Sympathetic activity–associated periodic repolarization dynamics predict mortality following myocardial infarction
Konstantinos D. Rizas, Tuomo Nieminen, Petra Barthel, Christine S. Zürn, Mika Kähönen, Jari Viik, Terho Lehtimäki, Kjell Nikus, Christian Eick, Tim O. Greiner, Hans P. Wendel, Peter Seizer, Jürgen Schreieck, Meinrad Gawaz, Georg Schmidt, Axel Bauer
Konstantinos D. Rizas, Tuomo Nieminen, Petra Barthel, Christine S. Zürn, Mika Kähönen, Jari Viik, Terho Lehtimäki, Kjell Nikus, Christian Eick, Tim O. Greiner, Hans P. Wendel, Peter Seizer, Jürgen Schreieck, Meinrad Gawaz, Georg Schmidt, Axel Bauer
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Clinical Research and Public Health

Sympathetic activity–associated periodic repolarization dynamics predict mortality following myocardial infarction

Abstract

Background. Enhanced sympathetic activity at the ventricular myocardium can destabilize repolarization, increasing the risk of death. Sympathetic activity is known to cluster in low-frequency bursts; therefore, we hypothesized that sympathetic activity induces periodic low-frequency changes of repolarization. We developed a technique to assess the sympathetic effect on repolarization and identified periodic components in the low-frequency spectral range (≤0.1 Hz), which we termed periodic repolarization dynamics (PRD).

Methods. We investigated the physiological properties of PRD in multiple experimental studies, including a swine model of steady-state ventilation (n = 7) and human studies involving fixed atrial pacing (n = 10), passive head-up tilt testing (n = 11), low-intensity exercise testing (n = 11), and beta blockade (n = 10). We tested the prognostic power of PRD in 908 survivors of acute myocardial infarction (MI). Finally, we tested the predictive values of PRD and T-wave alternans (TWA) in 2,965 patients undergoing clinically indicated exercise testing.

Results. PRD was not related to underlying respiratory activity (P < 0.001) or heart-rate variability (P = 0.002). Furthermore, PRD was enhanced by activation of the sympathetic nervous system, and pharmacological blockade of sympathetic nervous system activity suppressed PRD (P ≤ 0.005 for both). Increased PRD was the strongest single risk predictor of 5-year total mortality (hazard ratio 4.75, 95% CI 2.94–7.66; P < 0.001) after acute MI. In patients undergoing exercise testing, the predictive value of PRD was strong and complementary to that of TWA.

Conclusion. We have described and identified low-frequency rhythmic modulations of repolarization that are associated with sympathetic activity. Increased PRD can be used as a predictor of mortality in survivors of acute MI and patients undergoing exercise testing.

Trial registration. ClinicalTrials.gov NCT00196274.

Funding. This study was funded by Angewandte Klinische Forschung, University of Tübingen (252-1-0).

Authors

Konstantinos D. Rizas, Tuomo Nieminen, Petra Barthel, Christine S. Zürn, Mika Kähönen, Jari Viik, Terho Lehtimäki, Kjell Nikus, Christian Eick, Tim O. Greiner, Hans P. Wendel, Peter Seizer, Jürgen Schreieck, Meinrad Gawaz, Georg Schmidt, Axel Bauer

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Figure 5

PRD in post-MI patients.

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PRD in post-MI patients. (A) Typical dT° signal (blue line) obtained fr...
(A) Typical dT° signal (blue line) obtained from a 50-year-old post-MI patient who survived the 5-year follow-up period. The signal shows characteristic low-frequency oscillations. For better illustration of these oscillations, a low-pass filter was applied and plotted on top of the original signal (black line). (B) Typical dT° signal (red line) from a 75-year-old post-MI patient who suddenly died 8 months after MI. Compared with the survivor, the amplitude of PRD was substantially enhanced. (C) Cumulative mortality rates of patients stratified by PRD of 5.75 deg2 or more. (D) Cumulative mortality rates of patients stratified by PRD of 5.75 deg2 or more and presence of diabetes mellitus.