Regions of Highly Recurrent Electrogram Morphology With Low Cycle Length Reflect Substrate for Atrial Fibrillation.

Traditional anatomically guided ablation and attempts to perform electrogram-guided atrial fibrillation (AF) ablation (CFAE, DF, and FIRM) have not been shown to be sufficient treatment for persistent AF. Using biatrial high-density electrophysiologic mapping in a canine rapid atrial pacing model of AF, we systematically investigated the relationship of electrogram morphology recurrence (EMR) (Rec% and CLR) with established AF electrogram parameters and tissue characteristics. Rec% correlates with stability of rotational activity and with the spatial distribution of parasympathetic nerve fibers. These results have indicated that EMR may therefore be a viable therapeutic target in persistent AF.

Recent advances in gene therapy for atrial fibrillation.

Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments for AF are suboptimal as they are not targeting the molecular mechanisms underlying AF. In this regard, gene therapy is emerging as a promising approach for mechanism-based treatment of AF. In this review, we summarize recent advances and challenges in gene therapy for this important cardiovascular disease.

Autonomic Dysfunction and Neurohormonal Disorders in Atrial Fibrillation.

Atrial fibrillation (AF) is the most commonly diagnosed arrhythmia and eludes an efficacious cure despite an increasing prevalence and a significant association with morbidity and mortality. In addition to an array of clinical sequelae, the origins and propagation of AF are multifactorial. In recent years, the contribution from the autonomic nervous system has been an area of particular interest. This review highlights the relevant physiology of autonomic and neurohormonal contributions to AF origin and maintenance, the current state of the literature on targeted therapies, and the path forward for clinical interventions.

VEGF receptor targeted imaging of angiogenic response to limb ischemia in diabetic vs. non-diabetic Yucatan minipigs.

BACKGROUND: New therapies to treat diabetic peripheral artery disease (PAD) require target-specific non-invasive imaging modalities to follow efficacy. As a translational study, we performed targeted imaging of receptors for vascular endothelial growth factor (VEGF) in response to anterior femoral artery occlusion (FAO) in Yucatan minipigs and compare the normal response to response in diabetic Yucatan minipigs. METHODS: Eleven Yucatan minipigs, 6 non-diabetic (non-D) and 5 purpose bred diabetic (D) (Sinclair, Auxvasse MO), underwent intravascular total occlusion of the anterior femoral artery (FA). At days 1 and 28, pigs underwent SPECT/CT 201Tl hindlimb perfusion imaging and at day 7 were injected with [99mTc]DOTA-PEG-scVEGF (scV/Tc) tracer targeting VEGF receptor, and underwent biopsies of the hindlimb muscles for gamma counting and histology, followed by imaging. One day after the final scan, pigs underwent contrast angiography of the lower extremities. Counts from scans were converted to percentage injected activity (%IA). RESULTS: Perfusion was lower in the occluded hindlimb compared to non-occluded on day 1 in both the D and non-D pigs. At day 7, scV/Tc count ratio of counts from ROIs drawn in proximal gastrocnemius muscle for the occluded over non-occluded limb was significantly higher in non-D vs. D pigs (1.32 ± 0.06 vs. 1.04 ± 0.13, P = 0.02) reflecting higher level of angiogenesis. Perfusion increased between days 1 and 28 in the muscles in the occluded limb for the non-diabetic pigs while the diabetic pig showed no increase (+ 0.13 ± 0.08 %IA vs. - 0.13 ± 0.11, P = 0.003). The anterior FA showed poor contrast filling beyond occluder and qualitatively fewer bridging collaterals compared to non-D pigs at 28 days. CONCLUSION: VEGF receptor targeted imaging showed the effects of diabetes to suppress angiogenesis in response to occlusion of the anterior femoral artery of purpose bred diabetic Yucatan minipigs and indicates potential applicability as a marker to follow efficacy of novel therapies to improve blood flow by stimulating angiogenesis in diabetic PAD.

Assessment of a Noninvasive Chronic Glucose Monitoring System in Euglycemic and Diabetic Swine (Sus scrofa).

Models of type-I diabetes are well-characterized and commonly used in the preclinical evaluation of drugs and medical devices. The diabetic minipig is an excellent example of a translational model. However, chronic glucose monitoring in this species can be challenging; frequent blood sampling can be technically difficult and poorly tolerated in conscious swine. Skin-patch continuous blood glucose monitors are FDA-approved for human use and offer a potential refinement to cageside blood collection. However, this modality has not been evaluated in pigs. In this study, young adult male STZ-induced diabetic Yucatan minipigs (n = 4) and healthy York pigs (n = 4) were implanted with a 14-d skin-patch continuous glucose monitor. Readings from continuous glucose monitors were time-matched to whole blood samples, with glucose measurements performed using point-of-care blood glucose monitors, serum chemistry or both. The aims of the study were to assess if a continuous glucose monitoring system could accurately detect glucose levels in swine, and to compare the readings toboth point-of-care glucometers and serum chemistry results. We hypothesized that a continuous glucose monitoring system would accurately detect glucose levels in swine in comparison with a validated analyzer and could serve as an animal welfarerefinement for studies of diabetes. We found that the continuous glucose monitor used in this study provided an adequateadjunct for clinical management in the stable diabetic pig and a minimally invasive and inexpensive option for colony maintenanceof chronically diabetic swine.

Bilateral Arteriovenous Shunts as a Method for Evaluating Tissue-Engineered Vascular Grafts in Large Animal Models.

There remains a need for large animal models to evaluate tissue-engineered vascular grafts (TEVGs) under arterial pressure to provide preclinical data for future potential human clinical trials. We present a comprehensive method for the interrogation of TEVGs, using an ovine bilateral arteriovenous (AV) shunt implantation model. Our results demonstrate that this method can be performed safely without complications, specifically acute heart failure, steal syndrome, and hypoxic brain injury, and it is a viable experimental paradigm. Our method allows for a non-invasive evaluation of TEVGs in terms of graft flow, graft diameter, and graft patency, while also allowing for graft needle puncture under ultrasound guidance. In addition, traditional pathological analysis, histology, and immunohistochemistry may be performed with the contralateral side providing paired control data to eliminate inter-subject variability while reducing the total number of animals. Further, we present a review of existing literature of preclinical evaluation of TEVGs in large animal models as AV conduits.