Impact of baseline ECG characteristics on changes in cardiac biomarkers and echocardiographic metrices after acute myocardial infarction treated with Empagliflozin

The EMMY trial was a multicentre, investigator-initiated, placebo-controlled, double-blind trial, which enrolled 476 patients immediately following AMI and the first study demonstrating a significant reduction in NT-proBNP-levels as well as significant improvements in cardiac structure and function in patients after acute myocardial infarction treated with empagliflozin vs. placebo. However, hardly any data are available investigating the prognostic role of baseline electrocardiogram metrics in SGLT2-inhibitor-treated patients. This post-hoc analysis investigated the association of baseline ECG metrics collected in one centre of the trial (181 patients) with changes in structural and functional cardiac parameters as well as cardiac biomarkers in response to Empagliflozin treatment. A total of 181 patients (146 men; mean age 58 ± 14 years) were included. Median PQ-interval was 156 (IQR 144–174) milliseconds (ms), QRS width 92 (84–98) ms, QTc interval 453 (428–478) ms, Q-wave duration 45 (40–60) ms, Q-wave amplitude 0.40 (0.30–0.70) millivolt (mV), and heart rate was 71 (64–85) bpm. For functional cardiac parameters (LVEF and E/eʹ) of the entire cohort, a greater decrease of E/eʹ from baseline to week 26 was observed in shorter QRS width (P = 0.005).Structural cardiac endpoints were only found to have a significant positive correlation between LVEDD and Q wave duration (P = 0.037). Higher heart rate was significantly correlated with better response in LVEF (P = 0.001), E/eʹ (P = 0.021), and NT-proBNP (P = 0.005). Empagliflozin-treatment showed no interaction with the results. Baseline ECG characteristics post AMI are neither predictive for beneficial NTproBNP effects of Empagliflozin post AMI, nor for functional or structural changes within 26 weeks post AMI.


Study variables
Exploratory variables were electrocardiographic parameters of 12-lead ECG recordings 1 day post AMI (P-wave duration and amplitude, QRS width and amplitude, QTc interval, PR interval, cardiac axis, Sokolow-Lyon Index, ST-segment elevation and depression, T-wave inversions, heart rate, Q-wave duration and amplitude) defined as mean duration (milliseconds, ms) and mean amplitude (millivolt, mV).Blood samples were collected and centrally analysed from all study patients at baseline and after 6 and 26 weeks at the clinical institute for medical and chemical laboratory diagnostics (CIMCL) of the Medical University of Graz.

Baseline characteristics
A complete case analysis of the metrics of the Graz Cohort in the EMMY trial with available ECG at baseline was performed.Baseline measurements of clinical characteristics and ECG metrics were summarized as median with interquartile range (IQR) for continuous variables and frequencies with percentages (%) for categorical variables.Baseline measurements of clinical characteristics and ECG metrics were compared with treatment group using Chi-square or Fischer Exact tests for categorical variables and Wilcoxon rank-sum test for continuous variables.P values < 0.05 were considered statistically significant in all performed tests.

Association analysis
A linear mixed effect model (LMEM) was fitted to analyze the association of each ECG metric with the percentage change over time for the primary and secondary endpoints of the EMMY trial.The interaction of each ECG metric with empagliflozin treatment was analyzed for each endpoint.The continuous ECG metrics were also transformed into tertiles to investigate the magnitude of change in endpoints with respect to the strata of these metrices (Supplementary Table 2).The results of continuous ECG metrices were reported for tertiles only in the
The electrical axis analysis revealed that 58.6% had left axis deviation, 38.7% normal axis, 2.2% right axis deviation, and 0.55% had extreme axis deviation.
The majority of patients (87.6%) experienced ST-elevation myocardial infarction (STEMIs).The ST-elevation was still present in 64.1% of patients 1-day after AMI with a median of 0.10 (0.10-0.

Association of ECG metrics with cardiac outcomes
No interaction between baseline ECG parameters, treatment groups and EMMY outcomes could be detected in the cohort analysed (Table 3).Therefore, both groups (Empagliflozin and placebo) were merged to analyse the association of baseline ECG metrices with changes in cardiac outcomes regardless of SGLT2-i treatment.
The heart rate was found to have significant positive associations with changes in NTproBNP (P = 0.005), LVEF (P = 0.001), and E/eʹ (P = 0.021) highlighting worse response of functional cardiac parameters as well as lower reduction of NTproBNP in higher heart rate.

Discussion
The administration of 10 mg Empagliflozin has beneficial cardiac effects including reduction in NTproBNP levels as well as improvements in structural (LVESV and LVEDV) and functional cardiac parameters (LVEF, E/eʹ) compared to placebo after AMI if administered early after PCI 20 .Furthermore, the very early administration of SGLT2-inhibitors appears to have no disadvantages with respect to safety post AMI and was found to be effective in reducing NTproBNP levels and structural as well as functional cardiac parameters 22 .
Early ECG is essential in the initial diagnosis as well as in the follow-up of AMI 12,13 .A prolongation of electrocardiographic parameters such as QRS width or QTc interval is often reported post AMI and was identified to be associated with adverse cardiac outcome 17 .In patients with diabetes, SGLT2-inhibition appeared to be well-tolerated in terms of electrocardiographic changes by showing no significant difference in the duration of PR interval, QT interval and QRS width as well as no relevant changes in ST-T segments compared to non-SGLT2-i users 16 , however data on potential beneficial effect of SGLT2-Inhibition in patients suffering from MI expressed by ECG changes are missing.
Increased QRS width was observed to be often found in patients suffering from heart failure 17 and is associated with a higher incidence of worsening of HF, sudden death (SD), and cardiovascular death post MI 23 .Hence, these patients appear to be at higher risk for hospitalisation for heart failure and might even more from a treatment with SGLT2-inhibitors.Similarly, a prolongation of the QTc interval in chronic heart failure patients was assessed to be an independent predictor for all-cause mortality, sudden death and progressive heart failure death 24 .Further, in symptomatic ischemic cardiomyopathy and left ventricular systolic dysfunction lethal outcomes following Q-wave infarction were revealed 25 .This sub-analysis reports a prolonged QTc interval as well as Q-wave duration one day post MI, whereas median QRS was normal (Table 2).However, no significant correlations were identified between these parameters and LVEF after 6 and 26 weeks in the overall cohort in our post-hoc analysis.Based on these findings supported by the result of the EMMY trial showing a significant increase in LVEF with Empagliflozin, baseline ECG parameters are not predictive for the better LVEF response to Empagliflozin.
Positive correlations of cardiac diastolic function parameters (LAV, LAVI, E/A) and QTc interval have already been prescribed by Li et al. revealing protective effects of moderate QTc intervals on diastolic function 26 .Further, a significant shortening of P-wave duration was observed for Empagliflozin reflecting an improvement in left atrial volume or conduction 19 .QRS width significantly correlated with E/eʹ, highlighting a better response of diastolic function in patients with a smaller QRS, which could be in line with potential anti-remodelling effects of early applied neurohumoral therapy post AMI.This analysis identified no further significant correlation of baseline ECG parameters and E/eʹ indicating no predictive value of baseline ECG findings.www.nature.com/scientificreports/NTproBNP levels were found to be a predictor in cardiovascular outcome and a strong significant clinical predictor for clinical events when combined with the prolongation of the QTc interval in STEMI patients 27 .Moreover, NTproBNP as well as troponin levels after AMI also offer a good estimation of infarct size 28 and were associated with worsening of heart failure 29 , whereas troponin levels were significantly associated with QRS duration 30 .This highlights that large infarct size with LV-dysfunction, manifesting with highly elevated troponin and NTproBNP levels, are at higher risk of developing a ventricular conduction disorder with prolongation of the QRS width predicting worse cardiac outcome.Nevertheless, our analysis revealed no significant correlation between baseline ECG findings and NTproBNP as well as Troponin T levels, supporting the notion that baseline ECG characteristics are neither predictive for NTproBNP or troponin changes over time.
SGLT2-inhibitors and Glucagon-like peptide-1 (GLP-1) receptor agonists show blood pressure lowering effects, but only GLP-1 receptor agonists increase heart rate 31 , whereas Empagliflozin did not have a significant impact on heart rate in a previous investigation 17 .Large clinical outcome trials have reported that higher heart rates are associated with worsening of chronic heart failure [32][33][34] and an increase in troponin levels in AMI 35 .Supported by the data that Empagliflozin significantly increases systolic as well as diastolic function post MI 20 , and in line with the data from this analysis, no significant increase in heart rate was revealed with SGLT2-inhibitor treatment 17 .However, significant positive correlations of heart rate with LVEF, E/eʹ, and NTproBNP were identified for having a response of functional cardiac parameters as well as the decrease of NTproBNP is worse in higher heart rates that goes in line with adverse cardiac remodelling, highlighting the importance of early initiation of a neurohumoral therapy post AMI including betablockers.
A large meta-analysis reported significant improvement of LVEF, E/eʹ, LVESD, LVEDD, LVM and LAVI in patients treated with SGLT2-inhibitors independent of diabetes status 36 , which is in line with the result of the EMMY trial for AMI 20 .Larger left ventricular volumes were also found to be associated with QRS width as well as Q-waves after anterior MI and was inversely associated with LVEF 37 .The potential for better LV-recovery in HFrEF treated with ARNIs was described to be better in patients with shorter QRS complex 38 .Our analysis did not identify any significant associations of LV-volumes and LV-diameters with baseline QRS width.LVEDD was only found to have a significant positive correlation to Q-wave duration, highlighting that infarct size with myocardial scaring is predictive for adverse cardiac remodeling.However, patients receiving SGLT2-i treatment post AMI were found to have a significant reduction in LV-size in the EMMY trial compared to patients not receiving SGLT2-inhibition 11 and appear to show positive effects regarding cardiac remodeling independent of baseline electrocardiographic characteristics.
EMMY reported a significant reduction in cardiac biomarkers as well as functional and structural cardiac parameters, however, the trial was not powered for hard clinical endpoints.First evidence of SGLT2-I use post AMI arrived from the "Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure" (DAPA-MI) trial, which identified significant benefits in improvement of cardiometabolic outcomes but no impact on the composite of cardiovascular death or hospitalization for heart failure compared with placebo was observed 39 .Furthermore, the primary outcome was independent of LVEF.In the recently published outcome trial "Empagliflozin after Acute Myocardial Infarction" (EMPACT-MI) trial Empagliflozin did not significantly lower the risk of hospitalization of heart failure or all-cause death post AMI compared to placebo 40 .Based on the findings of the huge clinical outcome trials and the EMMY trial, SGLT2-i appear to have beneficial effects post MI independent of diabetes status, however, further research in this area must be performed.

Conclusion
The EMMY trial highlights ameliorating effects of SGLT2-inhibition after AMI by significantly reducing NTproBNP levels and showing significant effects on structural and functional cardiac parameters, however DAPA-MI as well as EMPACT-MI failed to show significant difference concerning hospitalisation from heart failure and all-cause death and thus, further research in this area must be performed.www.nature.com/scientificreports/P-wave duration could be successfully measured in all included patients, however only 5 patients had a prolonged P-wave durations) and therefore, a correlation analysis between endpoints and P-wave duration (≥ 120 ms and < 120 ms) was not feasible.
Given the small number of patients and lack of follow-up ECGs up to week 26, this sub-analysis offers the first clinical evidence showing baseline ECG-independent changes in response of cardiac biomarkers as well as structural and functional cardiac endpoints in SGLT2-I users and non-SGLT2-I users post AMI, however the results did not differ between Empagliflozin and placebo.

Figure 2 .
Figure 2. Correlation plots of QRS width (in ms) with NTproBNP and LVEF at week 26.

Table 1 .
Baseline characteristics of study participants with available ECG data (N = 181).LVEDV left ventricular enddiastolic volume, LVESV left ventricular endsystolic volume, SD standard deviation, IQR interquartile range.

Table 3 .
Interaction analysis of ECG parameters and treatment groups with EMMY outcomes.CI confidence interval, LVEF left ventricular ejection fraction, LVESD left ventricular endsystolic diameter, LVEDD left ventricular enddiastolic diameter, LVESV left ventricular endsystolic volume, LVEDV left ventricular enddiastolic volume.