Ami E. Iskandrian

A Randomized, Double-Blind, Placebo-Controlled Trial of Ad5FGF-4 Gene Therapy and its Effect on Myocardial Perfusion in Patients with Stable Angina

OBJECTIVES The primary objective of this study was to determine whether intracoronary administration of the adenoviral gene for fibroblast growth factor (Ad5FGF-4) can improve myocardial perfusion compared with placebo. BACKGROUND Animal studies and observational clinical studies have shown improvement in perfusion of the ischemic myocardium using genes encoding angiogenic growth factors; however, randomized, double-blind data in humans are lacking. METHODS We performed a randomized, double-blind, placebo-controlled trial of intracoronary injection of 10(10) adenoviral particles containing a gene encoding fibroblast growth factor (Ad5FGF-4) to determine the effect on myocardial perfusion. Fifty-two patients with stable angina and reversible ischemia comprising >9% of the left ventricle on adenosine single-photon emission computed tomography (SPECT) imaging were randomized to gene therapy (n = 35) or placebo (n = 17). Clinical follow-up was performed, and 51 (98%) patients underwent a second adenosine SPECT scan after 8 weeks. RESULTS Overall (n = 52), the mean total perfusion defect size at baseline was 32.4% of the left ventricle, with 20% reversible ischemia and 12.5% scar. At eight weeks, Ad5FGF-4 injection resulted in a significant reduction of ischemic defect size (4.2% absolute, 21% relative; p < 0.001) and placebo-treated patients had no improvement (p = 0.32). Although the change in reversible perfusion defect size between Ad5FGF-4 and placebo was not significant (4.2% vs. 1.6%, p = 0.14), when a single outlier was excluded a significant difference was observed (4.2% vs. 0.8%, p < 0.05). Ad5FGF-4 was well tolerated and did not result in any permanent adverse sequelae. CONCLUSIONS Intracoronary injection of Ad5FGF-4 showed an encouraging trend for improved myocardial perfusion; however, further studies of therapeutic angiogenesis with Ad5FGF-4 will be necessary.

Effects of Age, Gender, Obesity, and Diabetes on the Efficacy and Safety of the Selective A2A Agonist Regadenoson Versus Adenosine in Myocardial Perfusion Imaging: Integrated ADVANCE-MPI Trial Results

OBJECTIVES To compare the effects of age, gender, body mass index, and diabetes on the safety and efficacy of regadenoson stress myocardial perfusion imaging, and to assess the noninferiority of regadenoson to adenosine for the detection of reversible myocardial perfusion defects. BACKGROUND Previous reports have shown that a fixed unit bolus of regadenoson is safe and noninferior to adenosine for the detection of reversible perfusion defects by radionuclide imaging. METHODS Using a database of 2,015 patients, we evaluated the effects of age, gender, body mass index, and diabetes on the safety and efficacy of regadenoson compared to adenosine. RESULTS For detection of ischemia relative to adenosine, noninferiority was demonstrated for all patients (agreement rate difference 0%, 95% CI -6.2% to +6.8%). The average agreement rate between adenosine-adenosine and adenosine-regadenoson were 0.62 +/- 0.03 and 0.63 +/- 0.02. Detection of ischemia was also comparable in specific subgroups. Agreement was less for both agents in women versus men with moderate and large areas of ischemia. Compared to adenosine, regadenoson had a lower combined symptom score and less chest pain, flushing, and throat, neck, or jaw pain, but more headache and gastrointestinal discomfort. This was true in nearly all subgroups. Regadenoson patients reported feeling more comfortable (1.7 +/- .02 vs. 1.9 +/- 0.03, p < 0.001). Based on the overall tolerability score, women felt less comfortable than men with both stress agents. Image quality was rated good or excellent in 92% for both agents. CONCLUSIONS Regadenoson can be safely administered as a fixed unit bolus and is as efficacious as adenosine in detecting ischemia regardless of age, gender, body mass index, and diabetes. Regadenoson is better tolerated overall and across various subgroups.

The scope of coronary heart disease in patients with chronic kidney disease.

Chronic kidney disease (CKD) affects approximately 13% of the U.S. population and is associated with increased risk of cardiovascular complications. Once renal replacement therapy became available, it became apparent that the mode of death of patients with advanced CKD was more likely than not related to cardiovascular compromise. Further observation revealed that such compromise was related to myocardial disease (related to hypertension, stiff vessels, coronary heart disease, or uremic toxins). Early on, the excess of cardiovascular events was attributed to accelerated atherosclerosis, inadequate control of blood pressure, lipids, or inflammatory cytokines, or perhaps poor glycemia control. In more recent times, outcome research has given us further information that relates even lesser degrees of renal compromise to an excess of cardiovascular events in the general population and in those with already present atherosclerotic disease. As renal function deteriorates, certain physiologic changes occur (perhaps due to hemodynamic, inflammatory, or metabolic changes) that decrease oxygen-carrying capacity of the blood by virtue of anemia, make blood vessels stiffer by altering collagen or through medial calcinosis, raise the blood pressure, increase shearing stresses, or alter the constituents of atherosclerotic plaque or the balance of thrombogenesis and thrombolysis. At further levels of renal dysfunction, tangible metabolic perturbations are recognized as requiring specific therapy to reduce complications (such as for anemia and hyperparathyroidism), although outcome research to support some of our current guidelines is sorely lacking. Understanding the process by which renal dysfunction alters the prognosis of cardiac disease might lead to further methods of treatment. This review will outline the relationship of CKD to coronary heart disease with respect to the current understanding of the traditional and nontraditional risk factors, the role of various imaging modalities, and the impact of coronary revascularization on outcome.

Regadenoson: a new myocardial stress agent.

Vasodilator stress myocardial perfusion imaging (MPI) accounts for up to 50% of all stress MPI studies performed in the U.S. In 2008, the Food and Drug Administration approved regadenoson for stress testing in conjunction with MPI. Regadenoson, unlike adenosine, is a selective A(2A) agonist that is given as an intravenous bolus at a fixed dose, with less undesirable side effects including atrioventricular block and bronchospasm. Unlike adenosine, regadenoson could be used in patients with mild-to-moderate reactive airway disease. This review will summarize the pre-clinical and clinical data on regadenoson, as they specifically relate to its use as a vasodilator stress agent, currently the only approved selective A(2A) agonist.

Prognostic value of myocardial perfusion imaging in predicting outcome after renal transplantation.

Cardiovascular disease is a significant cause of morbidity and mortality after renal transplantation. Pretransplant screening in a subset of these patients for occult coronary artery disease (CAD) may improve outcome. The objective of this study was to examine the outcome of 600 patients after renal transplantation for end-stage renal disease. Prospective outcome data were collected on 600 consecutive patients who had renal transplantation between 1996 and 1998 at our institution at 42 +/- 12 months after surgery. Stress single-photon emission computed tomographic (SPECT) myocardial perfusion imaging was performed in 174 patients before surgery, 136 (78%) of whom had diabetes mellitus. There were a total of 59 events: 17 cardiac deaths, 14 nonfatal myocardial infarctions, and 28 noncardiac deaths. There were 12 cardiac events and 11 noncardiac deaths among those who had SPECT myocardial perfusion imaging. In a multivariate analysis that included important risk factors, age (p = 0.03 and 0.003, respectively) and diabetes (p = 0.02 and 0.005, respectively) were the predictors of total events and cardiac events in patients who did not undergo stress SPECT perfusion imaging. In the subgroup who had stress perfusion imaging, an abnormal perfusion SPECT study was the only predictor of cardiac events (p = 0.006). The 42-month cardiac event-free survival rate was 97% in patients with normal SPECT images and 85% in patients with abnormal SPECT images (RR 5.04, 95% confidence interval 1.4 to 17.6, p = 0.006). Thus, there is a 2.8% event rate per year after renal transplantation, and approximately 50% of these events are noncardiac. In high-risk patients (most of whom had diabetes) with preoperative stress perfusion imaging, those with normal images had significantly lower cardiac events than those with abnormal images. These results have important implications in patient screening and postoperative management.

Regadenoson Induces Comparable Left Ventricular Perfusion Defects as Adenosine A Quantitative Analysis From the ADVANCE MPI 2 Trial

OBJECTIVES This study sought to determine whether regadenoson induces left ventricular perfusion defects of similar size and severity as seen with adenosine stress. BACKGROUND Total and ischemic left ventricular perfusion defect size predict patient outcome. Therefore, it is important to show that newer stressor agents induce similar perfusion abnormalities as observed with currently available ones. METHODS The ADVANCE MPI 2 (Adenosine versus Regadenoson Comparative Evaluation for Myocardial Perfusion Imaging) study was a prospective, double-blind, randomized trial comparing image results in patients undergoing standard gated adenosine single-photon emission computed tomography (SPECT) myocardial perfusion imaging who were then randomized in a 2:1 ratio to either regadenoson (N = 495) or a second adenosine SPECT (N = 260). Quantitative SPECT analysis was used to determine total left ventricular perfusion defect size and the extent of ischemia. Quantification was performed by a single observer who was blinded to randomization and image sequence. RESULTS Baseline gated perfusion results were similar in patients randomized to adenosine or regadenoson. No significant differences in total (11.5 +/- 15.7 vs. 11.4 +/- 15.8, p = 0.88) or ischemic (4.8 +/- 9.2 vs. 4.6 +/- 8.9, p = 0.43) perfusion defect sizes were observed between the regadenoson and adenosine groups, respectively. Linear regression showed a close correlation between adenosine and regadenoson for total (r = 0.97, p < 0.001) and ischemic (r = 0.95, p < 0.001) left ventricular perfusion defects. Serial differences in total (-0.03 +/- 3.89 vs. -0.13 +/- 4.16, p = 0.73) and ischemic (0.15 +/- 4.08 vs. 0.25 +/- 3.81, p = 0.74) perfusion defect size and left ventricular ejection fraction (0.12 +/- 0.32 vs. 0.15 +/- 0.35, p = 0.27) from study 1 to study 2 were virtually identical in patients randomized to regadenoson versus adenosine, respectively. The good correlation between serial adenosine and regadenoson studies regarding total (0.41 +/- 5.43 vs. 0.21 +/- 5.23, p = 0.76) and ischemic (0.17 +/- 5.31 vs. 0.23 +/- 6.08, p = 0.94) perfusion defects persisted in the subgroup of 308 patients with an abnormal baseline SPECT. CONCLUSIONS Applying quantitative analysis, regadenoson induces virtually identical scintigraphic results as adenosine regarding the size and severity of left ventricular perfusion defects and the extent of scintigraphic ischemia.

Repeatability and reproducibility of phase analysis of gated single-photon emission computed tomography myocardial perfusion imaging used to quantify cardiac dyssynchrony.

BackgroundA novel method to quantify dyssynchrony has been developed using phase analysis of gated single-photon emission computed tomography perfusion imaging. We report on the effect of variability in image reconstruction on the phase analysis results (repeatability) and on the interobserver and intraobserver reproducibility of the technique. MethodsPhase standard deviation (SD) and bandwidth are phase indices that quantify dyssynchrony. To evaluate repeatability, raw data sets were processed twice in 50 patients with left ventricular dysfunction and 50 normal controls. To determine the optimal processing method, two replicated phase analysis results were obtained using automated and manual base parameter placement. Reproducibility of the phase analysis was determined using the data from 20 patients. ResultsIn normal controls, manual base parameter placement improves repeatability of the phase analysis as measured by the mean absolute difference between two reads for phase SD (12.0° vs. 1.2°, P<0.0001) and bandwidth (33.7° vs. 3.6°, P<0.0001). Repeatability is better for normal controls than for patients with left ventricular dysfunction for phase SD (1.2° vs. 6.0°, P<0.0001) and bandwidth (3.6° vs. 26.5°, P<0.0001). Reproducibility of the phase analysis is high as measured by the intraclass correlation coefficients for phase SD and bandwidth of 0.99 and 0.99 for the interobserver comparisons and 1.00 and 1.00 for the intraobserver comparisons. ConclusionA novel method to quantify dyssynchrony has been developed using gated single-photon emission computed tomography perfusion imaging. Manual base parameter placement reduces the effect that variability in image reconstruction has on phase analysis. A high degree of reproducibility of phase analysis is observed.

Prognosis in the era of comparative effectiveness research: Where is nuclear cardiology now and where should it be?

In our recently published review, we inadvertently omitted references to two studies. The results do not substantially change. By adding these references (128a and 128b), we now have 5 studies instead of 3 which makes up Figure 7. Below are the references as well as a corrected Figure 7. When pooling the event-free survival from five series including a total of 4,257 patients, the overall survival was 96.5% for a normal MFR as compared to 77.7% for an abnormal MFR (Figure 7) (126-128, 128a, 128b). References

Comparative Definitions for Moderate-Severe Ischemia in Stress Nuclear, Echocardiography, and Magnetic Resonance Imaging

The lack of standardized reporting of the magnitude of ischemia on noninvasive imaging contributes to variability in translating the severity of ischemia across stress imaging modalities. We identified the risk of coronary artery disease (CAD) death or myocardial infarction (MI) associated with ≥10% ischemic myocardium on stress nuclear imaging as the risk threshold for stress echocardiography and cardiac magnetic resonance. A narrative review revealed that ≥10% ischemic myocardium on stress nuclear imaging was associated with a median rate of CAD death or MI of 4.9%/year (interquartile range: 3.75% to 5.3%). For stress echocardiography, ≥3 newly dysfunctional segments portend a median rate of CAD death or MI of 4.5%/year (interquartile range: 3.8% to 5.9%). Although imprecisely delineated, moderate-severe ischemia on cardiac magnetic resonance may be indicated by ≥4 of 32 stress perfusion defects or ≥3 dobutamine-induced dysfunctional segments. Risk-based thresholds can define equivalent amounts of ischemia across the stress imaging modalities, which will help to translate a common understanding of patient risk on which to guide subsequent management decisions.

The effects of medications on myocardial perfusion.

Antianginal and lipid-lowering medications may modify the results of stress myocardial perfusion imaging. Several studies have shown the beneficial potential of these agents in suppressing myocardial ischemia in patients with known coronary artery disease. The effects of nitrates, calcium-channel blockers, beta-blockers, and statins on myocardial perfusion imaging are likely attributable to changes in myocardial blood flow and myocardial oxygen supply-demand ratio. This comprehensive review examines relevant experimental and clinical published data. Technical issues in image interpretation specific to myocardial perfusion imaging and implications of use of cardiac medications to results of myocardial perfusion imaging are discussed.