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Journal of Applied Physiology... May 2021Volumetric muscle loss (VML) is the traumatic loss of muscle tissue that results in long-term functional impairments. Despite the loss of myofibers, there remains an...
Volumetric muscle loss (VML) is the traumatic loss of muscle tissue that results in long-term functional impairments. Despite the loss of myofibers, there remains an unexplained significant decline in muscle function. VML injury likely extends beyond the defect area, causing negative secondary outcomes to the neuromuscular system, including the neuromuscular junctions (NMJs), yet the extent to which VML induces denervation is unclear. This study systematically examined NMJs surrounding the VML injury, hypothesizing that the sequela of VML includes denervation. The VML injury removed ∼20% of the tibialis anterior (TA) muscle in adult male inbred Lewis rats ( = 43), the noninjured leg served as an intra-animal control. Muscles were harvested up to 48 days post-VML. Synaptic terminals were identified immunohistochemically, and quantitative confocal microscopy evaluated 2,613 individual NMJ. Significant denervation was apparent by 21 and 48 days post-VML. Initially, denervation increased ∼10% within 3 days of injury; with time, denervation further increased to ∼22% and 32% by 21 and 48 days post-VML, respectively, suggesting significant secondary denervation. The appearance of terminal axon sprouting and polyinnervation were observed as early as 7 days post-VML, increasing in number and complexity throughout 48 days. There was no evidence of VML-induced NMJ size alteration, which may be beneficial for interventions aimed at restoring muscle function. This work recognizes VML-induced secondary denervation and poor remodeling of the NMJ as part of the sequela of VML injury; moreover, secondary denervation is a possible contributing factor to the chronic functional impairments and potentially an overlooked treatment target. This work advances our understanding of the pathophysiologic complexity of volumetric muscle loss injury. Specifically, we identified secondary denervation in the muscle remaining after volumetric muscle loss injuries as a novel aspect of the injury sequela. Denervation increased chronically, in parallel with the appearance of irregular morphological characteristics and destabilization of the neuromuscular junction, which is expected to further confound chronic functional impairments.
Topics: Animals; Denervation; Disease Models, Animal; Male; Muscle, Skeletal; Muscular Diseases; Rats; Rats, Inbred Lew
PubMed: 33830817
DOI: 10.1152/japplphysiol.00049.2021 -
International Journal of Medical... 2023Skeletal muscle undergoes rapid and extensive atrophy following nerve transection though the underlying mechanisms remain incompletely understood. We previously showed...
Skeletal muscle undergoes rapid and extensive atrophy following nerve transection though the underlying mechanisms remain incompletely understood. We previously showed transiently elevated Notch 1 signaling in denervated skeletal muscle that was abrogated by administration of nandrolone (an anabolic steroid) combined with replacement doses of testosterone. Numb is an adaptor molecule present in myogenic precursors and skeletal muscle fibers that is vital for normal tissue repair after muscle injury and for skeletal muscle contractile function. It is unclear whether the increase in Notch signaling observed in denervated muscle contributes to denervation and whether expression of Numb in myofibers slows denervation atrophy. To address these questions, the degree of denervation atrophy, Notch signaling, and Numb expression was studied over time after denervation in C57B6J mice treated with nandrolone, nandrolone plus testosterone or vehicle. Nandrolone increased Numb expression and reduced Notch signaling. Neither nandrolone alone nor nandrolone plus testosterone changed the rate of denervation atrophy. We next compared rates of denervation atrophy between mice with conditional, tamoxifen-inducible knockout of Numb in myofibers and genetically identical mice treated with vehicle. Numb cKO had no effect on denervation atrophy in this model. Taken together, the data indicate that loss of Numb in myofibers does not alter the course of denervation atrophy and that upregulation of Numb and blunting of the denervation-atrophy induced activation of Notch do not change the course of denervation atrophy.
Topics: Animals; Mice; Muscle, Skeletal; Nandrolone; Testosterone; Atrophy; Denervation; Membrane Proteins; Nerve Tissue Proteins
PubMed: 36860669
DOI: 10.7150/ijms.77603 -
Journal of Human Hypertension Oct 2022The study aims to compare clinical outcomes following renal denervation (RDN) in hypertensive patients with atrial fibrillation (AF). Three online databases were... (Meta-Analysis)
Meta-Analysis Review
The study aims to compare clinical outcomes following renal denervation (RDN) in hypertensive patients with atrial fibrillation (AF). Three online databases were searched (MEDLINE, EMBASE and PubMed) for literature related to outcomes of RDN on hypertension and AF, between January 1, 2010, and June 1, 2021. Where possible, risk ratios (RR) and mean differences (MD) were combined using a random effects model. Significance was set at p ≤ 0.05. Seven trials were included that assessed the effect of adding RDN to pulmonary vein isolation (PVI) in patients with hypertension and AF. A total of 711 patients (329 undergoing PVI + RDN and 382 undergoing PVI alone), with an age range of 56 ± 6 to 68 ± 9 years, were included. Pooled analysis showed a significant lowering of AF recurrence in the PVI + RDN (31.3%) group compared to the PVI-only (52.9%) group (p < 0.00001). Pooled analysis of patients with resistant hypertension showed a significant mean reduction of systolic blood pressure (SBP) (-9.42 mm Hg, p = 0.05), but not diastolic blood pressure (DBP) (-4.11 mm Hg, p = 0.16) in favor of PVI + RDN. Additionally, the pooled analysis showed that PVI + RDN significantly improved estimated glomerular filtration rate (eGFR) (+10.2 mL/min per 1.73 m, p < 0.001) compared to PVI alone. RDN procedures in these trials have proven to be both safe and efficacious with an overall complication rate of 6.32%. Combined PVI and RDN is beneficial for patients with hypertension and AF. Combined therapy showed improvement in SBP and eGFR, reducing the risk of AF recurrence. RDN may serve as an innovative intervention in the treatment of AF.
Topics: Atrial Fibrillation; Catheter Ablation; Humans; Hypertension; Recurrence; Renal Artery; Sympathectomy; Treatment Outcome
PubMed: 35094013
DOI: 10.1038/s41371-022-00658-0 -
Experimental Physiology Sep 2019What is the central question of this study? The traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and...
NEW FINDINGS
What is the central question of this study? The traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation, which does not permit their individual study in different situations. What is the main finding and its importance? We have described a new surgical approach capable of selective denervation of the arterial (aortic and carotid) baroreceptors, keeping the carotid bodies (chemoreceptors) intact. It is understood that this technique might be a useful tool for investigating the relative role of the baro- and chemoreceptors in several physiological and pathophysiological conditions.
ABSTRACT
Studies have demonstrated that the traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation. The present study reports a new surgical approach to denervate the aortic and the carotid baroreceptors selectively, keeping the carotid bodies (peripheral chemoreceptors) intact. Wistar rats were subjected to specific aortic and carotid baroreceptor denervation (BAROS-X) or sham surgery (SHAM). Baroreflex activation was achieved by i.v. administration of phenylephrine, whereas peripheral chemoreflex activation was produced by i.v. administration of potassium cyanide. The SHAM and BAROS-X rats displayed significant hypertensive responses to phenylephrine administration. However, the reflex bradycardia following the hypertensive response caused by phenylephrine was remarkable in SHAM, but not significant in the BAROS-X animals, confirming the efficacy of the surgical procedure to abolish the baroreflex. In addition, the baroreflex activation elicited by phenylephrine increased carotid sinus nerve activity only in SHAM, but not in the BAROS-X animals, providing support to the notion that the baroreceptor afferents were absent. Instead, the classical peripheral chemoreflex hypertensive and bradycardic responses to potassium cyanide were similar in both groups, suggesting that the carotid body chemoreceptors were preserved after BAROS-X. In summary, we describe a new surgical approach in which only the baroreceptors are eliminated, while the carotid chemoreceptors are preserved. Therefore, it is understood that this procedure is potentially a useful tool for examining the relative roles of the arterial baroreceptors versus the chemoreceptors in several pathophysiological conditions, for instance, arterial hypertension and heart failure.
Topics: Animals; Aorta; Arteries; Baroreflex; Blood Pressure; Carotid Body; Chemoreceptor Cells; Denervation; Heart Rate; Hypertension; Male; Phenylephrine; Pressoreceptors; Rats; Rats, Wistar
PubMed: 31161612
DOI: 10.1113/EP087764 -
Jornal Brasileiro de Nefrologia Mar 2020Despite the current availability of safe and efficient drugs for treating hypertension, a substantial number of patients are drug-resistant hypertensives. Aiming this... (Review)
Review
Despite the current availability of safe and efficient drugs for treating hypertension, a substantial number of patients are drug-resistant hypertensives. Aiming this condition, a relatively new approach named catheter-based renal denervation was developed. We have now a clinically relevant time window to review the efficacy of renal denervation for treating this form of hypertension. This short review addresses the physiological contribution of renal sympathetic nerves for blood pressure control and discusses the pros and cons of renal denervation procedure for the treatment of resistant hypertension.
Topics: Adult; Blood Pressure; Humans; Hypertension, Renal; Kidney; Risk; Sympathectomy; Sympathetic Nervous System; Treatment Outcome
PubMed: 31939995
DOI: 10.1590/2175-8239-JBN-2018-0213 -
Journal of Hypertension Jan 2021To study patient and physician attitudes to pharmaceutical therapy and renal denervation for the management of hypertension.
OBJECTIVE
To study patient and physician attitudes to pharmaceutical therapy and renal denervation for the management of hypertension.
METHODS
Data were analyzed from 19 market research studies in Western Europe and the United States conducted between 2010 and 2019 to obtain quantitative and qualitative perspectives. The analysis incorporated insights from 2768 patients and the experiences of 1902 physicians either actively performing or interested to perform device procedures, or hypertension specialists who would refer patients for a device-based intervention.
RESULTS
Referring cardiologists and proceduralists were more likely to recommend the renal denervation procedure to patients with higher BP levels and a greater number of antihypertensive medications. Physicians perceived patient reluctance towards a procedure as an important obstacle to recommending renal denervation as a treatment option for uncontrolled hypertension. Patient interest in the renal denervation procedure did not correlate with BP severity (P = NS), and the highest preference for the procedure was in patients diagnosed with hypertension but not receiving treatment (P < 0.001). Patients who perceived high BP as a major problem (P = 0.029) and those who experienced side effects attributed to their BP medications (P = 0.006) had a higher preference for renal denervation.
CONCLUSION
Patients with hypertension often regard the choice of renal denervation to lower BP differently from physicians. A considerable proportion of hypertensive patients, especially those not taking medications, may prefer a device-based approach to reduce their BP.
Topics: Antihypertensive Agents; Blood Pressure; Denervation; Humans; Hypertension; Kidney; Pharmaceutical Preparations; Physicians; Sympathectomy; Treatment Outcome
PubMed: 32773653
DOI: 10.1097/HJH.0000000000002592 -
JACC. Clinical Electrophysiology Feb 2023Neuromodulation is increasingly recognized as a therapeutic strategy for patients with refractory ventricular arrhythmias (VAs). Percutaneous stellate ganglion blockade...
BACKGROUND
Neuromodulation is increasingly recognized as a therapeutic strategy for patients with refractory ventricular arrhythmias (VAs). Percutaneous stellate ganglion blockade (SGB), transcutaneous magnetic stimulation (TcMS), and surgical cardiac sympathetic denervation (CSD) have all been utilized in this setting.
OBJECTIVES
This study sought to characterize contemporary use and outcomes of these neuromodulation techniques for patients with refractory VA.
METHODS
This retrospective cohort study included all patients at the Hospital of the University of Pennsylvania with antiarrhythmic drug (AAD)-refractory VA from 2019 to 2021 who were treated with SGB, TcMS, or CSD.
RESULTS
A total of 34 patients (age 61 ± 14 years, 15 polymorphic VAs [44%], refractory to 1.8 ± 0.8 AADs) met inclusion criteria. SGB was performed on 11 patients (32%), TcMS on 19 (56%), and CSD on 7 (21%). Neuromodulation was associated with a reduction in the number of episodes of sustained VAs from 7 [IQR: 4-12] episodes in the 24 hours before the initial neuromodulation strategy to 0 [IQR: 0-1] episodes in the subsequent 24 hours (P < 0.001). During 1.2 ± 1.1 years of follow-up, 21 (62%) experienced recurrent VAs, and among those patients, the median time to recurrence was 3 [IQR: 1-25] days. Outcomes were similar among patients with monomorphic and polymorphic VAs. Among patients who had an acute myocardial infarction within 30 days before neuromodulation, the burden of VAs decreased from 11 [IQR: 7-12] episodes to 0 episodes in the 24 hours after treatment.
CONCLUSIONS
Autonomic neuromodulation with SGB, TcMS, or CSD in patients with AAD-refractory VAs is safe and results in substantial acute reduction of VA although recurrent arrhythmias are common, and not all patients experience a reduction in arrhythmia burden.
Topics: Humans; Middle Aged; Aged; Retrospective Studies; Arrhythmias, Cardiac; Heart; Anti-Arrhythmia Agents; Autonomic Nerve Block
PubMed: 36858681
DOI: 10.1016/j.jacep.2022.08.031 -
Cardiovascular Revascularization... Jan 2022The efficacy of renal denervation has been controversial, but the procedure has now undergone several placebo-controlled trials. New placebo-controlled trial data has... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The efficacy of renal denervation has been controversial, but the procedure has now undergone several placebo-controlled trials. New placebo-controlled trial data has recently emerged, with longer follow-up of one trial and the full report of another trial (which constitutes 27% of the total placebo-controlled trial data). We therefore sought to evaluate the effect of renal denervation on ambulatory and office blood pressures in patients with hypertension.
METHODS
We systematically identified all blinded placebo-controlled randomized trials of catheter-based renal denervation for hypertension. The primary efficacy outcome was ambulatory systolic blood pressure change relative to placebo. A random-effects meta-analysis was performed.
RESULTS
6 studies randomizing 1232 patients were eligible. 713 patients were randomized to renal denervation and 519 to placebo. Renal denervation significantly reduced ambulatory systolic blood pressure (-3.52 mmHg; 95% CI -4.94 to -2.09; p < 0.0001), ambulatory diastolic blood pressure (-1.93 mmHg; 95% CI -3.04 to -0.83, p = 0.0006), office systolic blood pressure size (-5.10 mmHg; 95% CI -7.31 to -2.90, p < 0.0001) and office diastolic pressure (effect size -3.11 mmHg; 95% CI -4.43 to -1.78, p < 0.0001). Adverse events were rare and not more common with denervation.
CONCLUSIONS
The totality of blinded, randomized placebo-controlled data shows that renal denervation is safe and provides genuine reduction in blood pressure for at least 6 months post-procedure. If this effect continues in the long term, renal denervation might provide a life-long 10% relative risk reduction in major adverse cardiac events and 7.5% relative risk reduction in all-cause mortality.
Topics: Antihypertensive Agents; Blood Pressure; Denervation; Humans; Hypertension; Kidney; Randomized Controlled Trials as Topic; Sympathectomy; Treatment Outcome
PubMed: 33551282
DOI: 10.1016/j.carrev.2021.01.031 -
Hypertension (Dallas, Tex. : 1979) Mar 2020The Asia Renal Denervation Consortium consensus conference of Asian physicians actively performing renal denervation (RDN) was recently convened to share up-to-date... (Review)
Review
The Asia Renal Denervation Consortium consensus conference of Asian physicians actively performing renal denervation (RDN) was recently convened to share up-to-date information and regional perspectives, with the goal of consensus on RDN in Asia. First- and second-generation trials of RDN have demonstrated the efficacy and safety of this treatment modality for lowering blood pressure in patients with resistant hypertension. Considering the ethnic differences of the hypertension profile and demographics of cardiovascular disease demonstrated in the SYMPLICITY HTN (Renal Denervation in Patients With Uncontrolled Hypertension)-Japan study and Global SYMPLICITY registry data from Korea and Taiwan, RDN might be an effective hypertension management strategy in Asia. Patient preference for device-based therapy should be considered as part of a shared patient-physician decision process. A practical population for RDN treatment could consist of Asian patients with uncontrolled essential hypertension, including resistant hypertension. Opportunities to refine the procedure, expand the therapy to other sympathetically mediated diseases, and explore the specific effects on nocturnal and morning hypertension offer a promising future for RDN. Based on available evidence, RDN should not be considered a therapy of last resort but as an initial therapy option that may be applied alone or as a complementary therapy to antihypertensive medication.
Topics: Blood Pressure; Consensus; Denervation; Humans; Hypertension; Kidney; Treatment Outcome
PubMed: 32008432
DOI: 10.1161/HYPERTENSIONAHA.119.13671 -
Journal of the American Heart... Feb 2024The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and renal function. Pathological increases in renal sympathetic nerve...
BACKGROUND
The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and renal function. Pathological increases in renal sympathetic nerve activity contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). We investigated the effects of renal sympathetic denervation performed at early or late stages of HFpEF progression.
METHODS AND RESULTS
Male ZSF1 obese rats were subjected to radiofrequency renal denervation (RF-RDN) or sham procedure at either 8 weeks or 20 weeks of age and assessed for cardiovascular function, exercise capacity, and cardiorenal fibrosis. Renal norepinephrine and renal nerve tyrosine hydroxylase staining were performed to quantify denervation following RF-RDN. In addition, renal injury, oxidative stress, inflammation, and profibrotic biomarkers were evaluated to determine pathways associated with RDN. RF-RDN significantly reduced renal norepinephrine and tyrosine hydroxylase content in both study cohorts. RF-RDN therapy performed at 8 weeks of age attenuated cardiac dysfunction, reduced cardiorenal fibrosis, and improved endothelial-dependent vascular reactivity. These improvements were associated with reductions in renal injury markers, expression of renal NLR family pyrin domain containing 3/interleukin 1β, and expression of profibrotic mediators. RF-RDN failed to exert beneficial effects when administered in the 20-week-old HFpEF cohort.
CONCLUSIONS
Our data demonstrate that early RF-RDN therapy protects against HFpEF disease progression in part due to the attenuation of renal fibrosis and inflammation. In contrast, the renoprotective and left ventricular functional improvements were lost when RF-RDN was performed in later HFpEF progression. These results suggest that RDN may be a viable treatment option for HFpEF during the early stages of this systemic inflammatory disease.
Topics: Humans; Male; Rats; Animals; Heart Failure; Stroke Volume; Tyrosine 3-Monooxygenase; Kidney; Sympathectomy; Inflammation; Norepinephrine; Fibrosis; Denervation
PubMed: 38353216
DOI: 10.1161/JAHA.123.032646