Akira Oshita

Leukocyte-Targeted Myocardial Contrast Echocardiography Can Assess the Degree of Acute Allograft Rejection in a Rat Cardiac Transplantation Model

Background—Repetitive endomyocardial biopsies are necessary to monitor the effects of immunosuppressants after cardiac transplantation. Contrast ultrasound with microbubble targeting of leukocytes detects acute leukocyte infiltration. We examined whether leukocyte-targeted myocardial contrast echocardiography (MCE) could provide for the quantitative assessment of acute cardiac rejection. Methods and Results—Hearts from Brown Norway rats or Lewis rats were transplanted into other Brown Norway rats. Isografts and groups of allografts either untreated or treated with cyclosporin A (CsA) at a low dose (3 mg · kg−1 · d−1) or high dose (10 mg · kg−1 · d−1) from 3 days before transplantation were compared at posttransplantation day 3. Echocardiography-derived left ventricular wall thickening was comparable among the 4 groups. Myocardial blood flow assessed with MCE, relating pulsing intervals with signal intensity (SI), was slightly decreased only in untreated allografts. However, myocardial SI (in gray levels) obtained after a 10-minute period allowing microbubble–leukocyte interactions after contrast injection exhibited a clear gradient in these groups (12±2 in untreated allografts, 9±5 in allografts treated with low-dose CsA, 6±3 in allografts treated with high-dose CsA, and 2±1 in isografts, P <0.001). The pattern of difference in SI among the groups agreed well with that in ED-1–positive cell (macrophage) count (25±7, 12±4, 5±3, and 1±0 cells per high-power field, respectively, P <0.001), which correlated with CD3-positive cell (T lymphocyte) count (33±5, 22±5, 9±4, and 1±0 cells per high-power field, respectively, P <0.001). Conclusions—Leukocyte-targeted MCE can noninvasively assess the degree of rejection in transplanted hearts by directly revealing the magnitude of intramyocardial infiltration of macrophages and T lymphocytes.

Potentiation of C-type natriuretic peptide with ultrasound and microbubbles to prevent neointimal formation after vascular injury in rats

OBJECTIVES Long-term intravenous infusion of high-dose C-type natriuretic peptide (CNP) is known to prevent neointimal formation after vascular injury. Ultrasound (US) irradiation during microbubbles (MBs) infusion (US/MBs) has been used for local delivery of bioactive agents. We examined whether short-term infusion of CNP could also inhibit neointimal development and whether combined US/MBs treatment at the beginning of the CNP infusion could enhance its effect. METHODS In the rat carotid artery-balloon injury model, the intima/media area (I/M) ratio 14 days after injury was compared among various short-term post-injury treatments. For combined US/MBs, a commercial echocardiograph (1.8 MHz, mechanical index 1.0) and albumin-coated octafluoropropane gas MBs were used. RESULTS Infusion of high-dose CNP (1.0 microg/kg/min) immediately after injury for only 24 h successfully reduced the I/M ratio (0.18+/-0.05) to 18% of the ratio in control rats (1.00+/-0.13) that underwent only balloon injury. Although low-dose CNP (0.1 microg/kg/min for 24 h) alone was not effective in reducing the I/M ratio (0.83+/-0.18), combined US/MBs treatment for the first 80 min of the infusion markedly reduced the I/M ratio (0.17+/-0.07), which persisted until 28 days after injury (0.16+/-0.04). CONCLUSIONS The effects of CNP on the events occurring early after arterial injury may be important in preventing subsequent neointimal development. Thus, intravenous infusion of CNP with US/MBs at its initiation may provide a clinically feasible anti-restenosis therapy applicable immediately after vascular interventions.

Coronary abnormal response has increased in Japanese patients: Analysis of 17 years’ spasm provocation tests in 2093 cases

BACKGROUND Abnormal coronary response on acetylcholine test is observed in patients with early coronary atherosclerosis. OBJECTIVES We analyzed retrospectively the abnormal response rate during 17 years of spasm provocation tests in 2093 consecutive patients. METHODS We performed 2093 spasm provocation tests, consisting of 1198 acetylcholine tests and 895 ergonovine tests, between January 1991 and December 2007. Spasm provocation test was mainly performed in patients with ischemic heart disease. Abnormal response was defined as transient >90% luminal narrowing during spasm provocation tests. We classified these 17 years into two periods: former period from January 1991 to December 2000, and the latter period from January 2001 to December 2007. In the former period, 1300 spasm provocation tests were performed and 793 spasm provocation tests were done in the latter period. RESULTS The incidences of hypertension, dyslipidemia, and diabetes mellitus were significantly increased in the latter period. The values of total cholesterol, triglycerides, and fasting blood sugar were also significantly increased in the latter period. The frequency of abnormal response in the latter period was significantly higher than that in the former period (46.0% vs. 33.2%, p<0.05). The frequency of abnormal coronary response to acetylcholine in the latter period was significantly higher than that in the former period (60.0% vs. 34.0%, p<0.01), whereas there was no difference concerning abnormal response of ergonovine between the two periods (31.9% vs. 30.7%, ns). CONCLUSIONS In Japanese patients, abnormal coronary response to acetylcholine has increased and coronary endothelial dysfunction is suggested to have progressed.

Vasospastic heart failure: Multiple spasm may cause transient heart failure?

BACKGROUND There have been no reports concerning the correlation between heart failure and coronary artery spasm. METHODS AND RESULTS From January 2000 to December 2007, 201 patients with heart failure were hospitalized at our institution. We could perform coronary arteriography and spasm provocation tests in 37 (22 men, 67±11 years) out of 201 patients with heart failure before discharge. Atrial fibrillation was observed in 13 patients (35%). After controlling heart failure and 24h cessation of vasoactive drugs, pharmacological spasm provocation tests were performed. Positive spasm was defined as >90%. Coronary spasm was observed in 12 patients (32%) and multiple spasm was recognized in 10 (83%) out of 12 patients. Though ejection fraction on admission was not different between the two groups (42±18% vs. 43±11%, ns), left ventricular end-diastolic and end-systolic dimension after medical therapy over 1 year was significantly smaller in patients with positive spasm than that in patients with negative spasm. There was no difference concerning medications except the administration of nitrate and nicorandil between two groups. CONCLUSIONS Coronary artery spasm, especially multiple spasm, may cause transient heart failure in a small part of unknown origin heart failure in Japan.

A case of a newly developed yellow neointima at stent implanted site 1 year after sirolimus-eluting stent placement: Angioscopic findings

Coronary angioscopy is a useful tool for understanding plaque characteristics through the plaque color and surface thrombus formation. We experienced an interesting case of a newly developed yellow neointima 400 days after a sirolimus-eluting stent implantation. A 72-year-old woman suffering from angina pectoris was admitted to our hospital. Coronary angiography revealed severe stenosis at the proximal left descending artery and she was implanted with a sirolimus-eluting stent. Coronary angioscopic observation immediately after stent implantation revealed the presence of yellow plaque only at the most severe stenosis lesion in the stent placement site. We performed a coronary angiography 400 days after the sirolimus-eluting stent implantation and did not find an in-stent restenosis. An intravascular ultrasound indicated minimum neointimal formation. By coronary angioscopy, we could clearly observe that the neointima had covered the surface of the stent struts; the stent struts were barely visible under the neointima. Surprisingly, neointima formed in response to the sirolimus-eluting stent was entirely yellow. Precise mechanisms of producing yellow neointima was unknown, we may observe a pathologic neointima induced by sirolimus-eluting stent.

Quantitative assessment of coronary stenosis by harmonic power Doppler with a simple pulsing sequence and vasodilator stress in patients.

OBJECTIVES We examined whether myocardial contrast echocardiography (MCE) with harmonic power Doppler (HPD) employing a simple ultrasound pulsing sequence enables estimation of the severity of coronary artery stenosis in patients. BACKGROUND Contrast intensity (CI) during MCE with intravenous microbubble infusion is dependent on the myocardial blood flow velocity (MBFV) and pulsing interval (PI). METHODS Based on an in vitro experiment, we devised the MBFV index calculated as the reciprocal of the magnitude of CI decay produced by abrupt PI shortening during intermittent imaging. In 68 coronary artery territories from 49 patients, myocardial HPD images were acquired during intravenous infusion of Levovist, while the long PI with 1:10 electrocardiographic gating was shortened to 1:1, both at baseline and during adenosine triphosphate infusion. The MBFV index in each coronary territory and MBFV reserve as the ratio between hyperemia and baseline were compared with the severity of corresponding coronary artery stenosis assessed by quantitative coronary angiography (QCA) or by pressure guide wire as the fractional flow reserve (FFR). RESULTS Both the MCE-derived MBFV index during hyperemia and MBFV reserve exhibited significant negative correlations with the QCA-derived stenosis severity (r = -0.56 and r = -0.64, respectively). The MBFV reserve positively correlated with FFR (r = 0.89). By combining the cutoff values of the MBFV index during hyperemia and MBFV reserve, > or =75% of stenoses defined by QCA were determined, with a sensitivity of 77.3%, specificity of 93.4%, and accuracy of 88.3%. CONCLUSIONS Shortening of PI during intravenous MCE with intermittent HPD imaging under vasodilator stress enables assessment of coronary artery stenoses in patients.

A recurrent coronary honeycomb-like structure: insights from angioscopy and optical coherence tomography.

A 64-year-old man with acute cerebral infarction underwent successful thrombolytic therapy, after which ECG indicated abnormal Q waves in leads V1–V3. There were no chest symptoms and his cardiac enzyme levels were normal, but he was referred to us for further evaluation. Resting T1–T201 myocardial perfusion scintigraphy and coronary computed tomography angiography were performed, and a cardiac fusion image was obtained (Fig. 1). A myocardial perfusion defect was observed in the vicinity of the left anterior ascending coronary artery, which was determined to be a previous, silent myocardial infarction.

Recommendations for performing acetylcholine tests safely: STOP dangerous complications induced by acetylcholine tests (STOP DCIAT)

OBJECTIVES We examined some recommendations for performing acetylcholine (ACh) tests safely. METHODS AND RESULTS We performed 1000 ACh tests from 1991 to December 2004. ACh was injected in incremental doses of 20/50/80 microg into the RCA and of 20/50/100 microg into the LCA. During these periods, we encountered various major/minor complications; 12 ventricular tachycardia (1.2%) necessary one dc, one ventricular fibrillation (0.1%) necessary dc, 3 shock like the left main stem spasm (0.3%), one cardiac tamponade necessary surgical drainage (0.1%), and 164 Paf (164/959:17.1%) necessary administration of antiarrhythmic agents to sinus rhythm in about one third patients (31.7%). We did not experience irreversible severe complications, such as acute myocardial infarction or death. RECOMMENDATIONS (1) Stand by direct current with pasting, (2) Thump version when ventricular tachycardia or fibrillation occurred, (3) Over infusion to avoid hypovolemia, (4) Perform angiography before complete spasm provocation if a severe spasm, (5) Drainage if cardiac tamponade occurred, (6) Cibenzoline or disopyramid administration when ACh induced paroxysmal atrial fibrillation, (7) Incremental ACh dose up should be performed, (8) Administer small amount of noradrenaline if shock observed and (9) Test shot should be performed before 1-min angiography. CONCLUSIONS We recommend STOP DCIAT for performing ACh tests safely.

Characterization of high-intensity plaques on noncontrast T1-weighted magnetic resonance imaging by coronary angioscopy

BACKGROUND A recent study showed that coronary high-intensity plaques (HIPs) visualized by noncontrast T1-weighted imaging (T1WI) in cardiac magnetic resonance were associated with coronary events. We used coronary angioscopy to analyze HIP plaque morphology. METHODS AND RESULTS A total 17 lesions from 17 patients with stable or unstable angina pectoris were evaluated at the culprit lesion by noncontrast T1WI using 1.5-T magnetic resonance; of them, nine (53%) were HIPs and eight (47%) were non-HIPs, and all were analyzed by coronary angioscopy. We assessed the existence of thrombus and plaque yellow color grade (YG). YG was assessed visually according to a four-grade scale: 0, white; 1, light yellow; 2, yellow; 3, intense yellow. The frequency of thrombus was significantly higher in HIPs than in non-HIPs (89% vs. 25%, respectively; p=0.007). YG was significantly more frequent in HIPs than in non-HIPs (2.2±0.4 vs. 0.7±0.7, respectively; p=0.01). CONCLUSIONS These data indicated that HIPs on noncontrast T1WI were associated with the presence of high-grade yellow plaque with thrombus.

Effect of microbubble fragility on transit rate measurement by contrast echography

We sought to propose a simplified method to measure flow velocity based on ultrasonic microbubble destruction, and investigated the effect of microbubble shell fragility on such measurement. Acoustic density (AD) from the second harmonic short axis image of flow was obtained at variable velocities (2 to 73 mm/s) in an in vitro model during long (1000 ms) and short (33 ms) interval ultrasound (US) pulsing, allowing complete and partial microbubble replenishment between pulses, respectively. Microbubbles with shell elastic modulus of 0.4 MPa and 16 MPa were tested. By shortening pulsing interval, AD diminished gradually, rather than abruptly, to a plateau level for both microbubbles. The extent of AD decay was greater for the fragile than the strong microbubbles. A linear relationship existed between the magnitude of AD decay and flow velocity only in the higher and lower velocity range for the fragile and the strong microbubbles, respectively. Thus, difference in contrast intensities during long and short pulsing intervals, respectively, allowing complete and partial replenishment may provide for velocity measurement, in which choice of optimal microbubble fragility for the range of velocity to measure may increase the accuracy.