Baroreflex Activation for the Treatment of Heart Failure

Autonomic dysregulation is a feature of heart failure (HF) characterized by sustained increase of sympathetic drive and by withdrawal of parasympathetic activity. Both maladaptations are independent predictors of poor long-term outcome in patients with HF. Considerable evidence exists that supports the use of pharmacologic agents that partially inhibit sympathetic activity as an effective long-term therapy for patients with HF; the classic example being the use of selective and nonselective β-adrenergic receptor blockers. In contrast, modulation of parasympathetic activation as potential therapy for HF has received only limited attention. This review discusses the results of recent preclinical animal studies that provide support for the possible use of baroreflex electrical stimulation, also known as baroreflex activation therapy (BAT), as a long-term therapeutic approach for the treatment of patients with chronic HF. In addition to exploring the effects of chronic BAT on left ventricular (LV) function and chamber remodeling, the review will also address the effects of long-term BAT on ventricular arrhythmias and on potential modifiers of the HF state that include maladaptations of both the nitric oxide and β-adrenergic receptor signal transduction pathways. The results of the preclinical studies conducted to date have shown that in dogs with advanced HF, monotherapy with BAT improves global LV systolic and diastolic function and partially reverses LV remodeling both globally and at cellular and molecular levels. In addition, BAT therapy was shown to markedly increase the threshold for lethal ventricular arrhythmias in dogs with chronic HF. These benefits of BAT support the continued exploration of this therapeutic modality for treating patients with chronic HF and those with increased risk of sudden cardiac death.     

The Effect of Seventy-Two-Hour Continuous Infusion of Long-Acting Natriuretic Peptide on Acute Ischemic Renal Failure in the Rat

Objectives. Atrial natriuretic peptide (ANP_1-28) protects the kidneys against acute renal failure in animals; however, its use in humans has been disappointing. Long-acting natriuretic peptide (LANP_1-30) has natriuretic and diuretic actions similar to ANP_1-28, but it has a longer half-life and a different receptor site. Therefore, this study's aim was to determine if LANP_1-30 has better renal protection than ANP_1-28, which may make it useful in the treatment of acute renal failure. Subjects/Methods. Three groups of male Sprague-Dawley rats were used, each with a body weight between 250-300 gm. Group 1 (ischemia only, n = 6) had a right nephrectomy followed by 30 minutes of left renal pedicle clamping. Group 2 (LANP Peptide treated, n = 7) had renal ischemia similar to Group 1, followed by an intraperitoneal bolus of 10 μg of LANP_1-30 and the placement of mini-osmotic pumps delivering LANP_1-30 at a rate of 1μg/hr for 72 hours. Group 3 (controls, n = 6) was used to measure the baseline creatinine level and had no renal ischemia or surgery. Results. Seventy-two hours post-renal ischemia, the weight loss in the ischemia group was similar to the peptide treated group (7.65 ± 1.14% and 10.03 ± 0.9% body weight loss, respectively, p?=?0.126). The ischemia group had significantly higher creatinine levels compared to the controls (66.3 ± 5.3 versus 30.1 ± 0.9 μmol/L, p?=?0.002). The peptide-treated group had higher creatinine (174.1 ± 77.8 versus 66.3 ± 5.3 μmol/L, p?=?0.035) and LANP_1-30 levels (673.14 ± 69.64 versus 45.83 ± 8.45 pg/mL, p?=?0.001) than the ischemia group. Conclusion. Prolonged use of LANP_1-30 has no renal protective effect.     

PTH‐enhanced structural allograft healing is associated with decreased angiopoietin‐2–mediated arteriogenesis,mast cell accumulation,and fibrosis

Recombinant parathyroid hormone (rPTH) therapy has been evaluated for skeletal repair in animal studies and clinical trials based on its known anabolic effects, but its effects on angiogenesis and fibrosis remain poorly understood. We examined the effects of rPTH therapy on blood vessel formation and osseous integration in a murine femoral allograft model, which caused a significant increase in small vessel numbers, and decreased large vessel formation (p < 0.05). Histology showed that rPTH also reduced fibrosis around the allografts to similar levels observed in live autografts, and decreased mast cells at the graft‐host junction. Similar effects on vasculogenesis and fibrosis were observed in femoral allografts from Col1caPTHR transgenic mice. Gene expression profiling revealed rPTH‐induced angiopoietin‐1 (8‐fold), while decreasing angiopoietin‐2 (70‐fold) at day 7 of allograft healing. Finally, we show anti‐angiopoietin‐2 peptibody (L1‐10) treatment mimics rPTH effects on angiogenesis and fibrosis. Collectively, these findings show that intermittent rPTH treatment enhances structural allograft healing by two processes: (1) anabolic effects on new bone formation via small vessel angiogenesis, and (2) inhibition of angiopoietin‐2–mediated arteriogenesis. The latter effect may function as a vascular sieve to limit mast cell access to the site of tissue repair, which decreases fibrosis around and between the fractured ends of bone. Thus, rPTH therapy may be generalizable to all forms of tissue repair that suffer from limited biointegration and excessive fibrosis. © 2013 American Society for Bone and Mineral Research.     

Ultrasound diagnosis of bony nerve entrapment: Case series and literature review

Introduction: Nerve entrapment due to osseous callus formation is a rare complication after bone fracture. Electrodiagnostic studies and routine radiographic imaging often fail to demonstrate the pathology. The diagnosis is difficult and is often made incidentally upon surgical exploration. Nerve ultrasonography has not been used routinely to assess such lesions. Methods: We report 5 cases of nerve entrapment in osseous callus after fractures that occurred in 2011 and 2012. The diagnosis was made by ultrasound (US). We then performed a review of the relevant literature. Conclusions: US is becoming an invaluable tool for diagnosing peripheral nerve entrapments. The current cases suggest that nerve US should be strongly considered as an adjunctive diagnostic tool for nerve palsies developing after trauma. Muscle Nerve 48 : 445–450, 2013