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(Circulation. 1997;96:4268-4272.)
© 1997 American Heart Association, Inc.

Articles

Dipyridamole-Induced Ischemia as a Prognostic Marker of Future Adverse Cardiac Events in Adult Patients With Hypertrophic Cardiomyopathy

Ettore Lazzeroni, MD, FESC; Eugenio Picano, MD, FESC; Letizia Morozzi, MD; Anna Rita Maurizio, MD; Giampaolo Palma, MD; Roberta Ceriati, MD; Emilio Iori, MD; Angela Barilli, MSc; ; (EPIC) Study Group, Subproject Hypertrophic Cardiomyopathy ;

From the Division of Cardiology, Parma Hospital, and CNR Institute of Clinical Physiology (E.P.), Pisa, Italy.

Correspondence to Dr Ettore Lazzeroni, MD, FESC, Divisione di Cardiologia, Azienda Ospedaliera, Via Gramsci 14, 43100 Parma, Italy. E-mail picano{at}po.ifc.pi.cnr.it

	Abstract

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Background Myocardial ischemia may play a role in the natural history of hypertrophic cardiomyopathy (HCM). To assess the relative prevalence and the prognostic value of dipyridamole-induced ischemia, 79 patients with HCM and without concomitant coronary artery disease (53 men; mean age, 46±15 years) underwent a high-dose (up to 0.84 mg/kg over 10 minutes) dipyridamole test with 12-lead ECG and two-dimensional echo monitoring and were followed up for a mean of 6 years.

Methods and Results Twenty-nine patients (37%) showed ECG (ie, ST depression 2 mV) signs of myocardial ischemia during dipyridamole test (group 1), whereas 50 (63%) had a negative test (group 2). No patient had transient wall motion abnormalities during the dipyridamole test. During the follow-up, 16 events (ie, left ventricular or atrial enlargement, unstable angina, syncope, atrial fibrillation, and bundle-branch block) occurred in 29 patients in group 1 and 5 in 50 patients in group 2 (55% versus 10%, P<.001). Patients with a positive dipyridamole test showed worse 72-month event-free survival rates compared with patients with a negative test (36.2% versus 84.2%, P<.001). A forward stepwise event-free survival analysis identified dipyridamole test positivity by ECG criteria (²=19.7, P=.0001), rest gradient (²=11.3, P=.0008), and age (²=4.1; P=.0413) as independent and additive predictors of subsequent events.

Conclusions ECG signs of myocardial ischemia elicited by dipyridamole are frequent in patients with HCM and identify patients at higher risk of cardiac events, suggesting a potentially important pathogenetic role of inducible myocardial ischemia in determining adverse cardiac events in these patients.

Key Words: echocardiography • prognosis • hypertrophy • cardiomyopathy

	Introduction

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The clinical outcome of hypertrophic cardiomyopathy (HCM) is extremely variable and unpredictable, and correct risk evaluation in individual patients remains a challenging task.^1–3

Among the factors potentially influencing the prognosis, myocardial ischemia is common in adult ^4–6 and young patients with HCM.^7,8 These patients frequently show ischemia-like ST-segment depression and perfusion defects, even in the absence of chest pain and in the presence of angiographically normal coronary arteries.^4–11 Stress-induced regional left ventricular dysfunction can also be observed in these patients when a significant epicardial coronary artery stenosis is present.¹² Myocardial ischemia is credited with playing a major role in the course of the disease by leading to progressive left ventricular fibrosis, dilatation, and transmural infarction.^13–15 Myocardial fibrosis may in turn form the electrophysiological substrate triggering life-threatening arrhythmias.¹⁶ However, prospective data on the prognostic impact of stress-induced myocardial ischemia in adult HCM patients are conspicuously lacking to date.^8,10,13,14 The safety, feasibility, and diagnostic value of the dipyridamole test for noninvasive identification of angiographically assessed coronary artery disease (CAD) in HCM patients has been previously shown.¹² To assess the prognostic value of stress-induced myocardial ischemia, a large group of adult HCM patients was evaluated by the dipyridamole test with 12-lead ECG and two-dimensional echocardiographic monitoring and followed up for a mean period of 72 months. To avoid the confounding effect of concomitant intrinsic CAD, we enrolled a selected population of patients with either angiographically assessed normal coronary arteries (n=45) or negativity of stress test and likelihood of atherosclerotic coronary disease <5% (n=34).¹⁷ Follow-up was both clinical (by regular outpatient visit) and echocardiographic (with resting two-dimensional echo at yearly control visits) to assess the clinical condition and left ventricular and atrial dilatation as predetermined meaningful end points.

	Methods

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Patients
Between 1985 and 1996, 126 patients with HCM were prospectively considered for dipyridamole echocardiography at the Division of Cardiology of two participating hospitals in Italy: Parma and Pisa. Of these patients, 68 were included in a previous report on the feasibility and diagnostic value of dipyridamole test.¹² The diagnosis of HCM was based on echocardiographic demonstration of a nondilated, hypertrophied left ventricle in the absence of another cardiac or systemic cause of ventricular hypertrophy.¹⁸ Indications for the study were history of typical or atypical chest pain and/or ischemia-like ST-segment changes either at baseline or during exercise testing, previous ischemic events, risk stratification, or referral for complete evaluation by a cardiologist. The following studies were performed at baseline evaluation: history and physical examination, 12-lead ECG, chest x-ray, M-mode and two-dimensional echocardiography with Doppler and color-Doppler study, and graded bicycle exercise stress test. Exclusion criteria were technically poor acoustic window (n=4), uninterpretable ECG (ie, left bundle block, ST-segment depression 2 mm and giant T waves) (n=5), severe global left ventricular dysfunction (n=3), severe concomitant asthma requiring chronic theophylline therapy (n=4), or refusal to enter the study (n=16). Therefore, a initial group of 94 patients underwent the dipyridamole test. Of this group, 60 patients also underwent coronary angiography within 1 month of the dipyridamole test. Indications for coronary angiography were the following: all patients with previous myocardial infarction and/or dipyridamole-induced echocardiographic (n=12) or ECG (n=32) signs of myocardial ischemia, and patients with a likelihood of atherosclerotic coronary disease >5% (n=16).¹⁷ In the 60 patients who submitted to coronary angiography, 45 had normal vessels and 15 had significant CAD; of these latter 15 patients, during the dipyridamole test, an echocardiographic positivity was found in 11 patients, 5 of whom had a previous myocardial infarction. We decided to exclude these 15 patients with angiographically assessed CAD from further analysis, because inclusion of patients with intrinsic CAD makes it difficult to evaluate the independent prognostic value of dipyridamole-induced ischemia.

A group of 79 patients finally entered the study (53 men and 26 women; age, 46±15 years; range, 21 to 75 years). Thirty-eight (48%) had history of chest pain, 39 (49%) experienced palpitations, 31 (39%) had dyspnea, 3 (4%) had syncope, and 1 had a clinically documented previous myocardial infarction. The mean septal thickness was 18.5±5 mm, mean fractional shortening was 39±7%, and mean left ventricular outflow gradients at rest, assessed by continuous-wave Doppler echocardiography, was 16±19 mm Hg.

Dipyridamole Echocardiography/ECG Test
After a dipyridamole infusion at the dosage of 0.56 mg/kg IV over 4 minutes followed by a 4-minute dipyridamole-free period, 0.28 mg/kg was administered over 2 minutes. Baseline studies included 12-lead ECG, blood pressure evaluation, standard parasternal and apical echocardiographic views, percent fractional shortening, and continuous Doppler left ventricular outflow-tract recording. Two-dimensional echocardiographs were obtained using commercially available imaging systems (Vingred 750 or Hewlett-Packard Sonos 2500 and 3.5-MHz transducers). During the procedure, blood pressure and 12-lead ECGs were taken every 2 minutes; two-dimensional echocardiograms were continuously recorded up to 10 minutes after the end of dipyridamole infusion. Every 2 minutes, percent fractional shortening and left ventricular outflow-tract Doppler were also recorded. The patients were instructed to avoid coffee and tea for at least 3 hours before the test and to stop all cardiac medications for at least 24 hours. Criteria for interruption of the dipyridamole infusion were achievement of the target heart rate, severe and continuous chest pain, new obvious wall motion abnormalities, significant cardiac arrhythmias, reduction in systolic blood pressure 40 mm Hg from baseline or a systolic blood pressure <100 mm Hg, or any side effect regarded as caused by dipyridamole. Aminophylline (240 mg IV) was injected as needed. ECG tracings were considered diagnostic of myocardial ischemia when an ST-segment shift of 2 mm at 80 ms after the J point was recorded. Two-dimensional echocardiographic videotaped and/or digitized images, obtained by a commercially available scanner, were analyzed by two independent observers unaware of other data; in case of disagreement, a third observer reviewed the study, and his or her judgment was binding. Regional wall motion was assessed according to the recommendations of the American Society of Echocardiography, with a 16-segment model and each segment scored from 1(normal) to 4 (dyskinetic).¹⁹ Positivity of the test by echocardiographic criteria was linked to the detection of a transient dyssynergy, absent or of a lesser degree during the basal examination. Any region already akinetic or dyskinetic in the baseline study was not considered for analysis. The previous assessed intraobserver and interobserver agreement regarding the presence or absence of test positivity was consistently >90%.²⁰ This low variability was linked to previous experiences in joint readings and an a priori decision to ignore minor, questionable degrees of hypokynesia, thus overcoming the otherwise more substantial variability between independent "expert" readers.²¹

Follow-up
Follow-up data were obtained over an average period of 6 years (minimum, 12 months). During the follow-up, only the first clinical event was considered for each patient. The following clinical features more probably related to ischemia were analyzed: cardiac death, myocardial infarction, unstable angina at rest with transient ST-segment alteration, and new onset of syncope. Left ventricular dilatation, left atrial enlargement, development of chronic atrial fibrillation, and new bundle-branch block were also considered. We decided before the analysis of data to accept as evidence of left ventricular and left atrial dilatation an increase of end-diastolic diameter >5 mm in serial echocardiographic examinations.

Angiographic Study
Patients underwent ventriculography and selective right and left coronary arteriography using the Judkins technique; multiple views of each vessel were obtained. A vessel was considered to have significant obstruction if its diameter assessed by caliper was narrowed by 50% with respect to the prestenotic tract.

Statistical Analysis
Univariate analysis for categorical variable was performed by use of the ² test with Yates' correction or Fisher's exact test. Continuous variables were analyzed by use of Student's t test when appropriate. The predictive value of the test for cardiac events was calculated according to the standard definitions. Survival distributions in patients with a positive and negative dipyridamole-ECG test were estimated by the Kaplan-Meier method by use of the LIFETEST procedure in the SAS statistical package (SAS Institute Inc). For testing equality of survival functions across strata, the procedure uses both the log rank and Wilcoxon tests. The association of some variables with survival time was also evaluated individually, by univariate test, and jointly after a forward stepwise entry approach, thus revealing the entry order of covariates that are added on the basis of the largest increase in the joint test statistic. Variables selected for examination were dipyridamole positivity by ECG criteria (yes/no), age (continuous values), sex, history of chest pain (yes/no), rest intraventricular gradient (millimeters of mercury), septal thickness (millimeters), and fractional shortening (percent). The required level of significance was P<.05.

	Results

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Dipyridamole Echocardiography/ECG Test
No patient developed left ventricular dysfunction during the test. There were no serious cardiac complications related to dipyridamole infusion, and the test was completed in all but two patients. Hypotensive reaction (ie, reduction in systolic blood pressure 40 mm Hg from baseline or a systolic blood pressure <100 mm Hg), reversed by aminophylline, occurred in eight patients, six of whom had a resting gradient >50 mm Hg. Transient and noncomplex ventricular arrhythmias (less than Lown class III) occurred in six patients.

According to the results of dipyridamole test, the 79 patients were subdivided into two groups. Twenty-nine patients (37%, group 1) had a positive test by ECG criteria (ie, diagnostic ST depression without dyssynergy). The test was negative by both echo and ECG criteria in 50 patients (63%, group 2). At entry into the study, the patients of group 1 were similar to the patients of group 2 regarding age, sex, degree of septal hypertrophy, end-diastolic diameter, and mean left ventricular outflow gradients at rest. Duration of follow-up was also similar. The two groups differ with respect to fractional shortening and history of chest pain (Table 1).

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of 79 Patients With Hypertrophic Cardiomyopathy With (Group 1) and Without (Group 2) Dipyridamole-Induced Ischemia-like ECG Changes

Events
During a mean follow-up of 72 months, no patient had cardiac death or myocardial infarction, but 21 patients suffered at least one adverse cardiac event: 2 had unstable angina, 2 had syncopes, 5 had ventricular dilatations, 6 had left atrial enlargements, 4 had atrial fibrillations, and 2 had bundle-branch blocks. Sixteen events occurred in 29 patients of group 1 and 5 in 50 patients of group 2 (55% versus 10%, P<.001). In particular, 2 unstable angina episodes, 2 syncopes, 4 left ventricular dilatations, 4 left atrial enlargements, 3 atrial fibrillations, and 1 bundle-branch block occurred in 29 patients with ST-segment depression, and only 5 events (ie, 1 left ventricular dilatation, 2 left atrial enlargements, 1 atrial fibrillation, and 1 bundle-branch block) occurred in 50 patients with a negative dipyridamole test (Table 2). The baseline and the follow-up echocardiographic findings of the individual study patients developing left ventricular or left atrial dilatation are reported in Table 3.

View this table: [in this window] [in a new window]   Table 2. Adverse Cardiac Events in 79 Patients With Hypertrophic Cardiomyopathy With and Without Dipyridamole-Induced Ischemia-like ECG Changes

View this table: [in this window] [in a new window]   Table 3. Echocardiographic Findings of Patients With Hypertrophic Cardiomyopathy Developing Left Ventricular or Left Atrial Dilatation During the Follow-up Period

The cardiac event rate was 7.9% per year in patients with a positive dipyridamole test compared with only 1.4% per year among those with a negative test. The positive predictive value of dipyridamole test in predicting adverse cardiac events was 55%, whereas the negative predictive value was 90%. The prevalence of dipyridamole-induced ST-segment depression was 76% in those individuals with and 22% in those without cardiac clinical events.

Event-free survival curves according to dipyridamole stress results are reported in the Figure. The 72-month event-free survival was 36.2% in the 29 patients with a positive test and 84.2% in the 50 patients with a negative test (P<.001). By univariate analysis, dipyridamole test positivity, rest gradient, history of chest pain, older age, and male sex influenced event-free survival time (Table 4). When a forward stepwise sequence of ² for the log rank test was used, only dipyridamole test positivity, rest gradient and age were independent and additive predictors of future adverse cardiac events (Table 5).

View larger version (12K): [in this window] [in a new window]   Figure 1. Kaplan-Maier curve indicating the cumulative event-free survival rates in patients with a positive dipyridamole echocardiographic–ECG test (DET +) and in patients with a negative test (DET -).

View this table: [in this window] [in a new window]   Table 4. Relation of Clinical and Echocardiographic Findings of 79 Patients With Hypertrophic Cardiomyopathy to Subsequent Cardiac Events by Univariate 2 for the Log Rank Test

View this table: [in this window] [in a new window]   Table 5. Tabe 5. Relation of Clinical and Echocardiographic Findings of 79 Patients With Hypertrophic Cardiomyopathy to Subsequent Cardiac Events by Forward Stepwise Sequence of 2 for the Log Rank Test

	Discussion

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The results of the present investigation involving a relatively large group of adult patients with HCM confirm that stress-induced ischemia is frequent in such patients (37%), even in the absence of angiographically assessed CAD.^{5–8,10–14} Stress-induced ST-segment depression predicts an unfavorable clinical outcome. In fact, patients with ischemia-like ST-segment depression have a higher likelihood of cardiac events, including unstable angina, left ventricular and atrial dilatation, atrial fibrillation, and syncope. In contrast, the absence of dipyridamole-induced ischemia is associated with a more benign outcome. The prognostic information of dipyridamole testing is independent and additive to that provided by other clinical and echocardiographic variables.

Moreover, a high-dose dipyridamole test was safe and feasible in patients with obstructive and nonobstructive forms of HCM, consistent with what was previously observed in HCM patients studied by a standard dipyridamole dose (0.56 mg/kg) combined with imaging techniques such as thallium scintigraphy and positron emission tomography.^{8,10,14,22,23} Hypotensive reactions induced by dipyridamole were probably due to its capacity to worsen outflow obstruction by a reduction in afterload and an augmentation of ventricular contractility. They were seldom observed and did not affect the safety profile of the dipyridamole test.

Mechanisms and Potential Effects of Myocardial Ischemia in HCM
In HCM, myocardial ischemia may also occur in patients with patent epicardial coronary arteries and may be due to several possible causes: inadequate capillary density caused by extensive myocardial hypertrophy, abnormalities of intramural small coronary arteries that may be present in hypertrophied and nonhypertrophied regions, abnormal myocellular architecture, decreased coronary vasodilator reserve caused by high left ventricular systolic and diastolic pressures, increased oxygen demand caused by hypertrophied myocardium, and episodes of tachycardia or tachyarrhythmias,^5,7,13,15,22 Whatever the underlying pathophysiological substrate, myocardial ischemia can be detected noninvasively during pharmacological stress testing through two different objective markers: ST-segment depression and transient regional left ventricular dysfunction. ST-segment depression is frequent and may occur in the absence of angiographically assessed CAD, whereas regional dysfunction is less frequent and requires the presence of underlying significant epicardial CAD.¹² The underlying mechanisms linking the pathophysiological entity of myocardial ischemia to cardiac events are complex, certainly multifactorial, and still incompletely understood. Recurrent episodes of ischemia may cause myocardial fibrosis and scarring; as a consequence, systolic and diastolic left ventricular function may be impaired with obvious potential worsening of the clinical course of HCM patients. Furthermore, inducible ischemia may also predispose to unstable angina, syncope, myocardial infarction, and sudden death.

Comparison With Previous Studies
Prognosis evaluation in HCM patients is a challenge.^1–3 Known risk factors for sudden death are "malignant" family history, symptomatic and/or sustained ventricular tachycardia, recurrent syncopes, and young age at initial presentation^3,16,24; high New York Heart Association functional class, impaired left ventricular function, and symptomatic supraventricular tachyarrhythmias lead to death as a result of heart failure. On the other hand, potential risk factors that require further investigation are some genetic abnormalities,²⁵ prior cardiac arrest, severity of left ventricular hypertrophy, exercise-induced hypotension,²⁶ severity of left ventricular outflow-tract obstruction, and inducible ventricular tachycardia.²⁷ Dipyridamole-induced ST-segment depression may represent an additional prognostic marker in this population. In HCM patients, the ST-segment depression has been described during rapid atrial pacing in association with metabolic evidence of myocardial ischemia²⁸ and in two isolated case reports preceding sudden death and/or cardiac arrest.^29,30 More recently, it has been demonstrated that HCM patients who develop ST depression during dipyridamole stress testing have lower coronary flow reserve than those without ECG changes.²³ This evidence suggests that ST-segment changes are not an ECG "noise" but reflect a true pathophysiological abnormality and, in some patients, a true myocardial ischemia, even in the presence of angiographically normal coronary arteries. Eliott et al⁸ have shown that in young HCM patients, ST-segment depression is associated with a history of typical angina and dyspnea. Dilsizian et al⁷ have shown that myocardial ischemia detected by scintigraphy is frequently related to cardiac arrest and syncope in young patients with HCM. In this selected group of 23 young patients ranging in age from 6 to 23 years, exercise test–induced ST-segment depression occurred in 5 of 6 patients with cardiac arrest, 3 of 6 with syncope, and 1 of 8 asymptomatic patients. Compared with our adult group, who underwent pharmacological stress testing, the patients of Dilsizian et al were much younger and were evaluated by exercise testing. Both studies, although methodologically different, suggest that stress-induced ST changes are not completely "innocent" findings but may be harbingers of future cardiac events, including ventricular dilatation.

In conclusion, dipyridamole-induced ischemia-like ECG changes are frequent in adult patients with HCM and normal coronary angiographic findings. ECG signs of myocardial ischemia elicited by dipyridamole identify patients at higher risk of cardiac events, ventricular and/or atrial dilatation, and atrial fibrillation, suggesting a potentially important pathogenetic role of inducible myocardial ischemia in determining adverse cardiac events.

Received June 19, 1997; revision received August 21, 1997; accepted September 1, 1997.

	References

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				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]

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