Michael R. Freeman

ST segment shift in unstable angina: pathophysiology and association with coronary anatomy and hospital outcome

The significance of ST segment shift with respect to coronary anatomy and hospital outcome was evaluated in 135 patients with unstable angina. ST shift was evident in 44% of patients on admission electrocardiogram (ECG) and in 66% on Holter monitor ECG. During hospitalization, 7% of patients had myocardial infarction, 4% died and 34% had urgent coronary revascularization. By comparing patients with and without ST shift on admission ECG, an unfavorable outcome was found in 55% versus 25% (p less than 0.005), multivessel disease in 77% versus 63% (p less than 0.05) and left main coronary artery stenosis in 22% versus 7% (p less than 0.025). When patients with and without ST shift on Holter monitor ECG were compared, an unfavorable outcome was found in 48% versus 20% (p less than 0.005), multivessel disease in 76% versus 54% (p less than 0.01) and left main coronary stenosis in 18% versus 4% (p less than 0.05). The duration of ST shift was also greater in patients with 1) unfavorable outcome (129 +/- 136 versus 52 +/- 111 min, p less than 0.01); 2) multivessel disease (98 +/- 129 versus 36 +/- 90 min, p less than 0.01); and 3) left main stenosis (150 +/- 147 versus 67 +/- 114 min, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Intracoronary thrombus and complex morphology in unstable angina. Relation to timing of angiography and in-hospital cardiac events.

In 78 consecutive patients with unstable angina, we performed coronary angiography randomized to either the first day of presentation or later during the hospital admission to assess the frequency of intracoronary thrombus and complex coronary morphology relative to the time of symptomatic presentation and the impact of these angiographic features on outcome. Early angiography (17 +/- 6 hours) was performed in 42 patients and late angiography in 36 patients (5.7 +/- 2.1 days). Twelve patients randomized to late angiography required urgent cardiac catheterization 3.9 +/- 2.2 days after admission. Coronary thrombi were present in 43% (18 of 42) of early angiography patients and in 38% (14 of 36) of late angiography patients (p = NS). Only 21% (five of 24) late elective angiography patients had coronary thrombi, but 75% (nine of 12) of late urgent angiography patients had thrombi (p less than 0.05 vs. both early and late elective angiography patients). There was no difference in the frequency of complex coronary morphology among patients randomized to early angiography (42%, or 15 of 36), late urgent angiography (42%, or five of 12), and late elective angiography (38%, or nine of 24). Cardiac events (death, myocardial infarction, and urgent revascularization) were more frequent in the patients with coronary thrombus (73%, or 23 of 32), complex coronary morphology (55%, or 16 of 29), and multiple-vessel disease (58%, or 29 of 50) than in the patients without these angiographic features (17%, or eight of 46; 31%, or 15 of 49; and 7%, or two of 28, respectively; all p less than 0.05). Multiple regression analysis demonstrated that coronary thrombus was the best angiographic predictor of cardiac events. Thus, angiographic detection of intracoronary thrombi varies according to the temporal relation between angiography and chest pain at rest.

Metaiodobenzylguanidine imaging in diabetes mellitus: Assessment of cardiac sympathetic denervation and its relation to autonomic dysfunction and silent myocardial ischemia

OBJECTIVES This study in patients with diabetes mellitus was undertaken 1) to evaluate cardiac sympathetic innervation in diabetic patients using metaiodobenzylguanidine (MIBG) imaging; 2) to study the relation between autonomic function assessed by clinical maneuvers and abnormalities in MIBG uptake; and 3) to examine the basis for our previous observation of an association between abnormalities in autonomic nervous system dysfunction and silent myocardial ischemia. BACKGROUND The clinical detection of autonomic dysfunction in diabetes mellitus has been linked to both abnormal perception of pain, including angina, and poor prognosis. METHODS Uptake of MIBG was measured by dual-isotope imaging in 23 normal subjects and 65 asymptomatic diabetic patients. Silent myocardial ischemia was defined as the presence of a reversible perfusion defect in patients with ST segment depression. RESULTS The MIBG uptake in the diabetic patients was significantly lower than that in normal subjects in the apex (67 +/- 17% vs. 82 +/- 7%, p = 0.0001), distal third (77 +/- 11% vs. 85 +/- 3%, p = 0.0001), proximal third (77 +/- 9% vs. 84 +/- 3%, p = 0.0001) and base (71 +/- 9% vs. 80 +/- 4%, p = 0.0001) of the left ventricle. Similarly, MIBG uptake was variable across different vascular territories. When MIBG uptake was corrected for perfusion abnormalities, diabetic patients had a greater MIBG uptake defect than normal subjects on visual score assessment (16 +/- 13 vs. 8 +/- 7%, p = 0.0002) and on quantitative MIBG mismatch assessment (13 +/- 15% vs. 2 +/- 2%, p = 0.0001). Diabetic patients with versus without autonomic dysfunction had more extensive MIBG uptake mismatch (17 +/- 17% vs. 4 +/- 6%, p = 0.0001). There was a greater diffuse abnormality in diabetic patients with versus without silent myocardial ischemia detected by sestamibi/MIBG uptake ratio (68 +/- 35% vs. 19 +/- 33%, p = 0.001). CONCLUSIONS Sympathetic cardiac innervation in normal subjects is inhomogeneous. In contrast to normal subjects, diabetic patients have evidence of a significant reduction in MIBG uptake, most likely on the basis of autonomic dysfunction. Furthermore, diabetic patients with silent myocardial ischemia have evidence of a diffuse abnormality in MIBG uptake, suggesting that abnormalities in pain perception may be linked to sympathetic denervation.

Positron emission tomography and recovery following revascularization (PARR-1): the importance of scar and the development of a prediction rule for the degree of recovery of left ventricular function.

OBJECTIVES The aim of this study was to determine whether the extent of viability or scar is important in the amount of recovery of left ventricular (LV) function, and to develop a model for predicting recovery after revascularization that could be tested in a randomized trial. BACKGROUND F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) is used to define viable myocardium in patients with coronary artery disease (CAD) and severe LV dysfunction and to guide revascularization decisions. Whether this approach improves clinical outcomes has not been tested in a randomized trial. Before doing so, an objective model for prediction of recovery is required. METHODS A total of 82 patients with CAD and an ejection fraction (EF) < or =35% had FDG PET perfusion imaging before revascularization. Complete follow-up was available on 70 patients (86%). Patients had radionuclide angiograms at baseline and three months post-revascularization. RESULTS Diabetes (p = 0.029), time to operation (p = 0.008), and scar score (p = 0.001) were significant independent predictors of the change in EF. Previous coronary artery bypass graft confounded the effect of age. There was a significant interaction between the perfusion tracer used and mismatch score (p = 0.02). The multivariable prediction model incorporating PET and clinical variables had a goodness of fit with p = 0.001. Across tertiles of scar scores (I, small: 0% to 16%; II, moderate: 16% to 27.5%; III, large: 27.5% to 47%), the changes in EFs were 9.0 +/- 1.9%, 3.7 +/- 1.6%, and 1.3 +/- 1.5% (p = 0.003: I vs. III), respectively. CONCLUSIONS In patients with severe LV dysfunction, the amount of scar was a significant independent predictor of LV function recovery after revascularization. A combination of PET and clinical parameters predicts the degree of recovery. This model is being applied in a large randomized controlled trial to determine the effectiveness of therapy guided by FDG PET.

Reversible regional wall motion abnormalities on exercise technetium-99m–gated cardiac single photon emission computed tomography predict high-grade angiographic stenoses

OBJECTIVES We sought to determine the level of angiographic stenosis at which reversible regional wall motion abnormalities (RWMA) are present on exercise stress technetium-99m (Tc-99m)- gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), and whether assessments of stress and rest RWMA add incremental diagnostic information. BACKGROUND Stress and rest gated SPECT MPI enables the detection of post-exercise stunning. Although some studies have correlated RWMA to the severity of MPI defects, only one previous study correlated RWMA on gated MPI to angiographic findings. However, this correlation excluded patients with rest perfusion defects and did not involve gating of rest images. METHODS One hundred patients undergoing angiography within six months of exercise stress Tc-99m (sestamibi)-gated SPECT MPI (in the absence of interim cardiac events or revascularization) were recruited. Images were acquired 15 to 30 min after stress and interpreted without knowledge of the Duke treadmill score, left ventricular ejection fraction and angiographic data. RESULTS The sensitivity of reversible RWMA for angiographic stenoses >70% was 53%, with a specificity of 100%. The presence of reversible RWMA was able to stratify patients with angiographic stenoses of 50% to 79% and 80% to 99% with a high positive predictive value. A good correlation was noted between the presence of reversible RWMA and the coronary artery jeopardy score (R = 0.49, p < 0.0001). Multivariate analysis showed that the post-stress RWMA, Duke treadmill and reversible RWMA scores were significant predictors of angiographic severity. CONCLUSIONS Post-stress and reversible RWMA, as shown by exercise stress Tc-99m-gated SPECT MPI, are significant predictors of angiographic disease and add incremental value to MPI for the assessment of angiographic severity.

Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial.

OBJECTIVES We sought to determine: 1) whether F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) parameters identify high-risk patients who gain benefit from revascularization; 2) whether there is a cut point for such benefit; and 3) predictors of outcome in patients with severe left ventricular (LV) dysfunction due to coronary artery disease. BACKGROUND Patients with ischemic LV dysfunction might benefit from revascularization but not without risk. The FDG PET imaging can detect viable myocardium that recovers after revascularization. In the PARR-2 (PET and Recovery Following Revascularization-2) trial, FDG PET imaging showed a nonsignificant trend for improved outcome compared with standard care. Understanding the predictors of outcome from this prospective trial should help better identify patients at risk and which patients most benefit from revascularization. METHODS This post hoc analysis included 182 patients with left ventricular ejection fraction (LVEF) <35% and coronary artery disease, being considered for revascularization work-up, and randomized to the PET arm of PARR-2. The primary outcome was a composite of cardiac death, myocardial infarction, or cardiac repeat hospital stay at 1 year. RESULTS There is an interaction between PET mismatch and protocol revascularization such that higher mismatch, when combined with revascularization, yields fewer primary outcome events (p = 0.02). On the basis of adjusted Cox modeling, with reduced mismatch (<7%), the risk is not significantly different with or without revascularization. As mismatch increases above this mark, risk is reduced with revascularization. Increasing creatinine (for a 10-mumol/l increase: hazard ratio: 1.03, 95% confidence interval: 1.01 to 1.06, p = 0.010) is also associated with increased risk, whereas decreasing LVEF (for a 2% decrease: hazard ratio: 1.08, 95% confidence interval: 0.99 to 1.18, p = 0.087) trends toward an association with increased risk. CONCLUSIONS In this post hoc analysis, patients with ischemic cardiomyopathy with larger amounts of mismatch have improved outcome with revascularization. Renal function was also an independent predictor of outcome. The FDG PET seems to define high-risk patients that gain benefit from revascularization. (PET and Recovery Following Revascularization [PARR 2]; NCT00385242).

CCS/CAR/CANM/CNCS/CanSCMR joint position statement on advanced noninvasive cardiac imaging using positron emission tomography, magnetic resonance imaging and multidetector computed tomographic angiography in the diagnosis and evaluation of ischemic heart disease – executive summary

BACKGROUND Over the past few decades, advanced imaging modalities with excellent diagnostic capabilities have emerged. The aim of the present position statement was to systematically review existing literature to define Canadian recommendations for their clinical use. METHODS A systematic literature review to 2005 was conducted for positron emission tomography (PET), multidetector computed tomographic angiography and magnetic resonance imaging (MRI) in ischemic heart disease. Papers that met the criteria were reviewed for accuracy, prognosis data and study quality. Recommendations were presented to primary and secondary panels of experts, and consensus was achieved. RESULTS Indications for PET include detection of coronary artery disease (CAD) with perfusion imaging, and defining viability using fluorodeoxyglucose to determine left ventricular function recovery and/or prognosis after revascularization (class I). Detection of CAD in patients, vessel segments and grafts using computed tomographic angiography was considered class IIa at the time of the literature review. Dobutamine MRI is class I for CAD detection and, along with late gadolinium enhancement MRI, class I for viability detection to predict left ventricular function recovery. Imaging must be performed at institutions and interpreted by physicians with adequate experience and training. CONCLUSIONS Cardiac imaging using advanced modalities (PET, multidetector computed tomographic angiography and MRI) is useful for CAD detection, viability definition and, in some cases, prognosis. These modalities complement the more widespread single photon emission computed tomography and echocardiography. Given the rapid evolution of technology, initial guidelines for clinical use will require regular updates. Evaluation of their integration in clinical practice should be ongoing; optimal use will require proper training. A joint effort among specialties is recommended to achieve these goals.

Angiographic morphology in unstable angina pectoris

Complex morphology occurs frequently in unstable angina; however, its relation to symptomatic presentation, timing of angiography and hospital outcome has not been investigated. Accordingly, coronary angiography was performed 5 +/- 2 days after qualifying rest pain in 101 consecutive patients presenting with acute coronary insufficiency (n = 67) or crescendo angina (n = 34). Significant coronary artery disease was defined as any greater than or equal to 50% stenosis, and complex morphology as any stenosis with irregularity, overhang or thrombus. Eight of the 67 patients presenting with acute coronary insufficiency later proved to have a myocardial infarction as the qualifying event (creatine kinase twice normal with elevation of MB fraction). There were no myocardial infarctions in the crescendo angina group. Complex morphology occurred in 61% of patients. Thrombus alone occurred in 27% of patients with unstable angina without myocardial infarction, with similar frequencies between the 2 clinical groups. In contrast, intraluminal thrombi were identified in 78% of patients with acute coronary insufficiency who later proved to have a myocardial infarction as the qualifying event. The need for urgent catheterization (less than 48 hours) prompted by recurrent symptoms was associated with the angiographic findings of intraluminal thrombus (46%) and complex morphology (83%). The presence of complex morphology and intracoronary thrombus was associated with a higher incidence of in-hospital cardiac events, i.e., revascularization, myocardial infarction and death, independent of the incidence of multivessel disease.

Thrombolysis in unstable angina: Randomized double-blind trial of t-PA and placebo

BackgroundBecause coronary thrombosis is important in the pathogenesis of unstable angina and correlates with in-hospital cardiac events, we hypothesized that thrombolytic therapy would decrease cardiac events. Methods and ResultsWe randomized 70 patients with unstable angina to tissue-type plasminogen activator (t-PA) (0.49 MU/kg for 1 hour followed by 0.07 MU/kg per hour for 9 hours) or placebo. All patients received full doses of intravenous heparin for 96 hours and aspirin (325 mg beginning at 72 hours). The primary end points of the study were in-hospital death, myocardial infarction, and urgent revascularization. Three secondary end points were also evaluated. Myocardial perfusion was assessed with resting planar thallium scintigraphy 90 minutes after initiation of therapy. Silent ischemia was assessed with 48-hour Holter monitoring for ST shift beginning at time of initiation of drug therapy. Coronary angiography was performed at 18±6 hours and analyzed quantitatively to assess the stenosis responsible for unstable angina, the presence of intraluminal filling defects consistent with intracoronary thrombus, and stenosis morphology and severity. There was no difference in total in-hospital cardiac events between patients receiving t-PA (5% or 14%) and those receiving placebo (7% or 20%) (p =0.83). Resting thallium defects were larger in the patients receiving t-PA than in those receiving placebo (130±118 versus 76±84°, p < 0.04), and this difference persisted when corrected for previous infarction. Although the numbers of patients with ST shift were similar, the duration of ST shift was significantly longer in the patients receiving t-PA than with placebo (20±46 versus 3±10 minutes, p < 0.045). The frequency of intracoronary thrombi in patients with stenoses greater than 50% was significantly less in patients treated with t-PA (11 of 22, 52%) as compared with placebo (23 of 25, 92%) (p = 0.002), but there was no significant difference in minimal lesion cross-sectional area (0.49±0.42 versus 0.57±1.08 cm2, p = 0.75) or ulceration index (0.79±0.16 versus 0.77±0.15, p = 0.71) of the culprit artery ConclusionsWe conclude that a prolonged infusion of t-PA in unstable angina reduces intracoronary thrombi but does not significantly decrease in-hospital cardiac events. The sample size, however, does not provide sufficient power to rule out a treatment effect. Paradoxically, there appears to be an increase in ST shift and worsening of myocardial perfusion with t-PA compared with therapy with heparin alone.

Abnormalities of cardiac sympathetic function in pacing-induced heart failure as assessed by [123I]metaiodobenzylguanidine scintigraphy.

BACKGROUND Increased activity of the sympathetic nervous system contributes significantly to the pathophysiology of heart failure. However, cardiac efferent sympathetic function has not been well characterized in this disorder. In this study, we evaluated cardiac sympathetic innervation using [123I]metaiodobenzylguanidine (MIBG) and compared this with left ventricular (LV) tissue norepinephrine concentration and myocardial perfusion, assessed by 201Tl, in a canine model of heart failure. METHODS AND RESULTS Planar and tomographic cardiac imaging was performed for MIBG and 201Tl in 23 dogs: 8 normal dogs (group 1) and 15 dogs with heart failure induced by right ventricular pacing at 250 beats per minute either continuously for 3 weeks (group 2) or intermittently for 7 weeks (group 3). Plasma and LV tissue norepinephrine concentrations were also measured. Scintigraphic studies in group 2 demonstrated reduced cardiac MIBG activity at heart failure (0.17 +/- 0.04 versus 0.29 +/- 0.05 counts per megabecquerel per pixel at baseline, mean +/- SD; P = .0001), whereas thallium activity was unchanged from baseline. This reduction in cardiac MIBG activity with heart failure was associated with increased intraimage variability in the distribution of MIBG activity (21 +/- 8% versus 13 +/- 7% at baseline, mean +/- SD; P = .0001). The MIBG heart-to-lung ratio was calculated for all groups to control for the inhibitory effect that plasma norepinephrine has on the neuronal uptake of MIBG. There was a positive correlation between LV tissue norepinephrine and the MIBG heart-to-lung ratio (r = .67; P < .001; n = 22), for which the group 2 heart failure animals had the lowest values. No relation existed between plasma norepinephrine concentration and the MIBG heart-to-lung ratio. In addition, regional LV tissue norepinephrine concentration and MIBG activity were both lowest at the apex in normal (group 1) and heart failure (group 2) dogs. The MIBG heart-to-lung ratio also correlated inversely with cardiac filling pressure (r = -.59; P < .05) and heart rate (r = -.65; P < .01) and positively with cardiac output (r = .53; P < .05). CONCLUSIONS Heart failure is associated with severe cardiac adrenergic dysfunction manifested by reduced MIBG activity and increased heterogeneity in the LV distribution of MIBG. Furthermore, MIBG scintigraphy is a simple noninvasive method for assessing global and regional LV tissue norepinephrine levels.