. Besides, although right baroreceptor regulation was proved to be dominant in the baroreflex stimulation,23 MSCS can be later conducted on the left side to make comparison.
5. CONCLUSIONS
This study demonstrated that MSCS treatment can lower the blood pressure and heart rate in prehypertensive and hypertensive patients. This initial result encourages further studies to establish the efficacy of MSCS in treating resistant hypertension. Portable, wearable, or wireless devices for magnetic brain stimulation are under‐developing. We think the results of the current study provided proof for a new treatment concept. For patients with resistant hypertension, blood pressure could be lowered with portable, wearable, or wireless focal magnetic stimulation devices. If feasible device for MSCS can be invented, it will be of great clinic value.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGMENTS
The authors thank Youliang Chen for his assistance in software.
Li R, Dai Z, Ye R, Liu X, Xia Z, Xu G. Magnetic stimulation of carotid sinus as a treatment for hypertension. J Clin Hypertens. 2019;21:299–306. 10.1111/jch.13470
Li and Dai contributed equally to this work.
Funding information
The project was partly supported by National Natural Science Foundation of China (No. 81300244, 81400993, 81571143 and 81671172), Chinese Postdoctoral Science Fund (No. 2015M572815), the Project of Clinical Advanced Techniques, Primary Research & Development Plan of Jiangsu Province (BE2017719), and the Pediatric Medical Innovation Team of Jiangsu Province (CXTDA2017022).
Contributor Information
Zhengkun Xia, Email: njxzk@126.com.
Gelin Xu, Email: gelinxu@nju.edu.cn.
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