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.

Neuromodulation Approaches for Cardiac Arrhythmias: Recent Advances.

PURPOSE OF REVIEW: This review aims to describe the latest advances in autonomic neuromodulation approaches to treating cardiac arrhythmias, with a focus on ventricular arrhythmias. RECENT FINDINGS: The increasing understanding of neuronal remodeling in cardiac diseases has led to the development and improvement of novel neuromodulation therapies targeting multiple levels of the autonomic nervous system. Thoracic epidural anesthesia, spinal cord stimulation, stellate ganglion modulatory therapies, vagal stimulation, renal denervation, and interventions on the intracardiac nervous system have all been studied in preclinical models, with encouraging preliminary clinical data. The autonomic nervous system regulates all the electrical processes of the heart and plays an important role in the pathophysiology of cardiac arrhythmias. Despite recent advances in the clinical application of cardiac neuromodulation, our comprehension of the anatomy and function of the cardiac autonomic nervous system is still limited. Hopefully in the near future, more preclinical data combined with larger clinical trials will lead to further improvements in neuromodulatory treatment for heart rhythm disorders.

Differential effect of ganglionic plexi ablation in a patient with neurally mediated syncope and intermittent atrioventricular block.

AIMS: In patients with severe neurally mediated syncope (NMS), radiofrequency catheter ablation (RFA) of ganglionic plexi (GP) has been proposed as a new therapeutic approach. Cardio-inhibitory response during NMS is usually related to the sinoatrial (SA) and less frequently to atrioventricular (AV) node. Differential effect of GP ablation on SA and AV node is poorly understood. METHODS AND RESULTS: We report a case of a 35-year-old female with frequent symptomatic episodes of advanced AV block treated by anatomically guided RFA at empirical sites of GPs. After RFA at the septal portion of the right atrium-superior vena cava junction, heart rate accelerated from 62 to 91 beats/min and PR interval prolonged from 213 to 344 ms. Sustained first-degree AV block allowed to observe directly the effects of subsequent RFA on the AV nodal properties. Subsequent RFA at right- and left-sided aspects of the inter-atrial septum had no further effect on heart rate and PR interval. Ablation at the inferior left GP was critical for restoration of normal AV conduction (final PR interval of 187 ms). No bradycardia episodes were observed by implantable loop recorder during the follow-up of 10 months and the patient was symptomatically improved. CONCLUSION: This is the first clinical case showing the differential effect of GP ablation on SA and AV nodal function, and critical importance of targeting the GP at the postero-inferior left atrium. The successful procedure corroborates clinical utility of ablation treatment instead of pacemaker implantation in selected patients with cardio-inhibitory NMS.

New therapies for arterial hypertension.

Arterial hypertension is the most common chronic disease in developed countries and it is the leading risk factor for stroke, ischemic heart disease, congestive heart failure, chronic renal failure and peripheral artery disease. Its prevalence appears to be about 30-45% of the general population. Recent European guidelines estimate that up to 15-20% of the hypertensive patients are not controlled on a dual antihypertensive combination and they require three or more different antihypertensive drug classes to achieve adequate blood pressure control. The guidelines confirmed that diuretics, beta-blockers, calcium-channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in combination therapy. Very few antihypertensive agents have reached the market over the last few years, but no new therapeutic class has really emerged. The long-term adherence to cardiovascular drugs is still low in both primary and secondary prevention of cardiovascular diseases. In particular, the issue of compliance is persistently high in hypertension, despite the fixed-dose combination therapy. As a consequence, a cohort of high-risk hypertensive population, represented by patients affected by refractory and resistant hypertension, can be identified. Therefore, the need of controlling BP in high-risk patients may be addressed, in part, by the development of new drugs, devices and procedures that are designed to treat hypertension and comorbidities. In this review we will comprehensively discuss the current literature on recent therapeutic advances in hypertension, including both medical therapy and interventional procedures.

Permanent sinus dysfunction after pulmonary vein isolation ablation: observations and potential mechanisms.

Although transient sinus arrest has been reported during pulmonary vein isolation (PVI), the long-term impairment of sinus node after PVI has not been described. In this report, we present a case of sinus node dysfunction necessitating a permanent pacemaker, caused during PVI. Clinical data, intracardiac electrograms, and cardiac imaging were incompatible with previous sinus node dysfunction, sinus node artery occlusion, or an ectopic atrial rhythm from the pulmonary veins. Impairment of the neural pathways connecting the ganglionated plexi of the right superior pulmonary veins with the sinus node is a possible underlying mechanism.

Non-pharmacological modulation of the autonomic tone to treat heart failure.

The autonomic nervous system has a significant role in the pathophysiology and progression of heart failure. The absence of any recent breakthrough advances in the medical therapy of heart failure has led to the evolution of innovative non-pharmacological interventions that can favourably modulate the cardiac autonomic tone. Several new therapeutic modalities that may act at different levels of the autonomic nervous system are being investigated for their role in the treatment of heart failure. The current review examines the role of renal denervation, vagal nerve stimulators, carotid baroreceptors, and spinal cord stimulators in the treatment of heart failure.

Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial.

OBJECTIVES: The aim of this study was to investigate whether the combination of conventional pulmonary vein isolation (PVI) by circumferential antral ablation with ganglionated plexi (GP) modification in a single ablation procedure, yields higher success rates than PVI or GP ablation alone, in patients with paroxysmal atrial fibrillation (PAF). BACKGROUND: Conventional PVI transects the major left atrial GP, and it is possible that autonomic denervation by inadvertent GP ablation plays a central role in the efficacy of PVI. METHODS: A total of 242 patients with symptomatic PAF were recruited and randomized as follows: 1) circumferential PVI (n = 78); 2) anatomic ablation of the main left atrial GP (n = 82); or 3) circumferential PVI followed by anatomic ablation of the main left atrial GP (n = 82). The primary endpoint was freedom from atrial fibrillation (AF) or other sustained atrial tachycardia (AT), verified by monthly visits, ambulatory electrocardiographic monitoring, and implantable loop recorders, during a 2-year follow-up period. RESULTS: Freedom from AF or AT was achieved in 44 (56%), 39 (48%), and 61 (74%) patients in the PVI, GP, and PVI+GP groups, respectively (p = 0.004 by log-rank test). PVI+GP ablation strategy compared with PVI alone yielded a hazard ratio of 0.53 (95% confidence interval: 0.31 to 0.91; p = 0.022) for recurrence of AF or AT. Fluoroscopy duration was 16 ± 3 min, 20 ± 5 min, and 23 ± 5 min for PVI, GP, and PVI+GP groups, respectively (p < 0.001). Post-ablation atrial flutter did not differ between groups: 5.1% in PVI, 4.9% in GP, and 6.1% in PVI+GP. No serious adverse procedure-related events were encountered. CONCLUSIONS: Addition of GP ablation to PVI confers a significantly higher success rate compared with either PVI or GP alone in patients with PAF.

Contribution of fibrosis and the autonomic nervous system to atrial fibrillation electrograms in heart failure.

BACKGROUND: Fibrotic and autonomic remodeling in heart failure (HF) increase vulnerability to atrial fibrillation (AF). Because AF electrograms (EGMs) are thought to reflect the underlying structural substrate, we sought to (1) determine the differences in AF EGMs in normal versus HF atria and (2) assess how fibrosis and nerve-rich fat contribute to AF EGM characteristics in HF. METHODS AND RESULTS: AF was induced in 20 normal dogs by vagal stimulation and in 21 HF dogs (subjected to 3 weeks of rapid ventricular pacing at 240 beats per minute). AF EGMs were analyzed for dominant frequency (DF), organization index, fractionation intervals (FIs), and Shannon entropy. In 8 HF dogs, AF EGM correlation with underlying fibrosis/fat/nerves was assessed. In HF compared with normal dogs, DF was lower and organization index/FI/Shannon entropy were greater. DF/FI were more heterogeneous in HF. Percentage fat was greater, and fibrosis and fat were more heterogeneously distributed in the posterior left atrium than in the left atrial appendage. DF/organization index correlated closely with %fibrosis. Heterogeneity of DF/FI correlated with the heterogeneity of fibrosis. Autonomic blockade caused a greater change in DF/FI/Shannon entropy in the posterior left atrium than left atrial appendage, with the decrease in Shannon entropy correlating with %fat. CONCLUSIONS: The amount and distribution of fibrosis in the HF atrium seems to contribute to slowing and increased organization of AF EGMs, whereas the nerve-rich fat in the HF posterior left atrium is positively correlated with AF EGM entropy. By allowing for improved detection of regions of dense fibrosis and high autonomic nerve density in the HF atrium, these findings may help enhance the precision and success of substrate-guided ablation for AF.

Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi.

AIMS: Previous studies showed that autonomic activation by high-frequency electrical stimulation (HFS) during myocardial refractoriness evokes rapid firing from pulmonary vein (PV) and atria, both in vitro and in vivo. This study sought to investigate the autonomic mechanism underlying the rapid firings at various sites by systematic ablation of multiple ganglionated plexi (GP). METHODS AND RESULTS: In 43 mongrel dogs, rapid firing-mediated atrial fibrillation (AF) was induced by local HFS (200 Hz, impulse duration 0.1 ms, train duration 40 ms) to the PVs and atria during myocardial refractoriness. The main GP in the atrial fat pads or the ganglia along the ligament of Marshall (LOM) were then ablated. Ablation of the anterior right GP and inferior right GP significantly increased the AF threshold by HFS at the right atrium and PVs. The AF threshold at left atrium and PVs was significantly increased by ablation of the superior left GP and inferior left GP, and was further increased by ablation of the LOM. Ablation of left- or right-sided GP on the atria had a significant effect on contralateral PVs and atrium. Administration of esmolol (1 mg/kg) or atropine (1 mg) significantly increased AF threshold at all sites. CONCLUSION: HFS applied to local atrial and PV sites initiated rapid firing via activation of the interactive autonomic network in the heart. GP in either left side or right side contributes to the rapid firings and AF originating from ipsolateral and contralateral PVs and atrium. Autonomic denervation suppresses or eliminates those rapid firings.

Responses of opioid and serotonin containing medullary raphe neurons to electroacupuncture.

The midline medulla oblongata, which includes the nucleus raphe obscurus, raphe magnus and raphe pallidus (NRP), is involved in regulation of cardiovascular responses. Opioids and serotonin (5-HT) are thought to function as important neurotransmitters in this region. We previously have demonstrated that electroacupuncture (EA) at the Neiguan-Jianshi acupoints (P5-P6, overlying the median nerves) attenuates sympathoexcitatory blood pressure reflexes through its influence on several brain regions. However, the role of these three raphe nuclei in the acupuncture responses is unknown. In baroreceptor denervated and vagotomized cats, the present study evaluated c-Fos activation in the raphe nuclei induced by EA and examined its relationship to enkephalin and 5-HT. To enhance detection of perikarya containing enkephalin, colchicine (90-100 microg/kg) was administered into the subarachnoid space in anesthetized cats 28-30 h before the placement of acupuncture needles at P5-P6 acupoints with or without electrical stimulation for 30 min. Perikarya containing the opioid and 5-HT were found in the raphe nuclei of all animals following application of colchicine. Compared to controls without electrical stimulation (n=5), c-Fos immunoreactivity and neurons double-labeled with c-Fos and either enkephalin or 5-HT were found more frequently in all three midline medullary nuclei, especially in NRP (n=6, all P<0.05) of EA-treated cats. Moreover, neurons triple-labeled with c-Fos, enkephalin and 5-HT were noted frequently in the NRP following EA stimulation. These results suggest that the medullary raphe nuclei, particularly the NRP, process somatic signals during EA and participate in EA-related modulation of cardiovascular function through an opioid or serotonergic mechanism.

Involvement of nuclei in the hypothalamus in cardiac sympathoexcitatory reflexes in cats.

The hypothalamus is considered to be an important area in the central regulation of cardiovascular function. However, its role in processing excitatory cardiovascular reflexes induced by stimulation of cardiac afferents has not been established. In the present study, using c-Fos immunoreactivity, we located neurons in the hypothalamus activated by inputs from cardiac sympathetic afferents. Following bilateral barodenervation and cervical vagotomy in anesthetized cats, bradykinin (BK, 1-10 microg, in 0.1 ml; n=7) was applied repetitively (6x, every 20 min) to the anterior epicardial surface of the left ventricle. This chemical stimulation caused consistent excitatory cardiovascular reflexes characterized by increases in blood pressure (BP) and heart rate (HR), while the vehicle for BK (0.9% saline, n=6) produced no such responses. Compared to control cats, c-Fos immunoreactive cells were significantly increased (P<0.05) in the arcuate nucleus (ARC), dorsal hypothalamic area (HDA), dorsomedial nucleus, paraventricular hypothalamic nucleus (PVN) and periventricular nucleus in the BK-treated animals. More neurons double-labeled with c-Fos and nitric oxide synthase (NOS) were observed in the PVN following epicardial application of BK (P<0.05). There was no significant increase in co-localization of these two labelings in the other nuclei. These results suggest that several nuclei in the hypothalamus respond to activation of cardiac sympathetic afferents, leading to sympathoexcitatory reflexes. Nitric oxide (NO) may function as a neurotransmitter or as a neuromodulator in the PVN during these cardiac-cardiovascular responses.