Glycaemia and cardiac arrhythmias in people with type 1 diabetes: A prospective observational study.

AIM: To investigate the impact of hypoglycaemia, hyperglycaemia and glycaemic variability on arrhythmia susceptibility in people with type 1 diabetes. MATERIALS AND METHODS: Thirty adults with type 1 diabetes were included in a 12-month observational exploratory study. Daytime and night-time incident rate ratios (IRRs) of arrhythmias were determined for hypoglycaemia (interstitial glucose [IG] <3.9 mmol/L), hyperglycaemia (IG >10.0 mmol/L) and glycaemic variability (standard deviation and coefficient of variation). RESULTS: Hypoglycaemia was not associated with an increased risk of arrhythmias compared with euglycaemia and hyperglycaemia combined (IG ≥ 3.9 mmol/L). However, during daytime, a trend of increased risk of arrhythmias was observed when comparing time spent in hypoglycaemia with euglycaemia (IRR 1.08 [95% CI: 0.99-1.18] per 5 minutes). Furthermore, during daytime, both the occurrence and time spent in hyperglycaemia were associated with an increased risk of arrhythmias compared with euglycaemia (IRR 2.03 [95% CI: 1.21-3.40] and IRR 1.07 [95% CI: 1.02-1.13] per 5 minutes, respectively). Night-time hypoglycaemia and hyperglycaemia were not associated with the risk of arrhythmias. Increased glycaemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during night-time. CONCLUSIONS: Acute hypoglycaemia and hyperglycaemia during daytime may increase the risk of arrhythmias in individuals with type 1 diabetes. However, no such associations were found during night-time, indicating diurnal differences in arrhythmia susceptibility.

Exercise-related hypoglycaemia induces QTc-interval prolongation in individuals with type 1 diabetes.

AIMS: To investigate changes in cardiac repolarisation during exercise-related hypoglycaemia compared to hypoglycaemia induced at rest in people with type 1 diabetes. MATERIAL AND METHODS: In a randomised crossover study, 15 men with type 1 diabetes underwent two separate hyperinsulinaemic euglycaemic-hypoglycaemic clamp experiments during Holter-ECG monitoring. One experiment included a bout of moderate-intensity cycling exercise (60 min) along with declining plasma glucose (PG; Clamp-exercise). In the other experiment, hypoglycaemia was induced with the participants at rest (Clamp-rest). We studied QTc interval, T-peak to T-end (Tpe) interval and hormonal responses during three steady-state phases: (i) baseline (PG 4.0-8.0 mmol/L); (ii) hypoglycaemic phase (PG <3.0 mmol/L); and (iii) recovery phase (PG 4.0-8.0 mmol/L). RESULTS: Both QTc interval and Tpe interval increased significantly from baseline during the hypoglycaemic phase but with no significant difference between test days. These changes were accompanied by an increase in plasma adrenaline and a decrease in plasma potassium on both days. During the recovery phase, ΔQTc interval was longer during Clamp-rest compared to Clamp-exercise, whereas ΔTpe interval remained similar on the two test days. CONCLUSIONS: We found that both exercise-related hypoglycaemia and hypoglycaemia induced at rest can cause QTc-interval prolongation and Tpe-interval prolongation in people with type 1 diabetes. Thus, both scenarios may increase susceptibility to ventricular arrhythmias.

Type 2 diabetes mellitus and higher rate of complete atrioventricular block: a Danish Nationwide Registry.

AIMS: The present study aimed to determine the association between Type 2 diabetes mellitus (T2DM) and third-degree (complete) atrioventricular block. METHODS AND RESULTS: This nationwide nested case-control study included patients older than 18 years, diagnosed with third-degree atrioventricular block between 1 July 1995 and 31 December 2018. Data on medication, comorbidity, and outcomes were collected from Danish registries. Five controls, from the risk set of each case of third-degree atrioventricular block, were matched on age and sex to fit a Cox regression model with time-dependent exposure and time-dependent covariates. Subgroup analysis was conducted with Cox regression models for each subgroup. We located 25 995 cases with third-degree atrioventricular block that were matched with 130 004 controls. The mean age was 76 years and 62% were male. Cases had more T2DM (21% vs. 11%), hypertension (69% vs. 50%), atrial fibrillation (25% vs. 10%), heart failure (20% vs. 6.3%), and myocardial infarction (19% vs. 9.2%), compared with the control group. In Cox regression analysis, adjusting for comorbidities and atrioventricular nodal blocking agents, T2DM was significantly associated with third-degree atrioventricular block (hazard ratio: 1.63, 95% confidence interval: 1.57-1.69). The association remained in several subgroup analyses of diseases also suspected to be associated with third-degree atrioventricular block. There was a significant interaction with comorbidities of interest including hypertension, atrial fibrillation, heart failure, and myocardial infarction. CONCLUSION: In this nationwide study, T2DM was associated with a higher rate of third-degree atrioventricular block compared with matched controls. The association remained independent of atrioventricular nodal blocking agents and other comorbidities known to be associated with third-degree atrioventricular block.

Acute changes in plasma glucose increases left ventricular systolic function in insulin-treated patients with type 2 diabetes and controls.

AIMS: We aimed to evaluate the effect of acute hyperglycaemia and hypoglycaemia on cardiac function in patients with type 2 diabetes (T2D) and a control group. MATERIALS AND METHODS: In a nonrandomized interventional study, insulin-treated patients with T2D (N = 21, mean ± SD age 62.8 ± 6.5 years, body mass index [BMI] 29.0 ± 4.2 kg/m2 , glycated haemoglobin [HbA1c] 51.0 ± 5.4 mmol/mol [6.8 ± 0.5%]) and matched controls (N = 21, mean ± SD age 62.2 ± 8.3 years, BMI 29.2 ± 3.5 kg/m2 , HbA1c 34.3 ± 3.3 mmol/L [5.3 ± 0.3%]) underwent one experimental day with plasma glucose (PG) clamped at three different 30-minute steady-state levels: (1) fasting plasma glucose (FPG); (2) hyperglycaemia (FPG + 10 mmol/L); and (3) hyperinsulinaemic hypoglycaemia (PG <3.0 mmol/L). Cardiac function was evaluated during each steady state by echocardiography. RESULTS: Acute hyperglycaemia increased left ventricular (LV) ejection fraction from baseline in patients with T2D (mean [95% confidence interval] 4.5 percentage points [1.1; 7.9]) but not in controls (2.0 percentage points [-1.4; 5.4]). Mitral annular peak systolic velocity (s') increased during hyperglycaemia in both patients and controls (0.4 m/s [0.2;0.6] and 0.6 m/s [0.4; 0.8], respectively), whereas global longitudinal strain rate only increased in the controls (-0.05 s-1 [-0.12; 0.02] and -0.11 s-1 [-0.18; -0.03], respectively). All measures of LV systolic function increased markedly during hypoglycaemia (P <0.01 for all). No interaction between group and PG level on cardiac function was observed. CONCLUSIONS: Acute hyperglycaemia and hypoglycaemia increase LV systolic function, with no difference between patients with T2D and controls. Standardization of PG may improve reproducibility when evaluating LV systolic function in patients with T2D.

Associations of hypoglycemia, glycemic variability and risk of cardiac arrhythmias in insulin-treated patients with type 2 diabetes: a prospective, observational study.

BACKGROUND: Insulin-treated patients with type 2 diabetes (T2D) are at risk of hypoglycemia, which is associated with an increased risk of cardiovascular disease and mortality. Using a long-term monitoring approach, we investigated the association between episodes of hypoglycemia, glycemic variability and cardiac arrhythmias in a real-life setting. METHODS: Insulin-treated patients with T2D (N = 21, [mean ± SD] age 66.8 ± 9.6 years, BMI 30.1 ± 4.5 kg/m2, HbA1c 6.8 ± 0.4% [51.0 ± 4.8 mmol/mol]) were included for a one-year observational study. Patients were monitored with continuous glucose monitoring ([mean ± SD] 118 ± 6 days) and an implantable cardiac monitor (ICM) during the study period. RESULTS: Time spend in hypoglycemia was higher during nighttime than during daytime ([median and interquartile range] 0.7% [0.7-2.7] vs. 0.4% [0.2-0.8]). The ICMs detected 724 episodes of potentially clinically significant arrhythmias in 12 (57%) participants, with atrial fibrillation and pauses accounting for 99% of the episodes. No association between hypoglycemia and cardiac arrhythmia was found during daytime. During nighttime, subject-specific hourly incidence of cardiac arrhythmias tended to increase with the occurrence of hypoglycemia (incident rate ratio [IRR] 1.70 [95% CI 0.36-8.01]) but only slightly with increasing time in hypoglycemia (IRR 1.04 [95% CI 0.89-1.22] per 5 min). Subject-specific incidence of cardiac arrhythmias during nighttime increased with increasing glycemic variability as estimated by coefficient of variation whereas it decreased during daytime (IRR 1.33 [95% CI 1.05-1.67] and IRR 0.77 [95% CI 0.59-0.99] per 5% absolute increase, respectively). CONCLUSIONS: Cardiac arrhythmias were common in insulin-treated patients with T2D and were associated with glycemic variability, whereas arrhythmias were not strongly associated with hypoglycemia. TRIAL REGISTRATION: NCT03150030, ClinicalTrials.gov, registered May 11, 2017. https://clinicaltrials.gov/ct2/show/NCT03150030.

Acute hypoglycemia and risk of cardiac arrhythmias in insulin-treated type 2 diabetes and controls.

OBJECTIVE: Hypoglycemia is associated with an increased risk of cardiovascular disease including cardiac arrhythmias. We investigated the effect of hypoglycemia in the setting of acute glycemic fluctuations on cardiac rhythm and cardiac repolarization in insulin-treated patients with type 2 diabetes compared with matched controls without diabetes. DESIGN: A non-randomized, mechanistic intervention study. METHODS: Insulin-treated patients with type 2 diabetes (n = 21, age (mean ± s.d.): 62.8 ± 6.5 years, BMI: 29.0 ± 4.2 kg/m2, HbA1c: 6.8 ± 0.5% (51.0 ± 5.4 mmol/mol)) and matched controls (n = 21, age: 62.2 ± 8.3 years, BMI 29.2 ± 3.5 kg/m2, HbA1c: 5.3 ± 0.3% (34.3 ± 3.3 mmol/mol)) underwent a sequential hyperglycemic and hypoglycemic clamp with three steady-states of plasma glucose: (i) fasting plasma glucose, (ii) hyperglycemia (fasting plasma glucose +10 mmol/L) and (iii) hyperinsulinemic hypoglycemia (plasma glucose < 3.0 mmol/L). Participants underwent continuous ECG monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained. RESULTS: Both groups experienced progressively increasing heart rate corrected QT (Fridericia's formula) interval prolongations during hypoglycemia ((∆mean (95% CI): 31 ms (16, 45) and 39 ms (24, 53) in the group of patients with type 2 diabetes and controls, respectively) with similar increases from baseline at the end of the hypoglycemic phase (P = 0.43). The incidence of ventricular premature beats increased significantly in both groups during hypoglycemia (P = 0.033 and P < 0.0001, respectively). One patient with type 2 diabetes developed atrial fibrillation during recovery from hypoglycemia. CONCLUSIONS: In insulin-treated patients with type 2 diabetes and controls without diabetes, hypoglycemia causes clinically significant and similar increases in cardiac repolarization that might increase vulnerability for serious cardiac arrhythmias and sudden cardiac death.

Early ICD implantation in cardiac arrest survivors with acute coronary syndrome - predictors of implantation, ICD-therapy and long-term survival.

Objectives. Implantable cardioverter defibrillator (ICD) implantation in patients resuscitated from out-of-hospital cardiac arrest (OHCA) due to acute myocardial infarction (AMI) is controversial. Design. Consecutive OHCA-survivors due to AMI from two Danish tertiary heart centers from 2007 to 2011 were included. Predictors of ICD-implantation, ICD-therapy and long-term survival (5 years) were investigated. Patients with and without ICD-implantation during the index hospital admission were included (later described as early ICD-implantation). Patients with an ICD after hospital discharge were censored from further analyses at time of implantation. Results. We identified 1,457 consecutive OHCA-patients, and 292 (20%) of the cohort met the inclusion criteria. An ICD was implanted during hospital admission in 78 patients (27%). STEMI and successful revascularization were inversely and independently associated with ICD-implantation (ORSTEMI = 0.37, 95% CI: 0.14-0.94, ORrevasc = 0.11, 0.03-0.36) whereas age, sex, LVEF <35%, comorbidity burden or shockable first OHCA-rhythm were not associated with ICD-implantation. Appropriate ICD-shock therapy during the follow-up period was noted in 15% of patients (n = 12). Five-year mortality-rate was significantly lower in ICD-patients (18% vs. 28%, plogrank = 0.02), which was persistent after adjustment for prognostic factors (HR = 0.44 (95% CI: 0.23-0.88)). This association was no longer found when using first event (death or appropriate shock whatever came first) as outcome variable (plogrank = 0.9). Conclusions. Mortality after OHCA due to AMI was significantly lower in patients with early ICD-implantation after adjustment for prognostic factors. When using appropriate shock and death as events, ICD-patients had similar outcome as patients without an ICD, which may suggest a survival benefit due to appropriate device therapy.

Temporal Incidence of Appropriate and Inappropriate Therapy and Mortality in Secondary Prevention ICD Patients by Cardiac Diagnosis.

OBJECTIVES: This study sought to estimate the temporal development in rates and incidences of appropriate and inappropriate implantable cardioverter-defibrillator (ICD) therapy and shocks by cardiac diagnosis in a real-world population of patients with secondary prevention ICDs. BACKGROUND: Data on cardiac diagnoses and temporal development of ICD therapies in patients with secondary prevention ICDs are limited. METHODS: Patients (N = 4,587) with a secondary prevention ICD were identified from the Danish Pacemaker and ICD Register (January 1, 2007, to December 31, 2016) and linked to nationwide administrative registers. The outcome of appropriate and inappropriate ICD therapy and all-cause mortality were analyzed by annual event rates, cumulative incidence plots, and Cox regression models. RESULTS: During a mean follow-up of 3.6 ± 2.4 years, 1,362 patients (30%) experienced appropriate ICD therapy (16.8% shocks), and 350 patients (7.6%) experienced inappropriate ICD therapy (4.6% shocks). From 2007 to 2016, there was a significant temporal reduction in both appropriate and inappropriate ICD therapy from 28.2 (95% confidence interval [CI]: 21.6 to 37.0) to 7.9 (95% CI: 6.8 to 9.1) and 10.0 (95% CI: 6.4 to 15.5) to 1.0 (95% CI: 0.7 to 1.5) per 100 person-years (p for trends <0.001). Multivariate Cox regression analyses showed that arrhythmogenic right ventricular cardiomyopathy was associated with the highest probability of appropriate ICD therapy (hazard ratio: 2.45; 95% CI: 1.77 to 3.39; p < 0.0001), whereas patients with hypertrophic cardiomyopathy had the lowest probability (hazard ratio: 0.62; 95% CI: 0.42 to 0.93; p = 0.0196) when compared to patients with ischemic heart disease. CONCLUSIONS: In this nationwide real-life cohort of patients with secondary prevention ICDs, we observed a significant temporal decline in delivered appropriate and inappropriate shocks and ICD therapies in the last decade. A large proportion of patients still experienced ICD therapy but with significant differences by cardiac diagnosis.

Incidence of appropriate implantable cardioverter-defibrillator therapy and mortality after implantable cardioverter-defibrillator generator replacement: results from a real-world nationwide cohort.

AIMS: The safety of omitting implantable cardioverter-defibrillator (ICD) generator replacement in patients with no prior appropriate therapy, comorbid conditions, and advanced age is unclear. The aim was to investigate incidence of appropriate ICD therapy after generator replacement. METHODS AND RESULTS: We identified patients implanted with a primary prevention ICD (n = 4630) from 2007 to 2016, who subsequently underwent an elective ICD generator replacement (n = 670) from the Danish Pacemaker and ICD Register. The data were linked to other databases and evaluated the outcomes of appropriate therapy and death. Predictors of ICD therapy were identified using multivariate Cox regression analyses. A total of 670 patients underwent elective ICD generator replacement. Of these, 197 (29.4%) patients had experienced appropriate therapy in their 1st generator period. During follow-up of 2.0 ± 1.6 years, 95 (14.2%) patients experienced appropriate therapy. Predictors of appropriate therapy in 2nd generator period was low initial left ventricular ejection fraction (≤25%) [hazard ratio (HR) 1.87, confidence interval (CI) 1.13-1.95] and appropriate therapy in 1st generator period (HR 3.95, CI 2.57-6.06). For patients with appropriate therapy in 1st generator period, 4-year incidence of appropriate therapy was 50.6% vs. 16.4% in those without (P < 0.001). Among patients >80 years with no prior appropriate therapy 8.8% of patients experienced appropriate therapy after replacement. Comorbidity burden and advanced age were associated with reduced device utilization after replacement and a high competing risk of death without preceding appropriate therapy. CONCLUSION: A significant residual risk of appropriate therapy in the 2nd generator was present even among patients with advanced age and with a full prior generator period without any appropriate ICD events.

Risk of atrial fibrillation in diabetes mellitus: A nationwide cohort study.

AIM: Diabetes has been associated with atrial fibrillation but the current evidence is conflicting. In particular knowledge regarding young diabetes patients and the risk of developing atrial fibrillation is sparse. The aim of our study was to investigate the risk of atrial fibrillation in patients with diabetes compared to the background population in Denmark. METHODS AND RESULTS: Through Danish nationwide registries we included persons above 18 years of age and without prior atrial fibrillation and/or diabetes from 1996 to 2012. The study cohort was divided into a background population without diabetes and a diabetes group. The absolute risk of developing atrial fibrillation was calculated and Poisson regression models adjusted for sex, age and comorbidities were used to calculate incidence rate ratios of atrial fibrillation. The total study cohort included 5,081,087 persons, 4,827,713 (95%) in the background population and 253,374 (5%) in the diabetes group. Incidence rates of atrial fibrillation per 1000 person years were stratified in four age groups from 18 to 39, 40 to 64, 65 to 74 and 75 to 100 years giving incidence rates (95% confidence intervals) of 0.02 (0.02-0.02), 0.99 (0.98-1.01), 8.89 (8.81-8.98) and 20.0 (19.9-20.2) in the background population and 0.13 (0.09-0.20), 2.10 (2.00-2.20), 8.41 (8.10-8.74) and 20.1 (19.4-20.8) in the diabetes group, respectively. The adjusted incidence rate ratios in the diabetes group with the background population as reference were 2.34 (1.52-3.60), 1.52 (1.47-1.56), 1.20 (1.18-1.23) and 0.99 (0.97-1.01) in the four age groups, respectively. CONCLUSION: Diabetes is an independent risk factor for developing atrial fibrillation/flutter, most pronounced in young diabetes patients. Routine screening for atrial fibrillation/flutter in diabetes patients might be beneficial and have therapeutic implications, especially in younger diabetes patients. TRANSLATIONAL PERSPECTIVE: Diabetes increases the risk of developing atrial fibrillation and especially young diabetes patients have a high relative risk. Increased focus on detecting atrial fibrillation in young diabetes patients might prove beneficial, and both anticoagulation treatment and anti-arrhythmic treatment strategies should be considered as soon as possible.

Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study.

STUDY QUESTION: What are the risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding associated with restarting antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation? METHODS: This Danish cohort study (1996-2012) included all patients with atrial fibrillation discharged from hospital after gastrointestinal bleeding while receiving antithrombotic treatment. Restarted treatment regimens were single or combined antithrombotic drugs with oral anticoagulation and antiplatelets. Follow-up started 90 days after discharge to avoid confounding from use of previously prescribed drugs on discharge. Risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding were estimated with competing risks models and time dependent multiple Cox regression models. STUDY ANSWER AND LIMITATIONS: 4602 patients (mean age 78 years) were included. Within two years, 39.9% (95% confidence interval 38.4% to 41.3%, n=1745) of the patients had died, 12.0% (11.0% to 13.0%, n=526) had experienced thromboembolism, 17.7% (16.5% to 18.8%, n=788) major bleeding, and 12.1% (11.1% to 13.1%, n=546) recurrent gastrointestinal bleeding. 27.1% (n=924) of patients did not resume antithrombotic treatment. Compared with non-resumption of treatment, a reduced risk of all cause mortality was found in association with restart of oral anticoagulation (hazard ratio 0.39, 95% confidence interval 0.34 to 0.46), an antiplatelet agent (0.76, 0.68 to 0.86), and oral anticoagulation plus an antiplatelet agent (0.41, 0.32 to 0.52), and a reduced risk of thromboembolism was found in association with restart of oral anticoagulation (0.41, 0.31 to 0.54), an antiplatelet agent (0.76, 0.61 to 0.95), and oral anticoagulation plus an antiplatelet agent (0.54, 0.36 to 0.82). Restarting oral anticoagulation alone was the only regimen with an increased risk of major bleeding (1.37, 1.06 to 1.77) compared with non-resumption of treatment; however, the difference in risk of recurrent gastrointestinal bleeding was not significant between patients who restarted an antithrombotic treatment regimen and those who did not resume treatment. WHAT THIS STUDY ADDS: Among patients with atrial fibrillation who experience gastrointestinal bleeding while receiving antithrombotic treatment; subsequent restart of oral anticoagulation alone was associated with better outcomes for all cause mortality and thromboembolism compared with patients who did not resume treatment. This was despite an increased longitudinal associated risk of bleeding. FUNDING, COMPETING INTERESTS, DATA SHARING: This study was supported by a grant from Boehringer-Ingelheim. Competing interests are available in the full paper on bmj.com. The authors have no additional data to share.