Predictors and Etiologies of Clinical Relapse Among Patients With Ulcerative Colitis in Deep Remission.

GOAL: The objective of this study was to evaluate for potential predictors and etiologies of clinical relapse among patients with ulcerative colitis in deep remission. BACKGROUND: Patients displaying deep (endoscopic and histologic) remission have a decreased cumulative risk of relapse in ulcerative colitis of <10% per year, but predictors and etiologies of relapse in this population are poorly understood. MATERIALS AND METHODS: We performed a retrospective cohort study utilizing electronic medical records at Tufts Medical Center to identify patients in deep remission, classified as having both endoscopic remission (Mayo Endoscopic Score of 0 or 1) and histologic remission (Simplified Geboes Score 0.2). We evaluated the cumulative risk of clinical relapse following attainment of deep remission and examined predictors and etiologies of relapse. RESULTS: Among 139 patients with ulcerative colitis in deep remission, the cumulative risk of relapse was <10% and <20% at 1 and 2 years. Patients with complete normalization of mucosa (Geboes=0) and normalization of C-reactive protein (<7.48 mg/dL) at the time of remission were associated with a lower risk of relapse. Discontinuation of therapy was the most commonly identified etiology of relapse. CONCLUSIONS: Patients in deep remission have a 1-year risk of clinical relapse of <10%, with those demonstrating a non-normalized mucosa or elevated C-reactive protein predictive of persistent relapse risk. Discontinuation of therapy or minor histologic changes may drive relapse among those in deep remission.

Regional variation of the inwardly rectifying potassium current in the canine heart and the contributions to differences in action potential repolarization.

The inward rectifier potassium current, IK1, contributes to the terminal phase of repolarization of the action potential (AP), as well as the value and stability of the resting membrane potential. Regional variation in IK1 has been noted in the canine heart, but the biophysical properties have not been directly compared. We examined the properties and functional contribution of IK1 in isolated myocytes from ventricular, atrial and Purkinje tissue. APs were recorded from canine left ventricular midmyocardium, left atrial and Purkinje tissue. The terminal rate of repolarization of the AP in ventricle, but not in Purkinje, depended on changes in external K(+) ([K(+)]o). Isolated ventricular myocytes had the greatest density of IK1 while atrial myocytes had the lowest. Furthermore, the outward component of IK1 in ventricular cells exhibited a prominent outward component and steep negative slope conductance, which was also enhanced in 10 mM [K(+)]o. In contrast, both Purkinje and atrial cells exhibited little outward IK1, even in the presence of 10 mM [K(+)]o, and both cell types showed more persistent current at positive potentials. Expression of Kir2.1 in the ventricle was 76.9-fold higher than that of atria and 5.8-fold higher than that of Purkinje, whereas the expression of Kir2.2 and Kir2.3 subunits was more evenly distributed in Purkinje and atria. Finally, AP clamp data showed distinct contributions of IK1 for each cell type. IK1 and Kir2 subunit expression varies dramatically in regions of the canine heart and these regional differences in Kir2 expression likely underlie regional distinctions in IK1 characteristics, contributing to variations in repolarization in response to in [K(+)]o changes.

Developmental changes in expression and biophysics of ion channels in the canine ventricle.

BACKGROUND: Developmental changes in the electrical characteristics of the ventricular myocardium are not well defined. This study examines the contribution of inwardly rectifying K(+) current (IK1), transient outward K(+) current (Ito), delayed rectifier K(+) currents (IKr and IKs) and sodium channel current (INa) to repolarization in the canine neonate myocardium. METHODS: Single myocytes isolated from the left ventricle of 2-3week old canine neonate hearts were studied using patch-clamp techniques. RESULTS: Neonate cells were ~6-fold smaller than those of adults (28.8±8.8 vs. 176±6.7pF). IK1 was larger in neonate myocytes and displayed a substantial inward component and an outward component with negative slope conductance, peaking at -60mV (4.13 pA/pF). IKr tail currents (at -40mV), were small (<20pA). IKs could not be detected, even after exposure to isoproterenol (100nM). Ito was also absent in the neonate, consistent with the absence of a phase 1 in the action potential. Peak INa, late INa and ICa were smaller in the neonate compared with adults. KCND3, KCNIP2 and KCNQ1 mRNA expression was half, while KCNH2 was equal and KCNJ2 was greater in the neonate when compared with adults. CONCLUSIONS: Two major repolarizing K(+) currents (IKs and Ito) present in adult ventricular cells are absent in the 2week old neonate. Peak and late INa are significantly smaller in the neonate. Our results suggest that the absence of these two currents in the neonate heart may increase the susceptibility to arrhythmias under certain long QT conditions.