BACKGROUND: The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH.
METHODS: Participants were adult outpatients with T2DM and CHD who exhibited TWH > 80 µV at baseline. They received a 25 mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p < 0.05) change in TWH following empagliflozin administration.
RESULTS: An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 97 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p = 0.01).
CONCLUSIONS: The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population.
BACKGROUND: NCT: 04117763.

BACKGROUND: Pulmonary vein isolation (PVI) modulates the intrinsic cardiac autonomic nervous system and reduces atrial fibrillation (AF) recurrence.
METHODS: In this retrospective analysis, we investigated the impact of PVI on ECG interlead P-wave, R-wave, and T-wave heterogeneity (PWH, RWH, TWH) in 45 patients in sinus rhythm undergoing clinically indicated PVI for AF. We measured PWH as a marker of atrial electrical dispersion and AF susceptibility and RWH and TWH as markers of ventricular arrhythmia risk along with standard ECG measures.
RESULTS: PVI acutely (16 ± 8.9 h) reduced PWH by 20.7% (from 31 ± 1.9 to 25 ± 1.6 µV, p < 0.001) and TWH by 27% (from 111 ± 7.8 to 81 ± 6.5 µV, p < 0.001). RWH was unchanged after PVI (p = 0.068). In a subgroup of 20 patients with longer follow-up (mean = 47 ± 3.7 days after PVI), PWH remained low (25 ± 1.7 µV, p = 0.01), but TWH partially returned to the pre-ablation level (to 93 ± 10.2, p = 0.16). In three individuals with early recurrence of atrial arrhythmia in the first 3 months after ablation, PWH increased acutely by 8.5%, while in patients without early recurrence, PWH decreased acutely by 22.3% (p = 0.048). PWH was superior to other contemporary P-wave metrics including P-wave axis, dispersion, and duration in predicting early AF recurrence.
CONCLUSIONS: The rapid time course of decreased PWH and TWH after PVI suggests a beneficial influence likely mediated via ablation of the intrinsic cardiac nervous system. Acute responses of PWH and TWH to PVI suggest a favorable dual effect on atrial and ventricular electrical stability and could be used to track individual patients\' electrical heterogeneity profile.

Sudden cardiac death (SCD) risk is elevated following acute myocardial infarction (MI). The time course of SCD susceptibility post-MI requires further investigation.
In this observational cohort study, we employed state-of-the-art noninvasive ECG techniques to track the daily time course of cardiac electrical instability and autonomic function following ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). Preventice BodyGuardian MINI-EL Holters continuously recorded ECGs for 7 days at hospital discharge and at 40 days for STEMI (N = 5) or at 90 days for NSTEMI patients (N = 5). Cardiac electrical instability was assessed by T-wave alternans (TWA) and T-wave heterogeneity (TWH); autonomic tone was determined by rMSSD-heart rate variability (HRV).
TWA was severely elevated (≥60 μV) in STEMI patients (80 ± 10.3 μV) at discharge and throughout the first recording period but declined by 50% to 40 ± 2.3 μV (p = .03) by Day 40 and remained in the normal range (<47 μV). TWH, a related phenomenon analyzed from 12-lead ECGs, was reduced by 63% in the five STEMI patients from discharge to normal (<80 μV) at follow-up (105 ± 27.3 to 39 ± 3.3 μV, p < .04) but increased by 65% in a STEMI case (89 to 147 μV), who received a wearable defibrillator vest and later implantable cardioverter defibrillator. In NSTEMI patients, TWA was borderline abnormal (47 ± 3.3 μV) at discharge and declined by 19% to normal (38 ± 1.2 μV) by Day 90 (p = .05). An overall reciprocal increase in rMSSD-HRV suggested recovery of vagal tone.
This study provides proof-of-principle for tracking post-MI SCD risk in individual patients with implications for personalized therapy.

A dire complication associated with chronic epilepsy is abrupt premature death, currently referred to as sudden unexpected death in epilepsy (SUDEP). Although the traditional view has been that SUDEP is due primarily to peri-ictal respiratory failure leading to cardiac asystole, mounting evidence implicates accelerated heart disease, leading to an \"epileptic heart\" condition, especially after age 40, as another potential cause of abrupt premature death, although cardiac death is specifically excluded by the standard definition of SUDEP. Sudden cardiac death in epilepsy carries a 2.8-fold greater risk than in the general population and is 4.5 times more frequent than SUDEP. This review will discuss the rationale for routine use of electrocardiograms to assess cardiac risk in patients with epilepsy and the impact of epilepsy treatments, namely antiseizure medications and chronic vagus nerve stimulation.

Heart failure with reduced left ventricular ejection fraction is a progressive disease that claims > 352,000 lives annually in the United States alone. Despite the development of an extensive array of pharmacologic and device therapies, prognosis remains poor. Disruption in autonomic balance in the form of heightened sympathetic nerve activity and reduced vagal tone have been established as major causes of heart failure progression. Interest in chronic neuromodulation mediated by vagus nerve stimulation (VNS) has intensified in recent years. This review focuses on four main goals: (1) To review the preclinical evidence that supports the concept of a cardioprotective effect of VNS on autonomic function and cardiac electrical stability along with the underlying putative mechanisms. (2) To present the initial clinical experience with chronic VNS in patients with heart failure and highlight the controversial aspects of the findings. (3) To discuss the latest findings of the multifactorial effects of VNS on autonomic tone, baroreceptor sensitivity, and cardiac electrical stability and the state-of-the-art methods employed to monitor these relationships. (4) To discuss the implications of the current findings and the gaps in knowledge that require attention in future investigations.

We examined whether T-wave heterogeneity (TWH) on the surface electrocardiographic (EKG) could predict epileptic seizure onset. Patients with electroencephalography-confirmed generalized tonic-clonic seizures (GTCS) (n = 6) exhibited abnormal elevations in TWH (>80 µV) at baseline (105 ± 20.4 µV), which increased from 30 min prior to seizure without heart rate increases > 2 beats/min until 10 min pre-seizure. Specifically, TWH on 3-lead surface EKG patch recordings increased from 1-hour baseline to 30 min (<0.05), 20 min (p < 0.002), 10 min (p = 0.01), and 1 min (p = 0.01) before seizure onset. At 10 min following GTCS, TWH returned to 110 ± 20.3 µV, similar to baseline (p = 0.54). This pre-ictal TWH warning pattern was not present in patients with psychogenic nonepileptic seizures (PNES) (n = 3), as TWH did not increase until PNES and returned to baseline within 10 min after PNES. Acute elevations in TWH may predict impending GTCS and may discriminate patients with GTCS from those with behaviorally similar PNES.

We investigated whether T-wave heterogeneity (TWH) can identify patients who are at risk for near-term cardiac mortality.
A nested case-control analysis was performed in the 888 patients admitted to the Emergency Department (ED) of our medical center in July through September 2018 who had ≥2 serial troponin measurement tests within 6 hr for acute coronary syndrome evaluation to rule-in or rule-out the presence of acute myocardial infarction. Patients who died from cardiac causes during 90 days after ED admission were considered cases (n = 20; 10 women) and were matched 1:4 on sex and age with patients who survived during this period (n = 80, 40 women). TWH, that is, interlead splay of T waves, was automatically assessed from precordial leads by second central moment analysis.
TWHV4-6 was significantly elevated at ED admission in 12-lead resting ECGs of female patients who died of cardiac causes during the following 90 days compared to female survivors (100 ± 14.9 vs. 40 ± 3.6 µV, p < .0001). TWHV4-6 generated areas under the receiver-operating characteristic (ROC) curve (AUC) of 0.933 in women (p < .0001) and 0.573 in men (p = .4). In women, the ROC-guided 48-µV TWHV4-6 cut point for near-term cardiac mortality produced an adjusted odds ratio of 121.37 (95% CI: 2.89-6,699.84; p = .02) with 100% sensitivity and 82.5% specificity. In Kaplan-Meier survival analysis, TWHV4-6  ≥ 48 µV predicted cardiac mortality in women during 90-day follow-up with a hazard ratio of 27.84 (95% CI: 7.29-106.36, p < .0001).
Elevated TWHV4-6 is associated with near-term cardiac mortality among women evaluated for acute coronary syndrome.

Reliable quantitative preimplantation predictors of response to cardiac resynchronization therapy (CRT) are needed.
We tested the utility of preimplantation R-wave and T-wave heterogeneity (RWH and TWH, respectively) compared to standard QRS complex duration in identifying mechanical super-responders to CRT and mortality risk.
We analyzed resting 12-lead electrocardiographic recordings from all 155 patients who received CRT devices between 2006 and 2018 at our institution and met class I and IIA American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines with echocardiograms before and after implantation. Super-responders (n=35, 23%) had ≥20% increase in left ventricular ejection fraction and/or ≥20% decrease in left ventricular end-systolic diameter and were compared with non-super-responders (n=120, 77%), who did not meet these criteria. RWH and TWH were measured using second central moment analysis.
Among patients with non-left bundle branch block (LBBB), preimplantation RWH was significantly lower in super-responders than in non-super-responders in 3 of 4 lead sets (P=.001 to P=.038) and TWH in 2 lead sets (both, P=.05), with the corresponding areas under the curve (RWH: 0.810-0.891, P<.001; TWH: 0.759-0.810, P≤.005). No differences were observed in the LBBB group. Preimplantation QRS complex duration also did not differ between super-responders and non-super-responders among patients with (P=.856) or without (P=.724) LBBB; the areas under the curve were nonsignificant (both, P=.69). RWHV1-3LILII ≥ 420 μV predicted 3-year all-cause mortality in the entire cohort (P=.037), with a hazard ratio of 7.440 (95% confidence interval 1.015-54.527; P=.048); QRS complex duration ≥ 150 ms did not predict mortality (P=.27).
Preimplantation interlead electrocardiographic heterogeneity but not QRS complex duration predicts mechanical super-response to CRT in patients with non-LBBB.

BACKGROUND: Experimental evidence suggests that ranolazine decreases susceptibility to ischemia-induced arrhythmias independent of effects on coronary artery blood flow.
OBJECTIVE: In symptomatic diabetic patients with non-flow-limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, we explored whether ranolazine reduces T-wave heterogeneity (TWH), an electrocardiographic (ECG) marker of arrhythmogenic repolarization abnormalities shown to predict sudden cardiac death.
METHODS: We studied all 16 patients with analyzable ECG recordings during rest and exercise tolerance testing before and after 4 weeks of ranolazine in the double-blind, crossover, placebo-controlled RAND-CFR trial (NCT01754259). TWH was quantified without knowledge of treatment assignment by second central moment analysis, which assesses the interlead splay of T waves in precordial leads about a mean waveform. Myocardial blood flow (MBF) was measured by positron emission tomography.
RESULTS: At baseline, prior to randomization, TWH during rest was 54 ± 7 μV and was not altered following placebo (47 ± 6 μV, p = .47) but was reduced by 28% (to 39 ± 5 μV, p = .002) after ranolazine. Ranolazine did not increase MBF at rest. Exercise increased TWH after placebo by 49% (to 70 ± 8 μV, p = .03). Ranolazine did not reduce TWH during exercise (to 75 ± 16 μV), and there were no differences among the groups (p = .95, ANOVA). TWH was not correlated with MBF at rest before (r2  = .07, p = .36) or after ranolazine (r2  = .23, p = .06).
CONCLUSIONS: In symptomatic diabetic patients with non-flow-limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, ranolazine reduced TWH at rest but not during exercise. Reduction in repolarization abnormalities appears to be independent of alterations in MBF.

Heart rate variability (HRV) modulates dynamics of ventricular repolarization. A diminishing value of HRV is associated with increased vulnerability to life-threatening ventricular arrhythmias, however the causal relationship is not well-defined. We evaluated if fixed-rate atrial pacing that abolishes the effect of physiological HRV, will alter ventricular repolarization wavefronts and is relevant to ventricular arrhythmogenesis. The study was performed in 16 subjects: 8 heart failure patients with spontaneous ventricular tachycardia [HFVT], and 8 subjects with structurally normal hearts (H Norm). The T-wave heterogeneity descriptors [total cosine angle between QRS and T-wave loop vectors (TCRT, negative value corresponds to large difference in the 2 loops), T-wave morphology dispersion, T-wave loop dispersion] and QT intervals were analyzed in a beat-to-beat manner on 3-min records of 12-lead surface ECG at baseline and during atrial pacing at 80 and 100 bpm. The global T-wave heterogeneity was expressed as mean values of each of the T-wave morphology descriptors and variability in QT intervals (QTV) as standard deviation of QT intervals. Baseline T-wave morphology dispersion and QTV were higher in HFVT compared to H Norm subjects (p ≤ 0.02). While group differences in T-wave morphology dispersion and T-wave loop dispersion remained unaltered with atrial pacing, TCRT tended to fall more in HFVT patients compared to H Norm subjects (interaction p value = 0.086). Atrial pacing failed to reduce QTV in both groups, however group differences were augmented (p < 0.0001). Atrial pacing and consequent loss of HRV appears to introduce unfavorable changes in ventricular repolarization in HFVT subjects. It widens the spatial relationship between wavefronts of ventricular depolarization and repolarization. This may partly explain the concerning relation between poorer HRV and the risk of ventricular arrhythmias.