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1 Reflex Cardiac Activity in Ischemia and Reperfusion Heart Rate Turbulence in Patients Undergoing Direct Percutaneous Coronary Intervention for Acute Myocardial Infarction Hendrik Bonnemeier, MD; Uwe K.H. Wiegand, MD; Julia Friedlbinder, MS; Simone Schulenburg, MD; Franz Hartmann, MD; Frank Bode, MD; Hugo A. Katus, MD, FESC; Gert Richardt, MD Background Abnormal heart rate turbulence (HRT) is associated with an increased risk of mortality in the chronic phase of myocardial infarction (MI) in the prethrombolytic and thrombolytic eras. However, the impact of direct percutaneous coronary intervention (PCI) on HRT in the acute phase of MI and its association to the epicardial infarct-related arterial flow has not been examined. Methods and Results We investigated HRT in 126 patients undergoing direct PCI for a first MI. Turbulence onset and turbulence slope were determined before reperfusion, during the initial 2 hours after reperfusion, and during hours 6 to 24 after reperfusion. HRT significantly improved after PCI. There were no significant differences in baseline clinical characteristics between Thrombolysis in Myocardial Infarction Trial classification (TIMI) 2 (n 28) and TIMI 3 (n 98) flow. After PCI, turbulence slope increased ( to ms/beat, P 0.001) and turbulence onset decreased ( % to %, P 0.01) in patients with TIMI 3 flow after PCI, whereas there were no significant alterations of turbulence slope ( to ms/beat) and turbulence onset ( % to %) in patients with TIMI 2 flow. Conclusions The improvement of HRT after successful reperfusion is a previously unreported effect of direct PCI for acute MI, reflecting rapid restoration of baroreceptor response. The persistent impairment of HRT after PCI in patients with TIMI 2 flow indicates a sustained blunted baroreflex response and may reflect a more severe microvascular dysfunction. (Circulation. 2003;108: ) Key Words: myocardial infarction heart rate turbulence percutaneous coronary intervention reperfusion Depressed baroreflex sensitivity in the chronic phase of myocardial infarction (MI) is a strong independent predictor for cardiac death. 1 Recently, Schmidt et al 2 were able to confirm these findings in 2 large post-mi samples from the prethrombolytic and thrombolytic eras. They introduced heart rate turbulence (HRT), a surrogate marker for baroreflex response, 3 characterized by a reflex early acceleration and a subsequent deceleration of sinus rhythm after a ventricular premature beat. Subgroup analysis of patients undergoing coronary angiography in the Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) study suggested that the major determinant for an enhanced baroreceptor response after MI is the patency of the artery to the infarct. 4 Patency is not perfusion; however, the optimal outcome after MI depends on complete and sustained reperfusion. 5 Despite angiographic evidence of an open feeder vessel, patients may have a mismatch between vascular patency and myocardial perfusion. 6 Incomplete tissue reperfusion, leading to microvascular dysfunction, is associated with an adverse outcome after MI. 7 Whether incomplete reperfusion also signifies impaired cardiac autonomic dysfunction with an attenuation of baroreceptor response has not been investigated. Moreover, there are almost no data on baroreceptor response before and after successful reperfusion in the acute phase of MI. Therefore, the main purpose of the present study was to assess the impact of a modern reperfusion strategy (ie, direct percutaneous coronary intervention [PCI]) on the evolution of HRT in the acute phase of MI and its association with the epicardial flow of the infarct-related artery. Methods Patient Population One hundred eighty-seven consecutive patients with acute STsegment elevation MI, in whom primary PCI was performed at our institution, were screened prospectively. Inclusion criteria were presence of chest pain associated with ST-segment elevation 0.1 mv in 2 leads of the surface ECG. Exclusion criteria were Received December 31, 2002; de novo received March 31, 2003; revision received June 2, 2003; accepted June 3, From the Medizinische Universität zu Lübeck, Medizinische Klinik II (H.B., U.K.H.W., J.F., S.S., F.H., F.B.), Lübeck, Germany; Ruprecht-Karls- Universität-Heidelberg, Innere Medizin III (H.A.K.), Heidelberg, Germany; and Herzzentrum Segeberger Kliniken, Kardiologie (G.R.), Bad Segeberg, Germany. Correspondence to Dr Hendrik Bonnemeier, Medizinische Klinik II, Medizinische Universität zu Lübeck, Ratzeburger Allee 160, D Lübeck, Germany American Heart Association, Inc. Circulation is available at DOI: /01.CIR D8 958

2 Bonnemeier et al Reflex Cardiac Activity in Ischemia and Reperfusion 959 cardiogenic shock, blood pressure 90 mm Hg and clinical signs of heart failure, left bundle branch block, pacemaker rhythm and rhythm other than sinus, age 75 years, prior MI or coronary artery bypass grafting, and coronary occlusions unsuitable for PCI. All patients gave informed consent for the research protocol, which had been approved by the local ethics committee. Catheterization, Hemodynamic Monitoring, and Blood Sampling Coronary angioplasty was performed by a percutaneous femoral approach. Calculation of left ventricular ejection fraction was performed off-line by quantitative measurements of end-diastolic and end-systolic area by using a computerized algorithm (QLVA, Medis Medical). For measurement of left ventricular end-diastolic filling pressure, hemodynamic waveforms were recorded by a computerized hemodynamic monitor (Cathcor, Siemens). Antegrade perfusion was graded according to the classification of the Thrombolysis in Myocardial Infarction (TIMI) Trial. 8 Stent implantation was performed if (1) TIMI flow was 2, (2) residual stenosis was 30%, or (3) extensive intimal dissection was present. If coronary flow appeared to be compromised, a glycoprotein IIb/IIIa receptor antagonist was administered. Arterial plasma concentrations of norepinephrine were investigated before PCI, 60 minutes after PCI, and 6 hours after PCI, by using a high-performance liquid chromatography method and electrochemical detection. 9 Measurement of HRT and Heart Rate Variability HRT was analyzed as previously described 2 from Holter recordings (Tracker II and III, Reynolds Medical), which were started at hospital admission. At the time of coronary artery reopening, the event marker on the Holter recording was set. All recordings were manually edited for exclusion of artifacts and noise. At least 18 hours of recording duration and at least 2 ventricular premature beats TABLE 1. Baseline Clinical Characteristics by TIMI Flow After PCI (VPBs) in the time interval before PCI, during the 2 hours after PCI, and during hours 6 to 24 after PCI were required for a Holter recording to be accepted as valid. HRT was characterized by 3 measures, ie, turbulence onset (TO), turbulence slope (TS), and turbulence timing (TT). TO expresses the proportional decrease of RR-interval directly after the compensatory pause of the VPB. TS, quantified by the steepest slope of the linear regression between RR-interval count and duration, expresses the subsequent increase of RR-intervals. TT is the first beat of the 5-beat RR-interval sequence, giving the maximal regression slope. 10 Furthermore, the mean RR-interval of 20 beats before the index VPB, the mean coupling interval, and the prematurity index, defined as the relative prematurity of the VPB to the underlying RR-interval was determined. In addition, 2 established parameters of time domain heart rate variability (HRV) were measured from the Holter recordings: SDNN (SD of normal-to-normal intervals) the most frequently used measure of HRV, reflecting overall variability and root mean square of successive difference of normal-to-normal intervals (rmssd), an established estimate for short-term components of HRV. Because there were various recording durations and amounts of analyzable RR-interval data, mean values of each of the hourly mean values were measured for HRV after PCI to ensure interindividual comparability. Statistical Analysis Statistical analyses were conducted with a commercially available software package (SPSS, version 9.0.1; SPSS Inc). Comparison between groups was performed by using a Mann-Whitney U test. Multiple comparisons between groups were performed by Bonferroni-corrected ANOVA for repeated measures. An -corrected paired Student s t test was performed for interval-tointerval comparisons. Spearman s rank correlation was used to assess the relation between HRT and clinical variables. HRT data in figures are presented as mean SEM. A 2-tailed significance level of 0.05 was used. TIMI 3 (n 98) Patients With Valid Recordings (n 126) TIMI 2 (n 28) P Age, y Gender, male/female 79/19 20/ Site of infarction, anterior/nonanterior 37/61 13/ Left ventricular ejection fraction, % Peak creatine kinase, U/L Peak lactate dehydrogenase, U/L TIMI grade before reperfusion Target lesion, LAD/RCA/LCX 37/53/8 13/11/4 0.43/0.17/0.41 Left ventricular end-diastolic pressure, mm Hg One-vessel disease 36 (36.7) 9 (32.1) 0.70 Killip class 2 19 (19.4) 9 (32.1) 0.09 Diabetes mellitus 15 (15.3) 7 (25.0) 0.23 Current smokers 54 (55.1) 17 (60.7) 0.29 Hypertension 58 (59.2) 12 (42.9) 0.14 Systolic blood pressure on admission, mm Hg Time from pain onset to reperfusion, h Serum potassium on admission, mmol/l Glycoprotein IIb/IIIa antagonists 10 (10.2) 11 (39.3) Blockers in the acute phase 39 (39.8) 11 (39.3) 0.77 Troponin T 0.1 ng/ml on hospital admission 53 (54.1) 15 (53.6) 0.75 Data are presented as mean SD, number of patients, or number (percent) of patients. LAD indicates left anterior descending artery; RCA, right coronary artery; and LCX, left circumflex artery.

3 960 Circulation August 26, 2003 Figure 1. Individual plots of HRT before PCI, within 2 hours after PCI, and within hours 6 to 24 after PCI in 126 patients undergoing PCI for acute MI. Results Patients Characteristics One hundred twenty-six of the 187 patients enrolled fulfilled the clinical and technical inclusion criteria and had valid Holter ECG recordings (median duration, 23 hours). Subgroup analysis based on TIMI flow after direct PCI revealed no significant differences in clinical characteristics between patients with TIMI 3 (n 98) and TIMI 2 (n 28) flow (Table 1), except for the more frequent use of glycoprotein IIb/IIIa antagonists (P 0.006) in the TIMI 2 subgroup. In the acute phase of MI, 40% of patients in both groups received intravenous -blockade. There were no statistically significant differences in estimates of size of MI and ventricular function, but there was a trend toward a more depressed left ventricular function and a higher cardiac enzyme release in TIMI 2 patients. Time Course of HRT TS increased (P 0.001) and TO decreased (P 0.01) directly after PCI, without further significant alterations during the following time period (Figure 1). RR-interval (P 0.001) and VPB-coupling interval (P 0.01) likewise increased after PCI and then remained constant within the observation period. HRT and TIMI Flow After PCI, only patients with TIMI 3 flow exhibited an increase of TS and a decrease of TO, whereas there were no significant alterations of these parameters in patients with TIMI 2 flow (Figure 2). Patients with TIMI 2 and 3 flow exhibited increases of mean RR-interval and VPB-coupling interval, and a constant VPB prematurity index, without significant differences between both groups before and after PCI. HRT and Systemic Norepinephrine Concentrations There was a moderate inverse correlation between TS and norepinephrine concentrations, before, early after, and late after direct PCI (Figure 3). TO and TT showed no significant correlations with norepinephrine concentrations. Within the observation period, norepinephrine concentrations were sig- Figure 2. HRT (mean SEM) before PCI, during 2 hours after PCI, and during hours 6 to 24 after PCI in patients with TIMI 2 (filled shapes) and TIMI 3 (open shapes) flow.

4 Bonnemeier et al Reflex Cardiac Activity in Ischemia and Reperfusion 961 Figure 3. Relationships between parameters of HRT (TS, top row; TO, bottom row) and norepinephrine concentrations (NE) before PCI, 60 minutes after PCI, and 6 hours after PCI. nificantly higher in the TIMI 2 subgroup (before PCI, P 0.04; 60 minutes after PCI, P 0.009; 6 hours after PCI, P 0.005, respectively) (Figure 4 and Table 2). Correlation Between Parameters There were moderate negative correlations of TS after PCI with age and left ventricular end-diastolic filling pressure, and there were positive correlations with ejection fraction, RR-interval, and HRV (Table 3). TO was moderately correlated with age and inversely correlated with RR-interval and HRV. There were no statistically significant relationships between parameters of HRT and the peak levels of cardiac enzyme release. Discussion In acute MI, the prognosis of patients with TIMI 2 flow is similar to that of patients with occluded infarct-related arteries (TIMI 0 and 1 flow), whereas prognosis of patients with TIMI 3 flow is superior. 11 We hypothesized that impairment of the arterial baroreflex is a major determinant of the poor prognosis of patients with incomplete reperfusion. The major finding of the present study is that successful early restoration of antegrade flow by means of mechanical reopening of the infarct-related coronary artery is associated with an immediate significant recovery in the baroreflex. Moreover, our data show that despite angiographic evidence of an open infarct-related coronary artery, a mismatch between patency and myocardial perfusion results in a persistently depressed baroreflex during the early postinfarction period. Therefore, our results suggest that it is not the patency of the infarctrelated artery per se, but the reperfusion of myocardial tissue that is beneficial, by improving electrical stability through restoration of baroreflex response. MI-Associated Baroreceptor Depression The present study indicates a lack of appropriate baroreflex activity in response to a hypotensive stimulus (ie, a VPB with a compensatory pause) in patients with incomplete reperfusion, as demonstrated by a blunted HRT. The mechanisms for the MI-associated depression of baroreceptor response are not well known. It may be owing to an increase of the threshold for a stimulus (eg, a VPB) to excite arterial baroreceptors, 12 or cardiac ventricular mechanoreceptors, 13 resulting in a sustained loss of vagal efferent activity. In incomplete reperfusion, a sustained release of neurohormonal products into the myocardium 14 may stimulate chemosensitive endings, which in turn cause a depression of the baroreflex. A disruption of vagal efferent neuronal function itself has also been shown in Figure 4. HRT and norepinephrine concentrations (mean SEM) in patients with TIMI 2 and TIMI 3 flow after direct PCI for acute MI.

5 962 Circulation August 26, 2003 TABLE 2. Norepinephrine Concentrations and Mean Values of Hourly Measured Heart Rate Variability in Patients With TIMI Perfusion Grade 2 and 3 After Direct PCI TIMI 3 (n 98) TIMI 2 (n 28) P Norepinephrine before PCI, pg/ml Norepinephrine 60 minutes after PCI, pg/ml Norepinephrine 6 hours after PCI, pg/ml SDNN (hourly mean value), ms rmssd (hourly mean value), ms Values are presented as mean SD. postischemic myocardium. 15 Recent experimental data suggest that baroreceptor depression is also mediated by a change in cardiac volume and/or compliance rather than simply by infarct size. 16 Consistent with that report, we observed a trend toward higher values for left ventricular end-diastolic filling pressure and lower values for left ventricular ejection fraction in TIMI 2 patients and moderate correlations of these hemodynamic parameters with HRT. TABLE 3. Correlation Between HRT After PCI and Age, Mean RR-Interval, HRV, LVEF, LVEDP, Peak CK, and Peak LDH Turbulence Onset Turbulence Slope Turbulence Timing Age (y) r P NS RR-interval (ms) r P SDNN (ms) r P rmssd (ms) r P LVEF (%) r P NS LVEDP (mm Hg) r P NS 0.04 NS Peak CK (U/L) r P NS NS NS Peak LDH (U/L) r P NS NS NS r indicates Spearman s rank correlation coefficient; LVEF, left ventricular ejection fraction; LVEDP, left ventricular end-diastolic pressure; CK, creatine kinase; and LDH, lactate dehydrogenase. Norepinephrine Concentrations and Baroreflex in Acute MI In accordance with previous findings in patients with chronic MI 17 and in healthy subjects, 18 we found only weak correlations of norepinephrine concentrations with baroreflex response. In the present study, norepinephrine concentrations were significantly higher in patients with incomplete reperfusion, reflecting a higher background efferent sympathetic activation. 19 Because patients with incomplete reperfusion also exhibited a sustained impairment of baroreflex sensitivity, there are 3 possible dependencies between the sympathetic activity and the baroreflex: (1) the MI-associated baroreflex impairment can be ascribed to sympathetic overactivity, (2) the baroreflex impairment is responsible for increased norepinephrine levels, or (3) the concomitant baroreflex impairment and sympathetic overactivity are not directly interrelated. With regard to the first theory, Mircoli et al 20 suggested that sympathetic overactivity is a determinant of baroreflex impairment. Excess systemic sympathetic activation modulates the baroreceptor reflex arch at the vagal neuroeffector junction, where norepinephrine can presynaptically antagonize acetylcholine release. 21 At the opposite end of the baroreflex arc, norepinephrine affects arterial distensibility of the carotid sinus and aorta, altering discharge of the baroreceptor organs. 22 In the present study, baroreflex function significantly improved after successful reperfusion without significant alterations in serum norepinephrine concentrations. Therefore, it is unlikely that baroreflex impairment is primarily caused by sympathetic overactivity. According to the second theory, an impairment of baroreceptor function may contribute to systemic sympathetic activation by an attenuation of inhibitory signals responsible for a reduction of the efferent sympathetic activity. In acute MI, norepinephrine is released in large amounts within the ischemic myocardium. 23 With additional vagal afferent suppression, the norepinephrine release is reportedly enhanced. 24 Incomplete reperfusion may lead to a higher norepinephrine release owing to an impairment of afferent vagal activity, whereas complete reperfusion may lead to lower norepinephrine levels owing to intact vagal afferent activity. Kawada et al 24 recently demonstrated that parasympathetic modulation of ischemia-induced myocardial norepinephrine release is controlled by reflex vagal afferent inhibition, whereas presyn-

6 Bonnemeier et al Reflex Cardiac Activity in Ischemia and Reperfusion 963 aptic inhibition of norepinephrine by enhanced local release of acetylcholine was found to be insignificant. 24,25 In the present study, the increase of baroreflex function after complete reperfusion was associated with only a mild and insignificant decrease of serum norepinephrine levels. Thus, it is also unlikely that baroreceptor impairment is the decisive mechanism for increased norepinephrine levels in acute MI. By exclusion, the third theory is the most plausible to us. Baroreflex function and norepinephrine concentrations in acute MI are not dependent on each other but rather share a common underlying determinant, myocardial reperfusion. Incomplete reperfusion may cause a sustained excitation of cardiac sympathetic nerve endings in the ischemic zone, leading to sympathetic reflex cardio-cardiac and cardiosystemic stimulation, as well as baroreflex sensitivity depression. 26 Heart Rate Variability and HRT in Acute MI Measures of reflex vagal activity (ie, baroreflex sensitivity and HRT) and measures of tonic vagal activity (ie, HRV) are not redundant but provide different information about cardiac parasympathetic function. 1,27 Consistent with previous studies, we were able to reproduce a weak correlation between HRT and HRV. In contrast to HRT, there were no significant differences in HRV after PCI in patients with TIMI 2 and 3 flow, suggesting that successful reperfusion mainly improves reflex vagal tone. It has been shown that vagal stimulation significantly reduces the occurrence of ventricular arrhythmias in acute MI, whereas an alteration of tonic vagal activity does not modify the occurrence of ventricular arrhythmias. 28 Therefore, we suggest that successful reperfusion in acute MI alleviates the detrimental effect of MI on vagal activity, which may contribute to increased electrical stability in the early phase of MI. Validity of HRT as a Risk Marker HRT has been shown to be a powerful predictor of mortality and sudden cardiac death after MI. 2,27 Compared with other risk stratifiers, however, the positive predictive value for adverse cardiac events is only modestly higher. 29 A considerable advantage of HRT is its applicability as a noninvasive risk marker in patients treated with -blockers, representing the majority of post-mi patients. 30 Also, HRT seems to be a predominantly vagal phenomenon and is completely abolished by atropine. 31 Therefore, HRT not only may serve as a risk stratifier for cardiac mortality in the chronic phase of MI but also may detect a pathological loss of reflex vagal activity in the acute phase of MI. It would be premature to consider HRT as a discriminator between complete and incomplete reperfusion. However, the reperfusion-dependent time course of HRT represents a previously unrecognized phenomenon, which needs further investigation for understanding the pathophysiological mechanisms of reperfusion on autonomic reflexes. Conclusions The present study is the first to demonstrate alterations of HRT in the acute phase of MI in patients undergoing modern reperfusion therapy and concomitant medical treatment. The improvement of HRT after successful reperfusion reflects a rapid restoration of baroreflex response. In contrast, the persistent impairment of HRT after PCI in patients with impaired coronary flow implies a sustained blunted baroreflex response and may reflect a more severe microvascular dysfunction. Therefore, complete reperfusion leads to both, myocardial salvage and autonomic salvage. Acknowledgments We are indebted to all the patients participating in this study. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Ri 423/4-2). References 1. 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