Background The contribution of intimal hyperplasia (IH) to arteriovenous fistula (AVF) failure is uncertain. This observational study assessed the relationship between preexisting, postoperative, and change in IH over time and AVF outcomes. Study Design Prospective cohort study with longitudinal assessment of IH at the time of AVF creation (pre-existing) and transposition (postoperative). Patients were followed-up for up to 3.3 years. Setting & Participants 96 patients from a single center who underwent AVF surgery initially planned as a two-stage procedure. Veins and AVF samples were collected from 66 and 86 patients, respectively. Matched-pair tissues were available from 56 of these patients. Predictors Pre-existing, postoperative and change in IH over time. Outcomes Anatomic maturation failure was defined as an AVF that never reached a diameter greater than 6 mm. Primary unassisted patency was defined as the time elapsed from the second-stage surgery until first intervention. Measurements Maximal intimal thickness in veins and AVF and change in intimal thickness over time. Results Pre-existing IH (> 0.05 mm) was present in 98% of the patients. In this group, the median intimal thickness increased 4.40-fold (IQR, 2.17- to 4.94-fold) between the AVF creation and transposition. However, this change was not associated with the preexisting thickness (r2=0.002; p=0.7). Ten of 96 AVFs (10%) never achieved maturation, while 70% of the vascular accesses remained patent at the end of the observational period. Postoperative IH was not associated with anatomic maturation failure using a univariate logistic regression. Pre-existing, postoperative, and change in IH over time had no effects on primary unassisted patency. Limitations The low number of patients from whom longitudinal tissue samples were available and the low incidence of anatomic maturation failure, which decreased the statistical power to find associations between end points and IH. Conclusions Pre-existing, postoperative, and change in IH over time were not associated with two-stage AVF outcomes.

The use of a pre-tied ligating loop is a good alternative to the cup biopsy forceps technique when acquiring laparoscopic liver biopsies in dogs.

Every heartbeat originates from a tiny tissue in the heart called the sinoatrial node (SAN). The SAN harbors only ≈10 000 cardiac pacemaker cells, initiating an electrical impulse that captures the entire heart, consisting of billions of cardiomyocytes for each cardiac contraction. How these rare cardiac pacemaker cells (the electrical source) can overcome the electrically hyperpolarizing and quiescent myocardium (the electrical sink) is incompletely understood. Due to the scarcity of native pacemaker cells, this concept of source–sink mismatch cannot be tested directly with live cardiac tissue constructs. By exploiting TBX18 induced pacemaker cells by somatic gene transfer, 3D cardiac pacemaker spheroids can be tissue‐engineered. The TBX18 induced pacemakers (sphTBX18) pace autonomously and drive the contraction of neighboring myocardium in vitro. TBX18 spheroids demonstrate the need for reduced electrical coupling and physical separation from the neighboring ventricular myocytes, successfully recapitulating a key design principle of the native SAN. β‐Adrenergic stimulation as well as electrical uncoupling significantly increase sphTBX18s' ability to pace‐and‐drive the neighboring myocardium. This model represents the first platform to test design principles of the SAN for mechanistic understanding and to better engineer biological pacemakers for therapeutic translation.

Complete atrioventricular block (CAVB) is a life-threatening arrhythmia. A small animal model of chronic CAVB that properly reflects clinical indices of bradycardia would accelerate the understanding of disease progression and pathophysiology, and the development of therapeutic strategies. We sought to develop a surgical model of CAVB in adult rats, which could recapitulate structural remodeling and arrhythmogenicity expected in chronic CAVB. Upon right thoracotomy, we delivered electrosurgical energy subepicardially via a thin needle into the atrioventricular node (AVN) region of adult rats to create complete AV block. The chronic CAVB animals developed dilated and hypertrophied ventricles with preserved systolic functions due to compensatory hemodynamic remodeling. Ventricular tachyarrhythmias, which are difficult to induce in the healthy rodent heart, could be induced upon programmed electrical stimulation in chronic CAVB rats and worsened when combined with β-adrenergic stimulation. Focal somatic gene transfer of TBX18 to the left ventricular apex in the CAVB rats resulted in ectopic ventricular beats within days, achieving a de novo ventricular rate faster than the slow atrioventricular (AV) junctional escape rhythm observed in control CAVB animals. The model offers new opportunities to test therapeutic approaches to treat chronic and severe CAVB which have previously only been testable in large animal models.

A major drawback of mechanical and prosthetic heart valves is their inability to permit somatic growth. By contrast, tissue-engineered pulmonary valves potentially have the capacity to remodel and integrate with the patient. For this purpose, adult stem cells may be suitable. Previously, human periodontal ligament cells (PDLs) have been explored as a reliable and robust progenitor cell source for cardiac muscle regeneration (Pelaez, D. Electronic Thesis and Dissertation Database, Coral Gables, FL, May 2011). Here, we investigate the potential of PDLs to support the valve lineage, specifically the concomitant differentiation to both endothelial cell (EC) and smooth muscle cell (SMC) types. We were able to successfully promote PDL differentiation to both SMC and EC phenotypes through a combination of stimulatory approaches using biochemical and mechanical flow conditioning (steady shear stress of 1 dyne/cm(2)), with flow-based mechanical conditioning having a predominant effect on PDL differentiation, particularly to ECs; in addition, strong expression of the marker FZD2 and an absence of the marker MLC1F point toward a unique manifestation of smooth muscle by PDLs after undergoing steady-flow mechanical conditioning alone, possible by only the heart valve and pericardium phenotypes. It was also determined that steady flow (which was performed using a physiologically relevant [for heart valves] magnitude of ~5-6 dynes/cm(2)) augmented the synthesis of the extracellular matrix collagen proteins. We conclude that under steady-flow dynamic culture environments, human PDLs can differentiate to heterogeneous cell populations that are relevant to heart valve tissue engineering. Further exploration of human PDLs for this purpose is thus warranted.