Effects of Chronic Baroreceptor Stimulation on the Autonomic Cardiovascular Regulation in Patients With Drug-Resistant Arterial Hypertension

Abstract

Abstract-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 185Ϯ31/ 109Ϯ24 mm Hg to 154Ϯ23/95Ϯ16 mm Hg (PϽ0.0001/Pϭ0.002). Mean heart rate decreased from 81Ϯ11 to 76Ϯ10 beats per minute Ϫ1 (Pϭ0.001). 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; PϽ0.001) were significantly changed during stimulation of the carotid baroreceptor, and heart rate turbulence onset was significantly decreased (turbulence onset: Ϫ0.002 versus Ϫ0.015 for off versus on; Pϭ0.004). 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. Key Words: baroreflex Ⅲ arterial hypertension Ⅲ electric baroreflex stimulation Ⅲ heart rate variability Ⅲ heart rate turbulence Ⅲ drug-resistant arterial hypertension Ⅲ cardiac autonomic system S ystemic arterial hypertension is one of the leading cardiovascular diseases in the world and a major cardiovascular risk for coronary artery disease, cerebrovascular disease, and heart and renal failure. Despite carefully assessing causes and stratifying therapeutic approaches using all of the existing antihypertensive pharmacological agents, not all hypertensive patients sufficiently respond to pharmacological treatment. Stimulation of the carotid baroreceptor (SCB) was considered several decades ago as a potential treatment for blood pressure (BP) lowering in humans. [1][2][3] The roles of carotid baroreceptors in acute regulation of BP and the acute effect of SCB are well documented. 3,4 However, whether arterial baroreceptors play a role in long-term regulation of arterial pressure is still debated, 5 and the benefit of chronic SCB as treatment of hypertension in humans is currently under investigation. Lohmeier et al 6,7 demonstrated that electric activation of the baroreflex lasting 7 days produces sustained hypotension in dogs usin...

The sympathetic nervous system and blood pressure in humans: implications for hypertension

“…10 Recent clinical interventions showing impressive blood pressure lowering effects by targeting reductions in SNA [11][12][13][14] and progress in the elucidation of the central sympathetic regulatory pathways altered in hypertension [15][16][17] are part of a renaissance of interest in the control of the sympathetic nervous system…”

“…98 Following animal studies first conducted over 50 years ago 99,100 and extensive technical development work, 101,102 surgical implantation of a device eliciting chronic carotid baroreflex stimulation (Rheo, CVRx, Minneapolis, MN, USA) has recently been demonstrated to effectively lower blood pressure and muscle SNA in humans. 14,71,72,103,104 This has been based on the recently resurrected idea that arterial baroreceptors control arterial pressure in the long term. 105 In his original study, Thrasher (2002) showed that unloading of baroreceptors at one carotid sinus (with all other arterial baroreceptors denervated) caused a sustained pressor response lasting up to 3 weeks in conscious dogs.…”

“…107,108 Potential caveats to this approach include its relative invasive nature compared with the renal nerve ablation technique, the potential for peri-operative complications and that significant blood pressure lowering is not always evident. 14 Intriguingly, deep brain stimulation of the ventrolateral periaqueductal grey matter area has also been shown to effectively reduce blood pressure in refractory hypertension. 109,110 Animal studies have identified the ventrolateral periaqueductal grey as a depressor area and shown that its stimulation elicits hypotension with peripheral vasodilatation, indicative of sympathetic withdrawal.…”

“…Evidence from studies in both patients and animal models of hypertension strongly implicate the chronic sympathetic neural activation in the aetiology and progression of hypertension (Figure 1). 2,[6][7][8][9] The use of regional surgical sympathectomy to treat hypertension over 50 years ago before the availability of antihypertensive medications that lower sympathetic activity provides an early indication of the clinical appreciation for a significant neurogenic component to hypertension.10 Recent clinical interventions showing impressive blood pressure lowering effects by targeting reductions in SNA [11][12][13][14] and progress in the elucidation of the central sympathetic regulatory pathways altered in hypertension [15][16][17] are part of a renaissance of interest in the control of the sympathetic nervous system …”

Novel Approaches in Hypertension Treatment - Modulation of the Sympathetic Overactivity

“…In a canine animal model, Lohmeier et al could demonstrate that activation of the baroreflex at the carotid artery by implanted pacemaker was able to reduce blood pressure as well as serum catecholamine levels [67,68]. This approach is currently in clinical evaluation for resistant hypertension [69]. Promising data from a clinical trial for baroreflex activation therapy has been published recently.…”