ABSTRACT
Background
Coronary microcirculation dysfunction can occur in patients with chest pain suggestive of coronary artery disease (CAD). The present study aimed to determine the diagnostic value of resting myocardial contrast echocardiography (MCE) for early CAD with myocardial microcirculation dysfunction by evaluating the continuous imaging time, peak time, and peak intensity.
Hypothesis
Resting MCE is an effective and noninvasive method for evaluation of coronary microcirculation dysfunction in patients with early coronary artery disease.
Methods
The present study included 20 consecutive patients without obvious clinical evidence of early CAD and 20 healthy volunteers. Resting MCE was performed to evaluate the myocardial microcirculation perfusion, and the follow‐up evaluation of myocardial microcirculation perfusion was performed with technetium 99 m 2‐methoxy‐isobutyl‐isonitrile (99mTc‐MIBI) single‐photon emission computed tomography (SPECT).
Results
Peak intensity was significantly lower in patients with high risk of CAD than in controls (P < 0.0001). The peak time and continuous imaging time were significantly higher in patients with high risk of CAD than in controls (P < 0.0001). None of the 40 subjects experienced discomfort, such as cough and chest tightness, during the resting MCE procedure, and the heart rate and blood pressure showed no abnormalities during the entire procedure. SPECT imaging showed reversible myocardial perfusion reduction in 80% (16/20) of the patients with high risk of CAD. Abnormalities of heart rate and blood pressure and adverse reactions were noted during the process of SPECT examination.
Conclusions
Resting MCE is an effective and noninvasive method for detecting abnormalities of coronary microcirculation and can help in the clinical analysis, risk assessment, and treatment of early occult CAD.
Introduction
Coronary artery disease (CAD) could be caused by insufficient blood supply or organic disease. The trait of insufficient blood supply can be observed at rest and during stress.1 Currently, coronary angiography is the gold standard for diagnosing CAD in clinical practice; however, the findings of the method correlate poorly with the degree of myocardial perfusion, and it is often difficult to distinguish patients with chest pain without underlying CAD or diagnostic electrocardiography changes from those suggestive of early CAD.2, 3 Rapid and accurate diagnosis is essential for the optimal management of patients with chest pain suspected with early CAD.
Myocardial contrast echocardiography (MCE) is a noninvasive technique that utilizes microbubbles, which possess intravascular rheological features similar to those of erythrocytes and reside only in the intravascular space, to generate myocardial opacification for the evaluation of myocardial perfusion territories.4 Recent studies have shown that coronary microvascular dysfunction occurs significantly more often in patients with angina.5 Also, coronary microvascular dysfunction triggering the reduction in myocardial perfusion ability was considered to be a cause of chest pain.6 Nonetheless, the use of stress MCE for detecting early CAD with the clinical symptom of chest pain is not appropriate, considering its complexity.7 These problems can be overcome with the use of resting qualitative and quantitative MCE, which has been shown to accurately predict cardiac events in ST‐elevation myocardial infarction (MI) patients undergoing reperfusion, as well as flow‐limiting CAD in patients with suspected CAD and after acute MI during vasodilator stress.8 Currently, resting MCE is considered a promising method to quantitatively evaluate myocardial microcirculation.
To date, the quantitative perfusion parameters that have been assessed with resting MCE include the perfusion score index, plateau signal intensity, rate of rise to a plateau that reflects myocardial blood velocity, and myocardial blood flow.9 However, large variations in the increasing slope of the time‐intensity curves result in poor reproducibility for assessing myocardial blood flow.10 The present study aimed to determine the diagnostic value of resting MCE for early CAD with myocardial microcirculation dysfunction by evaluating the continuous imaging time, peak time, and peak intensity.
Methods
Patient Population
The present study included 20 consecutive patients (12 male and 8 female; mean age, 45.2 ± 5 years) without obvious clinical evidence of epicardial stenosis, who underwent coronary angiography owing to chest pain or abnormal electrocardiography findings between February 2010 and December 2013. These patients were at high risk for CAD. The risk factors in the enrolled patients were (1) a family history of premature CAD; (2) a family history of diabetes mellitus (DM), overweight, and obesity (body mass index ≥25 kg/m2); (3) hypertension (HTN; sitting blood pressure ≥140/90 mm Hg or use of antihypertensive drugs); (4) lipid metabolism disorders (high‐density lipoprotein cholesterol levels <1.0 mmol/L, triglyceride levels ≥1.7 mmol/L, or use of lipid‐lowering drugs); (5) smoking history (frequency >10 cigarettes/d). Twenty healthy volunteers without DM, HTN, high cholesterol, or smoking history were included as controls (13 male and 7 female volunteers; mean age, 45.73 ± 4 years). The study protocol was approved by the ethics committee of Navy General Hospital, and informed consent was obtained from all study subjects. Before 2 days of examination, all patients went off caffeine or theophylline products to avoid their interference with heart rate.
Study Protocol
Subjects were placed in the left lateral position for locating the mid short‐axis section of the left ventricle at the level of the papillary muscle via echocardiography. The real‐time MCE imaging mode was used. An ultrasound contrast agent (SonoVue; Bracco Inc., Milan, Italy) was intravenously administered via the antecubital vein at a rate of 1 mL/min for 2 minutes (25 mg SonoVue was diluted in 5 mL saline). The Vivid 7 ultrasound system (GE Medical Systems, Horten, Norway) was used. The M3S probe of the ultrasound system was used at a frequency of 1.7 to 3.4 MHz and a mechanical index of 0.02. Immediately after contrast‐agent injection, fast, low‐angle shot (FLASH) frames, which could be transmitted every 10 to 15 cardiac cycles to produce bubble destruction, were obtained at the 4 time points: 30 seconds, 60 seconds, 90 seconds, and 120 seconds. The refilling process of myocardial microcirculation after FLASH frames was observed, and images of 10 cardiac cycles were continuously obtained to dynamically monitor the entire process, during which cardiac microbubbles repeatedly flashed and then reduced until complete disappearance. In all patients, coronary angiography was performed for examining the blood flow and whether the coronary artery lumen was normal. To confirm that the result of MCE was not affected by cardiac catheterization, the time interval between the MCE exams and coronary angiography was 3 to 5 days.
Echocardiography Analysis
The dynamic FLASH frames obtained during 10 consecutive cardiac cycles were replayed and analyzed using real‐time MCE software in the GE Vivid 7 system. From simultaneous electrocardiogram recordings, end‐diastolic images of the myocardial segment after the microbubble flash were obtained and included for analysis. The software automatically generated the time‐intensity curve of the ventricular myocardium. The highest point of the end‐diastolic curves presented the peak intensity of myocardial perfusion. The peak time was defined as the time taken to reach peak density after the microbubble flash. Additionally, the continuous imaging time was defined as the flashed time of microbubbles in myocardium from start to destroy, which was calculated with a timer‐equipped angiography machine. All the parameters of the myocardial segments were measured three times, and the average values of the parameters were used for analysis. The MCE process took 10 minutes.
Evaluation of Myocardial Microcirculation Perfusion Using Single‐Photon Emission Computed Tomography
The patients with a high risk of CAD discontinued β‐blockers and vasodilators for 24 hours before adenosine stress SPECT. Adenosine stress SPECT was performed 3 to 7 days after coronary angiography. A total dose of 0.8 mg/kg adenosine was administered at a rate of 0.14 mg · kg−1 · min−1 via peripheral intravenous injection for 6 minutes, and then after 3 minutes, technetium 99 m 2‐methoxy‐isobutyl‐isonitrile (99mTc‐MIBI; 740 MBq) was intravenously injected. Myocardial SPECT was performed 1 to 1.5 hours after injection of the imaging agent. The scintigraphic results were processed and analyzed by 2 experienced nuclear‐medicine physicians who were blinded to the clinical and echocardiographic findings of the patients. Electrocardiogram and blood pressure were monitored during the process of SPECT examination. The SPECT examination process took 10 minutes.
Statistical Analysis
Continuous data are presented as mean ± SD when appropriate, and categorical data are presented as frequencies and group percentages. Continuous data were evaluated using the unpaired t test, and categorical data were evaluated using the χ2 test. All statistical analyses were performed using SPSS version 13.0 (SPSS Inc., Chicago, IL). A P value <0.05 was considered to indicate statistical significance.
Results
Clinical Characteristics
The clinical characteristics of the enrolled participants are presented in Table 1. The effects for participant age and sex were nonsignificant. Of the 20 patients with high risk of CAD, 6 (30%) had a family history of premature CAD, 8 (40%) had HTN, 6 (30%) had DM, 5 (25%) had hyperlipidemia, and 6 (30%) were current or prior smokers. The total cholesterol levels were higher among the patients with high risk of CAD than among the controls (5.18 ± 0.42 vs 4.46 ± 0.38 mmol/L; P < 0.0001).
Table 1.
Clinical Characteristics of the Enrolled Subjects
| Controls, n = 20 | Patients With High Risk of CAD, n = 20 | |
|---|---|---|
| Age, y | 45.2 ± 4 | 46.1 ± 5 |
| Male sex | 12 (60) | 13 (65) |
| Family history of premature CAD | 0 (0) | 6 (30)a |
| HTN | 0 (0) | 8 (40)a |
| DM | 0 (0) | 6 (30)a |
| Hyperlipidemia | 0 (0) | 5 (25)a |
| TC, mmol/L | 4.46 ± 0.38 | 5.18 ± 0.42a |
| TG, mmol/L | 1.51 ± 0.54 | 1.65 ± 0.36 |
| HDL‐C, mmol/L | 1.27 ± 0.52 | 1.14 ± 0.45 |
| Current or prior smoker | 0 (0) | 6 (30)a |
Abbreviations: CAD, coronary artery disease; DM, diabetes mellitus; HDL‐C, high‐density lipoprotein cholesterol; HTN, hypertension; SD, standard deviation; TC, total cholesterol; TG, triglycerides.
Data are presented as n (%) or mean ± SD.
P < 0.05, controls vs patients with high risk of CAD.
Resting Myocardial Contrast Echocardiography
Ultrasound contrast agents were administered in all 40 subjects. Figures 1 and 2 present the first FLASH frames on MCE in the patients with high risk of CAD and controls, respectively. The peak intensity was significantly lower in the patients with high risk of CAD than in the controls (−28.3 ± 7.3 dB vs −16.2 ± 8.6 dB; P < 0.0001; Table 2). The peak time and continuous imaging time were significantly higher in the patients with high risk of CAD than in the controls (11.5 ± 0.8 seconds vs 6.2 ± 0.5 seconds, P < 0.0001; and 4.6 ± 0.9 minutes vs 2.3 ± 0.7 minutes, P < 0.0001, respectively).
Figure 1.
The first flash image on resting MCE in a patient with high risk of CAD. The refill peak intensity and the peak time were −27 dB and 11 s, respectively. Abbreviations: CAD, coronary artery disease; HR, heart rate; MCE, myocardial contrast echocardiography.
Figure 2.
The first flash image on resting MCE in a control patient. The refill peak intensity and the peak time were −20 dB and 8 s, respectively. Abbreviations: HR, heart rate; MCE, myocardial contrast echocardiography.
Table 2.
Myocardial Contrast Parameters of the Enrolled Subjects
| Peak Intensity, dB | Peak Time, s | Continuous Imaging Time, min | |
|---|---|---|---|
| Controls | −16.2 ± 8.6 | 6.2 ± 0.5 | 2.3 ± 0.7 |
| Patients with high risk of CAD | −28.3 ± 7.3a | 11.5 ± 0.8a | 4.6 ± 0.9a |
Abbreviations: CAD, coronary artery disease.
P < 0.05, controls vs patients with high risk of CAD.
The peak intensity of −16.2 ± 8.6 dB, peak time of 6.2 ± 0.5 seconds, and continuous imaging time of 2.3 ± 0.7 minutes in the controls were as the normal standards. Peak intensity lower than −16.2 ± 8.6 dB and the peak time and continuous imaging time, respectively, longer than 6.2 ± 0.5 seconds and 2.3 ± 0.7 minutes determined by resting MCE imaging were defined as microcirculation abnormalities. Eighteen patients with high risk of CAD showed microcirculation abnormalities, with 90% of positive rate (18/20). (The representative results of resting MCE imaging are displayed in the Supporting Information, figures 1, 2, and 3, in the online version of this article.) The results of coronary angiography showed slow blood flow but normal coronary artery lumen.
None of the 40 subjects experienced discomfort, such as cough and chest tightness, during the resting MCE procedure. Electrocardiography and blood pressure showed no abnormalities during the entire procedure.
Imaging With Single‐Photon Emission Computed Tomography
Imaging with SPECT showed reversible myocardial‐perfusion reduction in 16 patients with high risk of CAD, and the positive rate of myocardial‐perfusion reduction was 80%. The remaining 4 patients showed reduced myocardial perfusion when undergoing resting electrocardiography and stress myocardial perfusion imaging. However, it was not sufficient to diagnose severe ischemia or MI due to lesser extent of reduced myocardial perfusion. The clinical characteristics and echocardiographic parameters between the 4 patients with negative SPECTs and 16 patients with positive SPECTs indicated no significant difference (P > 0.05).
Hemodynamic and Adverse Reactions Response to Adenosine Stress
As shown in Table 3, the heart rate and blood pressure in patients undergoing adenosine SPECT were changed within one min of medication. Then the average heart rate was obviously increased by (15 ± 9 ) beats/min and the average blood pressure was decreased by (5 ± 10) mmHg after three minutes of medication. The heart rate and blood pressure began to recover after two minutes of drug withdrawal and then reached to the level before medication within five minutes.
Table 3.
Hemodynamic Changes Response to Adenosine Stress
| Time | HR, bpm | SBP, mm Hg | DBP, mm Hg |
|---|---|---|---|
| Resting state | 69 ± 13 | 120 ± 23 | 72 ± 17 |
| Medication for 3 min | 84 ± 18a | 115 ± 18 | 65 ± 14 |
| Drug withdrawal | 82 ± 16a | 114 ± 15 | 64 ± 13 |
| Drug withdrawal for 5 min | 70 ± 14 | 116 ± 16 | 70 ± 14 |
Abbreviations: DBP, systolic blood pressure; HR, heart rate; SBP, systolic blood pressure.
P < 0.05, resting state vs medication for 3 min, drug withdrawal, and drug withdrawal for 5 min, respectively.
Adverse reactions were found in 17 patients (85%) with high risk of CAD. The adverse reactions response to adenosine stress were mainly chest tightness (7 patients), hot flashes (5 patients) and palpitations (4 patients). These symptoms were mild and most of patients could relieve themselves. One patient occurred transient type 1 second degree AV block and patient occurred complete atrioventricular block was not found. Severe adverse reactions such as severe hypotension, severe arrhythmia or acute myocardial infarction were not occurred. Two patients with obvious chest tightness and chest pain were not medicated the maximum dosage of adenosine due to ahead of drug withdrawal when medication for five minutes.
Discussion
Myocardial contrast echocardiography has been used to identify regions that do not receive cardioplegic solutions.11 Studies have shown the accuracy of MCE in qualitatively and quantitatively assessing regional cardioplegia perfusion, appraising the extent of concealed regional ischemia, and predicting the protective effects of coronary collaterals during coronary occlusion.12, 13 An evaluation of myocardial perfusion and microvascular structural integrity was found to help predict the necessity of symptomatic treatment or surgical intervention for early CAD without specific clinical manifestations.14 Thus, we investigated the use of resting MCE in patients with early CAD but without abnormal findings on coronary angiography.
Microbubbles can be used as a contrast agent for ultrasound imaging, especially in echocardiography, owing to the high acoustic impedance mismatch between gases and blood or soft tissue. The microbubble acoustic backscatter signal partially relies on the frequency and power of the applied ultrasound and the properties of the surrounding medium.15 Previous studies have revealed that peak intensity in platform stage multiplied by curve rising slope represented the blood flow of myocardial microcirculation examined by resting MCE but brings about the poor reproducibility outcome of myocardial blood flow.16, 17 When the ultrasound waves pass through myocardial tissue with damaged microcirculation, the wave speed reduces, leading to a delay in microbubble destruction and imaging, which has been noted in the early phase of atherosclerotic vascular lesions.18 Hence, we used the continuous imaging time, peak time, and peak intensity as detection indicators of resting MCE in the present study, which have been shown to play a vital prognostic role in early atherosclerotic lesions.19, 20 The peak intensity was found to be significantly lower in myocardial tissue with impaired microcirculation that in normal myocardial tissue, and this difference was attributed to the reduction in capillary blood volume.21, 22 The continuous imaging time and peak time were higher in myocardial tissue with impaired microcirculation than in normal myocardial tissue, owing to the reduced capillary flow. These results were consistent with those for early atherosclerotic lesions.23, 24 Even in the resting state, the continuous imaging time, peak time, and peak intensity were significantly different between patients with chest pain suggestive of early CAD and healthy subjects. These results were consistent with those of coronary angiography, which showed slow blood flow in a normal coronary artery lumen, implying microcirculation dysfunction prior to coronary artery dissection.25, 26
Previously, patients with chest pain were not thoroughly investigated if no characteristic findings were noted on coronary angiography; and therefore, no diagnosis was made and no appropriate therapeutic intervention was provided. In our study, evaluating the continuous imaging time, peak time, and peak intensity of such patients examined by resting MCE showed 90% of patients with microcirculation abnormalities. Moreover, SPECT imaging showed that 80% of the patients with chest pain in the present study had reversible myocardial perfusion reduction, which further supports the results of resting MCE in these patients. The reasons that led to the inconsistent results on resting MCE examination and SPECT examination may be as follows: (1) The results on MCE may be false positive if subjects were obese. Obesity would objectively interfere the lung gas and then affect imaging quality of the MCE and cause measurement error of MCE parameters, thus affecting the credibility of the MCE results.27 (2) The results of SPECT imaging may be false negative. The left ventricular myocardium was divided into 17 myocardial segments to analyze, and the images analysis of short axis, horizontal axis, and vertical long axis was done with the qualitative and semiquantitative method.28 This would interfere with the credibility of the SPECT results. Nevertheless, it was also suggested that the values of the continuous imaging time, peak time, and peak intensity were closely associated with myocardial ischemia, which may help in the prognosis and treatment of patients with chest pain suggestive of early CAD.
With regard to side effects, none of the subjects showed toxicity or abnormalities of heart rate and blood pressure after administration of the SonoVue myocardial contrast agent, suggesting that the administration of SonoVue is safe during resting MCE in patients with early CAD. However, abnormalities of heart rate and blood pressure and adverse reactions such as chest tightness, hot flashes, and palpitations were noted during the process of SPECT examination. The results further demonstrated the advantage of resting MCE on the evaluation of coronary microcirculation dysfunction in patients with early CAD.
Study Limitations
The findings of the present study are limited by the small number of patients; therefore, the clinical implementation of the results may be restricted. Further studies with a large number of patients are needed to confirm our results. Moreover, the resting MCE procedure should be further optimized for the detection of early CAD.
Conclusion
In conclusion, resting MCE is an effective and noninvasive method for detecting abnormalities of coronary microcirculation and can help in the clinical analysis, risk assessment, and treatment of early occult CAD. Continuous imaging time, peak time, and peak intensity are the most appropriate indicators for the assessment of myocardial microcirculation dysfunction to evaluate early CAD, as these indicators are simple and relatively objective and have a low error rate and good repeatability.
Supporting information
FigS1
FigS2
FigS3
The authors have no funding, financial relationships, or conflicts of interest to disclose.
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Associated Data
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Supplementary Materials
FigS1
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