When introduced clinically 6 years ago, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication. The initial two studies, SYMPLICITY HTN-1 and HTN-2, demonstrated great magnitudes of blood pressure reduction within 6 mo of the procedure and were based on a number of assumptions that may not have been true, including strict adherence to medication and absence of white-coat hypertension. The SYM-PLICITY HTN-3 trial controlled for all possible factors believed to influence the outcome, including the addition of a sham arm, and ultimately proved the demise of the initial overly optimistic expectations. This trial yielded a much lower blood pressure reduction compared with the previous SYMPLICITY trials. Since its publication in 2014, there have been many analyses to try and understand what accounted for the differences. Of all the variables examined that could influence blood pressure outcomes, the extent of the denervation procedure was determined to be inadequate. Beyond this, the physiological mechanisms that account for the heterogeneous fall in arterial pressure following renal denervation remain unclear, and experimental studies indicate dependence on more than simply reduced renal sympathetic activity. These and other related issues are discussed in this paper. Our perspective is that renal denervation works if done properly and used in the appropriate patient population. New studies with new approaches and catheters and appropriate controls will be starting later this year to reassess the efficacy and safety of renal denervation in humans. denervation; hypertension; pathophysiology; renal nerves; resistance RESISTANT HYPERTENSION IS defined as failure to achieve a guideline-driven blood pressure of less than 140/90 mmHg in patients who are adherent to maximally tolerated doses of at least three antihypertensive drugs, including a diuretic appropriate for kidney function (13). Population-based studies published over the last decade indicate that anywhere from 3 to 12% of hypertensive patients in the United States have resistant hypertension, despite the abundance of efficacious blood pressure-lowering agents belonging to over seven drug classes (11,20,68). Moreover, in addition to the cardiovascular mortality risk directly linked to the extent of blood pressure elevation, resistant hypertensive patients frequently have additional risk factors such as obesity, diabetes, chronic kidney disease, and age over 55 and are therefore more likely to die from stroke, myocardial infarction, heart failure, and end-stage renal disease (47, 76).Since increased sympathetic activity was believed to be present in many patients with resistant hypertension, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication and was introduced for clinical use 6 years ago. In the open label, uncontrolled SYMPLICITY HTN-1 and SYMPLICITY HTN-2 trials, undertaken in patients with resistant hypertension, redu...

Iliescu R, Tudorancea I, Irwin ED, Lohmeier TE. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension. Am J Physiol Heart Circ Physiol 305: H1080 -H1088, 2013. First published August 2, 2013; doi:10.1152/ajpheart.00464.2013.-The sensitivity of baroreflex control of heart rate is depressed in subjects with obesity hypertension, which increases the risk for cardiac arrhythmias. The mechanisms are not fully known, and there are no therapies to improve this dysfunction. To determine the cardiovascular dynamic effects of progressive increases in body weight leading to obesity and hypertension in dogs fed a high-fat diet, 24-h continuous recordings of spontaneous fluctuations in blood pressure and heart rate were analyzed in the time and frequency domains. Furthermore, we investigated whether autonomic mechanisms stimulated by chronic baroreflex activation and renal denervation-current therapies in patients with resistant hypertension, who are commonly obese-restore cardiovascular dynamic control. Increases in body weight to ϳ150% of control led to a gradual increase in mean arterial pressure to 17 Ϯ 3 mmHg above control (100 Ϯ 2 mmHg) after 4 wk on the high-fat diet. In contrast to the gradual increase in arterial pressure, tachycardia, attenuated chronotropic baroreflex responses, and reduced heart rate variability were manifest within 1-4 days on high-fat intake, reaching 130 Ϯ 4 beats per minute (bpm) (control ϭ 86 Ϯ 3 bpm) and ϳ45% and Ͻ20%, respectively, of control levels. Subsequently, both baroreflex activation and renal denervation abolished the hypertension. However, only baroreflex activation effectively attenuated the tachycardia and restored cardiac baroreflex sensitivity and heart rate variability. These findings suggest that baroreflex activation therapy may reduce the risk factors for cardiac arrhythmias as well as lower arterial pressure. obesity; hypertension; heart rate variability; baroreflex; sympathetic nervous system THE CAUSAL LINK between obesity and hypertension is well recognized. Clinical and experimental evidence also indicate that obesity has a profound impact on cardiac automaticity (44), which may increase the risk for atrial and ventricular arrhythmias, leading causes of morbidity and mortality in the industrialized world (4,7,17,42,59,60). The mechanisms that mediate the proarrhythmogenic effects of obesity have received little attention. Low heart rate variability has been identified not only as a predictor of but also as a risk factor for developing life-threatening cardiac arrhythmias (7,8,26,46,50,56,57) and, together with impaired baroreflex control of heart rate, is a common finding in obese individuals (6,18,20,51,58). Alterations in cardiac autonomic neural regulation are the substrate for reductions in both heart rate variability and baroreflex sensitivity and, consequently, may increase risk for cardiac arrhythmias (7,8). While sustained activation of the sympathetic nervous system has been shown t...

Recent technical advances have led to the development of a medical device that can reliably activate the carotid baroreflex with an acceptable degree of safety. Because activation of the sympathetic nervous system plays an important role in the pathogenesis of hypertension and heart failure, the unique ability of this device to chronically suppress central sympathetic outflow in a controlled manner suggests potential value in the treatment of these conditions. This notion is supported by both clinical and experimental animal studies, and the major aim of this article is to elucidate the physiological mechanisms that account for the favorable effects of baroreflex activation therapy in patients with resistant hyper-tension and heart failure. Illumination of the neurohormonal, renal, and cardiac actions of baroreflex activation is likely to provide the means for better identification of those patients that are most likely to respond favorably to this device-based therapy.

Carotid bodies play a critical role in protecting against hypoxemia and their activation increases sympathetic activity, arterial pressure and ventilation, responses opposed by acute stimulation of the baroreflex. While chemoreceptor hypersensitivity is associated with sympathetically-mediated hypertension, the mechanisms involved and their significance in the pathogenesis of hypertension remains unclear. We investigated the chronic interactions of these reflexes in dogs with sympathetically-mediated, obesity-induced hypertension based on the hypothesis that hypoxemia and tonic activation of carotid chemoreceptors may be associated with obesity. After 5 weeks on a high-fat diet, the animals experienced a 35–40% weight gain, increases in arterial pressure from 106±3 to 123±3 mm Hg and respiratory rate from 8±1 to 12±1 breaths/min along with hypoxemia (PaO2= 81±3 mm Hg) but eucapnia. During 7 days of carotid baroreflex activation by electrical stimulation of the carotid sinus, tachypnea was attenuated and hypertension was abolished before these variables returned to pre-stimulation values during a recovery period. Following subsequent denervation of the carotid sinus region, respiratory rate decreased transiently in association with further sustained reductions in PaO2 (to 65±2 mm Hg) and substantial hypercapnia. Moreover, the severity of hypertension was attenuated from 125±2 to 116±3 mm Hg (45–50% reduction). These findings suggest that hypoxemia may account for sustained stimulation of peripheral chemoreceptors in obesity and that this activation leads to compensatory increases in ventilation and central sympathetic outflow that contributes to neurogenically-mediated hypertension. Furthermore, the excitatory effects of chemoreceptor hyperactivity are abolished by chronic activation of the carotid baroreflex.

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Arterial hypertension (HTN) is one of the most prevalent entities globally, characterized by increased incidence and heterogeneous pathophysiology. Among possible etiologies, oxidative stress (OS) is currently extensively studied, with emerging evidence showing its involvement in endothelial dysfunction and in different cardiovascular diseases (CVD) such as HTN, as well as its potential as a therapeutic target. While there is a clear physiological equilibrium between reactive oxygen species (ROS) and antioxidants essential for many cellular functions, excessive levels of ROS lead to vascular cell impairment with decreased nitric oxide (NO) availability and vasoconstriction, which promotes HTN. On the other hand, transcription factors such as nuclear factor erythroid factor 2-related factor 2 (Nrf2) mediate antioxidant response pathways and maintain cellular reduction–oxidation homeostasis, exerting protective effects. In this review, we describe the relationship between OS and hypertension-induced endothelial dysfunction and the involvement and therapeutic potential of Nrf2 in HTN.

Calcific aortic valve disease (CAVD) is a major cause of cardiovascular mortality and morbidity, with increased prevalence and incidence. The underlying mechanisms behind CAVD are complex, and are mainly illustrated by inflammation, mechanical stress (which induces prolonged aortic valve endothelial dysfunction), increased oxidative stress (OS) (which trigger fibrosis), and calcification of valve leaflets. To date, besides aortic valve replacement, there are no specific pharmacological treatments for CAVD. In this review, we describe the mechanisms behind aortic valvular disease, the involvement of OS as a fundamental element in disease progression with predilection in AS, and its two most frequent etiologies (calcific aortic valve disease and bicuspid aortic valve); moreover, we highlight the potential of OS as a future therapeutic target.

Aim: Activation of the sympathetic nervous system is common in resistant hypertension (RHT) and also in chronic kidney disease (CKD), a prevalent condition among resistant hypertensives. However, renal nerve ablation lowers blood pressure (BP) only in some patients with RHT. The influence of loss of nephrons per se on the antihypertensive response to renal denervation (RDNx) is unclear and was the focus of this study.Methods: Systemic hemodynamics and sympathetically mediated low frequency oscillations of systolic BP were determined continuously from telemetrically acquired BP recordings in rats before and after surgical excision of ∼80% of renal mass and subsequent RDNx.Results: After reduction of renal mass, rats fed a high salt (HS) diet showed sustained increases in mean arterial pressure (108 ± 3 mmHg to 128 ± 2 mmHg) and suppression of estimated sympathetic activity (∼15%), responses that did not occur with HS before renal ablation. After denervation of the remnant kidney, arterial pressure fell (to 104 ± 4 mmHg), estimated sympathetic activity and heart rate (HR) increased concomitantly, but these changes gradually returned to pre-denervation levels over 2 weeks of follow up. Subsequently, sympathoinhibition with clonidine did not alter arterial pressure while significantly suppressing estimated sympathetic activity and HR.Conclusion: These results indicate that RDNx does not chronically lower arterial pressure in this model of salt-sensitive hypertension associated with substantial nephron loss, but without ischemia and increased sympathetic activity, thus providing further insight into conditions likely to impact the antihypertensive response to renal-specific sympathoinhibition in subjects with CKD.