Advertisement

Effect of Empagliflozin Versus Placebo on Cardiac Sympathetic Activity in Acute Myocardial Infarction Patients with Type 2 Diabetes Mellitus: Rationale

  • Yoshiaki Kubota
  • Takeshi Yamamoto
  • Shuhei Tara
  • Yukichi Tokita
  • Kenji Yodogawa
  • Yuki Iwasaki
  • Hitoshi Takano
  • Yayoi Tsukada
  • Kuniya Asai
  • Masaaki Miyamoto
  • Yasushi Miyauchi
  • Eitaro Kodani
  • Naoki Sato
  • Jun Tanabe
  • Wataru Shimizu
Open Access
Study Protocol

Abstract

Introduction

Protection from lethal ventricular arrhythmias leading to sudden cardiac death is one of the most important problems after myocardial infarction. Cardiac sympathetic hyperactivity is related to poor prognosis and fatal arrhythmias and can be non-invasively assessed with heart rate variability, heart rate turbulence, T-wave alternans, late potentials, and 123I-meta-iodobenzylguanide (123I-MIBG) scintigraphy. Sodium glucose cotransporter 2 (SGLT2) inhibitors potentially reduce sympathetic nervous system activity that is augmented in part due to the stimulatory effect of hyperglycemia. The EMBODY trial is designed to determine whether the suppression of cardiac sympathetic activity induced by the SGLT2 inhibitor is accompanied by protection against adverse cardiovascular outcomes.

Methods

The EMBODY trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with acute MI and type 2 diabetes in Japan. A total of 98 patients will be randomized (1:1) to receive once-daily placebo or empagliflozin, an SGLT2 inhibitor, 10 mg. The primary end point is the change from baseline to 24 weeks in heart rate variability. Secondary end points include the change from baseline for other sudden cardiac death surrogate-markers such as heart rate turbulence, T-wave alternans, late potentials, and 123I-MIBG scintigraphy imaging. Adverse effects will be evaluated throughout the trial period.

Planned Outcomes

The EMBODY trial will evaluate the potential cardioprotective effect of empagliflozin and will provide additional important new data regarding its preventative effects on sudden cardiac death.

Trial Registration

Unique Trial Number, UMIN000030158 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000034442).

Funding

Nippon Boehringer Ingelheim and Eli Lilly and Company.

Keywords

Acute myocardial infarction Cardiac sympathetic activity Empagliflozin, sodium glucose cotransporter 2 (SGLT2) inhibitor Type 2 diabetes mellitus (T2DM) 

Abbreviations

AMI

Acute myocardial infarction

CAD

Coronary artery disease

CV

Cardiovascular

ECG

Electrocardiography

HF

High-frequency power

HRT

Heart rate turbulence

HRV

Heart rate variability

123I-MIBG

123I-meta-iodobenzylguanide

LF

Low-frequency power

LP

Late potentials

LVEF

Left ventricular ejection fraction

MI

Myocardial infarction

SCD

Sudden cardiac death

SGLT2

Sodium glucose cotransporter 2

T2DM

Type 2 diabetes mellitus

TWA

T-wave alternans

Introduction

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are known to not only remove insulin-independent glycemic toxicity, but also reduce blood pressure, body weight, and visceral fat [1]. The SGLT2 inhibitors have the potential to reduce sympathetic nervous system activity, which is augmented in part because of the stimulatory effect of hyperglycemia [2, 3]. Recently, results of the EMPAREG OUTCOME trial, which aimed to evaluate the long-term cardiovascular (CV) safety and benefits of empagliflozin, one of the SGLT2 inhibitors, as an add-on to standard anti-diabetic care, was published [4]. In this trial, empagliflozin significantly reduced the relative risk of CV death by 38% (including sudden cardiac death, SCD) and all-cause death by 32% during a median follow-up of 3.1 years [4]. It is of particular importance that empagliflozin reduced deaths from CV in the early phase (0–6 months) [4]. Protection against lethal ventricular arrhythmias leading to SCD is one of the most important aims after prevention of myocardial infarction (MI) [5]. Compared with individuals without diabetes, those with diabetes are at a 56% greater risk of death from an ST elevation myocardial infarction heart attack and at a 39% greater risk of death from a non-ST elevation MI [6]. Cardiac sympathetic hyperactivity is related to poor prognosis and fatal arrhythmias [7]. To date, noninvasive techniques such as T-wave alternans (TWA), late potentials (LP), heart rate turbulence (HRT), and heart rate variability (HRV) have been developed for this purpose. Considering the above factors, it is quite important to evaluate the effect of empagliflozin on the suppression of the induction of lethal ventricular tachyarrhythmias in the early phase. Thus, the EMBODY trial may provide the possible mechanisms by which empagliflozin reduces CV deaths, including SCD in acute MI (AMI) patients with type 2 diabetes mellitus (T2DM). We hypothesized that empagliflozin will ameliorate the abnormal sympathetic activity that contributes to SCD after AMI in patients with T2DM.

Methods and Design

Trial Overview

The EMBODY trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with AMI and T2DM in Japan. A total of 98 patients will be randomized (1:1) to receive once-daily placebo or once-daily empagliflozin (10 mg). We seek to assess the beneficial effect of empagliflozin on cardiac sympathetic activity in comparison with a placebo in relation to lethal ventricular tachyarrhythmias measured by ambulatory electrocardiography (ECG) (SCM-8000 Fukuda Denshi Co., Ltd. Tokyo, Japan) and 123I-meta-iodobenzylguanide (123I-MIBG) scintigraphy. The EMBODY trial was registered with the University Hospital Medical Information Network in November 2017 (UMIN ID: 000030158). The trial drugs will be provided by Boehringer Ingelheim (Germany). Ethics approval was obtained from the local institutional review board of each participating center and the trial complies with the Declaration of Helsinki.

Trial Population and Follow-Up

We will recruit a total of 98 patients across five sites in Japan from February 2018 to March 2019. The criteria established for enrollment are detailed in Table 1. Briefly, eligible patients include those with a diagnosis of T2DM and AMI. A single anti-diabetic agent indicates that each physician decides based on the patient’s individual characteristics or intolerance on metformin. After each patient has been provided written informed consent of the trial plan, randomized, and assigned to either the empagliflozin or placebo group, the follow-up visits will be scheduled at 4, 12, and 24 weeks (Table 2). They will receive standard treatment for their background disease, T2DM, and AMI during trial period (Fig. 1).
Table 1

Inclusion and exclusion criteria

Inclusion

Exclusion

1. Adults (aged ≥ 20 years)

1. Type 1 diabetes mellitus

2. Glycemic condition

2. Persistent atrial fiblilation

Subjects appropriately diagnosed as T2DM by the Japanese guideline[8]

3. Insulin and glucagon-like peptide-1 analog user

Drug-naïve subjects or taking single anti-diabetic agent

4. High dose of sulfonylurea (glimepiride > 2 mg, glibenclamide > 1.25 mg, glimicron > 40 mg)

T2DM patients who need to start or are possibly changing or adding an anti-diabetic agent

5. HbA1c ≥ 10%

3. Patients within 2–12 weeks after the onset of AMI, who can be discharged home

6. History of diabetic ketoacidosis or diabetic coma within 3 months prior to the randomization

7. Renal dysfunction (eGFR < 45 ml/min/1.73 m²)

8. Heart failure graded at NYHA functional class IV

9. Pregnancy or possible pregnancy and breast feeding

10. Lack of informed consent

11. Contraindications to empagliflozin according to the label

Table 2

Post-randomized follow-up visits at 4, 12, and 24 weeks

 

Screening

0 W (Baseline)

4 W (± 4 W)

12 W (± 4 W)

24 W (± 4 W)

Assessment of eligibility and informed consent

a

    

Randomization

 

a

   

Investigator visit

 

a

b

b

a

Body weight

 

a

b

b

a

Blood pressure and heart rate

 

a

b

b

a

TWA,LP,HRT, and HRV by ambulatory ECG

 

a

  

a

123I-MIBG scintigraphy

 

b

  

b

Blood sampling

 

a

b

b

a

Safety assessment, including events

  

b

b

a

W weeks(s), TWA T-wave alternans, LP late potentials, HRT heart rate turbulence, HRV heart rate variability, ECG electrocardiogram, 123I-MIBG 123I-meta-iodobenzylguanide

aPrimary or key secondary variables

bOptional

Fig. 1

Trial outline. Patients with acute myocardial infarction and type 2 diabetes mellitus will be randomly assigned to receive empagliflozin (10 mg/day) or placebo add-on to conventional therapy at 2 weeks after the onset of AMI. They will receive treatment for 24 weeks after stratified randomization

Randomization and Blinding

Patients with AMI and T2DM will be randomly assigned into an empagliflozin (10 mg/day) group or a placebo add-on to conventional therapy group 2 weeks after the onset of AMI based on allocation factors, baseline HbA1c value (less than 7.0% or ≧ 7.0%), and max CK (less than 3000 or  ≧ 3000 IU/l) by a dynamic allocation method. All patients will receive a drug (empagliflozin 10 mg or placebo, once daily) and be followed up for 24 weeks after stratified randomization. Glucose-lowering therapy will remain unchanged for the first 12 weeks after randomization. After week 12, investigators will be encouraged to adjust glucose-lowering therapy, including metformin, sulfonylurea, alpha glucosidase inhibitors, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors, at their discretion, to achieve glycemic control according to the Japan Diabetes Society guidelines [8].

Patients will not be able to use insulin, glucagon-like peptide-1 analog, or high doses of sulfonylurea (glimepiride > 2 mg, glibenclamide > 1.25 mg, glimicron > 40 mg) during the trial period. Patients will also receive treatment post-AMI with beta-blockers, anti-platelet therapy, statins, and renin-angiotensin system inhibitors in accordance with local guidelines [9] [10]. Throughout the trial, investigators will be encouraged to treat other cardiovascular risk factors (including dyslipidemia and hypertension) to achieve the best available standard treatment. After the trial has been completed, all patients can continue any anti-diabetic treatments in accordance with their individual condition.

Trial End Points

The primary end point of this trial is the change in HRV from baseline to 24 weeks. The HRV provides important information about the sympathovagal balance (low-frequency power, LF; high-frequency power, HF) of the heart. Traditionally, the HRV is analyzed using time and frequency domain methods.
  • Time domain analysis:
    1. 1.

      Mean RR interval for 24 h (mean NN)

       
    2. 2.

      Standard deviation of normal RR intervals (SDNN)

       
    3. 3.

      Standard deviation of all 5-min mean normal RR intervals (SDANN)

       
    4. 4.

      Square root of the mean of the sum of the squares of differences between adjacent RR intervals (r-MSSD)

       
    5. 5.

      Percentage of adjacent RR intervals differing by > 50 ms (pNN50)

       
  • Frequency domain analysis:
    1. 1.

      Total power (TP 0–0.4 Hz)

       
    2. 2.

      HF (0.15–0.4 Hz)

       
    3. 3.

      LF (0.04–0.15 Hz)

       
    4. 4.

      Sympathovagal balance (LF/HF ratio)

       
Secondary end points are to evaluate the change from baseline in the following measurements after add-on empagliflozin treatment with conventional therapy compared to the placebo throughout the trial period.
  1. (1)

    TWA, LP, and HRT assessed by ambulatory ECG (SCM-8000)

     
  2. 2)

    Cardiac sympathetic activity assessed by 123I-MIBG scintigraphy

     

Additionally, we will compare the changes from baseline in other variables, including glycemic and lipid profiles, uric acid, estimated glomerular filtration rate, body weight, blood pressure, and safety parameters, including adverse events (hypoglycemic episode, cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) after 24 weeks of treatment. We will provide results at each follow-up period (Table 2).

Statistical Considerations

Sample Size Estimation

Sample size was calculated for the LF/HF ratio, one of the parameters of the primary end point. As no previous studies have examined the effect of SGLT2 inhibitors on cardiac sympathetic activity, it is estimated that the mean difference in change between the empagliflozin and standard treatment from baseline to 24 weeks in the Ln LF/HF (ms2) will be 0.3 and the SD will be 0.5 (taken from previous studies using a similar approach) [11] [12] [13]. When the significance level is 5% (two sided), a sample size of 88 patients per arm will provide a power of 80% for the comparison. It is estimated that at least 10% of randomized patients will not be treated or will have a baseline value or at least one post-baseline value missing, so will be removed from the analysis. Consequently, we assume that a total of 98 patients should be enrolled in this trial.

Statistical Analyses

Continuous variables will be expressed as mean ± standard deviation (SD), while categorical variables will be expressed as number (percentage). To compare characteristics in the empagliflozin and placebo groups, chi-square tests and independent t tests will be used for categorical and continuous variables, respectively. The relationships between the changes in HRV and each measurement listed will be evaluated using Pearson’s correlation coefficient. The principal investigator and a biostatistician will create a statistical analysis plan before patient recruitment and database locking have been completed. p ≤ 0.05 will be considered statistically significant. SAS version 9.4 (SAS Institute, Cary, NC, USA) will be used for statistical analyses.

Discussion

The mechanisms by which empagliflozin has a beneficial impact on the prevention of SCD and CV outcomes in AMI patients with T2DM have not yet been established. The EMBODY trial aims to reveal whether suppression of cardiac sympathetic activity is accompanied by protection from SCD.

Assessment by Ambulatory ECG

The evidence connecting the autonomic nervous system to life-threatening arrhythmias and to cardiovascular mortality is well established. There is a clear link between increasing sympathetic activity and/or decreasing vagal activity and a greater tendency for lethal ventricular arrhythmias during myocardial ischemia [14]. The HRV is a physiologic phenomenon characterized by beat-to-beat variation in cardiac cycle length, which is influenced by autonomic tone. Depressed HRV is currently considered a strong predictor of mortality and lethal ventricular arrhythmias in post-MI patients [15]. In many previous reports, depressed HRV was reported to be associated with adverse outcomes in survivors of acute MI [16, 17, 18, 19, 20, 21]. Depressed HRV compared with depressed left ventricular ejection fraction (LVEF) predicts arrhythmic rather than nonarrhythmic mortality [22, 23]. The integration of traditional risk stratifiers, such as LVEF and non-sustained ventricular tachycardia, with autonomic markers, such as HRV, provides a powerful approach to the ever-daunting problem of early identification of post-MI patients at a risk of cardiac and arrhythmic mortality [15, 24].

The TWA is a periodic beat-to-beat variation in the amplitude or morphology of the T wave on ECG. Beat-to-beat TWA is believed to reflect increased dispersion of ventricular repolarization, and it is known to often precede the development of lethal ventricular tachyarrhythmias [25, 26, 27]. Recent clinical trials have shown that a positive TWA result is associated with serious ventricular arrhythmic events and SCD [28, 29, 30]. It is currently recommended as a class IIa, level of evidence A, risk-stratification tool for post-MI patients [31].

HRT is characterized by fluctuations in electrocardiographic cycle length after a ventricular premature contraction. To date, HRT has been examined mainly in post-MI patients, and it is suggested that abnormal HRT is associated with increased mortality after MI [32, 33, 34]. Impaired HRT, abnormal TWA, and an ejection fraction < 0.50 beyond 8 weeks after MI reliably identifies patients at risk of serious events [29].

LPs are characterized by a high-frequency, low-amplitude signal at the tail of a QRS complex attributable to fragmented and delayed electrical conduction through the borders of a myocardial scar. Delayed conduction represented by LP allows reentry of electrical impulses and susceptibility to ventricular tachyarrhythmias. Previous studies have reported that LP is useful for identifying patients with ventricular tachycardia after MI [35, 36, 37].

Assessment By 123I-MIBG Scintigraphy

To explore the intracardiac sympathetic activity in detail, we will perform 123I-MIBG scintigraphy. Cardiac sympathetic activity can be non-invasively assessed with cardiac 123I-MIBG scintigraphy. 123I-MIBG uptake will be determined, specifically the early and late heart/mediastinal (H/M) ratio and cardiac washout rate. Cardiac sympathetic hyperactivity is reflected by a decreased 123I-MIBG late H/M ratio and increased washout rate. Both are associated with increased fatal arrhythmia and cardiac mortality [38].

After AMI, patients should be carefully managed with conventional therapy for T2DM and post-MI to prevent future CV events. To investigate the additional effect of empagliflozin on lethal ventricular tachyarrhythmias, we adopted a trial design comparing the effects of empagliflozin with a placebo on top of conventional therapy. Coronary artery disease (CAD) is prevented by interventions including statins against dyslipidemia. However, the reduction in the risk of CAD by statins has been reported to be only 30% [39]. Therefore, there has been a focus on further managing of the residual risk other than dyslipidemia. One of the few reports on this is the EMPAREG OUTCOME report [4], which reported improved prognosis in patients with DM and CAD including a history of MI.

This concept highlights the importance of developing a clinically feasible approach to select post-infarction patients who are at particularly high risk of predominantly arrhythmic death who would benefit from SGLT2 inhibitor therapy.

Trial Limitations

The main limitations of this trial will be the relatively small sample size. Although this research is a trial to examine the mechanisms by which empagliflozin has a beneficial impact on the prevention of SCD, to verify the results, real-world data accumulation is needed. Second, the trial period is 24 weeks. In the EMPAREG OUTCOME report, the reduction of CV death was observed during an early follow-up period (0–6 months), which may be attributable to decreased SCD with empagliflozin during this period. Thus, we expect that the 24-week assessment period will adequately demonstrate the effect of empagliflozin on cardiac sympathetic activity as a surrogate of lethal ventricular tachyarrhythmias. In addition, we will evaluate the effect of empagliflozin on the cardiac sympathetic activity during the chronic phase after AMI to avoid the potential confounding factor during the acute and sub-acute phase of AMI. Third, this trial will only be conducted in the Japanese population. Japanese patients with CAD generally receive adequate conventional therapy, including statins. Therefore, it is possible to determine the exact therapeutic effect of empagliflozin against residual risk. Fourth, beta-blockers will be not restricted during the trial period. Patients with LVEF < 40% and depressed HRV benefit from prophylactic antiarrhythmic treatment with beta-blockers [40]. Therefore, we will evaluate beta-blocker doses in the two groups. Fifth, tight glycemic control influenced the risk of cardiac autonomic neuropathy in T2DM patients [41, 42, 43]; we will evaluate glycemic control levels in the two groups.

Notes

Acknowledgements

The authors would like to thank all the staff and patients who are participating in the EMBODY trial. Current site investigators of the EMBODY trial include: Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan: Yu Hoshika, Kosuke Mozawa, Hideto Sangen, Yoichi Imori, Hideki Miyachi, Yusuke Hosokawa. Department of Cardiovascular Medicine, Nippon Medical School Chiba Hokuso Hospital, Chiba, Japan: Ayaka Shima, Masato Matsushita, Hidenori Komiyama, Hirotake Okazaki, Akihiro Shirakabe, Nobuaki Kobayashi. Department of Cardiovascular Medicine, Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan: Atsushi Tanida, Naoya Niwa, Toshinori Ko, Tsunenori Saito, Morisawa Taichirou, Keiichi Kobayashi. Department of Cardiovascular Medicine, Nippon Medical School Musashi Kosugi Hospital, Tokyo, Japan: Masahiro Ishikawa. Department of Cardiovascular Medicine, Shizuoka Medical Center, Shizuoka, Japan: Erito Furuse, Keishi Suzuki. Consultancy and a part of the trial management are provided by DOT WORLD Co., Ltd.

Funding

This trial is funded by Nippon Boehringer Ingelheim and Eli Lilly and Co. The funding agencies had no role in designing or conducting the trial.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions

Yoshiaki Kubota, Kenji Yodogawa, Yuki Iwasaki, and Wataru Shimizu conceived the presented idea. Takeshi Yamamoto, Shuhei Tara, Yukichi Tokita, Hitoshi Takano, Yayoi Tsukada, and Masaaki Miyamoto developed the theory and performed the computations. Yoshiaki Kubota, Kuniya Asai, Yasushi Miyauchi, and Wataru Shimizu verified the analytical methods. Yasushi Miyauchi, Eitaro Kodani, Naoki Sato, Jun Tanabe, and Wataru Shimizu encouraged Yoshiaki Kubota to investigate and supervised the findings of this work. All authors read and approved the final manuscript.

Disclosures

Yoshiaki Kubota, Takeshi Yamamoto, Shuhei Tara, Yukichi Tokita, Kenji Yodogawa, Yuki Iwasaki, Hitoshi Takano, Yayoi Tsukada, Kuniya Asai, Masaaki Miyamoto, Yasushi Miyauchi, Eitaro Kodani, Naoki Sato, and Jun Tanabe declared no conflicts of interest. Wataru Shimizu has received honoraria and research grants from Boehringer Ingelheim.

Compliance with Ethics Guidelines

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All study participants will provide informed consent.

Data Availability

The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Open Access

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

References

  1. 1.
    Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262–74.CrossRefPubMedGoogle Scholar
  2. 2.
    Villafana S, Huang F, Hong E. Role of the sympathetic and renin angiotensin systems in the glucose-induced increase of blood pressure in rats. Eur J Pharmacol. 2004;506:143–50.CrossRefPubMedGoogle Scholar
  3. 3.
    Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12:90–100.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefPubMedGoogle Scholar
  5. 5.
    Hayashi M, Shimizu W, Albert CM. The spectrum of epidemiology underlying sudden cardiac death. Circ Res. 2015;116:1887–906.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Alabas OA, Hall M, Dondo TB, Rutherford MJ, Timmis AD, Batin PD, et al. Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study. J Epidemiol Community Health. 2016;71:25–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Verschure DO, van Eck-Smit BL, Somsen GA, Knol RJ, Verberne HJ. Cardiac sympathetic activity in chronic heart failure: cardiac 123I-mIBG scintigraphy to improve patient selection for ICD implantation. Neth Heart J. 2016;24:701–8.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, Araki E, et al. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. J Diabetes Investig. 2010;19:212–28.Google Scholar
  9. 9.
    O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;127:e362–425.CrossRefPubMedGoogle Scholar
  10. 10.
    Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Circulation. 2014;130:2354–94.CrossRefPubMedGoogle Scholar
  11. 11.
    Malfatto G, Facchini M, Sala L, Branzi G, Bragato R, Leonetti G. Effects of cardiac rehabilitation and beta-blocker therapy on heart rate variability after first acute myocardial infarction. Am J Cardiol. 1998;81:834–40.CrossRefPubMedGoogle Scholar
  12. 12.
    Ulgen MS, Akdemir O, Toprak N. The effects of trimetazidine on heart rate variability and signal-averaged electrocardiography in early period of acute myocardial infarction. Int J Cardiol. 2001;77:255–62.CrossRefPubMedGoogle Scholar
  13. 13.
    Lampert R, Ickovics JR, Viscoli CJ, Horwitz RI, Lee FA. Effects of propranolol on recovery of heart rate variability following acute myocardial infarction and relation to outcome in the beta-blocker heart attack trial. Am J Cardiol. 2003;91:137–42.CrossRefPubMedGoogle Scholar
  14. 14.
    Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation. 1988;78:969–79.CrossRefPubMedGoogle Scholar
  15. 15.
    Camm AJ, Pratt CM, Schwartz PJ, Al-Khalidi HR, Spyt MJ, Holroyde MJ, et al. Mortality in patients after a recent myocardial infarction: a randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation. 2004;109:990–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Schwartz PJ, La Rovere MT. ATRAMI: a mark in the quest for the prognostic value of autonomic markers. Autonomic tone and reflexes after myocardial infarction. Eur Heart J. 1998;19:1593–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256–62.CrossRefPubMedGoogle Scholar
  18. 18.
    Cripps TR, Malik M, Farrell TG, Camm AJ. Prognostic value of reduced heart rate variability after myocardial infarction: clinical evaluation of a new analysis method. Br Heart J. 1991;65:14–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Farrell TG, Bashir Y, Cripps T, Malik M, Poloniecki J, Bennett ED, et al. Risk stratification for arrhythmic events in postinfarction patients based on heart rate variability, ambulatory electrocardiographic variables and the signal-averaged electrocardiogram. J Am Coll Cardiol. 1991;18:687–97.CrossRefPubMedGoogle Scholar
  20. 20.
    Bigger JT Jr, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation. 1992;85:164–71.CrossRefPubMedGoogle Scholar
  21. 21.
    Camm AJ, Malik M, Bigger JT, Breithardt G, Cerutti S, Cohen R, et al. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task force of the European society of cardiology and the North American society of pacing and electrophysiology. Circulation. 1996;93:1043–65.CrossRefGoogle Scholar
  22. 22.
    Odemuyiwa O, Malik M, Farrell T, Bashir Y, Poloniecki J, Camm J. Comparison of the predictive characteristics of heart rate variability index and left ventricular ejection fraction for all-cause mortality, arrhythmic events and sudden death after acute myocardial infarction. Am J Cardiol. 1991;68:434–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation. 1992;85:I77–91.PubMedGoogle Scholar
  24. 24.
    La Rovere MT, Pinna GD, Hohnloser SH, Marcus FI, Mortara A, Nohara R, et al. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation. 2001;103:2072–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Shimizu W, Antzelevitch C. Cellular and ionic basis for T-wave alternans under long-QT conditions. Circulation. 1999;99:1499–507.CrossRefPubMedGoogle Scholar
  26. 26.
    Grabowski M, Karpinski G, Filipiak KJ, Opolski G. Images in cardiovascular medicine. drug-induced long-QT syndrome with macroscopic T-wave alternans. Circulation. 2004;110:e459–60.CrossRefPubMedGoogle Scholar
  27. 27.
    Armoundas AA, Nanke T, Cohen RJ. Images in cardiovascular medicine. T-wave alternans preceding torsade de pointes ventricular tachycardia. Circulation. 2000;101:2550.CrossRefPubMedGoogle Scholar
  28. 28.
    Salerno-Uriarte JA, De Ferrari GM, Klersy C, Pedretti RF, Tritto M, Sallusti L, et al. Prognostic value of T-wave alternans in patients with heart failure due to nonischemic cardiomyopathy: results of the ALPHA Study. J Am Coll Cardiol. 2007;50:1896–904.CrossRefPubMedGoogle Scholar
  29. 29.
    Exner DV, Kavanagh KM, Slawnych MP, Mitchell LB, Ramadan D, Aggarwal SG, et al. Noninvasive risk assessment early after a myocardial infarction the REFINE study. J Am Coll Cardiol. 2007;50:2275–84.CrossRefPubMedGoogle Scholar
  30. 30.
    Chow T, Kereiakes DJ, Onufer J, Woelfel A, Gursoy S, Peterson BJ, et al. Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (microvolt T wave alternans testing for risk stratification of post-myocardial infarction patients) trial. J Am Coll Cardiol. 2008;52:1607–15.CrossRefPubMedGoogle Scholar
  31. 31.
    Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for practice guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death). J Am Coll Cardiol. 2006;48:e247–346.CrossRefPubMedGoogle Scholar
  32. 32.
    Schmidt G, Malik M, Barthel P, Schneider R, Ulm K, Rolnitzky L, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet. 1999;353:1390–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Ghuran A, Reid F, La Rovere MT, Schmidt G, Bigger JT Jr, Camm AJ, et al. Heart rate turbulence-based predictors of fatal and nonfatal cardiac arrest (the autonomic tone and reflexes after myocardial infarction substudy). Am J Cardiol. 2002;89:184–90.CrossRefPubMedGoogle Scholar
  34. 34.
    Miwa Y, Miyakoshi M, Hoshida K, Yanagisawa R, Abe A, Tsukada T, et al. Heart rate turbulence can predict cardiac mortality following myocardial infarction in patients with diabetes mellitus. J Cardiovasc Electrophysiol. 2011;22:1135–40.CrossRefPubMedGoogle Scholar
  35. 35.
    Savard P, Rouleau JL, Ferguson J, Poitras N, Morel P, Davies RF, et al. Risk stratification after myocardial infarction using signal-averaged electrocardiographic criteria adjusted for sex, age, and myocardial infarction location. Circulation. 1997;96:202–13.CrossRefPubMedGoogle Scholar
  36. 36.
    Gomes JA, Cain ME, Buxton AE, Josephson ME, Lee KL, Hafley GE. Prediction of long-term outcomes by signal-averaged electrocardiography in patients with unsustained ventricular tachycardia, coronary artery disease, and left ventricular dysfunction. Circulation. 2001;104:436–41.CrossRefPubMedGoogle Scholar
  37. 37.
    el-Sherif N, Denes P, Katz R, Capone R, Mitchell LB, Carlson M, et al. Definition of the best prediction criteria of the time domain signal-averaged electrocardiogram for serious arrhythmic events in the postinfarction period. The cardiac arrhythmia suppression trial/signal-averaged electrocardiogram (CAST/SAECG) substudy investigators. J Am Coll Cardiol. 1995;25:908–14.CrossRefPubMedGoogle Scholar
  38. 38.
    Jacobson AF, Senior R, Cerqueira MD, Wong ND, Thomas GS, Lopez VA, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol. 2010;55:2212–21.CrossRefPubMedGoogle Scholar
  39. 39.
    Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland coronary prevention study group. N Engl J Med. 1995;333:1301–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Boutitie F, Boissel JP, Connolly SJ, Camm AJ, Cairns JA, Julian DG, et al. Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT investigators. Circulation. 1999;99:2268–75.CrossRefPubMedGoogle Scholar
  41. 41.
    Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–93.CrossRefPubMedGoogle Scholar
  42. 42.
    Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy: a position statement by the American diabetes association. Diabetes Care. 2017;40:136–54.CrossRefPubMedGoogle Scholar
  43. 43.
    Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep. 2014;14:528.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2018

Authors and Affiliations

  • Yoshiaki Kubota
    • 1
  • Takeshi Yamamoto
    • 1
  • Shuhei Tara
    • 1
  • Yukichi Tokita
    • 1
  • Kenji Yodogawa
    • 1
  • Yuki Iwasaki
    • 1
  • Hitoshi Takano
    • 1
  • Yayoi Tsukada
    • 1
  • Kuniya Asai
    • 1
  • Masaaki Miyamoto
    • 1
  • Yasushi Miyauchi
    • 2
  • Eitaro Kodani
    • 3
  • Naoki Sato
    • 4
  • Jun Tanabe
    • 5
  • Wataru Shimizu
    • 1
  1. 1.Department of Cardiovascular MedicineNippon Medical School HospitalTokyoJapan
  2. 2.Department of Cardiovascular MedicineNippon Medical School Chiba Hokusoh HospitalChibaJapan
  3. 3.Department of Cardiovascular MedicineNippon Medical School Tama-Nagayama HospitalTokyoJapan
  4. 4.Department of Cardiovascular MedicineNippon Medical School Musashi Kosugi HospitalKawasaki-shiJapan
  5. 5.Department of Cardiovascular MedicineShizuoka Medical CenterShizuokaJapan

Personalised recommendations