Addition of Exercise to Dipyridamole Stress Echocardiography in Order to Carry on the Ischemic Cascade: Role in the Diagnosis of Coronary Artery Disease and Prognostic Value.

BACKGROUND: Sensitivity of dipyridamole stress echocardiography (SE) is often lower than required. The aim of the present work is the evaluation of the association of dipyridamole and exercise echocardiography.
METHODS: From June 2007 to January 2011, 259 consecutive patients referred to Camposampiero Echocardiography Laboratory underwent SE. Stress protocol started with dipyridamole infusion of 0.84 mg/kg over 6 min. In patients without a new dyssynergy after dipyridamole, SE was carried on with supine exercise. If endocardial border detection was suboptimal, ultrasound contrast agent was used. Coronary angiography was performed in positive patients. The events recorded during the follow-up were cardiac death, nonfatal myocardial infarction (hard events), and coronary revascularization.
RESULTS: Of 259 patients, 74 had a positive result: 37 were positive after infusion of dipyridamole, and 37 became positive during exercise. All 74 positive patients underwent coronary angiography: 67 had significant coronary artery disease (36 positive with dipyridamole, and 31 positive with exercise), and 7 had not significant artery disease. In positive patients, the coronary revascularizations were 40. Furthermore, 3 of the 185 negative patients underwent coronary revascularization. During follow-up of 20 ± 10 months, 6 (8.1%) hard events occurred in positive patients. No hard event was observed in negative patients.
CONCLUSIONS: Dipyridamole SE with the addition of exercise can be proposed as a strategy to carry on the ischemic cascade and to identify the patients who elude the dipyridamole alone SE. A negative result is suggestive of a very good prognosis, free from hard events at 20 ± 10 months.

INTRODUCTION

Stress echocardiography (SE) is based on the application of a pharmacological or physical stress able to induce myocardial ischemia that can be observed as a new regional wall motion dyssynergy.[1] The main pharmacological stressors used are dipyridamole that causes flow maldistribution and dobutamine that causes an increase of the myocardial oxygen demand.[23] The first step of the ischemic cascade is a flow maldistribution. Subsequently, hypoperfusion causes metabolic alterations, and diastolic dysfunction occurs. Regional wall motion dyssynergies are observed later, followed by electrocardiographic (ECG) changes and chest pain.[4]

Perfusion scintigraphy investigates the earlier step in this cascade: from this feature comes the high sensitivity of this technique. On the other hand, both the law[5] and the referral guidelines for medical imaging[6] recommend a justified, optimized, and responsible use of testing with ionizing radiation. This has encouraged the use of nonionizing techniques (especially in Europe) as SE that had a great development and reached accuracy comparable to scintigraphy. Nevertheless, we must observe that the rise in accuracy is given by a higher specificity while sensitivity is often not so bright, in particular, if we consider SE in daily clinical practice out of scientific trials.

One of the first strategies adopted to increase the sensitivity was the association of atropine if no end-point was reached after infusion of dobutamine[7] or dipyridamole.[8] Atropine promotes the ischemic cascade in a different way as it causes an increase of heart rate (HR), without inotropic action or vasodilatation. It is not surprising that high-dose dipyridamole given alone over 6 min has higher sensitivity than standard dose over 10 min with the addition of atropine.[9] Furthermore, adverse events as prolonged ischemia or atropine intoxication are possible, especially when it is associated to dobutamine.[10] The association of dipyridamole and dobutamine was also proposed:[1112] the combination of these pharmacological stressors gave an increase in sensitivity but did not found application in clinical practice. Nevertheless, these studies underline that a single pharmacological stressor may be insufficient to induce ischemia in a certain number of patients, and further strategies should be adopted to reach sensitivity comparable to nuclear perfusion stress techniques.

The aim of the present work is the evaluation of the association of dipyridamole and exercise, to increase the sensitivity. This association was first proposed by Picano in 1988,[13] but at that time, there were too much technical difficulties and this protocol was no longer used. Now, echocardiography machines give images with higher definition, endocardial border can be enhanced by ultrasound contrast agents, and supine exercise is performed on ergometers that can be inclined laterally, thus increasing the feasibility of this test. This association could be particularly relevant in clinical settings, in which sensitivity has to be high, or in selected occupational classes (i.e., pilots or drivers).

METHODS

From June 2007 to January 2011, 259 consecutive patients (179 men, 80 women; mean age [±standard deviation (SD)] 58 ± 12 years) referred to our Echocardiography Laboratory were included in this retrospective observational study. The patients underwent SE for one of these indications: (a) Non conclusive or uninterpretable exercise test result, (b) first step evaluation of nonacute chest pain, (c) functional evaluation in patients with known coronary artery stenosis of unclear significance. Exclusion criteria were a contraindication to dipyridamole and/or inability to exercise. Informed written consent to the test was obtained from all patients. If endocardial border detection was suboptimal, ultrasound contrast agent (Sonovue, Bracco-Byk Gulden, Konstanz, Germany) for left ventricle opacification was used (84 patients, 32%). All patients with positive stress echo result underwent coronary angiography.

Stress protocol

According to the European Association of Echocardiography (EAE) guidelines,[2] stress protocol started with dipyridamole intravenous infusion of 0.84 mg/kg over 6 min (dipyridamole step).[9] In patients with normal (or unchanged) regional kinesis after dipyridamole infusion, SE was carried on with supine exercise (exercise step) with a protocol of 25 W incremental work every 2 min.

Diagnostic end-points (interruption criteria) of SE were: Achievement of target HR; obvious echocardiographic positivity (new or worsening dyssynergy); hypertension with systolic blood pressure (BP) >240 mmHg or diastolic BP >120 mmHg; symptomatic hypotension, with >40 mmHg drop in BP; sustained supraventricular or ventricular arrhythmias; and severe chest pain. New ECG repolarization alterations in the presence of normal or hyperkinetic response were not an interruption criterion. If an echocardiographic positivity (new or worsening dyssynergy) was observed after dipyridamole infusion, a diagnostic criterion was reached and SE was interrupted before exercise.

Exercise step was followed by 2 min of 25 W recovery; then, aminophylline 120 mg was administered to all patients.

The examination was performed under the monitoring of 12-lead ECG, BP, and oxygen saturation. Echocardiographic imaging was performed with iE33 Philips Ultrasound System (Andover, USA), with continuously monitoring and intermittently storing. Left ventricular regional kinesis was stored at baseline, at the end of dipyridamole infusion, at peak exercise, and at recovery with an assessment of a wall motion score index calculated with the 16-segment model of the left ventricle.[14] A quad-screen format was used for comparative analysis.

Coronary angiography in multiple views was performed in 88 patients. A vessel was considered to have significant obstruction if its diameter was narrowed by ≥75% with respect to the prestenotic tract (≥50% for left main).

Follow-up

Follow-up data were collected with reviews of the patient's hospital chart, periodic visits in our outpatient clinic, and telephone interviews with patients and relatives. The clinical events recorded during the follow-up were cardiac death, nonfatal myocardial infarction (hard events), and need for coronary revascularization (surgery or angioplasty). Cardiac death was defined as death due to acute myocardial infarction, heart failure, fatal arrhythmias, or sudden death. The diagnosis of acute myocardial infarction was made on the basis of symptoms, ECG changes, and cardiac enzyme level increase.

Statistical analysis

Values were expressed as the mean ± SD for continuous variables. Continuous variables were compared with the Student's unpaired t-test, whereas differences of categorical variables were assessed by the Chi-square test. A multivariate logistic regression was used to evaluate the association between clinical variables and SE result. P < 0.05 was considered statistically significant.

RESULTS

The study population consist of 259 patients; baseline characteristics are reported in Table 1. Of 259 patients, 37 (14.3%) were positive after infusion of dipyridamole, and further 37 (14.3%) became positive during the exercise step: total positive patients were 74 (28.6%). Patients negative at both steps were 185 (71.4%). All 74 positive patients underwent coronary angiography: 67 had significant coronary artery disease. In 36 of 37 patients who were positive at dipyridamole step (without exercise), coronary angiography evidenced the presence of significant coronary artery lesions and only one patient was a false positive in this subgroup. On the other hand, the addition of exercise step allowed to recognize 37 more positive patients: 31 of these had a significant coronary artery disease, and 6 were false positive [Figure 1]. The most part of negative patients did not undergo coronary angiography or coronary CT angiography because the prosecution of the diagnostic pathway with invasive examinations or exposure to X-ray should not be justified.

Table 1

Baseline characteristics of the study population

	n (%)
Number of patients	259
Age	58.0±12.0
Sex
Male	179 (69)
Family history of CAD	77 (30)
Diabetes	33 (13)
Hyperlipidemia	106 (41)
Hypertension	131 (51)
Smoking	19 (7)
Previous smoking	44 (17)
Chest pain	127 (49)
Previous revascularization	58 (23)

CAD=Coronary artery disease

Figure 1

Stress echocardiography results and angiography results

Univariate analysis of variables in positive and negative patients is resumed in Table 2. In multivariate analysis, age, male sex, prior revascularization, and chest pain are independent predictors of a positive result at SE [Table 3]. Comparison between positive patients at dipyridamole step and positive patients after addition of exercise [Table 4] shows significant differences in HR at peak, systolic BP at peak, rate pressure product, percentage of HR target reached, increase in HR, and increase in systolic BP.

Table 2

Univariate analysis of baseline variables

	Positive SE, n=74 (%)	Negative SE, n=185 (%)	P
Age	64.9±9.3	55.2±11.9	<0.001
Sex
Male	63 (85.1)	116 (62.7)	<0.001
Family history of CAD	24 (32.4)	53 (28.6)	NS
Diabetes	16 (21.6)	17 (9.2)	0.007
Hyperlipidemia	40 (54.1)	66 (35.7)	0.007
Hypertension	48 (64.9)	83 (44.9)	0.004
Previous revascularization	31 (41.9)	27 (14.6)	<0.001
Smoking	5 (6.7)	14 (7.5)	NS
Previous smoking	17 (23.0)	27 (14.6)	NS
Chest pain	47 (63.5)	80 (43.2)	0.003

SE=Stress echocardiography, CAD=Coronary artery disease, NS=Not significant

Table 3

Multivariate logistic regression analysis

	OR	P
Sex
Male	4.52	<0.001
Age	1.07	<0.001
Previous revascularization	2.28	0.026
Chest pain	2.60	0.006
Hypertension	/	NS
Hyperlipidemia	/	NS
Diabetes	/	NS

NS=Not significant, OR=Odds ratio

Table 4

Stress echocardiography parameters in positive patients at dipyridamole step and exercise step

	Dipyridamole step positive SE (n=37)	Exercise step positive SE (n=37)	P
Rest HR (bpm)	67.4±12.1	63.6±12.0	NS
Peak HR (bpm)	88.2±18.4	108.5±25.6	0.001
Rest BP (mmHg)	138.6±19.6	130.0±17.5	NS
Peak BP (mmHg)	129.0±20.2	154.0±26.1	<0.001
Rate-pressure product	11,386±3074	17,127±6519	<0.001
Peak HR/target HR (%)	57.8±11.4	68.7±14.4	0.001
HR increase (%)	31.7±22.1	73.1±38.0	<0.001
BP increase (%)	−6.4±12.1	19.1±18.5	<0.001
Peak WMSI	1.4±0.2	1.3±0.2	NS

SE=Stress echocardiography, HR=Heart rate, BP=Blood pressure, WMSI=Wall motion score index, NS=Not significant

Exercise produced a positive result at 25 W in 7 patients, at 50 W in 10 patients, and at 75 W in 9 patients: in these 26 patients (70% positive exercise patients), test was positive at low workload (75 W or less).

Adverse events that required medical care occurred in three patients (1.2%): A dyspneic crisis with bronchoconstriction and desaturation (89% in ambient) regressed with O2, hypotension with presyncope regressed with Trendelenburg position, and sustained ECG alterations in a positive patient with transient chest pain and regional wall motion dyssynergy. On the other hand, headache and heat localized in the face often occurred during dipyridamole infusion (30%–40% patients). Six patients (2.3%) at the end of exercise had a modest vagal reaction, quickly regressed.

In the 74 positive patients, the coronary revascularizations (Percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting [CABG]) were 40, most of all in the 1st month after the SE. In the 37 patients positive at dipyridamole step, revascularizations were 23 (15 PTCA, 8 CABG) and in the 37 patients positive at exercise step revascularizations were 17 (16 PTCA, 1 CABG). Furthermore, 3 (1.6%) of the 185 negative patients underwent coronary revascularization (3 PTCA).

During a mean follow-up of 20 ± 10 months, 6 (8.1%) hard events occurred in positive patients: one patient died before hospitalization planned for coronary angiography, and five patients presented a nonfatal myocardial infraction. No hard event was observed in negative patients.

DISCUSSION

The accelerated dose of dipyridamole is recommended in EAE SE consensus[2] and it is presented as a more sensitive alternative to standard-dose plus atropine. Nevertheless, data from daily clinical practice are not so bright as scientific trials. The proposal of a new stress protocol comes from the remark that sensitivity of SE is often inadequate to stop the diagnostic course in case of a negative result: dipyridamole alone is not able to induce ischemia in a certain number of patients with significant coronary lesions.

Our work shows that the addition of the exercise allowed the identification of 31 patients with significant coronary artery disease that during dipyridamole infusion did not develop dyssynergies; 17 of them underwent coronary revascularization, with a change in the course of their coronary artery disease. An interesting observation is that most part of positive results at exercise step is registered at low workload (70% of positive results were observed at 75 W or less): steal phenomena induced by dipyridamole are a very good substrate for exercise step that increasing myocardial oxygen demand can bring on regional wall motion alteration.[9] The increase of myocardial oxygen demand is caused not only by the increase of HR but also by the increase of BP. After dipyridamole infusion, we observe a modest increase in HR, followed by a stronger increase during exercise. BP instead has a little decrease after dipyridamole infusion and a significant increase during exercise. Hence, BP has a crucial role in exercise step as it generates an effective increase of afterload and systolic subendocardial stress.[15] Furthermore, this inclination at the positive result at low workload gives a reason for the safety of this protocol: few patients (1.2%) required medical intervention, compared with the higher occurrence of complications reported in other stress association (i.e., dipyridamole plus atropine, 3%–4%).

We are aware of the limitations of this work, based on retrospective observational data. After SE, the diagnostic course was different for positive and negative patients: coronary angiography was performed in all positive patients, and only in 14 negative patients, hence for most of the negative patients, we have no information about gold standard diagnostic. On the other hand, ethical and legal motivations give justification of this choice. Hence, we cannot calculate the value of the sensitivity of SE preformed with this association; nevertheless, the exercise step can only make positive a result that was negative at the dipyridamole step (instead positive dipyridamole results are conclusive): It seems evident that the addition of exercise cannot decrease the sensitivity.

From a prognostic point of view, risk stratification cannot be based only on anatomical criteria; randomized trials show that anatomy-guided revascularization, in the absence of inducible ischemia, has a neutral or detrimental effect on survival.[16171819] In our work only three negative patients (1.6%) required elective coronary angiography and PTCA; none of the negative patients presented hard events.

CONCLUSION

The addition of exercise can be proposed as a strategy to carry on the ischemic cascade and to identify the patients who elude the dipyridamole alone SE: The flow maldistribution cannot be directly observed; thus, the addition of exercise gives a determinant contribution to develop wall motion alterations. The current technologies allow a good feasibility, and safety is high. A negative result is suggestive of a very good prognosis, free from hard events at 20 ± 10 months.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.