- Email: [email protected]
Loratidine improves ischemic parameters of exercise stress test in patients with acute myocardial infarction
Loratidine improves ischemic parameters of exercise stress test in patients with acute myocardial infarction Okan Erdogan, MD, FESC, Armagan Altun, MD, FESC, Sabri Gazi, MD, and Gultac Ozbay, MD Edirne, Turkey
Background: This study sought to determine whether adding an anti-histaminic medication, loratidine, to anti-ischemic treatment would ameliorate or improve ischemic parameters induced by exercise stress test in patients who suffered an acute myocardial infarction. Methods:
Twenty stable patients with acute inferior myocardial infarction who had a positive EST were randomly allocated into 2 groups, A and B. Patients in group A and B received a 10 mg loratidine tablet added daily to their antiischemic regimen for 7 days during the second and third week post-event, respectively. At the end of each period they underwent an exercise stress test (EST). Exercise parameters in each group were then compared before and after loratidine therapy.
Results:
Both groups showed improvements in exercise parameters after loratidine therapy compared to basal EST results. STmax ( group A: 1.9 ⫾ 0.74 vs 0.9 ⫾ 1.29 mm, P ⫽ .046; group B: 2.5 ⫾ 0.71 vs 1.4 ⫾ 1.17 mm, P ⫽ .041), STlead ( group A: 3.4 ⫾ 1.08 vs 1.5 ⫾ 2.12, P ⫽ .027; group B: 4.6 ⫾ 1.71 vs 2.22 ⫾ 2.25, P ⫽ .011), STtotal ( group A: 4.7 ⫾ 2.18 vs 2.1 ⫾ 3.11 mm, P ⫽ .024; group B: 7.9 ⫾ 2.92 vs 3.33 ⫾ 3.81 mm, P ⫽ .005).
Conclusion: Our study revealed that loratidine, a histamine-1 receptor blocker, improves ischemic parameters of EST when given as additive therapy to a routine anti-ischemic regimen during the sub-acute phase of myocardial infarction. (Am Heart J 2004;148:e24.) Inflammation of atherosclerotic coronary artery plaques plays an important role in thrombotic coronary events.1 Inflammatory cells such as lymphocytes and macrophages accumulate within the plaque and cause its rupture.2 It has been recently shown that mast cells also accumulate at the site of rupture in coronary atherosclerotic plaques.3,4 When stimulated, mast cells release histamine that is a powerful vasoconstrictor in atherosclerotic coronary segments and other vasoactive substances that may ultimately be responsible for coronary spasm.5,6 It has also been shown that the concentration of histamine in the coronary circulation is elevated shortly before coronary spasm with ensuing attacks of angina.7 Coronary vasospasm plays a major role in occlusive coronary thrombosis.8,9 The action of histamine via histamine-1 (H-1) receptors on smooth muscle cells in the medial layer of coronary
From Department of Cardiology, School of Medicine, Trakya University, Edirne, Turkey. Reprint requests: Okan Erdogan, MD, Arseven Sitesi Villa Konutlari No: 2, Edirne Turkey 22030. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2004.04.048
arteries is mainly vasoconstriction.10 Additionally, the vasoconstrictive response to histamine, especially in atherosclerotic segments, is likely to be vigorous because the damaged endothelium is incapable of synthesizing and secreting sufficient amounts of vasodilatory mediators.11 According to above-mentioned findings and mechanisms, it is obvious that the plaque rupture in acute myocardial infarction (MI) and the subsequent process of thrombotic and vasospastic components are partially mediated through mast cells and their secreted mediators such as histamine and chymase localized to the adventitial and medial layers of atherosclerotic segments where the plaque is prone to rupture. If there is a predominant role of mast cell and its mediator histamine on the process of MI, especially during the early period of the event when the action of histamine is suspected to be the greatest, then its deleterious vasoconstrictive action might be inhibited by blocking its effect on specific H-1 receptors. To our knowledge, this assumption has not been investigated before. Therefore, we planned a prospective clinical study to find out whether there would be any clinical anti-ischemic additive effect of a selective H-1 receptor blocker antihistaminic, namely loratidine, in patients who have recently suffered an acute myocardial infarction.
American Heart Journal December 2004
c2 Erdogan et al
Figure 1
Table I. Clinical characteristics of patients in both study groups Group A (n ⴝ 10) Group B (n ⴝ 10)
Diagram demonstrating the study design (EST: exercise stress test).
Methods Patients and study protocol Stable patients with acute inferior MI and no contraindication to exercise stress test (EST) underwent an EST with a modified Bruce protocol between the seventh and ninth days after the event. Patients who demonstrated a positive EST and who did not have certain conditions such as heart failure, bundle branch block, body mass index ⬎ 30 kg/m2, valvular heart disease, and electrocardiographic criteria for ventricular hypertrophy, were enrolled in the study. The institutional ethical review board of our medical school approved the study protocol and all patients gave verbal informed consent. Twenty such patients who fulfilled the above-mentioned criteria were randomly allocated into 2 groups (first patient in group A, the second in group B, etc.). Patients in both groups received optimal medical therapy throughout the study period. Patients in group A had a 10 mg tablet of loratidine added daily to their anti-ischemic regimen for 7 days, commencing on the first day of their first positive EST. After 7 days, with loratidine on board, they underwent a second EST. On that day, patients stopped taking loratidine and, a week later, they performed a third and last EST without loratidine on board. Patients in group B, however, took their routine anti-ischemic therapy on the first day of their first positive EST and continued the same regimen for the next week. On the first day of the next week, they underwent the second EST and began taking loratidine in addition to their regular medical regimen, and continued for 1 week. On the seventh day, Group B performed the third and last EST with loratidine on board (Figure1).
EST and measurement of variables Treadmill EST with modified Bruce protocol was performed at the end of each period. Heart rate, blood pressure, and 12-lead ECG recordings were simultaneously obtained before exercise and during the test and continued until STsegment changes resolved. The EST was terminated when ⱖ1 of the following end points were reached: physical exhaustion, progressive angina, dyspnea, extreme fatigue, severe arrhythmia, or ST-segment depression ⬎3 mm. The diagnostic criteria used for myocardial ischemia was 1 mm horizontal or down-sloping ST-segment depression measured at 0.08 sec later from the J point. At the end of the study period and after all test results were obtained, the measure-
Age Male BMI (kg/m2) Hypertension Diabetes Smoking Family history Previous MI Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Trombolytic therapy Aspirin -Blocker ACE-I Statin Ca-channel blocker Diuretic
57.4 ⫾ 7.4* 9 29.3 ⫾ 4.4 3 3 6 5 2 185 ⫾ 40 110 ⫾ 33 39 ⫾ 5 151 ⫾ 76 5 10 9 8 10 1 0
49.5 ⫾ 7.0* 10 27.3 ⫾ 4.5 1 2 7 1 0 197 ⫾ 48 124 ⫾ 37 43 ⫾ 9 109 ⫾ 44 7 10 6 4 8 0 1
BMI, Body mass index; MI, myocardial infarction; ACE-I, angiotensin-converting enzyme inhibitor; Ca, calcium. *P ⫽ .015.
ments were blindly performed by 1 of the authors who was unaware of patients’ groups and therapy states. The following parameters were compared: time to 1 mm ST-segment depression (ST 1mm), maximum ST-segment depression (STmax), lead numbers of ST-segment depression (STlead), total ST-segment depression (STtotal), total exercise time (ET), time to ST-segment depression recovery (STrec), heart rate (initial and peak exercise: HRi, HRp), systolic and diastolic blood pressures (initial and peak exercise: SBPi, SBPp, DBPi, DBPp) and double product (initial and peak exercise: DPi, DPp).
Statistical analysis SPSS version 10.0 (Chicago, Illinois, USA) was used for statistical analysis. The values of age, body mass index, and blood pressure are expressed as the mean ⫾ SD. Baseline variables were compared between the 2 groups by means of a Mann-Whitney U test. Changes in variables in each subject were analyzed by Friedman analysis of variance (ANOVA) & Kendall’s concordance and Wilcoxon matched pair test. A P ⬍ .05 was considered significant.
Results Clinical characteristics of patients in both groups are given in Table I. Patients in group A were older than patients in group B (P ⫽ .015), whereas the other parameters of both groups were comparable. Table II demonstrates the changes of EST variables in group A. Compared to baseline measurements, parameters such as STmax, STlead, STtotal, and STrec significantly decreased after 1 week of treatment with loratidine.
American Heart Journal Volume 148, Number 6
Erdogan et al c3
Table II. Changes of baseline (1 week after the event), second (1 week later after loratidine was added to anti-ischemic therapy) and third (1 week after loratidine was discontinued) exercise stress test (EST) results in patients of group A (n ⫽ 10)
HRi (beats/min) SBPi (mm Hg) DBPi (mm Hg) DPi (beats ⫻ mm Hg/min) ST1mm (s) STmax (mm) STlead STtotal (mm) ET (s) HRp (beats/min) SBPp (mm Hg) DBPp (mm Hg) DPp (beats ⫻ mm Hg/min) STrec (s)
Baseline
Second EST
Third EST
74 ⫾ 14 123 ⫾ 19 75 ⫾ 10 9152 ⫾ 2835 462 ⫾ 170 1.9 ⫾ 0.74* 3.4 ⫾ 1.08† 4.7 ⫾ 2.18‡ 649 ⫾ 218㛳 123 ⫾ 8 148 ⫾ 25 75 ⫾ 11 18154 ⫾ 3536 252 ⫾ 74§
73 ⫾ 12 123 ⫾ 17 76 ⫾ 12 8899 ⫾ 1792 252 ⫾ 331 0.9 ⫾ 1.29* 1.5 ⫾ 2.12† 2.1 ⫾ 3.11‡ 786 ⫾ 90㛳 133 ⫾ 19 152 ⫾ 21 79 ⫾ 12 20108 ⫾ 3871 90 ⫾ 124§
75 ⫾ 20 122 ⫾ 17 77 ⫾ 10 9151 ⫾ 2988 330 ⫾ 359 0.9 ⫾ 1.1* 1.8 ⫾ 2.1† 2.6 ⫾ 3.37‡ 806 ⫾ 115㛳 135 ⫾ 18 161 ⫾ 27 79 ⫾ 11 22448 ⫾ 5225 120 ⫾ 130§
ST1mm, Time to 1 mm ST-segment depression; STmax, maximum ST-segment depression; STlead, lead numbers of ST-segment depression; STtotal, total ST-segment depression; ET, total exercise time; HRi, HRp, heart rate (initial and peak exercise); SBPi, SBPp, DBPi, DBPp, systolic and diastolic blood pressures (initial and peak exercise); DPi, DPp, double product (initial and peak exercise); STrec, time to ST-segment depression recovery. *Friedman ANOVA test 2 ⫽ 6.4, P ⫽ .04, Wilcoxon; baseline-second P ⫽ .046, baseline-third, P ⫽ .026. †Friedman ANOVA test 2 ⫽ 7.75, P ⫽ .021, Wilcoxon; baseline-second, P ⫽ .027, baseline-third, P ⫽ .027. ‡Friedman ANOVA test 2 ⫽ 6.1; P ⫽ .048, Wilcoxon; baseline-second, P ⫽ .024, baseline-third, P ⫽ .017. §Friedman ANOVA test 2 ⫽ 7.2, P ⫽ .027, Wilcoxon; baseline-second, P ⫽ .018, baseline-third, P ⫽ .039. 㛳Wilcoxon; baseline-third, P ⫽ .017, baseline-second, P ⫽ .065.
Figure 2
Significant improvement of ischemic parameters (ST max, ST lead and ST total) induced by exercise stress test (EST) are demonstrated after adding loratidine at the end of the second week (2. EST) and persistence throughout the third week.
However, after loratidine therapy was discontinued, those parameters such as STlead, STtotal, and STrec slightly, but not significantly, increased compared to exercise stress test (EST) results on loratidine therapy (Figure 2). Table III demonstrates the changes of EST variables in group B. Patients in group B received loratidine therapy after the second EST. The third EST on loratidine therapy showed that parameters such as STmax, STlead, and STtotal significantly decreased compared to both baseline and second EST results (Figure 3). ET of the third EST also increased compared to previous ESTs.
Discussion The findings of our study revealed that adding loratidine (a second generation, non-sedative, specific H-1 receptor blocker) to an anti-ischemic regimen in patients who suffered an acute MI significantly improved ischemic parameters induced by an EST that was performed 2 and 3 weeks after the event. It is well known that the entire adventitial layer of the infarct-related coronary artery was affected by an inflammatory process.4 In the infarct-related coronary arteries of MI patients, the segments including the plaque rupture responsible for the infarction contained the greatest numbers of adventitial mast cells and, even in the normal segments of the infarct-related artery, the mast cell densities were higher than in the corresponding segments of the control arteries.4 The close relation between the adventitial mast cells and the media where small numbers of mast cells were also present suggests that part of the histamine released from the stimulated adventitial mast cells could diffuse directly into the media.4 Subsequently, if histamine bound to H-1 receptors on smooth muscle cells in the medial layer, especially in atherosclerotic segments where the opposing vasodilatory action is diminished, it will cause vasoconstriction.10,11 This histamine-related mechanism is, however, 1 of the several factors involved in plaque rupture and subsequent thrombotic process as well as vasoconstrictive process. We, therefore, hypothesized whether it might be possible to ameliorate the ongoing myocardial ischemia in patients with acute MI by blocking the effects of hista-
American Heart Journal December 2004
c4 Erdogan et al
Table III. Changes of baseline (one week after the event), second (after the second week only on anti-ischemic therapy) and third (one week later after loratidine was added to anti-ischemic therapy) exercise stress test (EST) results in patients of group B (n ⫽ 10)
HRi (beats/min) SBPi (mm Hg) DBPi (mm Hg) DPi (beats ⫻ mm Hg/min) ST 1mm (s) STmax (mm) STlead STtotal (mm) ET (sec) HRp (beats/min) SBPp (mm Hg) DBPp (mm Hg) DPp (beats ⫻ mm Hg/min) STrec (s)
Baseline
Second EST
Third EST
71 ⫾ 8 122 ⫾ 24 70 ⫾ 8 8052 ⫾ 1681 457 ⫾ 270* 2.5 ⫾ 0.71† 4.6 ⫾ 1.71‡ 7.9 ⫾ 2.92§ 716 ⫾ 215㛳 130 ⫾ 18 153 ⫾ 36 80 ⫾ 11 20235 ⫾ 6268 270 ⫾ 65
70 ⫾ 12 113 ⫾ 15 71 ⫾ 9 8024 ⫾ 2152 649 ⫾ 206* 2.3 ⫾ 1.34† 4.0 ⫾ 1.7‡ 7.6 ⫾ 5.56§ 778 ⫾ 149㛳 132 ⫾ 16 141 ⫾ 15 76 ⫾ 11 18288 ⫾ 3746 216 ⫾ 110
75 ⫾ 9 115 ⫾ 22 73 ⫾ 12 8583 ⫾ 1898 522 ⫾ 391 1.4 ⫾ 1.17† 2.22 ⫾ 2.25‡ 3.33 ⫾ 3.81§ 852 ⫾ 130㛳 142 ⫾ 17 147 ⫾ 19 81 ⫾ 11 20860 ⫾ 3345 174 ⫾ 164
ST1mm, Time to 1 mm ST-segment depression; STmax, maximum ST-segment depression; STlead, lead numbers of ST-segment depression; STtotal, total ST-segment depression; ET, total exercise time; HRi, HRp, heart rate (initial and peak exercise); SBPi, SBPp, DBPi, DBPp, systolic and diastolic blood pressures (initial and peak exercise); DPi, DPp, double product (initial and peak exercise); STrec, time to ST-segment depression recovery. *Wilcoxon; baseline-second, P ⫽ .038. †Friedman ANOVA test 2 ⫽ 8.2, P ⫽ .017, Wilcoxon; baseline-third, P ⫽ .041, second-third, P ⫽ .007. ‡Friedman ANOVA test 2 ⫽ 12.3, P ⫽ .002, Wilcoxon; baseline-third, P ⫽ .011, second-third, P ⫽ .027. §Friedman ANOVA test 2 ⫽ 16; P ⫽ .0001, Wilcoxon; baseline-third, P ⫽ .005, second-third, P ⫽ .005. 㛳Wilcoxon; baseline-third, P ⫽ .05; second-third, P ⫽ .034.
Figure 3
After adding loratidine, significant improvement of ischemic parameters (ST max, ST lead and ST total) induced by exercise stress test (EST) are demonstrated at the end of the third week (3. EST).
mine on receptor level. Indeed, when added to antiischemic regimen and given in therapeutic dose, loratidine significantly diminished the ischemic response induced by EST. According to previous studies, the level of immunoglobulin-E, the best known immunologic stimulus leading to degranulation of human mast cells, increases during the acute phase of acute coronary syndromes and gradually decreases by the end of the third week after the event.12,13 This temporal response of mast cell activation after an acute coronary
event led us to suppose that the histamine’s vasoconstrictive effect may be prolonged and persists a few weeks more after the event. Therefore, we added loratidine to the anti-ischemic regimen on the second week after the event in 1 group and on the third week in the other group to prevent any misinterpretation of its possible time-related anti-ischemic response. Loratidine significantly improved the ischemic threshold by changing exercise parameters such as STmax, STlead, STtotal, and STrec in patients of both groups. When the drug was commenced on the second week post-event, this improvement continued even longer and was slightly impaired during the subsequent week after loratidine was stopped. On the other hand, when loratidine was added to the anti-ischemic regimen on the third week, it again caused a dramatic improvement in exercise parameters compared to the initial and second weeks’ test results. This finding supports that the anti-ischemic effect of loratidine is not by chance and it does not depend on the time related self-healing process of myocardial ischemia. In conclusion, our study revealed that loratidine, an H-1 receptor blocker, is safe and useful when given as additive therapy to routine anti-ischemic regimens during the acute phase of MI. It improves ischemic parameters of EST and may be considered as an additive therapeutic drug in patients who suffered an acute MI. However, it should be borne in mind that our study is small-sized, well-delineated and a pilot study. Therefore, it should stimulate further prospective clinical studies that comprise large patient populations.
American Heart Journal Volume 148, Number 6
References 1. Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation 1994;89:503–5. 2. Van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89:36 – 44. 3. Kovanen PT, Kaartinen MK, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:1084 – 8. 4. Laine P, Kaartinen M, Penttila A, et al. Association between myocardial infarction and the mast cells in the adventitia of the infarctrelated coronary artery. Circulation 1999;99:361–9. 5. Galli SJ. New concepts about the mast cell. N Eng J Med 1993; 328:257– 65. 6. Ginsburg R, Bristow MR, Davies K, et al. Quantitative pharmacologic responses of normal and atherosclerotic isolated human epicardial coronary arteries. Circulation 1984;69:430 – 40.
Erdogan et al c5
7. Sakata Y, Komamura K, Hirayama A, et al. Elevation of the plasma histamine concentration in the coronary circulation in patients with variant angina. Am J Cardiol 1996;77:1121– 6. 8. Oliva PB, Breckinridge JC. Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation 1977; 56:366 –74. 9. Hackett D, Davies G, Chierchia S, et al. Intermittent coronary occlusion in acute myocardial infarction. N Eng J Med 1987;317: 1055–9. 10. Toda N. Mechanism of histamine actions in human coronary arteries. Circ Res 1987;61:280 – 6. 11. Kalsner S, Richards R. Coronary arteries of cardiac patients are hyper-reactive and contain stores of amines: a mechanism for coronary spasm. Science 1984;223:1435–7. 12. Erdogan O, Gul C, Altun A, et al. Increased immunoglobulin-E response in acute coronary syndromes. Angiology 2003;54:73–9. 13. Erdogan O, Altun A, Gul C, et al. C-reactive protein and immunoglobulin-E response to coronary artery stenting in patients with stable angina. Jpn Heart J 2003;44:593– 600.
Background: This study sought to determine whether adding an anti-histaminic medication, loratidine, to anti-ischemic treatment would ameliorate or improve ischemic parameters induced by exercise stress test in patients who suffered an acute myocardial infarction. Methods:
Twenty stable patients with acute inferior myocardial infarction who had a positive EST were randomly allocated into 2 groups, A and B. Patients in group A and B received a 10 mg loratidine tablet added daily to their antiischemic regimen for 7 days during the second and third week post-event, respectively. At the end of each period they underwent an exercise stress test (EST). Exercise parameters in each group were then compared before and after loratidine therapy.
Results:
Both groups showed improvements in exercise parameters after loratidine therapy compared to basal EST results. STmax ( group A: 1.9 ⫾ 0.74 vs 0.9 ⫾ 1.29 mm, P ⫽ .046; group B: 2.5 ⫾ 0.71 vs 1.4 ⫾ 1.17 mm, P ⫽ .041), STlead ( group A: 3.4 ⫾ 1.08 vs 1.5 ⫾ 2.12, P ⫽ .027; group B: 4.6 ⫾ 1.71 vs 2.22 ⫾ 2.25, P ⫽ .011), STtotal ( group A: 4.7 ⫾ 2.18 vs 2.1 ⫾ 3.11 mm, P ⫽ .024; group B: 7.9 ⫾ 2.92 vs 3.33 ⫾ 3.81 mm, P ⫽ .005).
Conclusion: Our study revealed that loratidine, a histamine-1 receptor blocker, improves ischemic parameters of EST when given as additive therapy to a routine anti-ischemic regimen during the sub-acute phase of myocardial infarction. (Am Heart J 2004;148:e24.) Inflammation of atherosclerotic coronary artery plaques plays an important role in thrombotic coronary events.1 Inflammatory cells such as lymphocytes and macrophages accumulate within the plaque and cause its rupture.2 It has been recently shown that mast cells also accumulate at the site of rupture in coronary atherosclerotic plaques.3,4 When stimulated, mast cells release histamine that is a powerful vasoconstrictor in atherosclerotic coronary segments and other vasoactive substances that may ultimately be responsible for coronary spasm.5,6 It has also been shown that the concentration of histamine in the coronary circulation is elevated shortly before coronary spasm with ensuing attacks of angina.7 Coronary vasospasm plays a major role in occlusive coronary thrombosis.8,9 The action of histamine via histamine-1 (H-1) receptors on smooth muscle cells in the medial layer of coronary
From Department of Cardiology, School of Medicine, Trakya University, Edirne, Turkey. Reprint requests: Okan Erdogan, MD, Arseven Sitesi Villa Konutlari No: 2, Edirne Turkey 22030. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2004.04.048
arteries is mainly vasoconstriction.10 Additionally, the vasoconstrictive response to histamine, especially in atherosclerotic segments, is likely to be vigorous because the damaged endothelium is incapable of synthesizing and secreting sufficient amounts of vasodilatory mediators.11 According to above-mentioned findings and mechanisms, it is obvious that the plaque rupture in acute myocardial infarction (MI) and the subsequent process of thrombotic and vasospastic components are partially mediated through mast cells and their secreted mediators such as histamine and chymase localized to the adventitial and medial layers of atherosclerotic segments where the plaque is prone to rupture. If there is a predominant role of mast cell and its mediator histamine on the process of MI, especially during the early period of the event when the action of histamine is suspected to be the greatest, then its deleterious vasoconstrictive action might be inhibited by blocking its effect on specific H-1 receptors. To our knowledge, this assumption has not been investigated before. Therefore, we planned a prospective clinical study to find out whether there would be any clinical anti-ischemic additive effect of a selective H-1 receptor blocker antihistaminic, namely loratidine, in patients who have recently suffered an acute myocardial infarction.
American Heart Journal December 2004
c2 Erdogan et al
Figure 1
Table I. Clinical characteristics of patients in both study groups Group A (n ⴝ 10) Group B (n ⴝ 10)
Diagram demonstrating the study design (EST: exercise stress test).
Methods Patients and study protocol Stable patients with acute inferior MI and no contraindication to exercise stress test (EST) underwent an EST with a modified Bruce protocol between the seventh and ninth days after the event. Patients who demonstrated a positive EST and who did not have certain conditions such as heart failure, bundle branch block, body mass index ⬎ 30 kg/m2, valvular heart disease, and electrocardiographic criteria for ventricular hypertrophy, were enrolled in the study. The institutional ethical review board of our medical school approved the study protocol and all patients gave verbal informed consent. Twenty such patients who fulfilled the above-mentioned criteria were randomly allocated into 2 groups (first patient in group A, the second in group B, etc.). Patients in both groups received optimal medical therapy throughout the study period. Patients in group A had a 10 mg tablet of loratidine added daily to their anti-ischemic regimen for 7 days, commencing on the first day of their first positive EST. After 7 days, with loratidine on board, they underwent a second EST. On that day, patients stopped taking loratidine and, a week later, they performed a third and last EST without loratidine on board. Patients in group B, however, took their routine anti-ischemic therapy on the first day of their first positive EST and continued the same regimen for the next week. On the first day of the next week, they underwent the second EST and began taking loratidine in addition to their regular medical regimen, and continued for 1 week. On the seventh day, Group B performed the third and last EST with loratidine on board (Figure1).
EST and measurement of variables Treadmill EST with modified Bruce protocol was performed at the end of each period. Heart rate, blood pressure, and 12-lead ECG recordings were simultaneously obtained before exercise and during the test and continued until STsegment changes resolved. The EST was terminated when ⱖ1 of the following end points were reached: physical exhaustion, progressive angina, dyspnea, extreme fatigue, severe arrhythmia, or ST-segment depression ⬎3 mm. The diagnostic criteria used for myocardial ischemia was 1 mm horizontal or down-sloping ST-segment depression measured at 0.08 sec later from the J point. At the end of the study period and after all test results were obtained, the measure-
Age Male BMI (kg/m2) Hypertension Diabetes Smoking Family history Previous MI Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (mg/dL) Trombolytic therapy Aspirin -Blocker ACE-I Statin Ca-channel blocker Diuretic
57.4 ⫾ 7.4* 9 29.3 ⫾ 4.4 3 3 6 5 2 185 ⫾ 40 110 ⫾ 33 39 ⫾ 5 151 ⫾ 76 5 10 9 8 10 1 0
49.5 ⫾ 7.0* 10 27.3 ⫾ 4.5 1 2 7 1 0 197 ⫾ 48 124 ⫾ 37 43 ⫾ 9 109 ⫾ 44 7 10 6 4 8 0 1
BMI, Body mass index; MI, myocardial infarction; ACE-I, angiotensin-converting enzyme inhibitor; Ca, calcium. *P ⫽ .015.
ments were blindly performed by 1 of the authors who was unaware of patients’ groups and therapy states. The following parameters were compared: time to 1 mm ST-segment depression (ST 1mm), maximum ST-segment depression (STmax), lead numbers of ST-segment depression (STlead), total ST-segment depression (STtotal), total exercise time (ET), time to ST-segment depression recovery (STrec), heart rate (initial and peak exercise: HRi, HRp), systolic and diastolic blood pressures (initial and peak exercise: SBPi, SBPp, DBPi, DBPp) and double product (initial and peak exercise: DPi, DPp).
Statistical analysis SPSS version 10.0 (Chicago, Illinois, USA) was used for statistical analysis. The values of age, body mass index, and blood pressure are expressed as the mean ⫾ SD. Baseline variables were compared between the 2 groups by means of a Mann-Whitney U test. Changes in variables in each subject were analyzed by Friedman analysis of variance (ANOVA) & Kendall’s concordance and Wilcoxon matched pair test. A P ⬍ .05 was considered significant.
Results Clinical characteristics of patients in both groups are given in Table I. Patients in group A were older than patients in group B (P ⫽ .015), whereas the other parameters of both groups were comparable. Table II demonstrates the changes of EST variables in group A. Compared to baseline measurements, parameters such as STmax, STlead, STtotal, and STrec significantly decreased after 1 week of treatment with loratidine.
American Heart Journal Volume 148, Number 6
Erdogan et al c3
Table II. Changes of baseline (1 week after the event), second (1 week later after loratidine was added to anti-ischemic therapy) and third (1 week after loratidine was discontinued) exercise stress test (EST) results in patients of group A (n ⫽ 10)
HRi (beats/min) SBPi (mm Hg) DBPi (mm Hg) DPi (beats ⫻ mm Hg/min) ST1mm (s) STmax (mm) STlead STtotal (mm) ET (s) HRp (beats/min) SBPp (mm Hg) DBPp (mm Hg) DPp (beats ⫻ mm Hg/min) STrec (s)
Baseline
Second EST
Third EST
74 ⫾ 14 123 ⫾ 19 75 ⫾ 10 9152 ⫾ 2835 462 ⫾ 170 1.9 ⫾ 0.74* 3.4 ⫾ 1.08† 4.7 ⫾ 2.18‡ 649 ⫾ 218㛳 123 ⫾ 8 148 ⫾ 25 75 ⫾ 11 18154 ⫾ 3536 252 ⫾ 74§
73 ⫾ 12 123 ⫾ 17 76 ⫾ 12 8899 ⫾ 1792 252 ⫾ 331 0.9 ⫾ 1.29* 1.5 ⫾ 2.12† 2.1 ⫾ 3.11‡ 786 ⫾ 90㛳 133 ⫾ 19 152 ⫾ 21 79 ⫾ 12 20108 ⫾ 3871 90 ⫾ 124§
75 ⫾ 20 122 ⫾ 17 77 ⫾ 10 9151 ⫾ 2988 330 ⫾ 359 0.9 ⫾ 1.1* 1.8 ⫾ 2.1† 2.6 ⫾ 3.37‡ 806 ⫾ 115㛳 135 ⫾ 18 161 ⫾ 27 79 ⫾ 11 22448 ⫾ 5225 120 ⫾ 130§
ST1mm, Time to 1 mm ST-segment depression; STmax, maximum ST-segment depression; STlead, lead numbers of ST-segment depression; STtotal, total ST-segment depression; ET, total exercise time; HRi, HRp, heart rate (initial and peak exercise); SBPi, SBPp, DBPi, DBPp, systolic and diastolic blood pressures (initial and peak exercise); DPi, DPp, double product (initial and peak exercise); STrec, time to ST-segment depression recovery. *Friedman ANOVA test 2 ⫽ 6.4, P ⫽ .04, Wilcoxon; baseline-second P ⫽ .046, baseline-third, P ⫽ .026. †Friedman ANOVA test 2 ⫽ 7.75, P ⫽ .021, Wilcoxon; baseline-second, P ⫽ .027, baseline-third, P ⫽ .027. ‡Friedman ANOVA test 2 ⫽ 6.1; P ⫽ .048, Wilcoxon; baseline-second, P ⫽ .024, baseline-third, P ⫽ .017. §Friedman ANOVA test 2 ⫽ 7.2, P ⫽ .027, Wilcoxon; baseline-second, P ⫽ .018, baseline-third, P ⫽ .039. 㛳Wilcoxon; baseline-third, P ⫽ .017, baseline-second, P ⫽ .065.
Figure 2
Significant improvement of ischemic parameters (ST max, ST lead and ST total) induced by exercise stress test (EST) are demonstrated after adding loratidine at the end of the second week (2. EST) and persistence throughout the third week.
However, after loratidine therapy was discontinued, those parameters such as STlead, STtotal, and STrec slightly, but not significantly, increased compared to exercise stress test (EST) results on loratidine therapy (Figure 2). Table III demonstrates the changes of EST variables in group B. Patients in group B received loratidine therapy after the second EST. The third EST on loratidine therapy showed that parameters such as STmax, STlead, and STtotal significantly decreased compared to both baseline and second EST results (Figure 3). ET of the third EST also increased compared to previous ESTs.
Discussion The findings of our study revealed that adding loratidine (a second generation, non-sedative, specific H-1 receptor blocker) to an anti-ischemic regimen in patients who suffered an acute MI significantly improved ischemic parameters induced by an EST that was performed 2 and 3 weeks after the event. It is well known that the entire adventitial layer of the infarct-related coronary artery was affected by an inflammatory process.4 In the infarct-related coronary arteries of MI patients, the segments including the plaque rupture responsible for the infarction contained the greatest numbers of adventitial mast cells and, even in the normal segments of the infarct-related artery, the mast cell densities were higher than in the corresponding segments of the control arteries.4 The close relation between the adventitial mast cells and the media where small numbers of mast cells were also present suggests that part of the histamine released from the stimulated adventitial mast cells could diffuse directly into the media.4 Subsequently, if histamine bound to H-1 receptors on smooth muscle cells in the medial layer, especially in atherosclerotic segments where the opposing vasodilatory action is diminished, it will cause vasoconstriction.10,11 This histamine-related mechanism is, however, 1 of the several factors involved in plaque rupture and subsequent thrombotic process as well as vasoconstrictive process. We, therefore, hypothesized whether it might be possible to ameliorate the ongoing myocardial ischemia in patients with acute MI by blocking the effects of hista-
American Heart Journal December 2004
c4 Erdogan et al
Table III. Changes of baseline (one week after the event), second (after the second week only on anti-ischemic therapy) and third (one week later after loratidine was added to anti-ischemic therapy) exercise stress test (EST) results in patients of group B (n ⫽ 10)
HRi (beats/min) SBPi (mm Hg) DBPi (mm Hg) DPi (beats ⫻ mm Hg/min) ST 1mm (s) STmax (mm) STlead STtotal (mm) ET (sec) HRp (beats/min) SBPp (mm Hg) DBPp (mm Hg) DPp (beats ⫻ mm Hg/min) STrec (s)
Baseline
Second EST
Third EST
71 ⫾ 8 122 ⫾ 24 70 ⫾ 8 8052 ⫾ 1681 457 ⫾ 270* 2.5 ⫾ 0.71† 4.6 ⫾ 1.71‡ 7.9 ⫾ 2.92§ 716 ⫾ 215㛳 130 ⫾ 18 153 ⫾ 36 80 ⫾ 11 20235 ⫾ 6268 270 ⫾ 65
70 ⫾ 12 113 ⫾ 15 71 ⫾ 9 8024 ⫾ 2152 649 ⫾ 206* 2.3 ⫾ 1.34† 4.0 ⫾ 1.7‡ 7.6 ⫾ 5.56§ 778 ⫾ 149㛳 132 ⫾ 16 141 ⫾ 15 76 ⫾ 11 18288 ⫾ 3746 216 ⫾ 110
75 ⫾ 9 115 ⫾ 22 73 ⫾ 12 8583 ⫾ 1898 522 ⫾ 391 1.4 ⫾ 1.17† 2.22 ⫾ 2.25‡ 3.33 ⫾ 3.81§ 852 ⫾ 130㛳 142 ⫾ 17 147 ⫾ 19 81 ⫾ 11 20860 ⫾ 3345 174 ⫾ 164
ST1mm, Time to 1 mm ST-segment depression; STmax, maximum ST-segment depression; STlead, lead numbers of ST-segment depression; STtotal, total ST-segment depression; ET, total exercise time; HRi, HRp, heart rate (initial and peak exercise); SBPi, SBPp, DBPi, DBPp, systolic and diastolic blood pressures (initial and peak exercise); DPi, DPp, double product (initial and peak exercise); STrec, time to ST-segment depression recovery. *Wilcoxon; baseline-second, P ⫽ .038. †Friedman ANOVA test 2 ⫽ 8.2, P ⫽ .017, Wilcoxon; baseline-third, P ⫽ .041, second-third, P ⫽ .007. ‡Friedman ANOVA test 2 ⫽ 12.3, P ⫽ .002, Wilcoxon; baseline-third, P ⫽ .011, second-third, P ⫽ .027. §Friedman ANOVA test 2 ⫽ 16; P ⫽ .0001, Wilcoxon; baseline-third, P ⫽ .005, second-third, P ⫽ .005. 㛳Wilcoxon; baseline-third, P ⫽ .05; second-third, P ⫽ .034.
Figure 3
After adding loratidine, significant improvement of ischemic parameters (ST max, ST lead and ST total) induced by exercise stress test (EST) are demonstrated at the end of the third week (3. EST).
mine on receptor level. Indeed, when added to antiischemic regimen and given in therapeutic dose, loratidine significantly diminished the ischemic response induced by EST. According to previous studies, the level of immunoglobulin-E, the best known immunologic stimulus leading to degranulation of human mast cells, increases during the acute phase of acute coronary syndromes and gradually decreases by the end of the third week after the event.12,13 This temporal response of mast cell activation after an acute coronary
event led us to suppose that the histamine’s vasoconstrictive effect may be prolonged and persists a few weeks more after the event. Therefore, we added loratidine to the anti-ischemic regimen on the second week after the event in 1 group and on the third week in the other group to prevent any misinterpretation of its possible time-related anti-ischemic response. Loratidine significantly improved the ischemic threshold by changing exercise parameters such as STmax, STlead, STtotal, and STrec in patients of both groups. When the drug was commenced on the second week post-event, this improvement continued even longer and was slightly impaired during the subsequent week after loratidine was stopped. On the other hand, when loratidine was added to the anti-ischemic regimen on the third week, it again caused a dramatic improvement in exercise parameters compared to the initial and second weeks’ test results. This finding supports that the anti-ischemic effect of loratidine is not by chance and it does not depend on the time related self-healing process of myocardial ischemia. In conclusion, our study revealed that loratidine, an H-1 receptor blocker, is safe and useful when given as additive therapy to routine anti-ischemic regimens during the acute phase of MI. It improves ischemic parameters of EST and may be considered as an additive therapeutic drug in patients who suffered an acute MI. However, it should be borne in mind that our study is small-sized, well-delineated and a pilot study. Therefore, it should stimulate further prospective clinical studies that comprise large patient populations.
American Heart Journal Volume 148, Number 6
References 1. Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation 1994;89:503–5. 2. Van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89:36 – 44. 3. Kovanen PT, Kaartinen MK, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995;92:1084 – 8. 4. Laine P, Kaartinen M, Penttila A, et al. Association between myocardial infarction and the mast cells in the adventitia of the infarctrelated coronary artery. Circulation 1999;99:361–9. 5. Galli SJ. New concepts about the mast cell. N Eng J Med 1993; 328:257– 65. 6. Ginsburg R, Bristow MR, Davies K, et al. Quantitative pharmacologic responses of normal and atherosclerotic isolated human epicardial coronary arteries. Circulation 1984;69:430 – 40.
Erdogan et al c5
7. Sakata Y, Komamura K, Hirayama A, et al. Elevation of the plasma histamine concentration in the coronary circulation in patients with variant angina. Am J Cardiol 1996;77:1121– 6. 8. Oliva PB, Breckinridge JC. Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation 1977; 56:366 –74. 9. Hackett D, Davies G, Chierchia S, et al. Intermittent coronary occlusion in acute myocardial infarction. N Eng J Med 1987;317: 1055–9. 10. Toda N. Mechanism of histamine actions in human coronary arteries. Circ Res 1987;61:280 – 6. 11. Kalsner S, Richards R. Coronary arteries of cardiac patients are hyper-reactive and contain stores of amines: a mechanism for coronary spasm. Science 1984;223:1435–7. 12. Erdogan O, Gul C, Altun A, et al. Increased immunoglobulin-E response in acute coronary syndromes. Angiology 2003;54:73–9. 13. Erdogan O, Altun A, Gul C, et al. C-reactive protein and immunoglobulin-E response to coronary artery stenting in patients with stable angina. Jpn Heart J 2003;44:593– 600.