Uremia increases QRS duration afterβ-adrenergic stimulation in mice

Abstract

Chronic kidney disease (CKD) and uremia increase the risk of heart disease and sudden cardiac death. Coronary artery disease can only partly account for this. The remaining mechanistic links between CKD and sudden death are elusive, but may involve cardiac arrhythmias. For the present study, we hypothesized that a thorough electrophysiological study in mice with CKD would provide us valuable information that could aid in the identification of additional underlying causes of sudden cardiac death in patients with kidney disease. Partial (5/6) nephrectomy (NX) in mice induced mild CKD: plasma urea in NX was 24 ± 1 mmol/L (n = 23) versus 12 ± 1 mmol/L (n = 22) in sham‐operated control mice (P < 0.05). Echocardiography did not identify structural or mechanical remodeling in NX mice. Baseline ECG parameters were comparable in conscious NX and control mice; however, the normal 24‐h diurnal rhythm in QRS duration was lost in NX mice. Moreover, β‐adrenergic stimulation (isoprenaline, 200 μg/kg intraperitoneally) prolonged QRS duration in conscious NX mice (from 12 ± 1 to 15 ± 2 msec, P < 0.05), but not in sham‐operated controls (from 13 ± 1 to 13 ± 2 msec, P > 0.05). No spontaneous arrhythmias were observed in conscious NX mice, and intracardiac pacing in anesthetized mice showed a comparable arrhythmia vulnerability in NX and sham‐operated mice. Isoprenaline (2 mg/kg intraperitoneally) changed the duration of the QRS complex from 11.2 ± 0.4 to 11.9 ± 0.5 (P = 0.06) in NX mice and from 10.7 ± 0.6 to 10.6 ± 0.6 (P = 0.50) in sham‐operated mice. Ex vivo measurements of cardiac ventricular conduction velocity were comparable in NX and sham mice. Transcriptional activity of Scn5a, Gja1 and several profibrotic genes was similar in NX and sham mice. We conclude that proper kidney function is necessary to maintain diurnal variation in QRS duration and that sympathetic regulation of the QRS duration is altered in kidney disease.

Prolonged QT intervals in mice with cardiomyocyte‐specific deficiency of the molecular clock

“…Under complete anaesthesia (2% isoflurane in O 2 ), telemetric devices (ETA‐F10, DataSciences International, MN, USA) were implanted subcutaneously on the back region between the scapulas as described previously 22,39 . Body temperature was monitored and kept at 36‐37°C during the entire procedure.…”

“…Under complete anaesthesia (2% isoflurane in O 2 ), telemetric devices (ETA-F10, DataSciences International, MN, USA) were implanted subcutaneously on the back region between the scapulas as described previously. 22,39 Body temperature was monitored and kept at 36-37°C during the entire procedure. Subcutaneous carprofen (10 mg/kg) and a lidocainebupivacaine mix (0.4 mg/kg and 1.0 mg/kg, respectively) were administered to all mice in the subcutaneous device pocket for post-operative analgesia.…”

A systematic review and meta-analysis of murine models of uremic cardiomyopathy

“…Furthermore, mild diastolic cardiac dysfunction was detected whereas systolic function or left ventricular dimensions were only rarely affected. [16][17][18][19][20][21] Six to 11 weeks after SNX, [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] increased blood pressure, cardiac hypertrophy, and systolic dysfunction were reported in only 40% to 50% of studies while cardiac fibrosis was identified in 2 of 3 studies. Although diastolic dysfunction was observed in 85% of studies, left ventricular diameter was only rarely affected.…”

Pro-oxidative priming but maintained cardiac function in a broad spectrum of murine models of chronic kidney disease

“…Over the past decade, multiple studies examined cardiac changes in CKD, especially using 5/6 Nx to induce CKD, however, the results are highly variable [ 11 ]. In fact, several studies reported that the mere induction of CKD induced the development of cardiac hypertrophy and even failure [ 14 , 28 ], while others observed more mild alterations to even no clear cardiac effects [ 29 , 30 ]. This may be related to the use of different mouse strains and methods of CKD induction, but also to differences in reported parameters.…”