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 . the main pharmacological stressors used are dipyridamole that causes flow maldistribution and dobutamine that causes an increase of the myocardial oxygen demand . regional wall motion dyssynergies are observed later , followed by electrocardiographic ( ecg ) changes and chest pain . 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 and the referral guidelines for medical imaging 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 or dipyridamole . 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 . furthermore , adverse events as prolonged ischemia or atropine intoxication are possible , especially when it is associated to dobutamine . the association of dipyridamole and dobutamine was also proposed : 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 , 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 ) . 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 . 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 . according to the european association of echocardiography ( eae ) guidelines , stress protocol started with dipyridamole intravenous infusion of 0.84 mg / kg over 6 min ( dipyridamole step ) . 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 . 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 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 . 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 . according to the european association of echocardiography ( eae ) guidelines , stress protocol started with dipyridamole intravenous infusion of 0.84 mg / kg over 6 min ( dipyridamole step ) . 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 . 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 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 . 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 . 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% ) . 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 . baseline characteristics of the study population cad = coronary artery disease 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 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 . univariate analysis of baseline variables se = stress echocardiography , cad = coronary artery disease , ns = not significant multivariate logistic regression analysis ns = not significant , or = odds ratio stress echocardiography parameters in positive patients at dipyridamole step and exercise step 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 1 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 . the accelerated dose of dipyridamole is recommended in eae se consensus and it is presented as a more sensitive alternative to standard - dose plus atropine . 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 . 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 . 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 . hence , we can not 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 can not decrease the sensitivity . from a prognostic point of view , risk stratification can not 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 . in our work only three negative patients ( 1.6% ) required elective coronary angiography and ptca ; none of the negative patients presented hard events . 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 can not be directly observed ; thus , the addition of exercise gives a determinant contribution to develop wall motion alterations . a negative result is suggestive of a very good prognosis , free from hard events at 20  10 months .
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 .