Endothelin-1 release during the early phase of reperfusion is a mediator of myocardial reperfusion injury.

PURPOSE: In acute myocardial infarction, left ventricular (LV) unloading reduces endothelin-1 (ET-1) release. We tested that endogenous ET-1 released during acute myocardial infarction might mediate ischemia/reperfusion (I/R) injury by stimulating increased intracellular calcium concentration, [Ca(2+)]i, and apoptosis. METHODS: Rabbits were subjected to 1 h of coronary artery occlusion followed by 3 h of reperfusion. Unloading was initiated 15 min prior to reperfusion and was maintained during reperfusion. The control group was subjected to reperfusion. Animals were treated with ET-1 receptor antagonist BQ123. In parallel, isolated rabbit cardiomyocytes subjected to simulated I/R with or without ET-1 or BQ123, intracellular Ca(2+) and cell death were assessed with flow cytometry. RESULTS: LV unloading prior to reperfusion reduced myocardial ET-1 release at 2 h of reperfusion. Infarct size was reduced in unloaded and BQ123 groups versus controls. LV unloading and BQ123 treatment reduced the percentage of apoptotic cells associated with increases in Bcl-2 protein levels in ischemic regions. BQ123 reduced both ET-1-induced [Ca(2+)]i increase and cell death for myocytes subjected to stimulated I/R. CONCLUSION: We propose that components of reperfusion injury involve ET-1 release which stimulates calcium overload and apoptosis. Intravenous ET-1 receptor blockade prior to reperfusion may be a protective adjunct to reperfusion therapy in acute myocardial infarction patients.

Intravascular photoacoustic imaging of exogenously labeled atherosclerotic plaque through luminal blood.

Combined intravascular ultrasound and intravascular photoacoustic (IVUS/IVPA) imaging has been previously established as a viable means for assessing atherosclerotic plaque morphological and compositional characteristics using both endogenous and exogenous contrast. In this study, IVUS/IVPA imaging of atherosclerotic rabbit aortas following systemic injection of gold nanorods (AUNRs) with peak absorbance within the tissue optical window is performed. Ex vivo imaging results reveal a high photoacoustic signal from localized AUNRs in regions with atherosclerotic plaques. Corresponding histological staining further confirms the preferential extravasation of AUNRs in atherosclerotic regions with compromised luminal endothelium and acute inflammation. The ability to detect AUNRs using combined IVUS and photoacoustic imaging in the presence of luminal saline and luminal blood is evaluated using both spectroscopic and single wavelength IVPA imaging techniques. Results demonstrate that AUNR detection within the arterial wall can be achieved using both methods, even in the case of imaging through luminal blood.

Feasibility of in vivo intravascular photoacoustic imaging using integrated ultrasound and photoacoustic imaging catheter.

Pilot studies of in vivo combined intravascular ultrasound (IVUS) and intravascular photoacoustic (IVPA) imaging are reported. A recently introduced prototype of an integrated IVUS/IVPA imaging catheter consisting of a single-element ultrasound transducer and a light delivery system based on a single optical fiber was adapted and used for in vivo imaging of a coronary stent deployed in a rabbit's thoracic aorta in the presence of luminal blood. The results suggest that in vivo IVUS/IVPA imaging is feasible using the integrated IVUS/IVPA imaging catheter. The challenges of in vivo combined IVUS/IVPA imaging are discussed, and further improvements on the design of the catheter and the clinical imaging system are proposed.

In vivo intravascular ultrasound-guided photoacoustic imaging of lipid in plaques using an animal model of atherosclerosis.

We present a preliminary study demonstrating the capability of ultrasound-guided intravascular photoacoustic (IVPA) imaging to visualize the depth-resolved distribution of lipid deposits in atherosclerotic plaques in vivo. Based on the characteristic optical absorption of lipid in the near infrared wavelength range, IVPA imaging at a single, 1720 nm, wavelength was used to provide a spatially-resolved, direct measurement of lipid content in atherosclerotic arteries. By overlaying an IVPA image with a spatially co-registered intravascular ultrasound (IVUS) image, the combined IVPA/IVUS image was used to visualize lipid distribution within the vessel wall. Ultrasound-guided IVPA imaging was performed in vivo in the abdominal aorta of a Watanabe heritable hyperlipidemic (WHHL) rabbit. Subsequently, the excised rabbit aorta filled with a solution of red blood cells (RBC) was then imaged ex vivo, and histology was obtained in the section adjacent to the imaged cross-section. To demonstrate the potential for future clinical application of IVPA/IVUS imaging, a sample of diseased human right coronary artery (RCA) was also imaged. Both in vivo and ex vivo IVPA images clearly showed the distribution of lipid in the atherosclerotic vessels. In vivo IVPA imaging was able to identify diffuse, lipid-rich plaques in the WHHL rabbit model of atherosclerosis. Furthermore, IVPA imaging at a single wavelength was able to identify the lipid core within the human RCA ex vivo. Our results demonstrate that ultrasound-guided IVPA imaging can identify lipid in atherosclerotic plaques in vivo. Importantly, the IVPA/IVUS images were obtained in presence of luminal blood and no saline flush or balloon occlusion was required. Overall, our studies suggest that ultrasound-guided IVPA imaging can potentially be used for depth-resolved visualization of lipid deposits within the anatomical context of the vessel wall and lumen. Therefore, IVUS/IVPA imaging may become an important tool for the detection of rupture-prone plaques.

Intravascular photoacoustic imaging of lipid in atherosclerotic plaques in the presence of luminal blood.

Intravascular photoacoustic (IVPA) imaging can characterize atherosclerotic plaque composition on the basis of the optical absorption contrast between different tissue types. Given the high optical absorption of lipid at 1720 nm wavelength, an atherosclerotic rabbit aorta was imaged at this wavelength ex vivo using an integrated intravascular ultrasound (IVUS) and IVPA imaging catheter in the presence of luminal blood. Strong optical absorption of lipid combined with low background signal from other tissues provides a high-contrast, depth-resolved IVPA image of lipid. The ability to image lipid at a single wavelength without removing luminal blood suggests that in vivo detection of lipid in atherosclerotic plaques using combined IVUS/IVPA imaging is possible.

Detection of lipid in atherosclerotic vessels using ultrasound-guided spectroscopic intravascular photoacoustic imaging.

Lipid is a common constituent in atherosclerotic plaques. The location and area of the lipid region is closely related to the progression of the disease. Intravascular photoacoustic (IVPA) imaging, a minimally invasive imaging modality, can spatially resolve the optical absorption property of arterial tissue. Based on the distinct optical absorption spectrum of fat in the near infrared wavelength range, spectroscopic IVPA imaging may distinguish lipid from other water-based tissue types in the atherosclerotic artery. In this study, a bench-top spectroscopic IVPA imaging system was used to ex-vivo image both atherosclerotic and normal rabbit aortas. By combing the spectroscopic IVPA image with the intravascular ultrasound (IVUS) image, lipid regions in the aorta were identified. The results demonstrated that IVUS-guided spectroscopic IVPA imaging is a promising tool to differentiate lipid in atherosclerosis.

On the possibility to detect lipid in atherosclerotic plaques using intravascular photoacoustic imaging.

Large lipid core is common in rupture-prone atherosclerotic plaques. Detection of the location and distribution of lipid in the atherosclerotic plaques can greatly benefit the diagnosis and treatment of vulnerable plaques. Recently introduced intravascular photoacoustic (IVPA) imaging - a technique to image the optical absorption property of tissue - can be used to detect and differentiate atherosclerotic plaques. In this work, we further investigated the ability of using spectroscopic IVPA imaging to visualize the lipid in atherosclerotic plaques. IVPA imaging was performed on an ex-vivo rabbit aorta in the 1200 - 1230 nm wavelength range. In the lipid-rich plaques, the photoacoustic signal strength within this spectral range behaved similar to the optical absorption spectrum of fatty tissue. To distinguish lipid from other types of tissue, correlation analysis was used. Specifically, intraclass correlation between the IVPA signals and the absorption spectrum of lipid reconstructed from multi-wavelength IVPA images was conducted on a pixel-by-pixel basis. The resulted correlation map showed the distribution of lipid in the atherosclerotic plaques. The distribution of lipid is further confirmed by histopathological analysis of tissue. The results of our study suggest that spectroscopic IVPA imaging, together with correlation analysis, may be used to detect lipid in atherosclerotic plaques.

Left ventricular unloading with intra-aortic counter pulsation prior to reperfusion reduces myocardial release of endothelin-1 and decreases infarction size in a porcine ischemia-reperfusion model.

OBJECTIVES: We tested the hypothesis that unloading the left ventricle with intra-aortic balloon counter-pulsation just prior to reperfusion provides infarct salvage compared with left ventricular (LV) unloading postreperfusion or reperfusion alone. BACKGROUND: Previous reports demonstrated infarct salvage with complete LV unloading with an LVAD prior to reperfusion; however, partial LV unloading using intra-aortic balloon pumps (IABPs) has not been evaluated. METHODS: Twenty-eight Yorkshire pigs were subjected to 1 hr of left anterior descending artery occlusion and 4 hr of reperfusion. An IABP was inserted and activated just prior to reperfusion (IABP-Pre), or 15 min after reperfusion (IABP-Post), or not at all (control). RESULTS: At baseline, the hemodynamic data were similar in the three groups. Myocardial infarct size expressed a percentage of zone at risk in control animals was 44.9% +/- 4.8%, IAPB-Pre group 20.9% +/- 5.1% (P < 0.05 compared to control), and IABP-Post group 33.2 +/- 6.1% (P = 0.16 vs. control group). There was a correlation between transcardiac endothelin-1 release at 15 min postreperfusion and infarct size (r = 0.59). CONCLUSION: LV unloading with an IABP prior to reperfusion reduces the extent of myocardial necrosis in hearts subjected to 1 hr of left anterior descending artery occlusion and 4 hr of reperfusion compared with either reperfusion alone or LV unloading after reperfusion. Inhibition of myocardial ET-1 release by LV unloading may be a significant mechanism of myocardial protection. These data suggest that in high-risk STEMI patients, IABP unloading prior to reperfusion might be more beneficial than IABP placement postreperfusion.

Left ventricular unloading before reperfusion reduces endothelin-1 release and calcium overload in porcine myocardial infarction.

OBJECTIVES: The aim of this study was to test the hypothesis that after an acute myocardial infarction, endothelin-1 release with subsequent calcium overload is a mediator of myocardial reperfusion injury, which can be inhibited, in part, by left ventricular unloading immediately before reperfusion. We recently have reported that left ventricular unloading before reperfusion reduces infarct size after acute myocardial infarction. However, the biologic mechanisms of infarct salvage in unloaded hearts subjected to ischemia/reperfusion remain undefined. METHODS: Twelve pigs were subjected to 1 hour of left anterior descending coronary artery occlusion followed by 4 hours of reperfusion. A left ventricular assist device was initiated 15 minutes before reperfusion and maintained during reperfusion (assist device group, n = 6). A control group (n = 6) was subjected to reperfusion alone. Infarct size, endothelin-1 plasma levels, intracellular calcium levels, and apoptosis were analyzed in both groups. RESULTS: At reperfusion, left ventricular unloading significantly decreased left ventricular end-diastolic and end-systolic pressures. Infarct size, expressed as a percentage of zone at risk, was also significantly reduced by 54% in the group with the left ventricular assist device compared with controls. Support with a left ventricular assist device reduced endothelin-1 release from the heart at 15 minutes, 30 minutes, and 1 hour of reperfusion. Myocardial release of endothelin-1 was significantly correlated with infarct size at 15 minutes of reperfusion (r = 0.79; P = .008). Left ventricular unloading caused a significant reduction of calcium overload and of the percentage of apoptotic cells in the ischemic region. CONCLUSION: Our findings suggest that endothelin-1 release and calcium overload are important mediators of reperfusion injury and that they can be significantly reduced by left ventricular unloading before coronary artery reperfusion during myocardial infarction.

Spectroscopic intravascular photoacoustic imaging to differentiate atherosclerotic plaques.

The potential of intravascular photoacoustic (IVPA) imaging to detect atherosclerosis was previously demonstrated using a 532 nm nanosecond pulsed laser and an intravascular ultrasound (IVUS) imaging catheter. However, to differentiate vulnerable plaques, the composition of plaques needs to be imaged. Therefore, we introduce a multi-wavelength photoacoustic imaging method to distinguish various types of plaques. Multi-spectral IVPA imaging of ex vivo samples of normal and atherosclerotic rabbit aorta was performed at several wavelengths within 680-900 nm range. The spectral variation of photoacoustic response was extracted and a spectroscopic analysis was performed. The results of our preliminary study suggest that the spectroscopic intravascular photoacoustic imaging technique can be used to differentiate fibrous and lipid components of the atherosclerotic plaques.

Intravascular ultrasound and photoacoustic imaging.

There is a need for an imaging technique that can reliably identify and characterize the vulnerability of atherosclerotic plaques. Catheter-based intravascular ultrasound (IVUS) is one of the imaging tools of the clinical evaluation of atherosclerosis. However, histopathological information obtained with IVUS imaging is limited. We present and discuss the applicability of a combined intravascular photoacoustic (IVPA) and intravascular ultrasound (IVUS) imaging approach to assess both vessel structure and tissue composition thus identifying rupture-prone atherosclerotic plaques. Photoacoustic (or optoacoustic and, generally, thermoacoustic) imaging relies on the absorption of electromagnetic energy, such as light, and the subsequent emission of an acoustic wave. Therefore, the amplitude and temporal characteristics of the photoacoustic signal is primarily determined by optical absorption properties of different types of tissues and can be used to differentiate the lipid, fibrous and fibro-cellular components of an inflammatory lesion. Simultaneous IVUS and IVPA imaging studies were conducted using 40 MHz clinical IVUS imaging catheter interfaced with a pulsed laser system. The performance of the IVPA/IVUS imaging was assessed using phantoms with point targets and vessel-mimicking phantoms. To detect the lipids in the plaque, ex-vivo IVPA imaging studies of a normal and an atherosclerotic rabbit aorta were performed at a 532 nm wavelength. To assess plaque composition, multi-wavelength (680-950 nm) spectroscopic IVPA imaging studies were carried out. Finally, molecular and cellular IVPA imaging was demonstrated using plasmonic nanoparticles. Overall, our studies suggest that plaque detection and characterization can be improved using the combined IVPA/IVUS imaging.

Intravascular photoacoustic imaging using an IVUS imaging catheter.

Catheter-based imaging of atherosclerosis with high resolution, albeit invasive, is extremely important for screening and characterization of vulnerable plaques. Currently, there is a need for an imaging technique capable of providing comprehensive morphological and functional information of plaques. In this paper, we present an intravascular photoacoustic imaging technique to characterize vulnerable plaques by using optical absorption contrast between normal tissue and atherosclerotic lesions. Specifically, we investigate the feasibility of obtaining intravascular photoacoustic (IVPA) images using a high-frequency intravascular ultrasound (IVUS) imaging catheter. Indeed, the combination of IVPA imaging with clinically available IVUS imaging may provide desired functional and morphological assessment of the plaque. The imaging studies were performed with tissue-mimicking arterial vessel phantoms and excised samples of rabbit artery. The results of our study suggest that catheter-based intravascular photoacoustic imaging is possible, and the combination of IVPA with IVUS has the potential to detect and differentiate atherosclerosis based on both the structure and composition of the plaque.

Ex vivo Characterization of Atherosclerosis using Intravascular Photoacoustic Imaging.

The imaging of plaque composition represents one of the important steps in the interventional management of atherosclerosis. Intravascular photoacoustic (IVPA) imaging has the potential to play a major role in the detection and differentiation of an atherosclerotic lesion. The difference in the optical properties of the arterial wall and plaque constituents could be utilized to obtain high resolution photoacoustic images. In this work, through ex vivo imaging studies using a rabbit model of atherosclerosis, we evaluate the ability of IVPA imaging to detect and characterize the plaque. Specifically, the difference in the magnitude of the photoacoustic signals from the free lipids, macrophage foam cells, blood and the rest of the arterial wall were helpful in providing the contrast and detecting the fibro-cellular inflammatory plaque. The constituents identified in the IVPA images were confirmed by the results from histology.

Mechanical left ventricular unloading prior to reperfusion reduces infarct size in a canine infarction model.

We tested the hypothesis that unloading the left ventricle just prior to reperfusion provides infarct size reduction compared with left ventricular (LV) unloading postreperfusion and reperfusion alone. Twenty-four mongrel dogs were subjected to 2 hr of left anterior descending artery occlusion and 4 hr of reperfusion. A transvalvular (TV) left ventricular assist device (LVAD) was inserted just prior to reperfusion and maintained during the rest of the experiment (LV Assist Pre group). In the LV Assist Post group, the TV LVAD was inserted and activated just after reperfusion. A control group was subjected to reperfusion alone with a sham-TV LVAD. At baseline, the hemodynamic data were similar in the three groups. Myocardial infarct size expressed as percentage of area at risk was significantly reduced in the LV Assist Pre group compared to the control group (P = 0.011) and to the LV Assist Post group (P < 0.05). At 4 hr of reperfusion, transmural myocardial blood flow in the ischemic zone was slightly higher in the animals unloaded prior to reperfusion compared to controls and significantly higher than in the LV Assist Post group (P = 0.04). Postreperfusion end-diastolic wall thickness returned to baseline level in the TV LV Assist Pre group compared to both controls and TV LV Assist Post group. In these latter two groups, a significant increase in postreperfusion end-diastolic wall thickness and contraction band necrosis in the central ischemic zone correlated well with the degree of reperfusion injury. LV unloading prior to, but not after, reperfusion reduces the extent of myocardial necrosis in canine hearts subjected to 2 hr of left anterior descending artery occlusion and 4 hr of reperfusion compared to either reperfusion alone or LV unloading after reperfusion.