Previous studies have quantified repolarization variability using time-domain, frequency-domain and non-linear analysis in mouse hearts. Here, we investigated the relationship between these parameters and ventricular arrhythmogenicity in a hypokalaemia model of acquired long QT syndrome. Methods: Left ventricular monophasic action potentials (MAPs) were recorded during right ventricular regular 8 Hz pacing during normokalaemia (5.2 mM [K+]), hypokalaemia modelling LQTS (3 mM [K+]) or hypokalaemia with 0.1 mM heptanol in Langendorff-perfused mouse hearts. Results: During normokalaemia, mean APD was 33.5±3.7 ms. Standard deviation (SD) of APDs was 0.63±0.33 ms, coefficient of variation was 1.9±1.0% and the root mean square (RMS) of successive differences in APDs was 0.3±0.1 ms. Low- and high-frequency peaks were 0.6±0.5 and 2.3±0.7 Hz, respectively, with percentage powers of 38±22 and 61±23%. Poincaré plots of APDn+1 against APDn revealed ellipsoid morphologies with SD along the line-of-identity (SD2) to SD perpendicular to the line-of-identity (SD1) ratio of 4.6±1.1. Approximate and sample entropy were 0.49±0.12 and 0.64±0.29, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.62±0.27 and 0.60±0.18, respectively. Hypokalaemia provoked ventricular tachycardia in six of seven hearts, prolonged APDs (51.2±7.9 ms), decreased SD2/SD1 ratio (3.1±1.0), increased approximate and sample entropy (0.68±0.08 and 1.02±0.33) and decreased short-term fluctuation slope (1.23 ± 0.20) (ANOVA, P<0.05). Heptanol prevented VT in all hearts studied without further altering the above repolarization parameters observed during hypokalaemia. Conclusion: Reduced SD2/SD1, increased entropy and decreased short-term fluctuation slope are associated with ventricular arrhythmogenesis in hypokalaemia. Heptanol exerts anti-arrhythmic effects without affecting repolarization variability.

Introduction: The presence of multiple comorbidities increases the risk of all-cause mortality, but the effects of the comorbidity sequence before the baseline date on mortality remained unexplored. This study investigated the relationship between coronary heart disease (CHD), atrial fibrillation (AF) and heart failure (HF) sequence on all-cause mortality risk in type 2 diabetes mellitus. Methods: This study included patients with type 2 diabetes mellitus prescribed antidiabetic/cardiovascular medications in public hospitals of Hong Kong between January 1st, 2009 and December 31st, 2009 with follow-up until death or December 31st, 2019. Cox regression was used to identify comorbidity sequences predicting all-cause mortality in patients with different medication subgroups. Results: A total of 249291 patients (age: 66.0±12.4 years, 47.4% male) were included. At baseline, 7564, 10900 and 25589 patients had AF, HF and CHD, respectively. Over follow-up (3524±1218 days), 85870 patients died (mortality rate: 35.7 per 1000 person-years). Sulphonylurea users with CHD developed later, but insulin users with CHD developing earlier, in the disease course had lower mortality risks. Amongst insulin users with two of the three comorbidities, CHD with preceding AF (hazard ratio [HR]: 3.06, 95% CI: [2.60-3.61], p<0.001) or HF (HR: 3.84 [3.47- 4.24], p<0.001) had a higher mortality. In users of lipid-lowering agents with all three comorbidities, those with preceding AF had higher risk of mortality (AF-CHD-HF: HR: 3.22, [2.24-4.61], p<0.001; AF-HF-CHD: HR: 3.71, [2.66-5.16], p<0.001). Conclusion: The sequence of comorbidity development affects the risk of all-cause mortality to varying degrees in diabetic patients on different antidiabetic/cardiovascular medications.