Comprehensive Preclinical Postmortem Evaluation of Valvular Prosthesis.

Transcatheter prosthetic valves are heralding a new era in interventional cardiology and affording real therapeutic options to categories of patients currently medically disqualified, namely the elderly and higher risk individuals. An increasing variety of novel artificial valve designs and delivery systems are being tested preclinically. Cardiologists and surgeons are generally well-equipped to assess deliverability and function; however, methods for pathological evaluation of animals enrolled in transcatheter valve implant testing are scant, often vague, and far from consensual. Through this manuscript, we present and discuss a comprehensive evaluation platform that is proving reliable, reproducible, effective, and applicable to most, if not all, types and locations of valvular prostheses.

A comparative observational multicenter analysis of the clinical performance of vascular compression devices following transradial arterial access / Análisis comparativo multicéntrico observacional del desempeño clínico de dispositivos de compresión vascular posterior a acceso arterial transradial

Abstract: Introduction: Multiple vascular compression aimed for transradial access have been developed. We aimed to compare the time required to achieve hemostasis in three different radial vascular compression devices. Methods: ST and non-ST elevation MI, unstable and stable angina as well as diagnostic coronary angiograms patients with transradial vascular access (TVA) in 2 centers were enrolled between June 2010-November 2010. Patients were divided according the TVA compression device (TAVCD) used. Group I received TR Band(tm) (Terumo, Tokyo, Japan), Group II received Neptuno(tm) (Biotronik, Berlin, Deutschland) and Group III received Finale(tm) (Merit Medical, South Jordan, UT).Patients were evaluated immediately after TVACD implantation and 24 hour post-procedure follow up. Results: 60 patients were enrolled in this observational study (Group I = 22 patients; Group II = 18; Group III = 20). All patients demonstrated evidence of radial pulse after hemostasis. 28% developed a superficial hematoma (Group I, 31%; Group II, 30%; Group III, 22%). Pain at the access site was uncommon among patients in both immediate and follow-up evaluations, however, 3% (Group I and II) presented paresthesia immediately following the procedure that resolved by the 24-hour evaluation. Conclusion: In our study, all three evaluated radial compression devices successfully achieved hemostasis regardless of the slight alterations of mechanism, yet similarity in aim of non-occlusive compression. Group I (TR band) had a slight increase in compression time recorded but all groups required an approximate three hours to display no evidence of bleeding. None of the patients in the study presented major vascular complications. We consider that further investigation of radial compression devices as compared to manual compression are necessary to evaluate their advantages and may further simplify the procedure

Resumen: Introducción: Múltiples dispositivos de compresión vascular para el acceso radial han sido desarrollados. Nuestro objetivo es comparar el tiempo requerido para lograr la hemostasis con tres diferentes dispositivos de compresión vascular radial. Métodos: Pacientes de angiografía coronaria de diagnóstico, con elevación y no elevación del ST, con angina de pecho inestable y estable, así como pacientes con acceso vascular radial (AVR) en dos centros, fueron incluidos entre junio y noviembre de 2010. Los pacientes fueron divididos según el dispositivo de compresión AVR (DCAVR) usado. Al Grupo I se le dio el TR Band(tm) (Terumo, Tokio, Japón), el Grupo II recibió el Neptuno(tm) (Biotronik, Berlín, Alemania) y el grupo III recibió el Final(tm) (Merit Medica, South Jordan, UT). Los pacientes fueron evaluados inmediatamente después de la implantación del DCAVR y a las 24 horas de postprocedimiento para seguimiento. Resultados: 60 pacientes fueron incluidos en este estudio observacional (Grupo I = 22 pacientes; Grupo II = 18; Grupo III = 20). Todos los pacientes mostraron evidencia de pulso radial después de la hemostasis. 28% desarrolló un hematoma superficial (Grupo I, 31%; Grupo II, 30%; Grupo III, 22%). El dolor en el sitio de acceso fue poco común entre los pacientes de los dos evaluaciones inmediatas y de seguimiento, sin embargo, el 3% (Grupo I y II) presentó parestesias inmediatamente después del procedimiento que se resolvieron para la evaluación de 24 horas. Conclusión: En nuestro estudio, los tres dispositivos de compresión radiales evaluados lograron con éxito la hemostasis sin importar las pequeñas variaciones del mecanismo, dando resultados similares en el objetivo de la compresión no oclusiva. Grupo I (Banda TR) tuvo un ligero aumento en el tiempo de compresión registrado pero todos los grupos requieren un tiempo aproximado de tres horas para mostrar ninguna evidencia de sangrado. Ninguno de los pacientes en el estudio presentó mayores complicaciones vasculares. Consideramos necesario hacer investigación adicional de los dispositivos de compresión radiales, en comparación con la compresión manual para evaluar sus ventajas y poder simplificar aún más el procedimiento.

Historical Incidence of Spontaneous Lesions in Kidneys from Naïve Swine Utilized In Interventional Renal Denervation Studies.

The use of preclinical animal models is integral to the safety assessment, pathogenesis research, and testing of diagnostic technologies and therapeutic interventions. With inherent similarity to human anatomy and physiology, various porcine models have been the preferred preclinical model in some research areas such as medical devices, wound healing, and skin therapies. The porcine model has been the cornerstone for interventional cardiology for the evaluation and development of this catheter-based renal denervation (RDN) therapy. The porcine model provides similar vascular access and renal neurovascular anatomy to humans. In these preclinical studies, the downstream kidneys from treated arteries are assessed for possible histopathological changes in the vessel dependent territories. In assessing renal safety following RDN, it becomes critical to distinguish treatment-related changes from pre-existing background pathologies. The incidence of background pathological changes in porcine kidneys has not been previously established in normal clinically healthy. Samples from the cranial, middle, and caudal portion of 331 naïve kidneys from 181 swine were processed histologically to slides and evaluated microscopically. The most commonly encountered spontaneous changes were chronic pyelonephritis found in nearly half of the evaluated naïve kidneys (∼40 %; score 1 = 91 %, score 2 = 8.4 %, score 3 = 0.76 %) followed by chronic interstitial inflammation in 9.7 % of the kidneys (score 1 = 90.6 %, score 2 = 9.4 %). Interestingly, there were a few rare spontaneous vascular changes that could potentially affect data interpretation in interventional and toxicology studies: arteritis and arteriolar dissection. The presence of pelvic cysts was a common occurrence (6.3 %) in the kidney. The domestic swine is a widely used preclinical species in interventional research, namely in the emerging field of transcatheter renal denervation. This retrospective study presents the historical incidence of spontaneous lesions recorded in the kidneys from naive pigs enrolled in renal denervation studies. There were commonly encountered changes of little pathological consequence such as pyelonephritis or pelvic cysts and rare vascular changes such as arteritis and arteriolar dissection that were of greater potential impact on study data interpretation. These results offer a benchmark by which to gage the potential effect of a procedure or treatment on renal histopathology in swine and assist in data interpretation.

Miniature Swine for Preclinical Modeling of Complexities of Human Disease for Translational Scientific Discovery and Accelerated Development of Therapies and Medical Devices.

Noncommunicable diseases, including cardiovascular disease, diabetes, chronic respiratory disease, and cancer, are the leading cause of death in the world. The cost, both monetary and time, of developing therapies to prevent, treat, or manage these diseases has become unsustainable. A contributing factor is inefficient and ineffective preclinical research, in which the animal models utilized do not replicate the complex physiology that influences disease. An ideal preclinical animal model is one that responds similarly to intrinsic and extrinsic influences, providing high translatability and concordance of preclinical findings to humans. The overwhelming genetic, anatomical, physiological, and pathophysiological similarities to humans make miniature swine an ideal model for preclinical studies of human disease. Additionally, recent development of precision gene-editing tools for creation of novel genetic swine models allows the modeling of highly complex pathophysiology and comorbidities. As such, the utilization of swine models in early research allows for the evaluation of novel drug and technology efficacy while encouraging redesign and refinement before committing to clinical testing. This review highlights the appropriateness of the miniature swine for modeling complex physiologic systems, presenting it as a highly translational preclinical platform to validate efficacy and safety of therapies and devices.

Biological effect on drug distribution and vascular healing via paclitaxel-coated balloon technology in drug eluting stent restenosis swine model.

OBJECTIVES: To evaluate the biological effect of a paclitaxel-coated balloon (PCB) technology on vascular drug distribution and healing in drug eluting stent restenosis (DES-ISR) swine model. BACKGROUND: The mechanism of action and healing response via PCB technology in DES-ISR is not completely understood. METHODS: A total of 27 bare metal stents were implanted in coronary arteries and 30 days later the in-stent restenosis was treated with PCB. Treated segments were harvested at 1 hr, 14 days and 30 days post treatment for the pharmacokinetic analysis. In addition, 24 DES were implanted in coronary arteries for 30 days, then all DES-ISRs were treated with either PCB (n = 12) or uncoated balloon (n = 12). At day 60, vessels were harvested for histology following angiography and optical coherence tomography (OCT). RESULTS: The paclitaxel level in neointimal tissue was about 18 times higher (P = 0.0004) at 1 hr Cmax , and retained about five times higher (P = 0.008) at day 60 than that in vessel wall. A homogenous distribution of paclitaxel in ISR was demonstrated by using fluorescently labeled paclitaxel. Notably, in DES-ISR, both termination OCT and quantitative coronary angioplasty showed a significant neointimal reduction and less late lumen loss (P = 0.05 and P = 0.03, respectively) post PCB versus post uncoated balloon. The PES-ISR + PCB group displayed higher levels of peri-strut inflammation and fibrin scores compared to the -limus DES-ISR + PCB group. CONCLUSIONS: In ISR, paclitaxel is primarily deposited in neointimal tissue and effectively retained over time following PCB use. Despite the presence of metallic struts, a uniform distribution was characterized. PCB demonstrated an equivalent biological effect in DES-ISR without significantly increasing inflammation. © 2015 Wiley Periodicals, Inc.

Safety and Clinical Outcome of the Delivery of Radiofrequency Nerve Ablation Therapy in a Renal Artery of Unusual Anatomy.

INTRODUCTION: Catheter-based renal sympathetic denervation is an emerging therapy for resistant hypertension (RHTN) patients, resulting in a significant blood pressure reduction. The presence of accessory renal arteries and anomalous branching patterns are reported in approximately 20-27 % of patients. However, accessory renal arteries, when smaller than 4 mm in diameter, they are out of the inclusion criteria for renal denervation therapy. For this reason patients with evidence of accessory renal arteries have been excluded in previous clinical trials. Recent data suggest that accessory renal arteries may play an important role in non-response therapy when they do not receive renal denervation treatment. CASE REPORT: In this report, we present the outcome of a patient with resistant hypertension and an anomalous right renal artery, having undergone denervation of both principal and accessory renal arteries. The renal ablation by radiofrequency energy of a distant accessory renal artery resulted in a safe procedure with no clinical complications. CONCLUSION: Consistent with literature the RDN of all, main and accessory renal arteries, was effective in decreasing patient blood pressure while decreasing the need for antihypertensive medication.

Neuromatous regeneration as a nerve response after catheter-based renal denervation therapy in a large animal model: immunohistochemical study.

BACKGROUND: Renal denervation (RDN) emerged as a therapeutic option for resistant hypertension. Nerve regrowth after RDN has been questioned. We aimed to characterize the nerve response after RDN. METHODS AND RESULTS: Swine underwent bilateral RDN and were followed up for 7, 30, and 90 days and evaluated with S100 (Schwann cell), tyrosine hydroxylase (TH; efferent nerves), and growth-associated protein 43 (neurite regeneration) markers. At 7 days, nerve changes consisted of necrosis associated with perineurial fibrosis and distal atrophy with inflammation. At 30 days changes were substituted by healing changes (ie, fibrosis). This response progressed through 90 days resulting in prominent neuroma formation. Immunohistochemistry at 7 days: TH staining was strongly decreased in treated nerves. Early regenerative attempts were observed with strongly TH and growth-associated protein 43 positive and weak S100 disorganized nerve sprouts within the thickened perineurium. Distal atrophic nerves show weak staining for all 3 markers. At 30 days, affected nerves show a weak TH and S100 staining. Evident growth-associated protein 43+ disorganized neuromatous tangles in the thickened perineurium of severed nerves were observed. At 90 days, some TH expression was observed together with prominent S100+ and growth-associated protein 43+ neuromatous tangles with disorganized architecture. The potential for regenerative activity is unlikely based on the disrupted architecture of these neuromatous tangles at the radiofrequency lesion sites. CONCLUSIONS: This study is the first documentation that a progressive regenerative response occurs as early as 7 days after RDN, resulting in a poorly organized neuromatous regeneration. This finding is of paramount importance to further establish the potential functional significance of a regeneration after RDN.