Renal Denervation in Hypertension.

The column in this issue is supplied by Drs. Benjamin Lee, MD, and Usman Ansari, DO. Dr. Lee is an assistant professor of clinical medicine at the Houston Methodist Institute for Academic Medicine and Weill Cornell Medical College. After earning his medical degree at Harvard Medical School, Dr. Lee completed a residency in internal medicine and a nephrology fellowship at the University of California San Francisco (UCSF) while simultaneously obtaining a master of advanced study in clinical research from the UCSF departments of Epidemiology and Biostatistics. He maintains his clinical practice with the Houston Kidney Consultants. Dr. Ansari earned a Doctor of Osteopathy from Touro University College of Osteopathic Medicine in California and is completing his internal medicine residency at Houston Methodist.

Renal denervation prevents myocardial structural remodeling and arrhythmogenicity in a chronic kidney disease rabbit model.

BACKGROUND: The electrophysiological (EP) effects and safety of renal artery denervation (RDN) in chronic kidney disease (CKD) are unclear. OBJECTIVE: The purpose of this study was to investigate the arrhythmogenicity of RDN in a rabbit model of CKD. METHODS: Eighteen New Zealand white rabbits were randomized to control (n = 6), CKD (n = 6), and CKD-RDN (n = 6) groups. A 5/6 nephrectomy was selected for the CKD model. RDN was applied in the CKD-RDN group. All rabbits underwent cardiac EP studies for evaluation. Immunohistochemistry, myocardial fibrosis, and renal catecholamine levels were evaluated. RESULTS: The CKD group (34.8% ± 9.2%) had a significantly higher ventricular arrhythmia (VA) inducibility than the control (8.6% ± 3.8%; P <.01) and CKD-RDN (19.5% ± 6.3%; P = .01) groups. In the CKD-RDN group, ventricular fibrosis was significantly decreased compared to the CKD group (7.4% ± 2.0 % vs 10.4% ± 3.7%; P = .02). Sympathetic innervation in the CKD group was significantly increased compared to the control and CKD-RDN groups [left ventricle: 4.1 ± 1.8 vs 0.8 ± 0.5 (102 µm2/mm2), P <.01; 4.1 ± 1.8 vs 0.9± 0.6 (102 µm2/mm2), P <.01; right ventricle: 3.6 ± 1.0 vs 1.0 ± 0.4 (102 µm2/mm2), P <.01; 3.6 ± 1.0 vs 1.0 ± 0.5 (102 µm2/mm2), P <.01]. CONCLUSION: Neuromodulation by RDN demonstrated protective effects with less structural and electrical remodeling, leading to attenuated VAs. In a rabbit model of CKD, RDN plays a therapeutic role by lowering the risk of VA caused by autonomic dysfunction.

Numerical simulation of electromagnetic heating process of biological tissue via time-fractional Cattaneo transfer equation.

In order to simulate the heat transfer in the process of hyperthermia, one-dimensional time-fractional Cattaneo heat transfer equation (TFHE) is established. Based on TFHE, the heat transfer model is solved by using finite difference method, because a single layer of biological tissue in vitro is irradiated by electromagnetic energy. The effect of power parameters (energy flux density P0, tissue attenuation coefficient h) and equation parameters (relaxation time τq and fractional order ß) on the prediction of temperature simulated by TFHE were studied. Furthermore, comparative studies on TFHE, Pennes and CV are performed and evaluated. In the heating process, because of the existence of relaxation time τq, the temperature response of TFHE and CV are later than Pennes, leading to the lower temperature prediction of TFHE and CV than that of Pennes. The shorter the time is, the higher the energy is, and the more obvious the difference is.

Effect of Renal Denervation on Cardiac Function and Inflammatory Factors in Heart Failure After Myocardial Infarction.

Heart failure (HF) affects around 100 million people and is a staggering burden for health care system worldwide. Rapid and sustained activation of inflammatory response is an important feature of HF after myocardial infarction. Sympathetic overactivation is also an important factor in the occurrence and progression of HF. The beneficial effect of renal denervation (RDN) has been demonstrated in HF. In the current study, we hypothesized that RDN improves cardiac function in HF canine models due to acute myocardial infarction (AMI) and reduced inflammation might be involved. Twenty-four beagles were randomized into the control (n = 8), HF (n = 8), and HF + RDN group (n = 8). The HF model after AMI was established by embolization the anterior descending distal artery with anhydrous ethanol in the HF and HF + RDN group. Bilateral renal artery ablation was performed in the HF + RDN group. Cardiac function, serum creatine kinase, creatine kinase-MB and NT-Pro BNP level, and expression of inflammation-related proteins in myocardial were examined. Because the paraventricular nucleus of the hypothalamus might be involved in inflammation-induced central neural excitation in HF and plays an important role in regulating extracellular fluid volume and sympathetic activity, expression of inflammation-related proteins in hypothalamus was also examined. AMI and post-AMI HF model was created successfully. Compared with the HF group, dogs in the HF + RDN group showed better cardiac function 4 weeks after AMI: lower left ventricular end-diastolic pressure, left ventricular end-diastolic dimension, and left ventricular end-systolic dimension and higher LEVF and left ventricular systolic pressure (P < 0.05 for all) were observed in the HF + RDN group. In addition, dogs in the HF + RDN group had slightly less ventricular fibrosis. Interestingly, RDN had lower expression of inflammation-related proteins including interleukin-6, tumor necrosis factors-α, nuclear factor κB, and monocyte chemotactic protein 1 (P < 0.05 for all) in both myocardial tissue and hypothalamus. RDN can improve cardiac function in dogs with HF after myocardial infarction. Our results suggested that RDN might affect cytokine-induced central neural excitation in HF and later affect sympathetic activity. Our results suggested a potential beneficial mechanism of RDN independent of mechanism involving renal afferent and efferent sympathetic nerves.

New approaches for treating atrial fibrillation: Focus on autonomic modulation.

Atrial fibrillation (AF) is a rapidly growing clinical problem in routine practice, both for cardiologists as well as general practitioners. Current therapies aimed at the management of AF include anti-arrhythmic drug therapy and catheter ablation. These therapies have a number of limitations and risks, and have disappointing long-term efficacy in maintaining sinus rhythm and improving hard clinical outcomes. Because of this, there is growing interest in pursuing alternative management strategies in patients with AF. This review seeks to highlight emerging AF therapies, with a specific focus on several modalities aimed at modulation of the autonomic nervous system. These therapies have shown promise in early pre-clinical and clinical trials, and represent exciting alternatives to standard AF treatment.

The Current Status of Devices for the Treatment of Resistant Hypertension.

Arterial hypertension is associated with increased cardiovascular morbidity and mortality. Although blood pressure-lowering therapies significantly reduce the risk of major cardiovascular events, blood pressure control remains unsatisfactorily low. Several device-based antihypertensive therapies have been investigated in patients with treatment-resistant hypertension and in patients unable or unwilling to adhere to antihypertensive medication. As the field of device-based therapies is subject to constant change, this review aims at providing an up-to-date overview of different device-based approaches for the treatment of hypertension. These approaches target the sympathetic nervous system (renal denervation, baroreflex amplification therapy, baroreflex activation therapy, and carotid body ablation) or alter mechanical arterial properties by creating an iliac arteriovenous fistula. Notably, the use of all of these treatment options is not recommended for the routine treatment of hypertension by current guidelines but should be investigated in the context of controlled clinical studies.

Diagnosis and management of resistant hypertension: state of the art.

Resistant hypertension is defined as a lack of ambulatory blood pressure response to optimized medical treatment after exclusion of secondary hypertension in patients who are fully adherent to antihypertensive therapy. Patients with resistant hypertension are at high risk of complications, particularly cardiovascular events, and optimization of medical treatment remains the cornerstone of their management. Such optimization should be based on simple algorithms and include the use of aldosterone antagonists. The available data from clinical trials do not support the use of device-based approaches such as renal denervation, baroreflex activation therapy or arteriovenous anastomosis for the treatment of resistant hypertension in the majority of patients. Therefore, device treatment remains a last-resort for patients with truly resistant hypertension in the context of clinical research in highly skilled tertiary referral centres. Future research should focus on improving understanding of the intrinsic (physiological and psychological factors) and extrinsic (environmental stressors) mechanisms that contribute to a lack of response to blood-pressure-lowering drugs in adherent patients. The use of biomarkers to identify patients with early target organ damage and new technologies, such as renal nerve stimulation, to predict blood pressure responses to renal denervation could aid the selection of patients who might benefit from device therapies.

Resistant Hypertension.

Conservatively, ten million people in the USA alone may suffer from RH and may be similarly prevalent elsewhere. Given the strong linear correlation between hypertension and cardiovascular outcomes, better control is paramount. We favor a multi-pronged approach. It may not suffice to address this by pharmacologic means only. Careful attention to modifiable risk factors, particularly sodium intake, adhering to a proper diet (i.e. DASH), and avoiding agents, i.e. non-steroidals, that can elevate the blood pressure, is key. Frequent follow up to establish the right treatment regimen and home blood pressuring monitoring can have a strong impact on control. Finally, consideration of device therapy may be a more viable option in the future.

Emerging concepts for patients with treatment-resistant hypertension.

Treatment-resistant hypertension (TRH) is defined as elevated blood pressure despite treatment with three properly dosed antihypertensive drugs, and is associated with adverse cardiovascular and renal outcomes and increased mortality. Treatment of patients with TRH focuses on maximizing the doses of antihypertensive drugs and adding drugs with complementary mechanisms of action, including a combination of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, calcium channel blockers, and thiazide-like diuretics. Randomized clinical trials have demonstrated the efficacy of the mineralocorticoid receptor antagonist spironolactone as a fourth-line therapy for patients with TRH. Other pharmacologic considerations include adding α-blockers, combined α-ß-blockers, centrally acting α-agonists, or direct vasodilators. However, a small, but important subset of patients remain hypertensive despite combination regimens with multiple antihypertensive drugs, underscoring the need for novel blood pressure-lowering therapies. Over recent years, alternative approaches for treating TRH have emerged, including agonists of natriuretic peptides, endothelin-receptor antagonists, and additional vasoactive drugs. Lastly, device-based interventions, such as renal denervation or carotid baroreflex activation, may supplement drug therapy for these patients. This review summarizes current knowledge on the management of TRH, with focus on novel therapeutic strategies designed to achieve optimal blood pressure control.

Blood Pressure Responses to Endovascular Stimulation: A Potential Therapy for Autonomic Disorders With Vasodilatation.

BACKGROUND: We have previously shown that sympathetic ganglia stimulation via the renal vein rapidly increases blood pressure. This study further investigated the optimal target sites and effective energy levels for stimulation of the renal vasculatures and nearby sympathetic ganglia for rapid increase in blood pressure. METHODS: The pre-study protocol for endovascular stimulations included 2 minutes of stimulation (1-150 V and 10 pulses per second) and at least 2 minutes of rest during poststimulation. If blood pressure and/or heart rate were changed during the stimulation, time to return to baseline was allowed prior to the next stimulation. RESULTS: In 11 acute canine studies, we performed 85 renal artery, 30 renal vein, and 8 hepatic vasculature stimulations. The mean arterial pressure (MAP) rapidly increased during stimulation of renal artery (95 ± 18 mmHg vs. 103 ± 15 mmHg; P < 0.0001), renal vein (90 ± 16 mmHg vs. 102 ± 20 mmHg; P = 0.001), and hepatic vasculatures (74 ± 8 mmHg vs. 82 ± 11 mmHg; P = 0.04). Predictors of a significant increase in MAP were energy >10 V focused on the left renal artery, bilateral renal arteries, and bilateral renal veins (especially the mid segment). Overall, heart rate was unchanged, but muscle fasciculation was observed in 22.0% with an output >10 V (range 15-150 V). Analysis after excluding the stimulations that resulted in fasciculation yielded similar results to the main findings. CONCLUSIONS: Stimulation of intra-abdominal vasculatures promptly increased the MAP and thus may be a potential treatment option for hypotension in autonomic disorders. Predictors of optimal stimulation include energy delivery and the site of stimulation (for the renal vasculatures), which informs the design of subsequent research.

Non-pharmacological methods in the treatment of resistant hypertension.

INTRODUCTION: Arterial hypertension is the most common chronic cardiovascular disease affecting about 25% of the adult population. Meta-analyses have demonstrated a linear relationship between blood pressure and the risk of cardiovascular events. Resistant hypertension defined as failure to reach blood pressure targets despite treatment with three antihypertensive drugs including a diuretic represents a serious clinical problem. It has been estimated that it affects between 8.9% and 12.8% of all treated hypertensive subjects. In resistant hypertension the optimal blood pressure is illusive despite very well tailored therapy. OBJECTIVE: Management of resistant hypertension is exactly the field where blood pressure-controlling non-pharmacological methods fit best. The present article aims at throwing light on these methods' principles of action, on who the target patient groups are and the respective results. Two methods are especially reviewed here: the carotid baroreflex stimulation and the transcatheter renal sympathetic denervation. Current results from the use of renal denervation suggest stable efficiency of the method, the results becoming significant 6 months after the procedure is applied and sustained for two years in the follow-up. As much as 90% of the treated patients respond to the procedure. The transcatheter renal denervation is associated with only 2.61% of procedural complications. The baroreflex carotid stimulation, too, is known to produce a stable effect on blood pressure: the effect become obvious at 12 months in 88% of the treated subjects. The neurologic complications associated with the procedure are reported to occur in 4.4% of cases. CONCLUSION: The present review article clearly demonstrates that non-pharmacological methods for treatment of resistant hypertension show great promise despite some open questions concerning their long term effects and procedural safety.

[Drug-independent blood pressure control through the autonomous nervous system]. / Nicht-medikamentöse Hypertoniebehandlung durch Beeinflussung des autonomen Nervensystems.

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.

Recent advancements in the treatment of resistant hypertension.

The 2008 scientific statement from the American Heart Association defined resistant hypertension as blood pressure remaining above goal (< 140/90 mm Hg for the general population and < 130/80 mm Hg for patients with diabetes or renal disease) despite the concurrent use of optimal doses of 3 antihypertensive agents of different classes, ideally including a diuretic. Since then, there has been increasing recognition and characterization of patients with resistant hypertension and development of treatment strategies to treat this high-risk population. The role of aldosterone in resistant hypertension has gained increasing recognition. In particular, there has been development of a strong body of evidence for the use of spironolactone as a highly effective antihypertensive agent. Furthermore, there is increasing evidence to link aldosterone with both resistant hypertension and obstructive sleep apnea, with preliminary studies suggesting that aldosterone antagonists may potentially be effective in treating both conditions. Finally, recent work has directed increased attention toward novel invasive strategies for the treatment of resistant hypertension, specifically baroreflex activation therapy with carotid stimulation and percutaneous renal artery denervation. Initial randomized controlled trials have shown that both of these methods may be used to safely lower blood pressure, thereby providing exciting and promising new tools in the armamentarium of options to treat resistant hypertension.

Blood pressure control in resistant hypertension: new therapeutic options.

Resistant hypertension, namely the hypertensive state characterized by the inability of multiple antihypertensive drug interventions to lower blood pressure to goal levels, represents a condition frequently detected in clinical practice. Its main features are represented by its heterogeneous etiology as well as its very high cardiovascular risk. This latter peculiarity has implemented the research for new approaches to the treatment of the disease. This article will focus on two of them, namely carotid baroreceptor electric stimulation and the renal denervation procedure. Clinical studies and large-scale clinical trials are presently ongoing with the aim of defining the long-term efficacy and safety profile of the two interventions.

Role of ventrolateral medulla in vasomotor regulation: a correlative anatomical and physiological study.

Two groups of experiments were carried out in rabbits. First, the ventrolateral reticular formation of the medulla oblongata was stimulated either by microinjection of sodium glutamate solution (exciting only cell bodies) or electrically (exciting cell bodies and axons). This region has been shown previously to contain a dense and compact group of bulbospinal cells. The effects of both electrical and chemical stimulation of specific sites were correlated with the density of ventrolateral bulbospinal cells at the same sites. Glutamate microinjection into the center of the group of bulbospinal cells elicited a very large and sustained increase in arterial pressure, whereas microinjection into sites outside this region elicited a very small or no response. These results suggest that it is the bulbospinal ventrolateral cells which mediate the pressor response to glutamate stimulation. Focal electrical stimulation in the ventrolateral medulla elicited increases in arterial pressure and decreases in femoral and renal vascular conductance, as well as a short-latency increase in renal sympathetic nerve activity. The most effective sites for focal electrical stimulation lay within the region of greatest density of bulbospinal cells; slightly less effective sites lay just rostral and caudal to this region. It is suggested that stimulation in these latter sites predominantly excites axons of passage. Secondly, the origin of afferent fibers to the ventrolateral vasomotor area was studied using the horseradish peroxidase (HRP) method. This revealed major projections from the medial part of the nucleus tractus solitarius and the parabrachial nucleus in the pons. The physiological and anatomical studies taken together are consistent with the hypothesis that the bulbospinal ventrolateral cells are vasomotor in function, and receive afferent inputs from brain stem nuclei which are known to play a role in autonomic regulation.

Mechanism of the redistribution of renal cortical blood flow during hemorrhagic hypotension in the dog.

Studies were performed to define the mechanisms involved in the redistribution of renal cortical blood flow to inner cortical nephrons which occurs during hemorrhagic hypotension in the dog. The radioactive microsphere method was utilized to measure regional blood flow in the renal cortex. Renal nerve stimulation decreased renal blood flow 40% but had no effect on the fractional distribution of cortical blood flow. Pretreatment with phenoxybenzamine, phentolamine, propranolol, or atropine did not alter the redistribution of cortical flow during hemorrhage. A reduction in renal perfusion pressure by aortic constriction caused a qualitatively similar alteration in regional blood flow distribution as occurred during hemorrhage. When perfusion pressure was kept constant in one kidney by aortic constriction followed by hemorrhage, no redistribution occurred in the kidney with a constant perfusion pressure while the contralateral kidney with the normal perfusion pressure before hemorrhage had a marked increase in the fractional distribution of cortical flow to inner cortical nephrons. Additionally, retransfusion had no effect on the fractional distribution of flow in the kidney in which perfusion pressure was maintained at the same level as during hemorrhage while in the contralateral kidney in which pressure increased to normal there was a redistribution of flow to outer cortical nephrons. These studies indicate that the redistribution of renal cortical blood flow which occurs during hemorrhage is not related to changes in adrenergic activity but rather to the intrarenal alterations which attend a diminution in perfusion pressure.