Atrial fibrillation (AF) is a common arrhythmia and is associated with significant morbidity and mortality. The pathogenesis of AF remains incompletely understood and management remains a difficult task. Over the past decade there has been accumulating evidence implicating inflammation in the pathogenesis of AF. Inflammation appears to play a significant role in the initiation and perpetuation of AF as well as the prothrombotic state associated with AF. Inflammatory biomarkers (C-reactive protein and interleukin-6) have been shown to be associated with the future development, recurrence and burden of AF, and the likelihood of successful cardioversion. Therapies directed at attenuating the inflammatory burden appear promising. Animal and clinical studies have evaluated statins, angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers, and corticosteroids for the treatment or prevention of AF. The purpose of this review is to provide current evidence on the relationship between inflammation and AF and potential therapies available to modulate the inflammatory state in AF.

The efficacy of biologic therapies in critical limb ischemia (CLI) remains elusive, in part, due to limitations in trial design and patient selection. Using a novel design, we examined the impact of complementing revascularization therapy with intramuscular JVS-100 – a non-viral gene therapy that activates endogenous regenerative repair pathways. In this double-blind, placebo-controlled, Phase 2B trial, we randomized 109 patients with CLI (Rutherford class V or VI) to 8 mg or 16 mg intramuscular injections of placebo versus JVS-100. Patients were eligible if they persistently had reduced forefoot perfusion, by toe–brachial index (TBI) or skin perfusion pressure (SPP), following successful revascularization with angiographic demonstration of tibial arterial flow to the ankle. The primary efficacy end point was a 3-month wound healing score assessed by an independent wound core laboratory. The primary safety end point was major adverse limb events (MALE). Patients’ mean age was 71 years, 33% were women, 79% had diabetes, and 8% had end-stage renal disease. TBI after revascularization was 0.26, 0.27, and 0.26 among the three groups (placebo, 8 mg, and 16 mg injections, respectively). Only 26% of wounds completely healed at 3 months, without any differences between the three groups (26.5%, 26.5%, and 25%, respectively). Similarly, there were no significant changes in TBI at 3 months. Three (2.8%) patients died and two (1.8%) had major amputations. Rates of MALE at 3 months were 8.8%, 20%, and 8.3%, respectively. While safe, JVS-100 failed to improve wound healing or hemodynamic measures at 3 months. Only one-quarter of CLI wounds healed at 3 months despite successful revascularization, highlighting the need for additional research in therapies that can improve microcirculation in these patients. ClinicalTrials.gov Identifier: NCT02544204

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Purpose: To present the 6-month results of the Stromal Cell–Derived Factor-1 Plasmid Treatment for Patients with Peripheral Artery Disease (STOP-PAD) trial. The trial was an attempt to alter the course of chronic limb-threatening ischemia (CLTI) with a biological agent vs placebo after successful arterial revascularization at or below the knee. Materials and Methods: The multicenter, randomized, double-blinded, placebo-controlled, phase 2B STOP-PAD trial ( ClinicalTrials.gov identifier NCT02544204) randomized 109 patients (mean age 71 years; 68 men) with Rutherford category 5 or 6 CLTI and evidence of persistent impaired forefoot perfusion following recent successful revascularization to 8- (n=34) or 16-mg (n=36) intramuscular injections of a non-viral DNA plasmid–based treatment vs placebo (n=34). The primary efficacy outcome was the 6-month wound healing score evaluated by an independent wound core laboratory; the primary safety endpoint was major adverse limb events (MALE), a composite of major amputation plus clinically-driven target lesion revascularization at 6 months. Results: Only one-third of the patients had complete wound healing at 6 months in the placebo (31%), 8-mg injection (33%), and 16-mg injection (33%) groups. In addition, the observed increase in the toe-brachial index from baseline to 6 months was statistically significant in each group; however, this did not result in lower rates of MALE at 6 months (24% in the placebo, 29% in the 8-mg injection, and 11% in the 16-mg injection groups). During the 6-month period, 6 patients (6%) died, and 24 patients (23%) had an amputation [only 4 (4%) major]. Conclusion: Combining revascularization and biological therapy failed to improve outcomes in CLTI at 6 months. STOP-PAD has provided insights for future trials to evaluate biological therapy.

It has been suggested that, by reducing the viscosity of blood, flow through capillaries is increased with consequent improvement in the symptoms of patients with peripheral vascular disease. We examined the effects of treatment with drugs purported to reduce blood viscosity to test the validity of this claim. Measurements of viscosity and the rate of blood flow to the leg were made in a group of patients before and after treatment with three different drugs--tetranicotinoylfructose (Bradilan), oxypentifylline (Trental) and cinnarizine (Stugeron). All patients had intermittent claudication in one leg and the distribution of arteriosclerosis was similar in each patient. After treatment there was little or no change in blood viscosity and no change in the rate of flow recorded in the symptomatic legs. We did not find any objective evidence to support the use of these drugs in patients with intermittent claudication.