Roberto Testa

Beneficial Effects of Intracoronary Adenosine as an Adjunct to Primary Angioplasty in Acute Myocardial Infarction

BACKGROUND The benefits of vessel recanalization in acute myocardial infarction (AMI) are limited by reperfusion damage. In animal models, adenosine limits reperfusion injury, reducing infarct size and improving ventricular function. The aim of this study was to evaluate the safety and feasibility of adenosine adjunct to primary PTCA in AMI. METHODS AND RESULTS Fifty-four AMI patients undergoing primary PTCA were randomized to intracoronary adenosine or saline. The 2 groups were similar for age, sex, and infarct location. Adenosine administration was feasible and well tolerated. PTCA was successful in all patients and resulted in TIMI 3 flow in all patients given adenosine and in 19 given saline (P<0.05). The no-reflow phenomenon occurred in 1 adenosine patient and in 7 saline patients (P=0.02). Creatine kinase was lower in the adenosine group, and a Q-wave MI developed in 16 adenosine patients and in 23 saline patients (P=0.04). Sixty-four percent of dyssynergic segments improved in the adenosine group and 36% in the saline group (P=0. 001). Function worsened in 2% of dysynergic segments in the adenosine group and in 20% in the saline group (P=0.0001). Adverse cardiac events occurred in 5 patients in the adenosine group and in 13 patients in the saline group (P=0.03). CONCLUSIONS Intracoronary adenosine administration is feasible and well tolerated in AMI. Adenosine adjunct to primary PTCA ameliorates flow, prevents the no-reflow phenomenon, improves ventricular function, and is associated with a more favorable clinical course.

Vasospastic ischemic mechanism of frequent asymptomatic transient ST-T changes during continuous electrocardiographic monitoring in selected unstable angina patients☆

Asymptomatic episodes of ST segment and/or T wave changes are often reported during Holter monitoring in patients with angina pectoris. However, the interpretation of such changes is debated relative to silent myocardial ischemia. We studied 11 patients admitted to the CCU because of frequent episodes of unstable anginal attacks who had undergone repeated periods of Holter monitoring, characterized by predominantly occurring asymptomatic episodes of ST segment and/or T wave changes associated with less frequent typical anginal attacks. In a total of 89 days of Holter monitoring, the patients evidenced 520 episodes of transient ECG changes including 180 of ST elevation, 73 of ST depression, and 267 of T wave alterations. Only 12% of episodes were symptomatic. Coronary injection during asymptomatic ST-T changes was performed in eight patients. In six it was possible to document spontaneous coronary spasm. In seven patients ergonovine administration induced anginal pain, ST-T changes, and coronary spasm. In all patients the anginal attacks completely disappeared with medical treatment and the asymptomatic episodes were abolished in six and reduced in four. Our findings support the hypothesis that in certain selected unstable anginal patients, transient asymptomatic ECG changes are caused by acute myocardial ischemia.

Alteration in regulation of myocardial blood flow in one-vessel coronary artery disease determined by positron emission tomography

The behavior of myocardial blood flow (MBF) regulation in territories supplied by angiographically normal vessels of patients with coronary artery disease (CAD) has been poorly investigated. Resting MBF and coronary reserve were evaluated in 32 patients with stable angina, no previous myocardial infarction, and isolated left anterior descending or left circumflex coronary artery stenosis (> or = 50% diameter narrowing). MBF was measured, in the absence of any medical therapy, by means of dynamic positron emission tomography and 13N-ammonia. MBF measurements at baseline and after intravenous dipyridamole (0.56 mg/kg administered over 4 minutes), were obtained both in the stenosis-related regions and in contralateral territories. As a control group, 14 normal subjects were evaluated according to the same protocol. At rest, the 32 patients with CAD had similar MBF values in the stenotic and remote regions (0.76 +/- 0.21 and 0.77 +/- 0.19 ml/min/g, respectively, p = NS); both these values were significantly (p < 0.01) reduced with respect to mean MBF in normal subjects (1.03 +/- 0.25 ml/min/g). The dipyridamole study was completed in 30 patients; these patients had lower values of maximal MBF in the stenotic than in the remote regions (1.52 +/- 0.65 vs 1.76 +/- 0.68 ml/min/g, p < 0.05); however, both these values were significantly reduced (p < 0.01) with respect to mean dipyridamole MBF in normal subjects (3.66 +/- 0.92 ml/min/g). Thus, in patients with CAD, resting and maximal MBF can be reduced not only in myocardial territories supplied by stenotic arteries, but also in territories supplied by angiographically normal arteries.

Which Variable of Stenosis Severity Best Describes the Significance of an Isolated Left Anterior Descending Coronary Artery Lesion?: Correlation Between Quantitative Coronary Angiography, Intracoronary Doppler Measurements and High Dose Dipyridamole Echocardiography

OBJECTIVES This study sought to investigate the angiographic or intracoronary Doppler variables of stenosis severity that best correlate with the results of dipyridamole echocardiography. BACKGROUND Quantitative coronary angiography and intracoronary Doppler flow velocity assessments are the commonly used techniques for the objective identification of significant coronary artery stenosis. METHODS Thirty patients with an isolated lesion of the left anterior descending coronary artery (LAD) were studied by means of on-line quantitative coronary arteriography, intracoronary Doppler flow velocity measurements and dipyridamole echocardiography 6 months after percutaneous transluminal coronary angioplasty. The quantitative arteriographic analyses were performed on-line; post-stenotic Doppler flow velocities were measured at baseline and after adenosine infusion. Angiographic and Doppler measurements were compared with the corresponding dipyridamole echocardiographic data and analyzed by discriminant analysis. RESULTS The dipyridamole echocardiographic response was positive in 11 patients (37%). The best cutoff values for predicting an abnormal echocardiographic response were 1) stenotic flow reserve of 2.8 (p = 0.0001); 2) 59% diameter stenosis (p = 0.0001); 3) minimal lumen diameter of 1.35 mm (p = 0.001); 4) coronary flow reserve of 2.0 (p = 0.0002); and 5) maximal peak velocity of 60 cm/s during hyperemia (p = 0.04). Multivariate analysis identified stenotic flow reserve as the only independent predictor of ischemia during dipyridamole echocardiography. CONCLUSIONS Stenotic flow reserve is the variable that best describes the functional significance of an isolated LAD lesion, and a value of 2.8 is the best predictor of a positive dipyridamole echocardiographic response. Furthermore, angiographic variables of stenosis severity relate to echocardiographic test results better than intracoronary Doppler variables.

Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina

OBJECTIVES We designed a study to explore the effect of glycoprotein (GP) IIb/IIIa blockade on the atherosclerotic plaque and distal coronary vasculature. BACKGROUND Platelet GP IIb/IIIa blockers have been proven to be beneficial in acute ischemic syndromes. This effect has also been attributed to the prevention of microvascular obstruction, although the underlying mechanisms have not been fully defined. METHODS Eighteen patients with unstable refractory angina pectoris underwent cardiac catheterization and angioplasty. Trans-stenotic and microvascular resistances to flow were measured at baseline, during hyperventilation, and after intracoronary adenosine. Measurements were repeated early after abciximab administration and after successful percutaneous transluminal coronary angioplasty. RESULTS Hyperventilation induced an ischemic attack in 12 of 18 patients and increased epicardial (12.8 +/- 16.9 vs. 6.1 +/- 6.1 mm Hg/ml per min, p < 0.05) and microvascular (9.9 +/- 7.5 vs. 6.8 +/- 5.8 mm Hg/ml per min, p < 0.05) coronary resistance. Abciximab had no significant effect on epicardial resistance, although it significantly reduced distal coronary resistance under all study conditions, including baseline (4.8 +/- 4.8 mm Hg/ml per min, p < 0.01), hyperventilation (5.1 +/- 5.4 mm Hg/ml per min, p < 0.01), and intracoronary adenosine (2.7 +/- 3.0 vs. 4.3 +/- 4.3 mm Hg/ml per min, p < 0.05). The hyperventilation test became negative in all patients after abciximab administration. CONCLUSIONS These observations confirm the immediate beneficial effects of platelet GP IIb/IIIa blockade with abciximab in acute ischemic syndromes and suggest that improvement of microvascular function may play a central role in the mechanism of action of this drug.

Residual coronary reserve despite decreased resting blood flow in patients with critical coronary lesions. A study by technetium-99m human albumin microsphere myocardial scintigraphy.

BackgroundExperimental data demonstrate the persistence of a transmural vasodilator reserve in the face of depressed resting myocardial perfusion. The present study was designed to determine whether resting myocardial hypoperfusion indicates exhausted coronary reserve (CR). Methods and ResultsFifteen patients with stable angina, isolated left anterior descending coronary artery (LAD) stenosis, and no previous myocardial infarction were evaluated by means of 99mTc human albumin microsphere scintigraphy. Regional myocardial perfusion and CR were assessed at baseline and after LAD papaverine (10–12 mg) by means of two microsphere injections in the left ventricle and compared with five normal subjects. Two 300-second scans were obtained with a mobile gamma camera positioned in the 70° left anterior oblique projection; actual microsphere distribution after papaverine was obtained by image subtraction. The two arterial input functions (basal and papaverine) were measured from the first-pass time-activity curves and validated with the reference arterial sample technique. From the comparison of circumferential profile analysis between patients and normal subjects, nine patients (group 1A) showed perfusion defects at rest (reduction of percent radioactivity below 2 SD of normal subjects) in the LAD territory, and the other six (group 1B) showed homogeneous perfusion. CR (papaverine/resting perfusion) was 3.8±0.2 and 1.51±0.27 in normal subjects and in ischemic patients, respectively (p<0.01). Despite resting hypoperfusion, group lA showed a papaverine-recruitable CR similar to that of group 1B (1.57±+0.33 and 1.43±0.16, respectively, p=NS). ConclusionIn patients with stable angina pectoris, isolated LAD stenosis, and no previous myocardial infarction, microsphere scintigraphy disclosed a high incidence of resting perfusion defects; in those patients, a residual CR was observed despite decreased resting blood flow.

Increase of Walking Capacity After Acute Aminophylline Administration in Intermittent Claudication

In the presence of peripheral atherosclerotic disease, inappropriate adeno sine release during exercise might promote excessive arteriolar dilation leading to steal phenomena and ischemia. In order to test this hypothesis, IV aminophylline (6 mg/kg over fifteen min utes), a dosage known to effectively block adenosine receptors, was acutely ad ministered—in a double-blind, placebo-controlled study design—in 13 patients with intermittent claudication and documented atherosclerotic disease. All pa tients performed two treadmill exercise tests at the same hour on two consecu tive days, five minutes after aminophylline or placebo administration randomly allocated. Pain-free time was 109±133 (mean±SD) seconds after placebo and 173±165 seconds after aminophylline (p < .01); maximum time to claudication was 273±191 seconds after placebo and 397±318 seconds after aminophylline (p < .05). The authors conclude that intravenous aminophylline markedly increases the walking capacity in patients with intermittent claudication, possibly by pre venting flow maldistribution phenomena through adenosine receptors block ade.

Findings from long-term electrocardiographic monitoring of patients with variant angina in a coronary care unit

Eleven patients with frequent episodes of variant angina underwent 24-hour electrocardiographic monitoring in a coronary care unit for a total of 70 days to assess circadian variation in ischemic episodes and its correlation with circadian heart rate (HR) rhythm. In each patient a series of 4 to 13 consecutive days, in the absence of therapy, with 8 or more ischemic episodes per day were analyzed. Harmonic regression models were fitted to the hourly number of ischemic episodes and the hourly values of HR. Out of 54 days, with 8 or more episodes per day for a total of 1,357 episodes, a circadian rhythm was observed for 34 days (64%), in at least 1 day in all patients and during the entire period of observation in only 3. Its presence was independent of the number of episodes; the peak of periodic functions occurred at 2.9 +/- 2.7 AM. A cadian rhythm for HR was observed in 61 of the 70 days (87%), consistently in 7 patients; the nadir occurred at 2.4 +/- 1.5 AM; simultaneous cycling in HR and transient ischemia was found on 32 days. The intrapatient difference between the peak and the nadir of the ischemic and the HR function was, on average, 2.6 +/- 3.3 hours. Thus, a circadian rhythm of ischemic episodes was present in all patients although it was not consistently present; simultaneous occurrence of circadian variation in ischemic episodes and HR was observed only in 60% of the days with a sufficiently high number of attacks and when this occurred, a significant phase shift was observed; occasional loss of HR cycling was observed in some patients, without an apparent cause.

Super-normal retention in hibernating myocardium: an ex-vivo study using the failing human heart

OBJECTIVE Although the relationship between delayed 201Tl distribution and blood flow in acutely ischemic and infarcted myocardium has been widely explored in the experimental setting, its behaviour in chronically hypoperfused dysfunctioning human myocardium has not yet been evaluated. METHODS In tissue samples of excised failing hearts taken from ischemic (IHD) patients and idiopathic dilated cardiomyopathy (IDC) controls, we evaluated the relationship between delayed 201Tl retention (4 h redistribution), blood flow (assessed by means of 99mTc-labelled human albumin microspheres injected during transplantation) and biochemically-assessed fibrosis. 201Tl activity was expressed as the percent of the activity in the region with highest flow and the least fibrosis. RESULTS Fibrosis and 201Tl activity were inversely related (r = -0.62, P = 0.0001). In IDC controls, low flows corresponded to uniformly preserved 201Tl retention. In IHD, 46 segments with flows < or = 0.60 ml.min-1.g-1 and 20 segments with flows > 0.60 ml.min-1.g1 showed matching delayed 201Tl retention and flow values; in the remaining 27, there was a disproportionately high tracer accumulation in comparison with flow (flow/201Tl mismatch). Despite significantly less fibrosis and lower flows, the mismatch segments showed significantly greater. 201Tl activity than the segments with concordantly high tracer retention and flow values. Conversely, at equivalent flow rates, the mismatch regions had less fibrosis than the areas with concordantly depressed 201Tl activity and perfusion. CONCLUSIONS This super-normal 201Tl retention in hibernating myocardium may indicate a mechanism of cell adaptation to chronic hypoperfusion.

Improvement of Walking Distance in Patients with Intermittent Claudication by Chronic Local Therapy with Isosorbide Dinitrate Ointment

Isosorbide dinitrate ointment (100 mg tid) was directly applied to 30 male patients with stable, documented intermittent claudication on the areas where ischemic pain was experienced. The symptom-free distance walked (DWA) and the maximum distance reached (MDR) basally, after one, three, six, and twelve months were evaluated by means of treadmill stress tests (TSTs) (angle 0°-velocity constant/patient). After the basal TST, patients were randomly divided into two groups: placebo group and therapy group (double blind), and a further TST was administered one month later. DWA results were 74±8 m vs 297 ±83 m and MDR results were 163 ±22 m vs 506 ±86 m in the therapy group (basal vs one month TST: p < .01) and 94±24 m vs 96±15 m and 232±53 m vs 183±26 m in the placebo group, respectively (basal vs one month TST: NS). Being confident that a significant placebo effect was absent, the authors opened the trial and treated all patients, repeating further TSTs at three, six, and twelve months. The following results were obtained: DWA was 84±13 m, 316±63 m, 374±55 m, and 452±61 m; and MDR was 197 ±29 m, 431 ±59 m, 514 ±57 m, and 547 ±59 m, respectively, in basal conditions and after three, six, and twelve months of treatment (p < .01 for all the values for both DWA and MDR vs basal values). These results suggest the effectiveness of this treatment, independently from a placebo effect, in improving walking tolerance in patients with intermittent claudication.