Kenneth C. Huber

Restenosis and the proportional neointimal response to coronary artery injury: Results in a porcine model☆

Restenosis is a reparative response to arterial injury occurring with percutaneous coronary revascularization. However, the quantitative characteristics of the relation between vessel injury and the magnitude of restenotic response remain unknown. This study was thus performed to determine the relation between severity of vessel wall injury and the thickness of resulting neointimal proliferation in a porcine model of coronary restenosis. Twenty-six porcine coronary artery segments in 24 pigs were subjected to deep arterial injury with use of overexpanded, percutaneously delivered tantalum wire coils. The vessels were studied microscopically 4 weeks after coil implantation to measure the relation between the extent of injury and the resulting neointimal thickness. For each wire site, a histopathologic score proportional to injury depth and the neointimal thicknesses at that site were determined. Mean injury scores were compared with both mean neointimal thickness and planimetry-derived area percent lumen stenosis. The severity of vessel injury strongly correlated with neointimal thickness and percent diameter stenosis (p less than 0.001). Neointimal proliferation resulting from a given wire was related to injury severity in adjacent wires, suggesting an interaction among effects at injured sites. If the results in this model apply to human coronary arteries, restenosis may depend on the degree of vessel injury sustained during angioplasty.

Percutaneous Left Atrial Appendage Closure for Stroke Prophylaxis in Patients With Atrial Fibrillation 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) Trial

Background— The multicenter PROTECT AF study (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) was conducted to determine whether percutaneous left atrial appendage closure with a filter device (Watchman) was noninferior to warfarin for stroke prevention in atrial fibrillation. Methods and Results— Patients (n=707) with nonvalvular atrial fibrillation and at least 1 risk factor (age >75 years, hypertension, heart failure, diabetes, or prior stroke/transient ischemic attack) were randomized to either the Watchman device (n=463) or continued warfarin (n=244) in a 2:1 ratio. After device implantation, warfarin was continued for ≈45 days, followed by clopidogrel for 4.5 months and lifelong aspirin. Study discontinuation rates were 15.3% (71/463) and 22.5% (55/244) for the Watchman and warfarin groups, respectively. The time in therapeutic range for the warfarin group was 66%. The composite primary efficacy end point included stroke, systemic embolism, and cardiovascular death, and the primary analysis was by intention to treat. After 1588 patient-years of follow-up (mean 2.3±1.1 years), the primary efficacy event rates were 3.0% and 4.3% (percent per 100 patient-years) in the Watchman and warfarin groups, respectively (relative risk, 0.71; 95% confidence interval, 0.44%–1.30% per year), which met the criteria for noninferiority (probability of noninferiority >0.999). There were more primary safety events in the Watchman group (5.5% per year; 95% confidence interval, 4.2%–7.1% per year) than in the control group (3.6% per year; 95% confidence interval, 2.2%–5.3% per year; relative risk, 1.53; 95% confidence interval, 0.95–2.70). Conclusions— The “local” strategy of left atrial appendage closure is noninferior to “systemic” anticoagulation with warfarin. PROTECT AF has, for the first time, implicated the left atrial appendage in the pathogenesis of stroke in atrial fibrillation. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00129545.

Outcome of Noncardiac Operations in Patients With Severe Coronary Artery Disease Successfully Treated Preoperatively With Coronary Angioplasty

The risk of perioperative myocardial infarction and death was evaluated in 50 patients (mean age, 68 years) with severe coronary artery disease who underwent a noncardiac operation after revascularization had been achieved by successful percutaneous transluminal coronary angioplasty. Before angioplasty, all patients were thought to be at high risk for perioperative complications on the basis of assessment of clinical variables and findings on specialized diagnostic tests. Of the 50 patients, 31 had Canadian Heart Association class III or IV angina or unstable angina. All patients who underwent functional testing had positive results. At catheterization, 38 patients (76%) had multivessel disease. The 50 patients underwent 54 noncardiac operations at a median of 9 days after angioplasty. The overall frequency of perioperative myocardial infarction was 5.6%, and the mortality was 1.9%. Two nonfatal non-Q-wave infarctions and one fatal Q-wave infarction occurred. In patients who have undergone successful angioplasty for severe coronary artery disease, the risk of major cardiac complications associated with a noncardiac surgical procedure is low.

Mismatch of left ventricular function and infarct size demonstrated by technetium-99m isonitrile imaging after reperfusion therapy for acute myocardial infarction : identification of myocardial stunning and hyperkinesia

Quantitation of perfusion defect size using tomographic imaging with technetium-99m-hexakis-2-methoxy isobutyl isonitrile was performed at the time of hospital discharge in 32 patients with a first myocardial infarction who underwent successful coronary reperfusion within 8 h of the onset of chest pain. Reperfusion was accomplished with thrombolysis or primary coronary angioplasty. Radionuclide angiography was performed at discharge and 6 weeks later. There was a close correlation between perfusion defect size and values for ejection fraction and regional wall motion both at discharge (r = -0.80 and -0.75, respectively) and 6 weeks later (r = -0.81 and -0.81, respectively). There was no overall group difference in ejection fraction between the value at discharge and at 6 weeks; however, five patients had a significant increase (greater than or equal to 0.08) and six had a significant decrease (greater than or equal to 0.08) in ejection fraction. In patients with a significant increase at 6 weeks, ejection fraction was significantly lower at discharge than the value predicted from perfusion defect size (0.37 +/- 0.09 measured versus 0.47 +/- 0.13 predicted, p less than 0.05) and it improved at 6 weeks to near predicted values (0.51 +/- 0.07). In patients with a significant decrease at 6 weeks, ejection fraction was significantly higher at discharge than the value predicted from perfusion defect size (0.60 +/- 0.10 measured versus 0.50 +/- 0.10 predicted, p less than 0.05) and it decreased at 6 weeks to near predicted levels (0.51 +/- 0.09). Left ventricular ejection fraction at the time of hospital discharge is a potentially misleading index of the efficacy of reperfusion therapy for myocardial infarction. In a significant minority (34%) of patients this index does not accurately reflect perfusion defect size, apparently because of the effects of myocardial stunning and compensatory hyperkinesia.

Primary Angioplasty in Myocardial Infarction: Assessment of Improved Myocardial Perfusion With Technetium-99m Isonitrile

Technetium-99m-hexakis-2-methoxy-2-isobutyl-isonitrile (technetium-99m isonitrile) is a new radiopharmaceutical compound that reflects myocardial perfusion. Its kinetics, especially its lack of redistribution after intravenous administration, permits the assessment of changes in myocardial perfusion without delay of therapy. Tomographic images at rest were obtained immediately and 6 to 10 days later in 17 consecutive patients undergoing successful primary angioplasty during their first transmural myocardial infarction. Thirteen patients had anterior infarction. The initial (acute) defect size before angioplasty of 48 +/- 17% of the left ventricle decreased significantly (p less than 0.0001) to 29 +/- 19% on the late scans. There was no correlation between the time to therapy and the reduction in defect size. Twelve of the 17 patients, including 7 of the 11 patients treated after 4 h, demonstrated a definite reduction in the initial defect size. Eight patients with angiographically proved persistent coronary occlusion underwent a similar imaging sequence. The initial defect size in this group remained unchanged on the late scans (24 +/- 16% versus 26 +/- 18%, p = NS). Primary angioplasty is an effective approach toward salvaging myocardium; comparison with thrombolytic drug therapy must await the results of controlled clinical trials.

Coronary Restenosis: Prospects for Solution and New Perspectives From a Porcine Model

Coronary restenosis, a major unresolved problem for percutaneous coronary revascularization procedures, has thus far been resistant to all therapeutic strategies. In part, ineffective treatment or prevention of coronary restenosis may be due to reliance on a conceptualization of the restenosis process that incompletely reflects the pathophysiologic factors associated with neointimal formation after arterial injury. In a porcine coronary restenosis model, three stages of neointimal growth after arterial injury have been identified: an early thrombotic stage, with platelets, fibrin, and erythrocytes; a cellular recruitment stage, with endothelialization and an infiltration by lymphocytes and monocytes; and a proliferative stage, in which smooth muscle cells migrate into and proliferate within the fibrin-rich degenerating thrombus. Evaluation of basic mechanisms responsible for neointimal formation has been possible with this model. In particular, a direct relationship exists between the depth of arterial injury and subsequent neointimal thickness. This relationship can be used for investigating the efficacy of new therapies. Treatment strategies for restenosis should be directed toward interference with the cellular or humoral events that lead to neointimal formation, with the specific goal of decreasing the neointimal volume. These strategies may include delivery of drugs to the site of arterial injury to limit the amount of early mural thrombus or decreasing subsequent cellular recruitment and proliferation as well as synthesis of extracellular matrix.

Effects of angiotensin converting enzyme inhibition on neointimal proliferation in a porcine coronary injury model

To assess the effectiveness of angiotensin converting enzyme inhibition in a proliferative porcine coronary restenosis model, 35 animals received orally administered trandolapril (10 mg) or captopril (200 mg) or no drug (control group) for 6 days before and 28 days after injury by oversized metallic coils in one or more coronary arteries. Twenty arterial lesions in the trandolapril group, 17 in the captopril group, and 18 in the control group were evaluated. There was no significant difference in neointimal thickness or percentage luminal area stenosis for the groups as a whole. However, in quantitative comparisons in which vessel injury score was used as a covariate, the fractional increase in mean neointimal thickness per unit of injury was significantly less for the trandolapril group (p = 0.019) but not for the captopril group when compared with control animals. In this model, neointimal proliferation from arterial injury was inhibited by angiotensin converting enzyme inhibition with trandolapril but only modestly. Such an effect may not be clinically significant.

LIMITATIONS OF THE ELECTROCARDIOGRAM IN ESTIMATING INFARCTION SIZE AFTER ACUTE REPERFUSION THERAPY FOR MYOCARDIAL INFARCTION

OBJECTIVE To assess the ability of the 12-lead electrocardiogram to estimate infarction size after reperfusion therapy for acute myocardial infarction. DESIGN The presence or absence of Q waves and the Selvester QRS score obtained before and after hospital discharge were compared with radionuclide estimates of infarction size and ejection fraction at discharge and 6 weeks later, regional wall motion at discharge and 6 weeks later, and myocardial perfusion defect size quantitated with Tc-99m-sestamibi at discharge. SETTING A tertiary referral center. PATIENTS A consecutive series of 43 patients with acute myocardial infarction who received acute reperfusion therapy and were assessed using 12-lead electrocardiography, radionuclide angiography, and Tc-99m-sestamibi tomographic imaging before discharge. INTERVENTIONS All 43 patients received acute reperfusion therapy: 21 patients received intravenous tissue plasminogen activator, and 22 patients underwent primary percutaneous transluminal coronary angioplasty. MAIN OUTCOME MEASURE The correlation of QRS score and Q waves with three radionuclide estimates of infarction size. RESULTS A significant correlation was found between myocardial perfusion defect size at discharge and both left ventricular ejection fraction and regional wall motion at discharge and 6 weeks later (r = -0.71 to -0.81; all comparisons, P less than 0.001). Little correlation was found between electrocardiographic findings and radionuclide measurements of left ventricular function and perfusion. Presence or absence of Q waves at discharge was not associated with any difference in ejection fraction, regional wall motion, or perfusion defect at discharge. No correlation was found between QRS score and ejection fraction or myocardial perfusion defect size at discharge. The QRS score at discharge correlated only weakly with regional wall motion at discharge and 6 weeks later. This lack of correlation was unchanged when electrocardiograms obtained after hospital discharge were analyzed. CONCLUSION Although inexpensive and readily available, the 12-lead electrocardiogram does not appear to provide a reliable estimate of infarction size after reperfusion therapy for acute myocardial infarction.

Assessment of Device-Related Thrombus and Associated Clinical Outcomes With the WATCHMAN Left Atrial Appendage Closure Device for Embolic Protection in Patients With Atrial Fibrillation (from the PROTECT-AF Trial).

Left atrial appendage closure with the WATCHMAN device is an alternative to anticoagulation for stroke prevention in selected patients with atrial fibrillation (AF). LA device-related thrombus (DRT) is poorly defined and understood. We aimed to (1) develop consensus echocardiographic diagnostic criteria for DRT; (2) estimate the incidence of DRT; and (3) determine clinical event rates in patients with DRT. In phase 1 (training), a training manual was developed and reviewed by 3 echocardiographers with left atrial appendage closure device experience. All available transesophageal (TEE) studies in the WATCHMAN left atrial appendage system for embolic protection in patients with atrial fibrillation (PROTECT-AF) trial patients with suspected DRT were reviewed in 2 subsequent phases. In phase 2 (primary blind read), each reviewer independently scored each study for DRT, and final echo criteria were developed. Unanimously scored studies were considered adjudicated, whereas all others were reevaluated by all reviewers in phase 3 (group adjudication read). DRT was suspected in 35 of 485 patients by the site investigator, the echocardiography core laboratory, or both; 93 of the individual TEE studies were available for review. In phase 2, 3 readers agreed on 67 (72%) of time points. Based on phases 1 and 2, 5 DRT criteria were developed. In phase 3, studies without agreement in phase 2 were adjudicated using these criteria. Overall, at least 1 TEE was DRT positive in 27 (5.7%) PROTECT-AF patients. Stroke, peripheral embolism, or cardiac/unexplained death occurred in subjects with DRT at a rate of 3.4 per 100 patient-years follow-up. In conclusion, DRT were identified on at least 1 TEE in 27 PROTECT-AF patients, indicating a DRT incidence of 5.7%. Primary efficacy events in patients with DRT occurred at a rate of 3.4 per 100 patient-years follow-up, intermediate in frequency between event rates previously reported for the overall device and warfarin arms in PROTECT-AF.

Variability in Anticoagulation Control Predicts Thromboembolism After Mechanical Cardiac Valve Replacement: A 23-Year Population-Based Study

OBJECTIVE To assess optimal control of blood anticoagulation to maximize antithrombotic protection after mechanical cardiac valve replacement. DESIGN A population-based study of 96 patients with a mean follow-up of 7.7 years (range, 1 month to 23 years) was performed in Olmsted County, Minnesota, and 10,301 prothrombin time (PT) ratios were determined after mechanical heart valve replacement. MATERIAL AND METHODS PT ratios were analyzed in a new time-dependent Cox proportional-hazards model by defining an algorithm for comparing variability in PT ratios at each month of follow-up and relating these to thromboembolic events. The new method was compared with several conventional time-independent definitions. RESULTS During 740 person-years of follow-up, 19 of 96 patients (20%) had 27 thromboembolic events. Of these 19 patients, 8 (42%) had events within 3 months after valve replacement. Freedom from any thromboembolic event was 72% at 15 years. The event rate was high (7.5% per year) during high variability and low (0.9% per year) during low variability in the PT ratio. This relationship was lost when time dependence was removed. More PT ratios were less than 1.5 during high (27%) than during low (19%) variability. Several conventional definitions of adequacy of anticoagulation that averaged PT ratios before a thromboembolic event or throughout follow-up or that compared the proportion of PT ratios above or below a fixed ratio did not define or only partially defined different thromboembolic risks. CONCLUSION Periods of high and low variability of PT ratios define high and low risk of thromboembolism, respectively.