Atrial fibrillation and risk of adverse outcomes in heart failure with reduced, mildly reduced, and preserved ejection fraction: A systematic review and meta-analysis.

INTRODUCTION: Heart failure (HF) and atrial fibrillation (AF) frequently co-exist. Contemporary classification of HF categorizes it into HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). Aggregate data comparing the risk profile of AF between these three HF categories are lacking. METHODS: We conducted a systematic review and meta-analysis aimed at determining any significant differences in AF-associated all-cause mortality, HF hospitalizations, cardiovascular mortality (CV), and stroke between HFrEF, HFmrEF, and HFpEF. A systematic search of PubMed, EMBASE, and Cochrane Library databases until February 28, 2023. Data were combined using DerSimonian-Laird random effects model. RESULTS: A total of 22 studies comprising 248 323 patients were retained: HFrEF 123 331 (49.7%), HFmrEF 40 995 (16.5%), and HFpEF 83 997 (33.8%). Pooled baseline AF prevalence was 36% total population, 30% HFrEF, 36% HFmrEF, and 42% HFpEF. AF was associated with a higher risk of all-cause mortality in the total population with pooled hazard ratio (HR) = 1.13 (95% confidence interval [CI] = 1.07-1.21), HFmrEF (HR = 1.25, 95% CI = 1.05-1.50) and HFpEF (HR = 1.16, 95% CI = 1.09-1.24), but not HFrEF (HR = 1.03, 95% CI = 0.93-1.14). AF was associated with a higher risk of HF hospitalizations in the total population (HR = 1.29, 95% CI = 1.14-1.46), HFmrEF (HR = 1.64, 95% CI = 1.20-2.24), and HFpEF (HR = 1.46, 95% CI = 1.17-1.83), but not HFrEF (HR = 1.01, 95% CI = 0.87-1.18). AF was only associated with CV in the HFpEF subcategory but was associated with stroke in all three HF subtypes. CONCLUSIONS: AF appears to be associated with a higher risk of all-cause mortality and HF hospitalization in HFmrEF and HFpEF. With these findings, the paucity of data and treatment guidelines on AF in the HFmrEF subgroup becomes even more significant and warrant further investigations.

Persistence of significant secondary mitral regurgitation post-cardiac resynchronization therapy and survival: a systematic review and meta-analysis : Mitral regurgitation and mortality post-CRT.

Cardiac resynchronization therapy (CRT) significantly reduces secondary mitral regurgitation (MR) in patients with severe left ventricular systolic dysfunction. However, uncertainty remains as to whether improvement in secondary MR correlates with improvement with mortality seen in CRT. We conducted a meta-analysis to determine the association of persistent unimproved significant secondary MR (defined as moderate or moderate-to-severe or severe MR) compared to improved MR (no MR or mild MR) post-CRT with all-cause mortality, cardiovascular mortality, and heart failure hospitalization. A systematic search of PubMed, EMBASE, and Cochrane Library databases till July 31, 2022 identified studies reporting clinical outcomes by post-CRT secondary MR status. In 12 prospective studies of 4954 patients (weighted mean age 66.8 years, men 77.8%), the median duration of follow-up post-CRT at which patients were re-evaluated for significant secondary MR was 6 months and showed significant relative risk reduction of 30% compared to pre-CRT. The median duration of follow-up post-CRT for ascertainment of main clinical outcomes was 38 months. The random effects pooled hazard ratio (95% confidence interval) of all-cause mortality in patients with unimproved secondary MR compared to improved secondary MR was 2.00 (1.57-2.55); p < 0.001). There was insufficient data to evaluate secondary outcomes in a meta-analysis, but limited data that examined the relationship showed significant association of unimproved secondary MR with increased cardiovascular mortality and heart failure hospitalization. The findings of this meta-analysis suggest that lack of improvement in secondary MR post-CRT is associated with significantly elevated risk of all-cause mortality and possibly cardiovascular mortality and heart failure hospitalization. Future studies may investigate approaches to address persistent secondary MR post-CRT to help improved outcome in this population.

Evolution and prognosis of tricuspid and mitral regurgitation following cardiac implantable electronic devices: a systematic review and meta-analysis.

AIMS: Significant changes in tricuspid regurgitation (TR) and mitral regurgitation (MR) post-cardiac implantable electronic devices (CIEDs) are increasingly recognized. However, uncertainty remains as to whether the risk of CIED-associated TR and MR differs with right ventricular pacing (RVP) via CIED with trans-tricuspid RV leads, compared with cardiac resynchronization therapy (CRT), conduction system pacing (CSP), and leadless pacing (LP). The study aims to synthesize extant data on risk and prognosis of significant post-CIED TR and MR across pacing strategies. METHODS AND RESULTS: We searched PubMed, EMBASE, and Cochrane Library databases published until 31 October 2023. Significant post-CIED TR and MR were defined as ≥ moderate. Fifty-seven TR studies (n = 13 723 patients) and 90 MR studies (n = 14 387 patients) were included. For all CIED, the risk of post-CIED TR increased [pooled odds ratio (OR) = 2.46 and 95% CI = 1.88-3.22], while the risk of post-CIED MR reduced (OR = 0.74, 95% CI = 0.58-0.94) after 12 and 6 months of median follow-up, respectively. Right ventricular pacing via CIED with trans-tricuspid RV leads was associated with increased risk of post-CIED TR (OR = 4.54, 95% CI = 3.14-6.57) and post-CIED MR (OR = 2.24, 95% CI = 1.18-4.26). Binarily, CSP did not alter TR risk (OR = 0.37, 95% CI = 0.13-1.02), but significantly reduced MR (OR = 0.15, 95% CI = 0.03-0.62). Cardiac resynchronization therapy did not significantly change TR risk (OR = 1.09, 95% CI = 0.55-2.17), but significantly reduced MR with prevalence pre-CRT of 43%, decreasing post-CRT to 22% (OR = 0.49, 95% CI = 0.40-0.61). There was no significant association of LP with post-CIED TR (OR = 1.15, 95% CI = 0.83-1.59) or MR (OR = 1.31, 95% CI = 0.72-2.39). Cardiac implantable electronic device-associated TR was independently predictive of all-cause mortality [pooled hazard ratio (HR) = 1.64, 95% CI = 1.40-1.90] after median of 53 months. Mitral regurgitation persisting post-CRT independently predicted all-cause mortality (HR = 2.00, 95% CI = 1.57-2.55) after 38 months. CONCLUSION: Our findings suggest that, when possible, adoption of pacing strategies that avoid isolated trans-tricuspid RV leads may be beneficial in preventing incident or deteriorating atrioventricular valvular regurgitation and might reduce mortality.

Temperature Changes During Electrophysiology Ablation in Veterans and 1-Year Success Rates: A Retrospective Pilot Analysis.

OBJECTIVES: The authors hypothesized that body core temperature during cardiac arrhythmia procedures in the electrophysiology laboratory declines, and examined the association of changes with the patient or procedural factors. They hypothesized that a greater degree of change negatively affects 1-year ablation success. DESIGN: Retrospective observational study. SETTING: Veteran's Administration Boston Healthcare System. PARTICIPANTS: Consecutive records of veterans undergoing ablation procedures under general anesthesia. INTERVENTIONS: Retrospective data collection and analysis from the electronic medical record. MEASUREMENTS AND MAIN RESULTS: Patient and procedural characteristics were collected from the electronic medical record. Core temperature data included baseline (BT) (following entry to the care process on the day of the procedure), the start (ST) and end of the procedure temperatures (ET), and their differences. The 1-year ablation success was assessed as described elsewhere in the literature. The authors used the paired t-test, linear, and logistic regression for hypothesis testing. Among 107 veterans, core temperatures were significantly lower between BT and ST, BT and ET, and ST and ET (p < 0.001 for all). One-year ablation success was 74.8% (n = 80). In multivariate logistic regression adjusted for age, body mass index and BTs showed a greater degree of change from BT to ET, and the ST-to-ET temperature was significantly associated with lower odds of success (odds ratios of 0.57 and 0.42, respectively; p < 0.05 for both). CONCLUSIONS: Core temperature declines during ablation. Greater temperature decline during general anesthesia was associated with lower 1-year ablation success rates.

Association of heart rate variability with progression of retinopathy among adults with type 2 diabetes.

AIM: We evaluated the associations of heart rate variability (HRV) with incident vision-threatening retinopathy and retinopathy progression among adults with type 2 diabetes. METHODS: Participants recruited to the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study with HRV measures at baseline were analysed. HRV measures included standard deviation of all normal-to-normal intervals (SDNN) and root mean square of successive differences between normal-to-normal intervals (rMSSD). Low SDNN was defined as SDNN <8.2 ms; low rMSSD as rMSSD <8.0 ms. We used multivariable adjusted Cox proportional hazards and modified Poisson regression models to generate risk estimates for incident vision-threatening retinopathy and retinopathy progression, respectively. RESULTS: A total of 5810 participants without incident vision-threatening retinopathy at baseline (mean age 62 years, 40.5% women, 63.5% White) were included. Over a median of 4.7 years, 280 incident vision-threatening retinopathy cases requiring treatment occurred. Low HRV (vs. normal HRV) was associated with higher risk of incident vision-threatening retinopathy (adjusted hazard ratio 1.32 [95%CI 1.03-1.71] and 1.14 [95%CI 1.01-1.28] for low SDNN and rMSSD, respectively). In the subset of 2184 participants with complete eye examinations at baseline and 4 years, 191 experienced retinopathy progression, and low HRV (vs. normal HRV) was associated with a higher risk of retinopathy progression (adjusted relative risks 1.36 [95%CI 1.01-1.83] and 1.36 [95%CI 1.01-1.84] for low SDNN and rMSSD, respectively). CONCLUSIONS: Cardiac autonomic neuropathy, as assessed by low HRV, was independently associated with increased risks of incident vision-threatening retinopathy and overall retinopathy progression in a large cohort of adults with type 2 diabetes.

Risk of ventricular arrhythmia in cardiac resynchronization therapy responders and super-responders: a systematic review and meta-analysis.

AIMS: Response to cardiac resynchronization therapy (CRT) is associated with improved survival, and reduction in heart failure hospitalization, and ventricular arrhythmia (VA) risk. However, the impact of CRT super-response [CRT-SR, increase in left ventricular ejection fraction (LVEF) to ≥ 50%] on VA remains unclear. METHODS AND RESULTS: We undertook a meta-analysis aimed at determining the impact of CRT response and CRT-SR on risk of VA and all-cause mortality. Systematic search of PubMed, EMBASE, and Cochrane databases, identifying all relevant English articles published until 31 December 2019. A total of 34 studies (7605 patients for VA and 5874 patients for all-cause mortality) were retained for the meta-analysis. The pooled cumulative incidence of appropriate implantable cardioverter-defibrillator therapy for VA was significantly lower at 13.0% (4.5% per annum) in CRT-responders, vs. 29.0% (annualized rate of 10.0%) in CRT non-responders, relative risk (RR) 0.47 [95% confidence interval (CI) 0.39-0.56, P < 0.0001]; all-cause mortality 3.5% vs. 9.1% per annum, RR of 0.38 (95% CI 0.30-0.49, P < 0.0001). The pooled incidence of VA was significantly lower in CRT-SR compared with CRT non-super-responders (non-responders + responders) at 0.9% vs. 3.8% per annum, respectively, RR 0.22 (95% CI 0.12-0.40, P < 0.0001); as well as all-cause mortality at 2.0% vs. 4.3%, respectively, RR 0.47 (95% CI 0.33-0.66, P < 0.0001). CONCLUSIONS: Cardiac resynchronization therapy super-responders have low absolute risk of VA and all-cause mortality. However, there remains a non-trivial residual absolute risk of these adverse outcomes in CRT responders. These findings suggest that among CRT responders, there may be a continued clinical benefit of defibrillators.

Cardiac arrhythmia services in Africa from 2011 to 2018: the second report from the Pan African Society of Cardiology working group on cardiac arrhythmias and pacing.

AIMS: Cardiac arrhythmia services are a neglected field of cardiology in Africa. To provide comprehensive contemporary information on the access and use of cardiac arrhythmia services in Africa. METHODS AND RESULTS: Data on human resources, drug availability, cardiac implantable electronic devices (CIED), and ablation procedures were sought from member countries of Pan African Society of Cardiology. Data were received from 23 out of 31 countries. In most countries, healthcare services are primarily supported by household incomes. Vitamin K antagonists (VKAs), digoxin, and amiodarone were available in all countries, while the availability of other drugs varied widely. Non-VKA oral anticoagulants (NOACs) were unequally present in the African markets, while International Normalized Ratio monitoring was challenging. Four countries (18%) did not provide pacemaker implantations while, where available, the implantation and operator rates were 2.79 and 0.772 per million population, respectively. The countries with the highest pacemaker implantation rate/million population in descending order were Tunisia, Mauritius, South Africa, Algeria, and Morocco. Implantable cardioverter-defibrillator and cardiac resynchronization therapy (CRT) were performed in 15 (65%) and 12 (52%) countries, respectively. Reconditioned CIED were used in 5 (22%) countries. Electrophysiology was performed in 8 (35%) countries, but complex ablations only in countries from the Maghreb and South Africa. Marked variation in costs of CIED that severely mismatched the gross domestic product per capita was observed in Africa. From the first report, three countries have started performing simple ablations. CONCLUSION: The access to arrhythmia treatments varied widely in Africa where hundreds of millions of people remain at risk of dying from heart block. Increased economic and human resources as well as infrastructures are the critical targets for improving arrhythmia services in Africa.

Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy?

Homeostasis around vascular endothelium is a function of the equilibrium between the bioavailability of nitric oxide (NO) and oxidizing reactive oxygen species (ROS). Within the vascular endothelium, NO enhances vasodilatation, reduces platelet aggression and adhesion (anti-thrombotic), prevents smooth muscle proliferation, inhibits adhesion of leukocytes and expression of pro-inflammatory cytokines genes (anti-inflammatory), and counters the oxidation of low density lipoprotein (LDL) cholesterol. A shift in the equilibrium that favours NO deficiency and ROS formation leads to endothelial dysfunction and cardiovascular disease. The synthesis of NO is catalysed by nitric oxide synthase and co-factored by tetrahydrobiopterin (BH4), nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), and flavin mononucleotide (FMN). The focus of this review is on endothelial nitric oxide synthase (eNOS), although we recognize that the other nitric oxide synthases may contribute as well. Levels of homocysteine and the active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF), play a determining role in circulating levels of nitric oxide. We review endothelial nitric oxide bioavailabilty in relation to endothelial dysfunction as well as the therapeutic strategies involving the nitric oxide synthesis pathway. Although folate supplementation improves endothelial function, results from large clinical trials and meta-analyses on palpable clinical endpoints have been inconsistent. There are however, encouraging results from animal and clinical studies of supplementation with the co-factor for nitric oxide synthesis, BH4, though its tendency to be oxidized to dihydrobiopterin (BH2) remains problematic. Understanding how to maintain a high ratio of BH4 to BH2 appears to be the key that will likely unlock the therapeutic potential of nitric oxide synthesis pathway.

Catheter ablation for atrial fibrillation in patients with significant mitral regurgitation: A systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is commonly associated with cardiac structural abnormalities including mitral regurgitation (MR). Contemporary guidelines recommend consideration of early rhythm control strategies including catheter ablation (CA) for AF. However, the long-term efficacy of CA is highly variable across studies and patient populations, and the effect of coexisting MR on AF recurrence remains unclear. OBJECTIVE: A systematic review and meta-analysis was performed to determine the impact of significant MR (defined as ≥moderate) on AF recurrence rate after CA and whether CA for AF is associated with significant changes in the severity of MR. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases for all English-language studies published to December 31, 2023, was performed. RESULTS: A total of 17 studies (N = 2624 patients) were retained for meta-analysis. The pooled recurrence proportion of AF after CA in patients with baseline significant MR was 36% (95% CI, 27%-46%) compared with 27% (14%-41%) in patients without. The pooled hazard ratio (95% CI) for AF recurrence after CA in the presence of significant MR was 2.47 (1.52-4.01; P < .001; Egger test P value, .0583). The pooled proportion of patients who witnessed MR improvement to nonsignificant (ie,

The impact of power output during percutaneous catheter radiofrequency ablation for atrial fibrillation on efficacy and safety outcomes: a systematic review.

INTRODUCTION: Percutaneous catheter radiofrequency ablation (RFA) has been widely used to treat patients with atrial fibrillation (AF). Success rates are, however, variable and optimal levels of power used and duration of power delivery have not been fully established. Different ablation centers continue to use various power protocols. We undertook a comprehensive systematic review to evaluate the impact of power output during RFA for AF on efficacy and safety. METHODS AND RESULTS: We systematically searched MEDLINE and Cochrane Central Register of Controlled Trials databases for studies on power output during percutaneous RFA for AF. The marked heterogeneous nature of the studies prohibited a meta-analysis. The main findings were (1) power output of ≤30 watts (W) has good safety profiles but low efficacy rates; (2) power output of >30 W-<45 W is safe with good efficacy; (3) power output of ≥ 45 W has a better efficacy profile but associated with a high risk of complications; (4) delivery of higher power of ≥ 45 W at shorter duration (15-20 seconds) is safe and efficacious; and (5) energy titration with visualization of microbubbles by intracardiac echocardiography (ICE) has better efficacy and safety profiles compared to RFA without ICE. CONCLUSIONS: Despite the overall reduced quality data relating power to outcomes of RFA for AF, the optimal power output showing good efficacy and safety profiles appears generically to be >30 W-<45 W, with significant variation in the literature.

Are arrhythmias the drivers of sudden cardiac death in heart failure with preserved ejection fraction? A review.

In patients with heart failure with preserved ejection fraction (HFpEF), sudden cardiac death (SCD) accounts for approximately 25-30% of all-cause mortality and 40% of cardiovascular mortality in properly adjudicated large clinical trials. The mechanism of SCD in HFpEF remains unknown but thought to be driven by arrhythmic events. Apart from atrial fibrillation, which is prevalent in approximately 45% of HFpEF patients, the true burden of other cardiac arrhythmias in HFpEF remains undetermined. The incidence and risk of clinically significant advanced cardiac conduction disease with bradyarrhythmias and ventricular arrhythmias remain less known. Recommendations have been made for long-term cardiac rhythm monitoring to determine the incidence of arrhythmias and clarify mechanisms and mode of death in HFpEF patients. In animal studies, spontaneous ventricular arrhythmias and SCD are significantly elevated in HFpEF animals compared with controls without heart failure. In humans, these studies are scant, with a few published small-size studies suggesting an increased incidence of ventricular arrhythmias in HFpEF. Higher rates of clinically significant conduction disease and cardiac pacing are seen in HFpEF compared with the general population. Excepting atrial fibrillation, the predictive effect of other arrhythmias on heart failure hospitalization, all-cause mortality, and precisely SCD remains unknown. Given the high occurrence of SCD in the HFpEF population, it could potentially become a target for therapeutic interventions if driven by arrhythmias. Studies to address these knowledge gaps are urgently warranted. In this review, we have summarized data on arrhythmias and SCD in HFpEF while highlighting avenues for future research in this area.

Cardiac autonomic dysfunction and risk of incident stroke among adults with type 2 diabetes.

Introduction: There is a dearth of data on the association between cardiac autonomic neuropathy (CAN) with incident stroke among individuals with diabetes mellitus. We evaluated this association in a large sample of adults with type 2 diabetes. Patients and methods: Participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study without atherosclerotic cardiovascular disease at baseline were included. CAN was assessed at baseline by heart rate variability (HRV) indices and QT index (QTI) calculated from 10-s resting electrocardiograms. HRV was assessed using standard deviation of all normal-to-normal R-Rs intervals (SDNN) and root mean square of successive differences between normal-to-normal R-R intervals (rMSSD). CAN was defined based on several composite measures of SDNN, QTI, resting heart rate and peripheral neuropathy. We used Cox proportional hazards regression to generate hazard ratios (HR) and 95% confidence intervals (CI) for incident stroke in relation to CAN. Results: A total of 3493 participants (mean age 62.2 years, 44.5% women, 62.9% White) were included. Over a median follow-up of 5.0 years, 50 stroke cases occurred (incidence rate 3.0/1000 person-years [95% CI 2.2-3.9]). After adjusting for confounders, low HRV was associated with a higher risk of stroke (HR of 2.20 [95% CI 1.23-3.93] and 1.88 [95% CI 1.04-3.41] for low SDNN and rMSSD, respectively). Participants with CAN (defined as lowest quartile of SDNN and highest quartiles of QTI and heart rate) had a 5.7-fold greater risk of stroke (HR 5.70, 95% CI 2.49-13.08). Discussion and conclusion: CAN was independently associated with an increased risk of incident stroke in a large cohort of adults with type 2 diabetes.

Blood Pressure Variability and Risk of Atrial Fibrillation in Adults With Type 2 Diabetes.

BACKGROUND: There is a paucity of epidemiological data on the association between long-term variability of blood pressure (BP) and incident atrial fibrillation (AF). OBJECTIVES: The purpose of this study was to evaluate the association of BP variability with incident AF in a large sample of adults with type 2 diabetes. METHODS: We included participants who had ≥5 BP measurements in the first 24 months of action to control cardiovascular risk in diabetes. The visit-to-visit variability of systolic blood pressure (SBP) and diastolic blood pressure (DBP) was estimated using the coefficient of variation, SD, and variability independent of the mean. Incident AF was recorded using follow-up electrocardiograms. Modified Poisson regression was used to generate risk ratios (RRs) and 95% CI for AF. RESULTS: A total of 8,399 participants were included (average age 62.6 ± 6.5 years, 38.8% women, 63.2% White). Over a median follow-up of 5 years, 155 developed AF. Compared to the lowest quartile, the highest quartile of BP variability was associated with an increased risk of AF (RR: 1.85 [95% CI: 1.13-3.03] and 1.63 [95% CI: 1.01-2.65] for coefficient of variation of SBP and DBP, respectively). Participants in the highest quartile of both SBP and DBP had a 2-fold higher risk of AF compared to those in the lowest 3 quartiles of both SBP and DBP (RR: 1.94; 95% CI: 1.29-2.93). CONCLUSIONS: In a large cohort of adults with type 2 diabetes, higher variability in SBP and DBP was independently associated with an increased risk of AF.

Cardiac autonomic neuropathy and risk of incident heart failure among adults with type 2 diabetes.

AIMS: Community-based data on the association between cardiac autonomic neuropathy (CAN) and incident heart failure (HF) in type 2 diabetes are limited. We evaluated the association of CAN with incident HF in adults with type 2 diabetes. METHODS AND RESULTS: This analysis included participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study without HF at baseline. CAN was assessed by electrocardiogram-based measures of heart rate variability (HRV) and QT interval index (QTI). HRV was measured using standard deviation of all normal-to-normal intervals (SDNN) and root mean square of successive differences between normal-to-normal intervals (rMSSD). CAN was defined using composite measures of the lowest quartile of SDNN and highest quartiles of QTI and heart rate. Multivariable Cox regression models were used to generate adjusted hazard ratios (aHR) for HF in relation to various CAN measures. A total of 7160 participants (mean age 62.3 [standard deviation 6.4] years, 40.8% women, 61.9% white) were included. Over a median follow-up of 4.9 years (interquartile range 4.0-5.7), 222 participants developed incident HF. After multivariable adjustment for relevant confounders, lower HRV as assessed by SDNN was associated with a higher risk of HF (aHR for the lowest vs highest quartile of SDNN: 1.70, 95% confidence interval [CI] 1.14-2.54). Participants with CAN (defined as lowest quartile of SDNN and highest quartiles of QTI and heart rate) had a 2.7-fold greater risk of HF (aHR 2.65, 95% CI 1.57-4.48). CONCLUSIONS: In a large cohort of adults with type 2 diabetes, CAN was independently associated with higher risk of incident HF.

Autonomic dysfunction and risk of severe hypoglycemia among individuals with type 2 diabetes.

There are limited data on the link between cardiac autonomic neuropathy (CAN) and severe hypoglycemia in type 2 diabetes. Here, we evaluated the associations of CAN with severe hypoglycemia among 7,421 adults with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes study. CAN was defined using ECG-derived measures. Cox's and Andersen-Gill regression models were used to generate HRs (HRs) for the first and recurrent severe hypoglycemic episodes, respectively. Over 4.7 years, there were 558 first and 811 recurrent hypoglycemic events. Participants with CAN had increased risks of a first episode or recurrent episodes of severe hypoglycemia. The intensity of glycemic management modified the CAN association with hypoglycemia. In the standard glycemic management group, compared with those of participants without CAN, HRs for a first severe hypoglycemia event and recurrent hypoglycemia were 1.58 and 1.96, respectively. In the intensive glycemic management group, HRs for a first severe hypoglycemia event and recurrent hypoglycemia were 1.10 and 1.24, respectively. In summary, CAN was independently associated with higher risks of a first hypoglycemia event and recurrent hypoglycemia among adults with type 2 diabetes, with the highest risk observed among those on standard glycemic management.

Severe Hypoglycemia and Incidence of QT Interval Prolongation Among Adults With Type 2 Diabetes.

CONTEXT: There is a paucity of large-scale epidemiological studies on the link between severe hypoglycemia (SH) and corrected QT (QTc) interval prolongation in type 2 diabetes (T2DM). OBJECTIVE: To evaluate the association of SH with QTc prolongation in adults with T2DM. METHODS: Prospective cohort analysis of participants enrolled in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study without QTc prolongation at baseline. SH was assessed over a 24-month period. Incident QTc prolongation was ascertained using follow-up electrocardiograms. Modified Poisson regression was used to generate the risk ratio (RR) and 95% CI for QTc prolongation. RESULTS: Among 8277 participants (mean age 62.6 years [SD 6.5], 38.7% women, 62.8% White), 324 had ≥1 SH episode (3.9%). Over a median of 5 years, 517 individuals developed QTc prolongation (6.3%). Participants with SH had a 66% higher risk of QTc prolongation (RR 1.66, 95% CI 1.16-2.38). The incidence of QTc prolongation was 10.3% (27/261) and 14.3% (9/63) for participants with 1 and ≥2 SH, respectively. Compared with no SH, RRs for patients with 1 and ≥2 SH episodes were 1.57 (95% CI 1.04-2.39) and 2.01 (95% CI 1.07-3.78), respectively. Age modified the association of SH with QTc prolongation (PInteraction = .008). The association remained significant among younger participants (<61.9 years [median age]: RR 2.63, 95% CI 1.49-4.64), but was nonsignificant among older participants (≥61.9 years: RR 1.37, 95% CI 0.87-2.17). CONCLUSION: In a large population with T2DM, SH was associated with an increased risk of QTc prolongation independently of other risk factors such as cardiac autonomic neuropathy. The association was strongest among younger participants.

Burden of Microvascular Disease and Risk of Atrial Fibrillation in Adults with Type 2 Diabetes.

BACKGROUND: Epidemiological data on the associations of microvascular disease with atrial fibrillation are scarce. We evaluated the associations of diabetes-related microvascular disease in multiple vascular beds and its burden with incident atrial fibrillation among adults with type 2 diabetes. METHODS: A total of 7603 participants with type 2 diabetes and without atrial fibrillation were assessed for diabetic kidney disease, retinopathy, or neuropathy at baseline in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. Incident atrial fibrillation events were adjudicated using follow-up electrocardiograms. Modified Poisson regression was used to generate risk ratios (RRs) and 95% confidence intervals (CIs) for atrial fibrillation. RESULTS: Of the 7603 participants (mean age 62.5 years, 38.0% women, 63.4% white), 63.3% (n = 4816) had microvascular disease-defined as the presence of ≥1 of: diabetic kidney disease, retinopathy, or neuropathy at baseline. Over a median of 7 years, there were 137 atrial fibrillation events (1.8%). Participants with microvascular disease had a 1.9-fold higher risk of incident atrial fibrillation compared with those without microvascular disease (RR 1.88; 95% CI, 1.20-2.95). Compared with no microvascular disease, the RRs for atrial fibrillation were 1.62 (95% CI, 1.01-2.61) and 2.47 (95% CI, 1.46-4.16) for those with 1 and ≥2 microvascular territories affected, respectively. The RRs for atrial fibrillation by type of microvascular disease were 1.57 (95% CI, 1.09-2.26), 0.95 (95% CI, 0.53-1.70), and 1.67 (95% CI, 1.15-2.44) for neuropathy, retinopathy, and diabetic kidney disease, respectively. CONCLUSIONS: In a large cohort of adults with type 2 diabetes, the presence of microvascular disease and its burden were independently associated with higher risk of incident atrial fibrillation.

Ventricular repolarization heterogeneity in patients with COVID-19: Original data, systematic review, and meta-analysis.

BACKGROUND: Coronavirus disease-2019 (COVID-19) has been associated with an increased risk of acute cardiac events. However, the effect of COVID-19 on repolarization heterogeneity is not yet established. In this study, we evaluated electrocardiogram (ECG) markers of repolarization heterogeneity in patients hospitalized with COVID-19. In addition, we performed a systematic review and meta-analysis of the published studies. METHODS: QT dispersion (QTd), the interval between T wave peak to T wave end (TpTe), TpTe/QT (with and without correction), QRS width, and the index of cardio-electrophysiological balance (iCEB) were calculated in 101 hospitalized COVID-19 patients and it was compared with 101 non-COVID-19 matched controls. A systematic review was performed in four databases and meta-analysis was conducted using Stata software. RESULTS: Tp-Te, TpTe/QT, QRS width, and iCEB were significantly increased in COVID-19 patients compared with controls (TpTe = 82.89 vs. 75.33 ms (ms), p-value = .005; TpTe/QT = 0.217 vs. 0.203 ms, p-value = .026). After a meta-analysis of 679 COVID-19 cases and 526 controls from 9 studies, TpTe interval, TpTe/QT, and TpTe/QTc ratios were significantly increased in COVID-19 patients. Meta-regression analysis moderated by age, gender, diabetes mellitus, hypertension, and smoking reduced the heterogeneity. QTd showed no significant correlation with COVID-19. CONCLUSION: COVID-19 adversely influences the ECG markers of transmural heterogeneity of repolarization. Studies evaluating the predictive value of these ECG markers are warranted to determine their clinical utility.

Long-Term Variability of Blood Pressure, Cardiovascular Outcomes, and Mortality: The Look AHEAD Study.

BACKGROUND: We evaluated the associations of visit-to-visit blood pressure (BP) variability with incident cardiovascular disease (CVD) and deaths in adults with type 2 diabetes. METHODS: We analyzed 4,152 participants in Look AHEAD (Action for Health in Diabetes) free of CVD events and deaths during the first 36 months of follow-up. Variability of systolic BP (SBP) and diastolic BP (DBP) across 4 annual visits was assessed using the intraindividual SD, variation independent of the mean, and coefficient of variation. Cox regression was used to generate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CVD (myocardial infarction [MI], stroke, or CVD-related deaths) and mortality. RESULTS: Over a median of 6.6 years, there were 220 MIs, 105 stroke cases, 62 CVD-related deaths, and 236 deaths. After adjustment for confounders including average BP, the aHRs for the highest (vs. lowest) tertile of SD of SBP were 1.98 (95% CI 1.01-3.92), 1.25 (95% CI 0.90-1.72), 1.26 (95% CI 0.96-1.64), 1.05 (95% CI 0.75-1.46), and 1.64 (95% CI 0.99-2.72) for CVD mortality, all-cause mortality, CVD, MI, and stroke, respectively. The equivalent aHRs for SD of DBP were 1.84 (95% CI 0.98-3.48), 1.43 (95% CI 1.03-1.98), 1.19 (95% CI 0.91-1.56), 1.14 (95% CI 0.82-1.58), and 0.97 (95% CI 0.58-1.60), respectively. CONCLUSIONS: In a large sample of individuals with type 2 diabetes, a greater variability in SBP was associated with higher cardiovascular mortality and CVD events; a higher variability in DBP was linked to increased overall and cardiovascular mortality.