Myocardial Perfusion
A study was done to prospectively compare patient outcomes after echocardiography for simultaneous myocardial perfusion and wall motion analysis (also called real-time myocardial contrast echocardiography-RTMCE) and conventional stress echocardiography. There had been no other prospective randomized studies prior to this one looking at this issue. The authors for this study looked to determine whether the differences in the test led to differences in the rate of angiography and revascularization, as well as predicting death. The patients were recruited from consecutive patients coming to the University of Nebraska Medical Center echo lab between 2007 and 2011 who had intermediate to high pre-test probability for coronary artery disease (CAD). This included patients hospitalized for chest pain. Mean age for study patients was 60 with a nearly equal male:female ratio. Follow up was captured for 2,014 patients for a median of 2.6 years. An abnormal myocardial perfusion/stress ECHO (RTMCE) occurred more often than an abnormal conventional stress echo (p < 0.001) and also resulted more often in revascularization (p=0.004). Resting wall motion abnormalities were more often seen with RTMCE (p < 0.01) and were an independent predictor of death/nonfatal myocardial infarction (MI) (p=0.005) for RTMCE but not for conventional stress echo. The conclusion was that perfusion imaging with RTMCE improved the detection of CAD during stress echocardiograms and identified those more likely to undergo revascularization following an abnormal study.1
In a 1997 study, 28 patients were given a single IV injection of an ultrasound enhancing agent and then harmonic transient response imaging was used to view the heart in multiple different imaging planes. Perfusion abnormalities were evident in the secondary and tertiary views only with 1 frame every multiple cardiac cycles. The conclusion was that an enhancing agent could accurately identify regional myocardial perfusion abnormalities. Sensitivity of 92% was noted and specificity of 84%.2
In 2001, a comparative study was done to examine the feasibility and accuracy of RTMCE in detecting abnormal myocardial perfusion during an exercise echo compared with radionuclide tomography. One hundred patients (2:1 men:women with median age of 57) with intermediate to high CAD probability underwent exercise echocardiography and had segmental perfusion assessed in real time before the test and at peak exercise using low mechanical index (0.3) and 0.3 mL bolus injections of the enhancing agent. All patients had rest thallium, stress sestamibi studies done during the same exercise. Forty-four of these patients had subsequent coronary angiography. Compared with angiography, sensitivity of RTMCE and tomography was comparable (75%) with a specificity ranging from 81-100%. The combination of RTMCE and wall motion had the best matching between sensitivity and specificity at 86% and 88% respectively with the highest accuracy (86%). The conclusions were described as “promising” with regard to adding RTMCE to conventional stress echo.3
One of the more recent large studies (2013), a large European multicenter study by Senior et al. was performed to compare microbubble enhanced myocardial contrast echocardiography with single-photon emission computed tomography (SPECT) relative to coronary angiography for assessment of coronary artery disease (CAD). Thirty-four centers were involved in this study and 628 total patients were included. The patients studied included 71% males and the mean age for the patients was 64 years. Ninety-nine percent of the patients had more than 1 cardiovascular risk factor. The methodology intent for this study was for the patients to undergo myocardial contrast echocardiogram (MCE) with an ultrasound enhancing microbubble agent, standard SPECT and quantitative coronary angiography within a 1-month time frame. The myocardial ischemia assessments were made by 3 independent, blind readers for MCE and 3 readers for SPECT with the majority agreement for each prevailing, and therefore, collapsed to 1 diagnosis per patient per technique and compared to coronary angiography which was read by 1 independent blinded reader. Of the 628 total patients, 516 underwent all 3 examinations. One hundred sixty-one (31%) had > 70% stenosis. One hundred thirty-one had single vessel disease and 30 had multi-vessel disease. Three hundred ten of these 516 patients (60%) had > 50% stenosis identified. Higher sensitivity was obtained with MCE than with SPECT, 75% vs. 49%; p < 0.0001. Specificity though was lower for MCE, 52% vs. 81%, p < 0.0001 for coronary artery stenosis > 70%. These findings were similar for patients with > 50%.4
The authors of this study did postulate that a contribution to the lower specificity of myocardial contrast echocardiography (MCE) may have been related to its sensitivity for microvascular disease. Microvascular disease was felt to likely be quite high in this study population. The authors admitted that single-center studies had often shown much better sensitivity and specificity for both MCE and SPECT testing. They suggested the possible role played by readers of the imaging who were completely unaware of individual patient characteristics which may have driven the lower sensitivity and specificity values. The authors also noted reader reproducibility issues were commonly seen in other studies as well. Lastly, the authors felt that fractional flow reserve with angiography would have provided better information, but it was unavailable at the time.
The Journal of the American Society of Echocardiography published a prospective randomized comparison in 2012 which compared the myocardial perfusion and wall motion analysis of real time MCE with conventional stress echocardiography. One thousand seven hundred seventy-six patients with suspicion of CAD were randomized to either non-RTMCE, for which contrast was used only as approved for the indication of enhancing left ventricular opacification, or RTMCE, for which UEA infusion was used in all cases to examine both wall motion and myocardial perfusion. Results showed that the patients randomized to RTMCE had significantly higher test positivity (22% for RTMCE vs 15% with non-RTMCE, P = 0.0002). The increased test positivity occurred without a difference in positive predictive value in predicting >50% diameter stenoses by coronary angiography (67% for non-RTMCE, 73% for RTMCE). Overall, the conclusion was that ultrasound enhancement for myocardial perfusion during a stress echo with dobutamine or exercise did improve the detection of CAD and that was mostly due to the detection of subendocardial wall thickening abnormalities that would have otherwise gone undetected.5
A large meta-analysis examined the prognostic value of myocardial perfusion imaging during contrast stress echocardiography in patients with known or suspected CAD. Conducted through May 2019, it encompassed 12 studies-7 dipyridamole and 5 exercise/dobutamine which had enrolled 5953 total patients, 47% female, for whom 8-80 months of follow-up occurred. Hazard ratios (HRs) revealed that a perfusion abnormality [pooled HR 4.75; 95% confidence interval (CI) 2.47–9.14] was a higher independent predictor of total events than abnormal wall motion (WM, pooled HR 2.39; 95% CI 1.58–3.61) and resting left ventricular ejection fraction (LVEF, pooled HR 1.92; 95% CI 1.44–2.55) with significant subgroup differences (P=0.002 compared with abnormal WM and 0.01 compared with abnormal LVEF). Abnormal myocardial perfusion was associated with higher risks for death [Risk ratio (RR) 5.24; 95% CI 2.91–9.43], non-fatal MI (RR 3.09; 95% CI 1.84–5.21) and need for coronary revascularization (RR 16.44; 95% CI 6.14–43.99). The authors concluded that myocardial perfusion analysis during stress echocardiography was an effective tool for prognosis in patients known or suspected to have coronary artery disease. They also felt the perfusion analysis added value to just LVEF or wall motion assessment in predicting clinical outcomes.6
Utilization of imaging in an emergency department context regarding risk-stratification for patients presenting with chest pain has also been an area of interest. Specifically, the ability to be able to assess both myocardial perfusion and regional function has often been theorized to provide incremental value over routine clinical and EKG evaluation within the ED. A study in 2004 looked at this issue. One thousand seventeen patients were studied, mean age 60, 53% male. Contrast echocardiography was performed in the ED with evaluation of regional function and myocardial perfusion. On follow up, 16.3% of the patients had early events (within 48 hours) such as death, acute MI, unstable angina, heart failure or revascularization. The addition of regional function analysis increased the prognostic information significantly (Bonferroni corrected P < 0.0001) for predicting these events. With myocardial perfusion added, significant prognostic information was also obtained (Bonferroni corrected P=0.0002). All these patients were followed for a median of 7.7 months and 28.7% had events. Adding regional function increased the ability to determine that risk significantly (Bonferroni corrected P < 0.0001), which was further increased by adding myocardial perfusion (Bonferroni corrected P < 0.0001). Overall, adding both regional function and myocardial perfusion evaluation provided significant value and indicated enhanced echocardiography could be a valuable tool for early triage and management in an ED setting with chest pain patients.7
Looking at post MI residual myocardial viability, a study was done to determine how well MCE predicted hard cardiac events. Ninety-nine stable patients underwent low-power MCE at 7 +/- 2 days after acute myocardial infarction (AMI). Contrast defect index (CDI) was obtained by adding contrast scores (1 = homogenous; 2 = reduced; 3 = minimal/absent opacification) in all 16 left ventricular (LV) segments divided by 16. At discharge, 68% of these patients had either undergone or were scheduled for revascularization. The patients were then followed for cardiac death and nonfatal AMI. Of the 99 patients, 95 were followed up. During the follow-up time of 46 +/- 16 months, there were 15 (16%) events (8 cardiac deaths and 7 nonfatal AMIs). Amongst several markers of prognosis, the extent of residual myocardial viability was an independent predictor of cardiac death (p = 0.01) and cardiac death or AMI (p = 0.002). A CDI of < or = 1.86 and < or = 1.67 predicted survival and survival or absence of recurrent AMI in 99% and 95% of the patients, respectively. The conclusion was made that the extent of residual myocardial viability predicted by MCE was a powerful independent predictor of hard cardiac events after AMI.8
In an earlier 2001 study, the issue of LV dysfunction after MI secondary to stunning and necrosis was considered. Thirty-four patients with recent MI and known residual wall motion abnormalities related to the infarct-related artery were examined to see if normal perfusion by myocardial contrast echocardiography (MCE) would accurately predict recovery of segmental left ventricular (LV) function. Each patient after a recent MI underwent baseline wall motion assessment and then had MCE 2 days after admission with follow-up echocardiography a mean of 55 days later. Results showed that perfusion by MCE predicted recovery of segmental function with a sensitivity of 77%, specificity of 83%, positive predictive value of 90% and overall accuracy of 79%. The mean wall motion score at follow-up was significantly better in perfused, compared with nonperfused, segments (1.4 vs. 2.2, p < 0.0001). Additionally, 90% of perfused segments improved, while the majority of nonperfused segments remained unchanged. The authors felt that MCE, by identifying stunned myocardium, could accurately predict recovery of segmental LV function in patients with recent MI.9
