Howard Swanton

Randomized Trial of Complete Versus Lesion-Only Revascularization in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI and Multivessel Disease: The CvLPRIT Trial

Background The optimal management of patients found to have multivessel disease while undergoing primary percutaneous coronary intervention (P-PCI) for ST-segment elevation myocardial infarction is uncertain. Objectives CvLPRIT (Complete versus Lesion-only Primary PCI trial) is a U.K. open-label randomized study comparing complete revascularization at index admission with treatment of the infarct-related artery (IRA) only. Methods After they provided verbal assent and underwent coronary angiography, 296 patients in 7 U.K. centers were randomized through an interactive voice-response program to either in-hospital complete revascularization (n = 150) or IRA-only revascularization (n = 146). Complete revascularization was performed either at the time of P-PCI or before hospital discharge. Randomization was stratified by infarct location (anterior/nonanterior) and symptom onset (≤3 h or >3 h). The primary endpoint was a composite of all-cause death, recurrent myocardial infarction (MI), heart failure, and ischemia-driven revascularization within 12 months. Results Patient groups were well matched for baseline clinical characteristics. The primary endpoint occurred in 10.0% of the complete revascularization group versus 21.2% in the IRA-only revascularization group (hazard ratio: 0.45; 95% confidence interval: 0.24 to 0.84; p = 0.009). A trend toward benefit was seen early after complete revascularization (p = 0.055 at 30 days). Although there was no significant reduction in death or MI, a nonsignificant reduction in all primary endpoint components was seen. There was no reduction in ischemic burden on myocardial perfusion scintigraphy or in the safety endpoints of major bleeding, contrast-induced nephropathy, or stroke between the groups. Conclusions In patients presenting for P-PCI with multivessel disease, index admission complete revascularization significantly lowered the rate of the composite primary endpoint at 12 months compared with treating only the IRA. In such patients, inpatient total revascularization may be considered, but larger clinical trials are required to confirm this result and specifically address whether this strategy is associated with improved survival. (Complete Versus Lesion-only Primary PCI Pilot Study [CvLPRIT]; ISRCTN70913605)

Human Ventricular Action Potential Duration During Short and Long Cycles Rapid Modulation by Ischemia

BACKGROUND Mechanisms underlying the initiation of ventricular arrhythmias in ischemia by a premature beat or after a pause remain unclear. The kinetics of electrical restitution, which is the modulation of action potential duration (APD) by an abrupt alteration in cycle length, may be important. METHODS AND RESULTS We recorded one or two simultaneous monophasic action potentials (MAPs) from the right ventricular septum during balloon occlusion of the left anterior descending coronary artery (LAD) (14 patients), which is expected to induce ischemia at the recording site, and during occlusion of the right coronary artery (RCA) (7 patients), which is not expected to induce ischemia at the recording area. The latter acted as a control. A test pulse sequence was incorporated whereby during steady-state pacing, test beats of altered cycle length were interpose. During LAD occlusion, APD for basic beats shortened from 260 +/- 4 to 236 +/- 4 ms (P < .0001), whereas the control group (RCA occlusion) showed no significant change (251 +/- 7 to 249 +/- 9 ms; P = NS). LAD occlusion resulted in flattening of the slope relating APD of test beats to diastolic interval (P = .001), whereas in the control group (RCA occlusion) the slope remained unchanged. Similar results were obtained during a second occlusion. CONCLUSIONS LAD occlusion in patients during balloon angioplasty shortened MAP duration of basic beats and minimized, abolished, or reversed the normal APD/diastolic-interval relation of test beats of altered cycle length at sites served by the occluded vessel. The results suggest that ischemia flattens the electrical restitution curve in the human endocardium. These findings may have important implications in arrhythmogenesis.

Monophasic action potential recordings during acute changes in ventricular loading induced by the Valsalva manoeuvre.

OBJECTIVE--The strong association between ventricular arrhythmia and ventricular dysfunction is unexplained. This study was designed to investigate a mechanism by which a change in ventricular loading could alter the time course of repolarisation and hence refractoriness. A possible mechanism may be a direct effect of an altered pattern of contraction on ventricular repolarisation and hence refractoriness. This relation has been termed contraction-excitation feedback or mechano-electric feedback. METHODS--Monophasic action potentials were recorded from the left ventricular endocardium as a measure of the time course of local repolarisation. The Valsalva manoeuvre was used to change ventricular loading by increasing the intrathoracic pressure and impeding venous return, and hence reducing ventricular pressure and volume (ventricular unloading). PATIENTS--23 patients undergoing routine cardiac catheterisation procedures: seven with no angiographic evidence of abnormal wall motion or history of myocardial infarction (normal), five with a history of myocardial infarction but with normal wall motion, and 10 with angiographic evidence of abnormal wall motion--with or without previous infarction. One patient was a transplant recipient and was analysed separately. SETTING--Tertiary referral centre for cardiology. RESULTS--In patients with normal ventricles during the unloading phase of the Valsalva manoeuvre (mean (SD)) monophasic action potential duration shortened from 311 (47) ms to 295 (47) ms (p less than 0.001). After release of the forced expiration as venous return was restored the monophasic action potential duration lengthened from 285 (44) ms to 304 (44) ms (p less than 0.0001). In the group with evidence of abnormal wall motion the direction of change of action potential duration during the strain phase was normal in 7/21 observations, abnormal in 6/21, and showed no clear change in 8/21. During the release phase 11/20 observations were normal, five abnormal, and four showed no clear change. In those with myocardial infarction four out of five patients had changes that resembled those with normal ventricles but the changes were less pronounced. There were no differences in any of the three groups between the changes in monophasic action potential duration in patients taking beta blockers and those who were not. The changes in monophasic action potential duration in the transplanted heart resembled those in the group with normal ventricles. Inflections on the repolarisation phase of the monophasic action potential consistent with early afterdepolarisations were seen in three of the patients with abnormal wall motion and in none of those with normal wall motion. CONCLUSIONS--These results are further evidence that changes in ventricular loading influence repolarisation. When wall motion was abnormal the effects on regional endocardial repolarisation were often opposite in direction to those when it was normal. Thus regional differences in wall motion could generate local electrophysiological inhomogeneity which may be relevant to the association of arrhythmia with impaired left ventricular function.

USE OF MONOPHASIC ACTION POTENTIAL RECORDINGS DURING ROUTINE CORONARY-ARTERY BYPASS SURGERY AS AN INDEX OF LOCALISED MYOCARDIAL ISCHAEMIA

In 8 patients undergoing routine coronary-artery bypass surgery, monophasic action potentials (MAPs) were measured by means of a hand-held pressure contact electrode to provide an index of local ischaemic changes. 4 patients received left internal mammary anastomoses (LIMA), and there were a total of 27 saphenous vein grafts (SVG). After completion of all grafts blood-flow to the myocardium was reduced for 90 s by means of different permutations of SVG and LIMA occlusion, either on or off bypass. In all patients MAPs indicated typical ischaemic changes. The high sensitivity of the method enables the study to be completed quickly and without hazard to the patient. The technique provides a new means to assess local ischaemia, the viability of specific areas of myocardium, and the efficiency of individual grafts during surgery.

Complete Versus Lesion-Only Primary PCI: The Randomized Cardiovascular MR CvLPRIT Substudy

Background Complete revascularization may improve outcomes compared with an infarct-related artery (IRA)-only strategy in patients being treated with primary percutaneous coronary intervention (PPCI) who have multivessel disease presenting with ST-segment elevation myocardial infarction (STEMI). However, there is concern that non-IRA PCI may cause additional non-IRA myocardial infarction (MI). Objectives This study sought to determine whether in-hospital complete revascularization was associated with increased total infarct size compared with an IRA-only strategy. Methods This multicenter prospective, randomized, open-label, blinded endpoint clinical trial evaluated STEMI patients with multivessel disease having PPCI within 12 h of symptom onset. Patients were randomized to either IRA-only PCI or complete in-hospital revascularization. Contrast-enhanced cardiovascular magnetic resonance (CMR) was performed following PPCI (median day 3) and stress CMR at 9 months. The pre-specified primary endpoint was infarct size on pre-discharge CMR. The study had 80% power to detect a 4% difference in infarct size with 100 patients per group. Results Of the 296 patients in the main trial, 205 participated in the CMR substudy, and 203 patients (98 complete revascularization and 105 IRA-only) completed the pre-discharge CMR. The groups were well-matched. Total infarct size (median, interquartile range) was similar to IRA-only revascularization: 13.5% (6.2% to 21.9%) versus complete revascularization, 12.6% (7.2% to 22.6%) of left ventricular mass, p = 0.57 (95% confidence interval for difference in geometric means 0.82 to 1.41). The complete revascularization group had an increase in non-IRA MI on the pre-discharge CMR (22 of 98 vs. 11 of 105, p = 0.02). There was no difference in total infarct size or ischemic burden between treatment groups at follow-up CMR. Conclusions Multivessel PCI in the setting of STEMI leads to a small increase in CMR-detected non-IRA MI, but total infarct size was not significantly different from an IRA-only revascularization strategy. (Complete Versus Lesion-Only Primary PCI Pilot Study [CvLPRIT]; ISRCTN70913605)

Direct effect of dobutamine on action potential duration in ischemic compared with normal areas in the human ventricle.

BACKGROUND AND OBJECTIVES The arrhythmogenic effect of beta-adrenoceptor stimulation is complex and may differ in ischemic and normal myocardium. In this study we examined the differential effect of beta-adrenergic stimulation on ventricular action potential duration and, hence, dispersion of repolarization in potentially ischemic versus nonischemic human ventricular myocardium. METHODS Simultaneous biventricular monophasic action potentials were recorded in 14 patients (28 recording sites) during infusion of dobutamine in incremental doses (low dose 5 micrograms/kg per min, high dose 10 to 15 micrograms/kg per min) during atrial pacing. Perfusion at the action potential recording site was assessed by incorporating myocardial perfusion scintigraphy with injection of technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile during the recording at peak doses of dobutamine. Action potential duration during dobutamine infusion was compared with that during atrial pacing to identical rates in the absence of dobutamine. RESULTS In 21 normal zone recordings, dobutamine produced a variable effect over that produced by atrial pacing to identical heart rates, either lengthening or shortening the action potential duration. The mean (+/- SEM) value for the additional effect of dobutamine was 0.9 +/- 2.5 ms with low doses and -4 +/- 2.6 ms with high doses (p = NS). In seven recordings from potentially ischemic zones, low dose dobutamine had a similar effect (mean change -3.4 +/- 6.5 ms; p = NS vs. normal zone values). However, the high dose dobutamine invariably shortened the action potential duration by a mean of -22.9 +/- 2.9 ms. (p less than 0.05 vs. low dose in ischemic areas, p less than 0.01 vs. normal zone recordings). Pacing alone or the addition of dobutamine had no significant effect on the normal dispersion of action potential duration between two nonischemic recording sites. In recordings in a normal and an abnormally perfused site, high dose dobutamine significantly altered the dispersion of action potential duration. CONCLUSIONS These results suggest a different effect of beta adrenergic stimulation in potentially ischemic compared with nonischemic human ventricular myocardium. The abnormal dispersion of repolarization thus created may well be important in beta-receptor-mediated arrhythmogenesis during myocardial ischemia.

Endocardial monophasic action potential recordings for the detection of muocardial ischemia in man: A study using atrial pacing stress and myocardial perfusion scintigraphy

In a study designed to appraise the use of monophasic action potentials (MAPs) to detect myocardial ischemia in endocardial recordings, changes in steady-state MAP duration were compared in recordings between normal and ischemic areas of myocardium identified by the use of a radionuclide tracer simultaneously with the MAP recording procedure. Single-site recordings were made from the left or right ventricular endocardium or both in 26 patients (32 recording sites) during atrial pacing up to angina threshold. Pacing was maintained for 2 minutes at each increment in heart rate and MAPs were recorded at the end of each 2-minute period. Perfusion defects produced by atrial pacing stress were detected using technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile injected at peak pacing stress. In 18 recordings from normally perfused areas of endocardium, MAP duration at 70% and 90% repolarization shortened by a mean (+/- SD) of 20.9 (3.7) msec and 22.0 (4.8 msec, respectively, for every 100 msec change in cycle length. This is in keeping with the effect of cycle length changes on the action potential duration. The extent of shortening was significantly greater (p less than 0.01) for 14 recordings from ischemic areas, being 32.0 (8.6) and 33.8 (9.7) msec, respectively, indicating the additional effect of localized myocardial ischemia. These results validate the applicability of the endocardially recorded MAPs for the detection of ischemia. Such methodology may provide a means of assessing therapeutic interventions aimed at the early phase of ischemia.

Vasodilator myocardial perfusion imaging: demonstration of local electrophysiological changes of ischaemia

Objective—To examine the incidence and severity of myocardial ischaemia provoked in the course of perfusion scintigraphy by coronary vasodilators using endocardial recordings of steady state monophasic action potentials as an independent marker of early localised myocardial ischaemia. Patients—31 men undergoing routine cardiac catheterisation for investigation of chest pain were studied. Setting—A tertiary cardiac referral centre. Design—Single site monophasic action potentials were recorded from the left or right ventricle or both (50 recording sites) during intravenous infusion of dipyridamole (0·015 mg/kg/min) for four minutes. Heart rate was held constant with atrial pacing at 20% above the patients resting rate. Technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile (MIBI) was administered four minutes after dipyridamole, and single photon emission tomographic imaging was performed an hour later. Rest images were obtained the next day (two day, two dose protocol). Recordings were divided into three groups based on the scintigraphic perfusion characteristics and coronary anatomical data for the action potential recording site: group 1—recordings from areas with a normal perfusion pattern (n = 30), group 2—recordings from areas with a perfusion defect and subtended by significantly narrowed coronary arteries without obvious angiographic collateral supply (n = 10), and group 3—recordings from areas with a perfusion defect and subtended by occluded arteries with angiographically evident collaterals from adjacent vessels (n = 10). Results—There were changes in the duration of the monophasic action potential indicative of ischaemia—that is, shortening of duration of steady state action potential—in 18 of the 20 recordings from areas of abnormal perfusion. Peak changes were apparent eight minutes from the start of the dipyridamole infusion. Mean (SEM) values for duration of the action potential between control and peak effect at eight minutes were 276·5 (5·3) ms ν 276·6 (5·4) for group 1 (NS), 289·6 (4·7) ms ν 278·4 (4·9) ms for group 2 (p < 0·001), and 269·6 (5·7) ms ν 242·0 (4·4) for group 3 (p < 0·0001). These changes were significantly different between the three groups (p < 0·01). ST segment changes on the surface electrocardiogram were seen in only eight patients, all with areas of viable myocardium supplied by collateral vessels. Conclusions—These data provide strong evidence for the presence of myocardial ischaemia in regions of reversible perfusion defects induced by dipyridamole. This study also shows that such ischaemia is more intense and more likely to be seen when myocardial viability is dependent on collateral circulation.

Infarct Size Following Treatment With Second‐ Versus Third‐Generation P2Y12 Antagonists in Patients With Multivessel Coronary Disease at ST‐Segment Elevation Myocardial Infarction in the CvLPRIT Study

Background Third‐generation P2Y12 antagonists (prasugrel and ticagrelor) are recommended in guidelines on ST‐segment elevation myocardial infarction. Mechanisms translating their more potent antiplatelet activity into improved clinical outcomes versus the second‐generation P2Y12 antagonist clopidogrel are unclear. The aim of this post hoc analysis of the Complete Versus Lesion‐Only PRImary PCI Trial‐CMR (CvLPRIT‐CMR) substudy was to assess whether prasugrel and ticagrelor were associated with reduced infarct size compared with clopidogrel in patients undergoing primary percutaneous coronary intervention. Methods and Results CvLPRIT‐CMR was a multicenter, prospective, randomized, open‐label, blinded end point trial in 203 ST‐segment elevation myocardial infarction patients with multivessel disease undergoing primary percutaneous coronary intervention with either infarct‐related artery–only or complete revascularization. P2Y12 inhibitors were administered according to local guidelines. The primary end point of infarct size on cardiovascular magnetic resonance was not significantly different between the randomized groups. P2Y12 antagonist administration was not randomized. Patients receiving clopidogrel (n=70) compared with those treated with either prasugrel or ticagrelor (n=133) were older (67.8±12 versus 61.5±10 years, P<0.001), more frequently had hypertension (49% versus 29%, P=0.007), and tended to have longer symptom‐to‐revascularization time (234 versus 177 minutes, P=0.05). Infarct size (median 16.1% [quartiles 1–3, 10.5–27.7%] versus 12.1% [quartiles 1–3, 4.8–20.7%] of left ventricular mass, P=0.013) and microvascular obstruction incidence (65.7% versus 48.9%, P=0.022) were significantly greater in patients receiving clopidogrel. Infarct size remained significantly different after adjustment for important covariates using both generalized linear models (P=0.048) and propensity score matching (P=0.025). Conclusions In this analysis of CvLPRIT‐CMR, third‐generation P2Y12 antagonists were associated with smaller infarct size and lower microvascular obstruction incidence versus the second‐generation P2Y12 antagonist clopidogrel for ST‐segment elevation myocardial infarction. Clinical Trial Registration URL: http://www.isrctn.com/ISRCTN70913605.

Reply : Complete Revascularization in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI: Is It Really What We Should Be Doing?

We read with interest the letter from Dr. Dastidar and colleagues in which they express their views and compare our report of the randomized CvLPRIT (Complete Versus Lesion-Only Primary PCI Trial) [(1)][1] with their in-house clinical experience. They suggest that the trial was not run according to