Cholecystokinin attenuates ß-cell apoptosis in both mouse and human islets.

Loss of functional pancreatic ß-cell mass and increased ß-cell apoptosis are fundamental to the pathophysiology of type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic ß-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing ß-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes ß-cell survival in rodent models of diabetes and aging. We demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a ß-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human ß-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases ß-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote ß-cell survival in human islets and has therapeutic potential to preserve ß-cell mass in diabetes and as an adjunct therapy after transplant.

Effect of Metabolic Syndrome on Anatomy and Function of the Lower Urinary Tract Assessed on MRI.

OBJECTIVE: To investigate the relationship between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) with functional and anatomic changes of the lower urinary tract with MRI. MATERIALS AND METHODS: The bladder and prostate of 95 subjects (56M, 39F) were segmented on T2-weighted pelvic MRI using Materialize Mimics 3D software. Bladder wall volume (BWV), post-void residual (PVR) and prostate volume (PV) were quantified from the 3D renderings. LUTS were quantified using validated questionnaires administered at the time of MRI. Wilcoxin rank sum, win ratio and chi-square tests were used to correlate symptom scores, BWV, PVR and PV in patients 1) without vs with MetS, 2) with mild (IPSS or UDI-6: 0-7) vs moderate-severe (IPSS: 8-35 or UDI-6: ≥8) and 3) normal vs enlarged prostates (>40cm3). Multivariate linear regression was used to determine predictors for BWV, PVR and PV. RESULTS: Men with MetS had increased BWV (66.8 vs 51.1cm3, P = .003), higher PVR (69.1 vs 50.5cc, P= .05) and increased PV (67.2 vs 40.1cm3, P= .01). Women without and with MetS had similar BWV, PVR and LUTS (P= .3-.78). There was no difference in prevalence of MetS, BWV, PVR or PV in men or women with mild vs moderate-severe LUTS (P = .26-.97). Men with enlarged prostates were more likely to have MetS (P = .003). There was no difference in BWV, PVR and LUTS for men with normal vs enlarged prostates (P= .44-.94). In men, BWV was highly correlated with MetS (P = .005) on regression analysis. CONCLUSION: MetS leads to detrusor hypertrophy and may contribute to impaired bladder function, likely related to the effect on the prostate.

Comprehensive non-invasive analysis of lower urinary tract anatomy using MRI.

PURPOSE: Anatomic changes that coincide with aging including benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) negatively impact quality of life. Use of MRI with its exquisite soft tissue contrast, full field-of-view capabilities, and lack of radiation is uniquely suited for quantifying specific lower urinary tract features and providing comprehensive measurements such as total bladder wall volume (BWV), bladder wall thickness (BWT), and prostate volume (PV). We present a technique for generating 3D anatomical renderings from MRI to perform quantitative analysis of lower urinary tract anatomy. METHODS: T2-weighted fast-spin echo MRI of the pelvis in 117 subjects (59F;58 M) aged 30-69 (49.5 ± 11.3) without known lower urinary tract symptoms was retrospectively segmented using Materialise software. Virtual 3D models were used to measure BWV, BWT, and PV. RESULTS: BWV increased significantly between the 30-39 and 60-69 year age group in women (p = 0.01), but not men (p = 0.32). BWV was higher in men than women aged 30-39 and 40-49 (p = 0.02, 0.05, respectively) ,but not 50-59 or 60-69 (p = 0.18, 0.16, respectively). BWT was thicker in men than women across all age groups. Regional differences in BWT were observed both between men and women and between opposing bladder wall halves (anterior/posterior, dome/base, left/right) within each sex in the 50-59 and 60-69 year groups. PV increased from the 30-39 to 60-69 year groups (p = 0.05). BWT was higher in subjects with enlarged prostates (> 40cm3) (p = 0.05). CONCLUSION: Virtual 3D MRI models of the lower urinary tract reliably quantify sex-specific and age-associated changes of the bladder wall and prostate.

Outcomes after pacemaker implantation in patients with new-onset left bundle-branch block after transcatheter aortic valve replacement.

New-onset left bundle branch block (N-LBBB) after transcatheter aortic valve replacement (TAVR) is a challenging clinical dilemma. In our single-center study, 60 out of 172 patients who underwent permanent pacemaker implantation (PPM) after TAVR had N-LBBB (34.9%). At a median follow-up duration of 357 days (IQR, 178; 560 days), two patients (3.5%) were completely pacemaker-dependent, and four others (7%) were partially dependent. Twelve patients (24%) recovered conduction in their left bundle at a median follow-up duration of 5 weeks (IQR, 4; 14 weeks). Due to the lack of clinical predictors of pacemaker dependency, active surveillance is warranted and may be an alternative to permanent pacemaker implantation.

Detection of Atrial Fibrillation and Atrial Flutter by Pacemaker Device Interrogation After Transcatheter Aortic Valve Replacement (TAVR): Implications for Management.

BACKGROUND: Atrial fibrillation (AF) and atrial flutter (AFL) are associated with increased risk of stroke and mortality after transcatheter aortic valve replacement (TAVR). Many episodes of new-onset AF/AFL (NOAF) occur after hospital discharge and may not be clinically apparent. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented AF. METHODS: From 2012 to 2017, patients who underwent pacemaker implantation after TAVR were reviewed, and pacemaker data from device checks were analyzed for detection of NOAF. Patients with prior AF/AFL were excluded. Secondary outcomes were mortality and ischemic stroke. RESULTS: A total of 172 patients underwent TAVR and pacemaker implantation, and 95 were without pre-existent AF/AFL. Over a median follow-up of 15 months, a total of 24 patients had NOAF (25%), of which 10 patients (10.5%) had manifest NOAF detected on electrocardiography, and 14 patients (14.7%) had subclinical NOAF first identified on device interrogation. The cumulative incidence of mortality was 16.7% for NOAF and 15.5% for normal sinus rhythm (P=.83). The cumulative incidence of stroke was 12.5% for NOAF and 1.4% for normal sinus rhythm (P=.04). Subclinical NOAF patients were less likely to be started on anticoagulation compared with manifest NOAF patients (70% vs 15.3%, respectively; P=.02). CONCLUSION: Subclinical NOAF is common after TAVR, usually occurs months after hospital discharge, and is associated with lack of anticoagulation therapy and increased risk of stroke. Prolonged surveillance of subclinical NOAF may be warranted after TAVR.

Dofetilide for suppression of atrial fibrillation in hypertrophic cardiomyopathy: A case series and literature review.

BACKGROUND: Limited medical options are available for rhythm control in patients with atrial fibrillation (AF) and hypertrophic cardiomyopathy (HCM). There are no published reports of dofetilide use in this population. METHODS: A retrospective chart review was conducted on 1,404 patients loaded on dofetilide for AF suppression at the Cleveland Clinic from 2008 to 2012, 25 of whom were found to have HCM. RESULTS: The HCM cohort was 32% female, 76% with persistent AF, mean age of 59 ± 10 years, and mean ejection fraction of 54 ± 9 %. Of the 25 patients, 21 were discharged on dofetilide, three discontinued during loading due to QTc prolongation, and one due to inefficacy. There were no adverse events during loading. Of those discharged on dofetilide, 11/21 (52%) were still on it at a median follow-up of 396 (198, 699) days at the time of the chart review. For those in whom it was discontinued, the median time on the drug was 301 (111, 738) days. Of the 10 patients who discontinued dofetilide during follow-up, six were due to inefficacy, one postablation, one postheart transplant, one due to death secondary to lung cancer, and one due to worsening edema. CONCLUSIONS: Dofetilide was well tolerated in this group of patients with AF and HCM and it facilitated management of AF in 21/25 (84%) patients. Further research is needed to assess the safety and efficacy of dofetilide in order to develop evidence-based guidelines for the pharmacological management of AF in this population.