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.

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.

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.

Voluntary Corn Oil Ingestion Increases Energy Expenditure and Interscapular UCP1 Expression Through the Sympathetic Nerve in C57BL/6 Mice.

SCOPE: Previously, it has been found that corn oil ingestion activates both the gustatory system and brain reward system, stimulating motivation for eating. In the present study, the effect of voluntary corn oil ingestion on body weight gain and energy metabolism in mice is investigated. METHODS AND RESULTS: Voluntary corn oil ingestion with normal chow feeding does not lead to higher body weight than that of only the chow-fed control group. Mice that ingested corn oil have a higher total caloric intake and energy expenditure than did mice in the control group. Further, voluntary corn oil ingestion significantly upregulates Ucp1 mRNA and protein in interscapular brown adipose tissue (IBAT). Finally, the sympathetic nerve connected to IBAT was surgically transacted, then the body weight is measured for 8 weeks. IBAT sympathetic nerve transection surgery does not affect the body weight gain and food intake; however, when mice ingested corn oil, it induces significant body weight gain without changing the total caloric intake. IBAT sympathetic nerve transection surgery significantly suppresses UCP1 upregulation by corn oil ingestion. CONCLUSION: The present data suggest that corn oil ingestion activates IBAT through the sympathetic nerve, upregulating UCP1 expression and increasing energy expenditure.

Renal sympathetic stimulation and ablation affect ventricular arrhythmia by modulating autonomic activity in a cesium-induced long QT canine model.

BACKGROUND: Our previous studies showed that renal sympathetic stimulation (RS) may facilitate ischemic ventricular arrhythmia (VA) by increasing left stellate ganglion (LSG) nerve activity, whereas renal sympathetic ablation (RA) may suppress VA. OBJECTIVE: The purpose of this study was to investigate whether renal sympathetic interventions also can affect VA by modulating LSG activity in a cesium-induced long QT canine model. METHODS: Twenty-four dogs were randomly divided into RS group (n = 8), RA group (n = 8), or control group (n = 8). Serum norepinephrine, LSG function, and LSG neural activity were measured before and 3 hours after RS or RA. Increasing doses of cesium chloride then were administered until a "threshold dose" produced sustained ventricular tachycardia or ventricular fibrillation. Early afterdepolarization amplitude, VA prevalence, and tachycardia threshold dose were compared among these groups. Nerve growth factor and c-fos protein expressed in the LSG also were examined. RESULTS: Serum norepinephrine, LSG function, and LSG neural activity were all significantly increased after 3 hours of RS and all were decreased 3 hours after RA. In addition, RS significantly decreased the tachycardia threshold dose, increased the early afterdepolarization amplitude, facilitated the incidence of VAs, and increased the expression of nerve growth factor and c-fos protein. In contrast, RA induced the opposite effects. CONCLUSION: RS promotes, whereas RA suppresses, the incidence of VAs in a canine model of cesium-induced long QT. Modulation of LSG neural activity by RS and RA may be responsible for these different effects.

Roles for the sympathetic nervous system, renal nerves, and CNS melanocortin-4 receptor in the elevated blood pressure in hyperandrogenemic female rats.

Women with polycystic ovary syndrome (PCOS) have hyperandrogenemia and increased prevalence of risk factors for cardiovascular disease, including elevated blood pressure. We recently characterized a hyperandrogenemic female rat (HAF) model of PCOS [chronic dihydrotestosterone (DHT) beginning at 4 wk of age] that exhibits similar characteristics as women with PCOS. In the present studies we tested the hypotheses that the elevated blood pressure in HAF rats is mediated in part by sympathetic activation, renal nerves, and melanocortin-4 receptor (MC4R) activation. Adrenergic blockade with terazosin and propranolol or renal denervation reduced mean arterial pressure (MAP by telemetry) in HAF rats but not controls. Hypothalamic MC4R expression was higher in HAF rats than controls, and central nervous system MC4R antagonism with SHU-9119 (1 nmol/h icv) reduced MAP in HAF rats. Taking a genetic approach, MC4R null and wild-type (WT) female rats were treated with DHT or placebo from 5 to 16 wk of age. MC4R null rats were obese and had higher MAP than WT control rats, and while DHT increased MAP in WT controls, DHT failed to further increase MAP in MC4R null rats. These data suggest that increases in MAP with chronic hyperandrogenemia in female rats are due, in part, to activation of the sympathetic nervous system, renal nerves, and MC4R and may provide novel insights into the mechanisms responsible for hypertension in women with hyperandrogenemia such as PCOS.

Research needs in the area of device-related treatments for hypertension.

Hypertension is the primary risk factor for cardiovascular and renal-disease endpoints. Medications help many patients but not all. Recently, two device-related treatments have been introduced, catheter-based renal denervation and electrical carotid sinus stimulation. Remuneration for these treatments is guaranteed in many countries even though basic information is missing. We draw attention to deficiencies in the database. For catheter-based renal denervation, few large-animal data are available to investigate the effect of the intervention on the histology of the arterial wall. No functional data are available regarding re-innervation. For carotid sinus stimulation, the situation is similar. Acute activation of either treatment seems to reduce sympathetic tone dramatically. However, whether or not the effects are sustained over time is unknown. No 'end-point' data are available for either treatment. Devices should be subjected to evidence-based standards before widespread introduction.

Timing and efficacy of alternative methods of sympathetic blockade.

Despite the presence of seven different antihypertensive drug classes and over 120 different antihypertensive medications, about 48 % of the 75 million people with hypertension are not reaching their target blood pressure goals. One of the reasons for this lack of control is the failure to adequately inhibit the sympathetic nervous system. Consequently, alternative therapies have been attracting interest. Recent technical advances targeting the sympathetic over-activity of the carotid sinuses (baroreflex activation therapy, BAT) and the renal sympathetic nerves (renal denervation therapy, RDT) have renewed interest in invasive therapies for the treatment of drug-resistant hypertension. Encouraging results from the recent Rheos Pivotal and Symplicity HTN-2 trials on the safety and efficacy of BAT and RDT, respectively, indicate that invasive approaches can safely reduce blood pressure in patients with resistant/refractory hypertension. These approaches, while still experimental in the US, are appropriate for those on more than three fully tolerated doses of antihypertensive medications whose blood pressure is not at goal, i.e. <140/90 mmHg. The present review is focused on the clinical implications of these two technics and when they are appropriate.

Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation.

BACKGROUND: We used high-frequency stimulation delivered during the refractory period of the atrium and pulmonary veins (PVs) to induce focal firing and atrial fibrillation (AF). This study was designed to demonstrate that bilateral low-level vagosympathetic nerve stimulation (LL-VNS) could suppress high-frequency stimulation-induced focal AF at atrial and PV sites. METHODS AND RESULTS: In 23 dogs anesthetized with Na-pentobarbital, electrodes in the vagosympathetic trunks allowed LL-VNS at 1 V below that which slowed the sinus rate or atrioventricular conduction. Multielectrode catheters were fixed at the right and left superior and inferior PVs and both atrial appendages. LL-VNS continued for 3 hours. At the end of each hour, the high-frequency stimulation algorithm consisting of a 40-ms train of stimuli (200 Hz; stimulus duration, 0.1 to 1.0 ms) was delivered 2 ms after the atrial pacing stimulus during the refractory period at each PV and atrial appendages site. The lowest voltage of high-frequency stimulation that induced AF was defined as the AF threshold. Five dogs without LL-VNS served as sham controls. Six dogs underwent LL-VNS after transection of bilateral vagosympathetic trunks. LL-VNS induced a progressive increase in AF threshold at all PV and atrial appendages sites, particularly significant (P<0.05) at the right superior PV, right inferior PV, left superior PV, and right atrial appendage. Bilateral vagosympathetic transection did not significantly alter the previous findings, and the 5 sham control dogs did not show changes in AF threshold at any site over a period of 3 hours. CONCLUSIONS: LL-VNS may prevent episodic AF caused by rapid PV and non-PV firing.

Systemically administered tempol reduces neuronal activity in paraventricular nucleus of hypothalamus and rostral ventrolateral medulla in rats.

OBJECTIVE: Systemic administration of the superoxide scavenger tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) reduces blood pressure (BP), heart rate (HR) and sympathetic nerve activity in normotensive and hypertensive animals. The global nature of the depressor response to tempol suggests an inhibitory influence on cardiovascular presympathetic regions of the brain. This study examined several possible mechanisms for such an effect. METHODS AND RESULTS: In urethane anesthetized rats, as expected, intravenous tempol (120 microg mol/kg) reduced mean arterial pressure, HR and renal sympathetic nerve activity (RSNA). Concomitant central neuronal recordings revealed reduced spontaneous discharge (spikes/s) of neurons in the paraventricular nucleus of hypothalamus (from 2.9 +/- 0.4 to 0.8+/- 0.2) and the rostral ventrolateral medulla (RVLM; from 9.8 +/- 0.5 to 7.2 +/-0.4), two cardiovascular and autonomic regions of the brain. Baroreceptor-denervated rats had exaggerated sympathetic and cardiovascular responses. Pretreatment with the hydroxyl radical scavenger dimethyl sulfoxide (intravenous) attenuated the tempol-induced decreases in BP, HR and RSNA, but the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (intravenous or intracerebroventricular) had no effect. CONCLUSION: These findings suggest that systemically administered tempol acts upon neurons in paraventricular nucleus and RVLM to reduce BP, HR and RSNA, perhaps by reducing the influence of reactive oxygen species in those regions. The arterial baroreflex modulates the depressor responses to tempol. These central mechanisms must be considered in interpreting data from studies using systemically administered tempol to assess the role of reactive oxygen species in cardiovascular regulation.

Effects of thermal stimulation, applied to the hindpaw via a hot water bath, upon ovarian blood flow in anesthetized nonpregnant rats.

The effects of thermal stimulation, applied to the hindpaw via a hot bath set to either 40 degrees C (non-noxious) or 49 degrees C (noxious), upon ovarian blood flow were examined in nonpregnant anesthetized rats. Ovarian blood flow was measured using a laser Doppler flowmeter. Blood pressure was markedly increased following 49 degrees C stimulation. Ovarian blood flow, however, showed no obvious change during stimulation, although a small increase was observed after stimulation. Ovarian blood flow and blood pressure responses to 49 degrees C stimulation were abolished after hindlimb somatic nerves proximal to the stimuli were cut. Heat stimulation (49 degrees C) resulted in remarkable increases in both ovarian blood flow and blood pressure in rats in which the sympathetic nerves supplying the ovary were cut but the hindlimb somatic nerves remained intact. The efferent activity of the ovarian plexus nerve was increased during stimulation at 49 degrees C. Stimulation at 40 degrees C had no effect upon ovarian blood flow, blood pressure or ovarian plexus nerve activity. Electrical stimulation of the distal part of the severed ovarian plexus nerve resulted in a decrease in both the diameter of ovarian arterioles, observed using a digital video microscope, and ovarian blood flow.The present results demonstrate that noxious heat, but not non-noxious warm, stimulation of the hindpaw skin in anesthetized rats influences ovarian blood flow in a manner that is attributed to reflex responses in ovarian sympathetic nerve activity and blood pressure.

Viscerosomatic interaction induced by myocardial ischemia in conscious dogs.

Studies tested the hypothesis that myocardial ischemia induces increased paraspinal muscular tone localized to the T(2)-T(5) region that can be detected by palpatory means. This is consistent with theories of manual medicine suggesting that disturbances in visceral organ physiology can cause increases in skeletal muscle tone in specific muscle groups. Clinical studies in manual and traditional medicine suggest this phenomenon occurs during episodes of myocardial ischemia and may have diagnostic potential. However, there is little direct evidence of a cardiac-somatic mechanism to explain these findings. Chronically instrumented dogs [12 neurally intact and 3 following selective left ventricular (LV) sympathectomy] were examined before, during, and after myocardial ischemia. Circumflex blood flow (CBF), left ventricular contractile function, electromyographic (EMG) analysis, and blinded manual palpatory assessments (MPA) of tissue over the transverse spinal processes at segments T(2)-T(5) and T(11)-T(12) (control) were performed. Myocardial ischemia was associated with a decrease in myocardial contractile function and an increase in heart rate. MPA revealed increases in muscle tension and texture/firmness during ischemia in the T(2)-T(5) segments on the left, but not on the right or in control segments. EMG demonstrated increased amplitude for the T(4)-T(5) segments. After LV sympathectomy, MPA and EMG evidence of increased muscle tone were absent. In conclusion, myocardial ischemia is associated with significant increased paraspinal muscle tone localized to the left side T(4)-T(5) myotomes in neurally intact dogs. LV sympathectomy eliminates the somatic response, suggesting that sympathetic neural traffic between the heart and somatic musculature may function as the mechanism for the interaction.

Ovarian blood flow responses to electroacupuncture stimulation depend on estrous cycle and on site and frequency of stimulation in anesthetized rats.

Electroacupuncture (EA) applied to the abdomen and hindlimb modulates the ovarian blood flow (OBF) response. The present study aimed to further elucidate the role of the site and the frequency of short-term EA stimulation and the influence of the estrous cycle on the OBF response using anesthetized rats. EA stimulation was applied to the abdominal or the hindlimb muscles at three different frequencies (2, 10, and 80 Hz) during the estrus or diestrus phase. Involvement of spinal and supraspinal reflexes in OBF responses to EA stimulation was investigated by spinal cord transection. Abdominal EA stimulation at 10 Hz increased the OBF response, whereas hindlimb EA stimulation at 10 Hz and abdominal and hindlimb stimulation at 80 Hz decreased the OBF response; 2-Hz EA caused no OBF response. The OBF response to abdominal EA was more pronounced in the estrus than the diestrus phase. The OBF response to abdominal and hindlimb EA stimulation at both 10 and 80 Hz was almost abolished, both after severance of the sympathetic nerves and after spinal cord transection. In conclusion, the OBF response to both abdominal and hindlimb EA stimulation was mediated as a reflex response via the ovarian sympathetic nerves, and the response was controlled via supraspinal pathways. Furthermore, the OBF response to segmental abdominal EA stimulation was frequency dependent and amplified in the estrous phase.

Chronic regional pain syndrome, type 1: Part II.

Chronic regional pain syndrome, type 1 (CRPS1) is a complex neurologic disease characterized by chronic, severe, burning pain; hyperesthesia; soft tissue swelling; dystrophy; hyperhidrosis; vasomotor and sudomotor instability; joint stiffness; and patchy osteoporosis. Five to six million people in the United States alone suffer from CRPS1. To date, CRPS1 is poorly understood and often is not recognized clinically. This syndrome requires early detection, pain control, and treatment in tandem with physical therapy to the affected area. Part I (published in September) discussed background information on CRPS1 and sympathetic nerve blocks. Part II focuses on the remaining treatment modalities (e.g., sympathectomy, physical therapy, stimulators, trigger point injections, acupuncture, tourniquet effects, placebo effects, amputation).

Sympathetic denervation of the upper limb improves forearm exercise performance and skeletal muscle bioenergetics.

BACKGROUND: Sympathetic activation may limit exercise performance by restraining muscle blood flow or by negatively affecting skeletal muscle metabolic behavior. To test this hypothesis, we studied the effect of thoracoscopic sympathetic trunkotomy (TST) on forearm exercise duration, blood flow, and muscle bioenergetics in 13 patients with idiopathic palmar hyperhidrosis. METHODS AND RESULTS: Heart rate and beat-by-beat mean arterial pressure were recorded at rest and during right and left rhythmic handgrip before and 4 to 7 weeks after right TST. Forearm blood flow was measured bilaterally at rest and on the right during exercise. Right forearm muscle phosphocreatine content and intracellular pH were assessed by (31)phosphorus magnetic resonance spectroscopy. After right TST, exercise duration increased from 8.9+/-1.4 to 13.4+/-1.8 minutes (P<0.0001) with the right forearm and from 5.7+/-0.4 to 7.6+/-0.9 minutes (P<0.05) with the left (P<0.05 for the interaction between treatment and side). Right forearm blood flow at rest was 66% higher (P<0.01) after right TST, but this difference decreased as the exercise progressed. After right TST, a significant reduction occurred in muscle acidification and phosphocreatine depletion during ipsilateral forearm exercise. This was associated with a significantly reduced mean arterial pressure response to right handgrip, whereas the pressor response to left handgrip did not change. CONCLUSIONS: Sympathetic denervation of the upper limb significantly improves forearm skeletal muscle bioenergetics and exercise performance in patients with idiopathic palmar hyperhidrosis.

Pretreatment with [131I] metaiodobenzylguanidine and surgical resection of advanced neuroblastoma.

Pretreatment with [131I] metaiodobenzylguanidine (MIBG) followed by surgical resection in advanced neuroblastoma (stage 3 and 4) has been studied in relation to resectability, morbidity and mortality, survival rate after two years, control of distant metastasis and serum levels of LDH as prognostic factors. Twenty-one patients with advanced neuroblastoma were primarily treated with MIBG radiotherapy, followed by surgical resection. Sixteen patients had stage 4 disease. Between 2 and 6 courses of MIBG treatment were given per patient. In 17 patients gross complete resection was achieved. Two patients developed complications directly related to the operation, one died as a result of this. The overall mortality was 38%. MIBG therapy resulted in partial response in 13 patients and in stable disease in 8 patients. Two years survival in the group with partial response was 86% and in the group with stable disease 28%. Because of the resulting excellent general condition of the patients the interval between pretreatment with MIBG and surgery could be very short. Follow-up till December 1994 showed that 13 children were alive for 3 to 47 months. Seven had no evidence of disease. Preoperative MIBG de novo treatment in advanced neuroblastoma is equal to induction chemotherapy, but less toxic.