The D-allele of the ACE polymorphism is related to increased QT dispersion in 609 patients after myocardial infarction

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1 European Heart Journal (2001) 22, doi: /euhj , available online at on The D-allele of the ACE polymorphism is related to increased QT dispersion in 609 patients after myocardial infarction A. Jeron 1, C. Hengstenberg 1, S. Engel 2,H.Löwel 2, G. A. J. Riegger 1, H. Schunkert 1 and S. Holmer 1 1 Innere Medizin II, Klinikum der Universität Regensburg, Regensburg, Germany; 2 GSF Forschungszentrum, Institut für Epidemiologie, Munich-Neuherberg, Germany Aims Prolongation of QT dispersion can be observed in some patients with myocardial infarction and serves as a possible independent risk factor for sudden cardiac death. Angiotensin-converting enzyme (ACE) inhibition has been shown to reduce QT dispersion in myocardial infarction patients. We hypothesized that ACE gene I/D polymorphism, which is known to modulate ACE activity, may also affect QT dispersion after myocardial infarction. Methods and Results We studied 609 myocardial infarction patients (532 men, aged ; mean 5 5 years after myocardial infarction) from a population-based myocardial infarction register by standardized questionnaire, anthropometry, ECG, echocardiography, and genotyping of ACE I/D polymorphism. In addition, 540 unaffected siblings (251 men, age years) of these patients were studied by the same protocol. As compared with their healthy siblings, mean QT dispersion was prolonged in myocardial infarction patients ( ms vs ms, respectively, P<0 001). QT dispersion was negatively correlated to left ventricular ejection fraction (P<0 005). The ACE DD-genotype was associated with longer QT dispersion in myocardial infarction patients ( ms vs ms in the II group, P<0 001). This association was noted to be strong in multivariate analyses that included age, gender, ejection fraction, left ventricular end-diastolic diameter, medication, and heart rate. In contrast, no association between the ACE DD-genotype and QT dispersion was detected in healthy siblings of myocardial infarction patients. Conclusion Thus, the ACE D-allele may be associated with increased QT dispersion in patients after myocardial infarction but not in healthy subjects. An interaction of myocardial damage and genetic predisposition that both enhance the activity of the renin angiotensin system may decrease the repolarization homogeneity of the heart. (Eur Heart J 2001; 22: , doi: /euhj ) 2001 The European Society of Cardiology Key Words: ACE polymorphism, renin angiotensin system, myocardial infarction, QT dispersion, remodelling. See page 618 for the Editorial comment on this article Introduction QT dispersion, a marker of repolarization homogeneity, is considered a predictor of sudden cardiac death and mortality in patients with myocardial infarction [1 3]. Despite some controversial data about the positive predictive value of increased QT dispersion [4], this ECG marker, which can be easily measured, appears to be a powerful tool for risk stratification in patients with Revision submitted 22 May 2000, and accepted 24 May Correspondence: Andreas Jeron, MD, Innere Medizin II, Klinikum der Universität Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, Germany X/01/ $35.00/0 impaired left ventricular function after myocardial infarction [5 7]. Recently, several studies reported improved QT dispersion after angiotensin II receptor blockade [8] or angiotensin converting enzyme (ACE) inhibitor therapy [9,10] in patients with myocardial infarction, suggesting that angiotensin II may directly or indirectly modulate QT dispersion. Thus, it has been suggested that improvement of repolarization homogeneity may be one mechanism that confers prognostic benefit by ACE inhibitors. Carriers of the D-allele of ACE insertion/deletion (I/D) polymorphism display elevated serum and cardiac ACE activity and thus may be exposed to higher angiotensin II levels than those with the I-allele [11 13]. A large 2001 The European Society of Cardiology

2 664 A. Jeron et al. body of literature suggests that this genetic variation, which includes associations of the D allele with myocardial infarction [14,15], hypertension [16], and left ventricular hypertrophy is of clinical relevance [16 18]. Furthermore, the DD-genotype was associated with augmented neurohumoral activation and cardiac dilatation, as well as poor prognosis after an acute myocardial infarction [19,20]. Based on these findings we hypothesized that ACE I/D polymorphism may be associated with QT dispersion after myocardial infarction. corrected QT interval was calculated according to the Bazet formula. QT dispersion was calculated as the maximal QT interval minus the minimal QT interval (QTmax QTmin) of the 12 leads if the QT interval was measurable in more than seven leads (mean ). Individuals with an ECG showing a bundle branch block pattern with a QRS duration greater than 120 ms were excluded from further analysis. Complete electrocardiographic data were available in 493 of 609 myocardial infarction patients and 441 of 540 siblings. Methods Study population Patients with myocardial infarction prior to the age of 60 years and their siblings were identified through the population-based Augsburg MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) myocardial infarction register. The diagnosis of myocardial infarction was established according to the MONICA diagnostic criteria [21]. Of 1254 patients contacted, 609 agreed to participate in the study (532 men, aged years). The results were compared with data of 540 healthy siblings (251 men, aged ) of these myocardial infarction patients who were examined by the same protocol. Male and female siblings as well as myocardial infarction patients were studied by clinical examination, blood testing and a standardized interview. None of the myocardial infarction patients had signs of acute myocardial infarction or unstable angina pectoris at the time of examination and recording of the ECG. Body weight and height were determined and body mass index was calculated. The investigation conforms with the principles outlined in the Declaration of Helsinki. Echocardiography The echocardiographic examination was carried out by a single experienced investigator blinded to the history and genotype of the patient. Left ventricular enddiastolic diameter and left ventricular end-systolic diameter were measured in the long parasternal axis view. Left ventricular ejection fraction was measured in the apical four chamber view according to the modified Simpson method as described [22]. Transmitral flow velocity patterns were assessed by pulsed wave Doppler. Electrocardiography A 12-lead resting ECG was recorded and stored in a digitized fashion. The QT interval in individual leads was computed by HP software PageWriter XL A (Hewlett Packard, Inc.) and double checked by an investigator blinded to the clinical data. The mean ACE polymorphism DNA was extracted from whole blood. The ACE polymorphism was analysed by polymerase chain reaction as described in detail [18]. A nested polymerase chain reaction amplification was performed to exclude mistyping of individuals homogenous for the D allele [23]. Complete genotypes were available in 606 myocardial infarction patients and 540 siblings. Statistics All statistics were calculated by the SPSS software 8.0 for Windows (SPSS, Inc). Student s t-test for comparison between two groups, and ANOVA with LSD post hoc test for multiple comparisons between more than two groups, were applied. Differences between myocardial infarction patients and siblings, with respect to non-parametric variables, were tested by the chi-square test. In addition, multiple regression analysis was performed. This included QT dispersion as a dependent variable and age, gender, therapy with ACE inhibitors or beta-blockers, left ventricular ejection fraction, left ventricular end-diastolic diameter and ACE genotype as independent covariates. All numbers were calculated as mean SE (standard error of the mean). Differences were considered significant for P<0 05. Results Study population On average, myocardial infarction patients were studied 5 5 years (range 1 10 years) after their first myocardial infarction. The mean age of the myocardial infarction patient group and the non-affected sibling group was similar (Table 1). As expected, the proportion of male individuals or those with decreased left ventricular ejection fraction was higher in the myocardial infarction patient group (Table 1). Moreover, as compared to their gender-matched siblings, myocardial infarction patients were characterized by increased left ventricular diameters, higher body mass index, higher prevalence

3 QT dispersion after MI 665 Table 1 Demographic and echocardiographic data in male and female myocardial infarction patients and unaffected siblings Males Females MI Siblings P MI Siblings P n Age (years) ns ns LVFS (%) ns LVEF (%) ns LVEDD (mm) LVESD (mm) BMI (kg. m 2 ) Syst. BP (mmhg) Diast. BP (mmhg) ns Diabetes (%) Medication (%) Beta blockers ACEI Nitrates Diuretics Ca Antag n=number of individuals in each group; LVFS=left ventricular fraction shortening; LVEF=left ventricular ejection fraction; LVEDD/ SD=left ventricular end diastolic diameter/systolic diameter; BMI=body mass index; syst/diast BP=systolic/diastolic blood pressure; ACEI=ACE inhibitors; P-values for comparison between myocardial infarction patients and siblings (t-test for parametric variables, chi-square test for non-parametric variables); ns=p>0 05. Table 2 Electrocardiographic data in male and female myocardial infarction patients and unaffected siblings Males Females MI Siblings P MI Siblings P Cycle length (ms) ns QT (ms) ns QTc (ms) ns QTd (ms) QT=QT interval; QTc=QT interval corrected for heart rate (Bazet Formula); QTd=QT dispersion. of diabetes mellitus as well as lower blood pressure (Table 1). The utilization of cardiovascular medication is also listed in Table 1. Resting heart rate was lower in the myocardial infarction group compared to the respective sibling groups (Table 2), probably due to the more extensive use of beta-blockers. The QT interval and the QT corrected interval were prolonged in male myocardial infarction patients compared to their brothers, and QT dispersion was significantly prolonged in male and female myocardial infarction patient groups compared to their respective sibling groups. Moreover, in myocardial infarction patients with reduced global left ventricular function (left ventricular ejection fraction 40%, n=60) QT dispersion was significantly prolonged as compared to myocardial infarction patients with left ventricular ejection fraction >40% (n=428; ms vs ms, respectively, P<0 0001). ACE polymorphism Neither in myocardial infarction patients nor in siblings of myocardial infarction patients was an association between ACE I/D polymorphism and left ventricular diameters or ejection fraction found. Likewise, the ratio of early to late peak diastolic transmitral flow velocity (E/A ratio), QT interval duration and cycle length were similar in the three genotype groups (Table 3). Moreover, no differences were found between the three genotype groups regarding the utilization of ACE inhibitors, diuretics, digitalis, or beta-blockers (data not shown). Myocardial infarction patients with the DD genotype showed significantly longer QT dispersion than myocardial infarction patients with the II or ID genotype (Fig. 1). In contrast, no significant difference between genotypes was seen in siblings of myocardial infarction patients (Fig. 1). The association of ACE polymorphism

4 666 A. Jeron et al. Table 3 ACE polymorphism and echo- and electrocardiographic findings Genotype II ID DD P MI patients n Age (years) ns QT interval (ms) ns QTc interval (ms) ns Cycle length (ms) ns LVEF (%) ns LVEDD (mm) ns LVESD (mm) ns E/A ns Siblings n Age (years) ns QT interval (ms) ns QTc interval (ms) ns Cycle length (ms) ns LVEF (%) ns LVEDD (mm) ns LVESD (mm) ns E/A ns QT=QT interval; QTc=QT interval corrected for heart rate (Bazet Formula); LVEF=left ventricular ejection fraction; LVEDD/SD=left ventricular end-diastolic diameter/systolic diameter; E/A=rate of early to late diastolic transmitral peak flow velocity. P-values are derived from ANOVA. with QT dispersion in myocardial infarction patients was significantly observed regardless of whether patients were on chronic ACE-inhibitor treatment or not. Patients on ACE-inhibition showed prolonged QT dispersion and lower ejection fraction compared to those without ACE-inhibitor intake (Table 4). A multivariate analysis was carried out in order to test the independent effects of age, gender, left ventricular ejection fraction, left ventricular end-diastolic diameter, heart rate, medication with ACE-inhibitors or betablockers and ACE polymorphism on QT dispersion in myocardial infarction patients. In the regression model, ACE polymorphism together with left ventricular ejection fraction and left ventricular end-diastolic diameter QT dispersion (ms) n ns Genotype II ID DD Figure 1 QT dispersion (in ms) in myocardial infarction patients ( ) and siblings ( ). Numbers of individuals in each genotype group are indicated. P-values are derived from ANOVA and LSD post hoc test. were identified as strong independent predictors of QT dispersion in myocardial infarction patients (Table 5). Discussion Prolongation of QT dispersion is frequently observed with left ventricular dilatation, low ejection fraction, and extensive cardiac scarring after myocardial infarction and is thought to indicate reduced repolarization homogeneity of a diseased heart [24]. Here we present data suggesting that genetic factors may also affect QT dispersion. Particularly, analysis of 493 myocardial infarction patients revealed a strong independent association of the ACE I/D polymorphism with QT dispersion. In contrast, this association is not observed in 441 healthy siblings of these myocardial infarction patients. Although this observational study does not conclusively link a pathophysiological mechanism to a prolongation of QT dispersion, the data once again emphasize the potential role of the renin angiotensin system in the morphological and electrophysiological remodelling process of the heart. Previous studies demonstrated that the ACE I/D polymorphism may affect cardiac dilatation and hypertrophy in myocardial infarction [20] or untreated hypertensive patients [11,25]. The DD genotype was also associated with electrocardiographic signs of left ventricular hypertrophy [18]. Post myocardial infarction remodelling and left ventricular hypertrophy are known to reflect cellular hypertrophy and interstitial fibrosis, that subsequently may result in prolonged action

5 QT dispersion after MI 667 Table 4 ACE genotype and QT dispersion in myocardial infarction patients with or without ACE inhibitor therapy Genotype II ID DD P MI Patients with ACE inhibitor (n) ns QTd (ms) LVEF (%) ns LVEDD (mm) ns MI patients without ACE inhibitor (n) QTd (ms) LVEF (%) ns LVEDD (mm) ns QTd=QT dispersion; LVEF=left ventricular ejection fraction; LVEDD=left ventricular enddiastolic diameter. P-values are derived from ANOVA. potential duration, QT interval duration and QT dispersion, as well as an increased risk of malignant arrhythmias [26]. Interestingly, a recent study by Anvari et al. demonstrated a higher prevalence of the ACE DD genotype in 100 patients with coronary artery disease and reduced left ventricular function who survived sudden cardiac death and received an implantable cardioverter defibrillator compared to those without sudden cardiac death and no need for an implantable cardioverter defibrillator [27]. In these individuals the ACE DD genotype was subsequently associated with an increased risk for malignant ventricular arrhythmias, as recorded by the implantable cardioverter defibrillator. Based on our findings one could speculate that prolongation of QT dispersion may be one mechanism causing such an association of malignant arrhythmias with a genetic variation of the renin angiotensin system. Importantly, no association of QT dispersion with the DD genotype was observed in siblings of similar age with undamaged hearts. Thus, in agreement with other phenotypic modulations related to ACE polymorphism, such as adaptive left ventricular hypertrophy after exercise, hypertension or myocardial infarction [11,25,28], this genetic modulation of repolarization homogeneity may take place particularly during an adaptive process. Table 5 Multiple linear regression analysis of factors with potential influence on QT dispersion in myocardial infarction patients (n=493) Variable Beta-coefficient (ms) P Gender (female vs male) Age (per year older) ACE inhibitors (yes vs no) Beta-blocker (yes vs no) LVEF (per 10% reduction) LVEDD (per 10 mm larger) ACE genotype (DD vs II) LVEF=left ventricular ejection fraction; LVEDD=left ventricular end-diastolic diameter. How to read the table: A 10 mm increase in left ventricular end-diastolic diameter results in a 13 9 ms prolongation of QT dispersion. The precise mechanism that links ACE I/D polymorphism and QT dispersion is unclear. However, ACE polymorphism clearly modulates ACE activity the D allele being associated with higher ACE activity and, thereby, may affect angiotensin II formation at some tissue sites including the myocardium [12 14]. Enhanced local angiotensin formation may induce cellular hypertrophy [29] and may modulate cardiac remodelling and fibrosis. This process ultimately may increase the action potential duration in some cardiac areas and, thus, prolong QT dispersion. This hypothesis is in agreement with data from pharmacological intervention studies that demonstrated a decrease in QT dispersion after angiotensin II blockade [8] or ACE inhibitor therapy [9,10,30]. The data in our observational study, showing that intake of ACE-inhibitors is associated with prolonged QT dispersion, is not contradictory to these results since patients on ACE-inhibitors appear more often to have systolic dysfunction, as indicated by a lower ejection fraction, that is clearly associated with prolonged QT dispersion. A limitation of the present observational study is that information on coronary patency was not available in myocardial infarction patients. However, there were no signs of ongoing ischaemia in these patients while the examinations took place. A second limitation is a lack of follow-up, such that we cannot estimate the predictive value of ACE polymorphism or prolonged QT dispersion on the risk of malignant arrhythmias in these myocardial infarction patients. In conclusion, in patients with previous myocardial infarction, ACE I/D polymorphism was identified as a strong, independent predictor of prolongation of QT dispersion. Large prospective studies examining the clinical implications of this relationship, with respect to survival or the need for antiarrhythmic therapy, are warranted. We appreciate the excellent work of the KORA field study team in Augsburg as well as the technical assistance by Ms Susanne Kürzinger, Mrs Melanie Pöll, and Mr Christian Baier. This study was supported by the Deutsche Forschungsgemeinschaft (DFG Ho1073/8-1).

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