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).

Figure 1. CONSORT flow diagrams.

Enrollment, follow-up, and analysis in the post-MI and stress-test cohorts.

Figure 2. Assessment of PRD.

(A) Illustration of the weight-averaged vector of repolarization (T°) for each T-wave from surface ECG recorded in the Frank leads configuration. (B) Three-dimensional visualization of successive T° vectors projected into virtual spheres. The angle dT° between successive repolarization vectors was used as an estimate of instantaneous repolarization instability. (C and D) The dT° signal exhibits characteristic low-frequency oscillations. C shows dT° values for beats #219-223, corresponding to the spheres in B. (E) Quantification of PRD using wavelet analysis. PRD was defined as the average wavelet coefficient corresponding to frequencies of 0.1 Hz or less.

Figure 3. Physiological and pharmacological provocations.

Effects of fixed atrial stimulation (i), tilt-table testing (ii), exercise (iii), and pharmacological beta blockade (iv) on PRD. PRD ratio was plotted on a logarithmic axis and used to quantify the effect of each procedure.

Figure 4. Effect of respiration on PRD in a volume-controlled ventilated swine.

(A) Signals of respiratory activity (green) and dT° (blue). Respiratory activity was recorded by a piezoelectric thoracic sensor. The dT° signal exhibits typical low-frequency oscillations occurring independently from respiratory activity. (B) Spectral analysis of respiratory activity and the dT° signal. Power spectra were normalized by their maximum value. (C) Cross-spectral analysis of respiratory activity and the dT° signal showing a lack of interference between both signals.

Figure 5. PRD in post-MI patients.

(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.