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Background: Chronic total occlusion (CTO) is found in 18-31% of patients who undergo coronary angiography. Successful recanalization of CTOs is associated with reduced recurrent angina pectoris rates and increased long-term survival. Although the success rate of CTO percutaneous coronary intervention (CTO-PCI) has improved, CTO-PCI remains technically challenging. The Fielder XT guidewire was designed for CTO lesions. To validate whether the use of the guidewire increases the success rate, we compared the results of CTO-PCI with or without the guidewire. We hypothesized that the use of Fielder XT guidewire can increase the success rate of CTO-PCI., Aim: To investigate whether the use of Fielder XT guidewire increases the final procedural success of CTO-PCI via the anterograde approach., Methods: Between January 2013 and December 2015, a retrospective study was conducted on 1230 consecutive patients with CTO who received PCI via the anterograde approach at the General Hospital of Northern Theater Command. The patients were divided into an XT Group ( n = 686) and a no-XT Group ( n = 544) depending on whether Fielder XT guidewire was used. Both groups were compared for clinical parameters, lesion-related characteristics, procedural outcomes and in-hospital complications. The data were statistically analyzed using Pearson's χ 2 test for categorical variables, and Students' t test was used to compare the quantitative data. Significant independent factors and a risk ratio with 95% confidence interval (CI) were assessed by multivariate logistic regression analysis., Results: In total, 1230 patients were recruited; 75.4% of the patients were male, and 55.8% of the patients were in the XT group. The overall success rate was 83.9%, with 87.8% in the XT group. Based on multivariate logistic regression analysis, factors positively associated with procedural success were the use of Fielder XT guidewire ( P = 0.005, 95%CI: 1.172-2.380) and systolic blood pressure ( P = 0.011, 95%CI: 1.003-1.022), while factors negatively associated with procedural success were blunt stump ( P = 0.013, 95%CI: 1.341-11.862), male sex ( P = 0.016, 95%CI: 0.363-0.902), New York Heart Association (NYHA) class ( P = 0.035, 95%CI: 0.553-0.979), contrast amount ( P = 0.018, 95%CI: 0.983-0.998) and occlusion time ( P = 0.009, 95%CI: 0.994-0.999). No significant differences were found between the XT group and the no-XT group with respect to clinical parameters, lesion-related characteristics, coronary artery rupture [3 (0.4%) vs 8 (1.5%), P = 0.056], in-hospital death [2 (0.3%) vs 6 (1.1%), P = 0.079] or in-hospital target lesion revascularization [3 (0.4%) vs 7 (1.3%), P < 0.099]. However, there were significant differences between the groups with respect to success rate [602 (87.8%) vs 430 (79.0%), P < 0.001], procedure time [(74 ± 23) vs (83 ± 21), P < 0.001], stent length [(32.0 ± 15.8) vs (37.3 ± 17.6), P < 0.001], contrast amount [(148 ± 46) vs (166 ± 43), P < 0.001], post-PCI myocardial infarction [43 (6.3%) vs 59 (10.8%), P = 0.004], major adverse cardiovascular event [44 (6.4%) vs 57 (10.7%), P = 0.007], side branch loss [31 (4.5%) vs 44 (8.1%), P = 0.009], contrast-induced nephropathy [29 (4.2%) vs 40 (7.4%), P = 0.018] and no reflow [8 (1.2%) vs 14 (2.9%), P = 0.034]., Conclusion: The use of Fielder XT guidewire shortens the Procedure and increases the success rate of CTO-PCI, and is also associated with reduced complication rates., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.

BACKGROUND Heat stroke is a life-threatening disease which is characterized by a high body temperature and multiple organ dysfunction syndrome. Vascular endothelial cell injury is a main feature of heat stroke. Little is known about the long noncoding RNA (lncRNA) and microRNA (miRNA) expression alternation in endothelial cell exosomes related to heat stroke. The aim of this study was to explore the changes of lncRNAs and miRNAs expression pattern in exosomes derived from vascular endothelial cells under heat stroke temperature conditions. MATERIAL AND METHODS Cultured medium exosomes from HUVECs (human vascular endothelial cells) either under normal temperature or heat stroke temperature conditions were harvested; then RNA was extracted and the lncRNAs and miRNAs were analyzed by high throughput sequencing. RESULTS Ten significantly upregulated and 10 downregulated lncRNAs were identified in exosomes derived from heat stroke temperature treated cells. Furthermore, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses were used to evaluate the signaling pathway of differential expressions in lncRNAs. Finally, the interaction network of lncRNAs-miRNAs-mRNA was uncovered using ceRNA (competing endogenous RNA) principle via prediction software. CONCLUSIONS These results indicate that the identified lncRNAs and miRNAs in endothelial cell exosomes might serve as non-invasive biomarkers for heat stroke.

Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer (GC), MACC1 has been shown to be involved in oncogenesis and tumor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelial-to-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry (VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment.

Objective: To establish a mouse model of abdominal aorta stenosis and analyze the alterations in the arterial wall response to high and low shear stress., Methods: Twenty mouse were randomized equally into 4 groups, including 3 test groups (1, 7 and 14 day groups) with surgically induced stenosis of the abdominal aorta, and a sham-operated group without stenosis. The hemodynamics and the internal diameter of the blood vessel were measured by color Doppler flow imaging. The wall shear stress was calculated by Poiseiulle hydrodynamics formula (τ(m)=η×4×V(m)/D). Pathological examination and immunohistochemistry were performed to observe the arterial morphological changes and the endothelial vascular cell adhesion molecule-1 (VCAM-1) expression. The intimal-media thickness of the aorta was measured and endothelial VCAM-1 expression analyzed quantitatively., Results: Regions of low and high flow shear stress were created upstream from the stenosis and within the stenosis, respectively. Compared with the sham-operated group, the mice with aorta stenosis showed gradually increased vascular intimal-media thickness and VCAM-1 expression intensity in the upstream aorta, but not within the regions of the stenosis., Conclusion: Vascular remodeling may occur shortly after exposure to low shear stress, which plays a significant role in initiation and progression of the pathological process of atherosclerosis mediated by VCAM-1, whereas high shear stress may exert an anti-atherosclerotic effect.

Objective: To compare the results of echocardiographic evaluation of pressure overload-induced cardiac remodeling in mice using different ultrasound machines., Methods: Eighteen C57 BL/6 mice were randomly divided into the sham-operated and the transverse aortic constriction (TAC) groups (n=9). Eight weeks after the operation, the cardiac function of TAC group was evaluated using Siemens ultrasonic instrument with 15L8 probe and the differences between the awake and anesthetized states were compared. The heart rate, left ventricular (LV) dimensions, systolic and diastolic functions were measured in both sham-operated and TAC groups using the Siemens ultrasonic instrument and a high-resolution ultrasonic imaging system for small animals (Vevo 770)., Results: Compared with the mice in wakefulness, the anesthetized mice showed significantly decreased heart rate and LV fractional shortening (P<0.001) and markedly increased LV end diastolic diameter and LV end systolic diameter (P<0.05). Both machines sensitively detected the cardiac remodeling of TAC mice in comparison with the sham-operated group. Compared with Siemens machine, Vevo 770 provided a higher resolution of 2D and M mode echocardiography with clearer Doppler frequency image of the mitral valve flow for evaluation of the LV diastolic function., Conclusion: Both machines are suitable for evaluating cardiac remodeling induced by pressure overload independent of anesthesia, though anesthesia depresses cardiac function. Vevo 770 is optimal to evaluate LV diastolic function in mice.

Objective: To assess the feasibility of usage of microbubbles conjugated with RGD peptides and contrast enhanced ultrasound (CEU) in detection of tumor angiogenesis., Methods: Lipid microbubbles (MB) were prepared, and the RGD peptides were covalently conjugated to the lipid shell of MB (MB(RGD)). Six nude mice with tumor created by dorsal inoculation of HepG2 tumor cells were used as the test group. Six nude mice without tumor were served as the control group. 10 minutes after bolus injection of MB and MB(RGD) randomly (30 min interval) via a tail vein catheter, CEU was performed on the tumors of the test group and the thigh skeletal muscles of control group. The video intensity (VI) of tumors and the skeletal muscles were measured. The tumors and the skeletal muscles were harvested for immunohistochemical examination., Results: Only a slight contrast enhancement of the tumor was seen with MB, and the VI was 5.33 ± 1.71. While a remarkable enhancement of the tumor was observed after injection of MB(RGD). The VI was up to 17.03 ± 3.58, 3.18 folds higher as compared with that obtained by injection of MB (P < 0.05). As expected, there were no obvious contrast enhancement of the skeletal muscles with both MB(RGD) and MB. There was a high expression of αvβ3-integrin in tumor neovascular endothelium, however, no apparent expression of αvβ3-integrin was observed in the skeletal muscle vascular endothelium., Conclusion: CEU with MB(RGD) can be used to effectively evaluate the angiogenesis of tumors, and it may greatly contribute to the early judgement of the nature of tumor.

Objective: To evaluate the changes of cerebral blood flow (CBF) with real-time contrast-enhanced ultrasound (CEU) in a canine model of acute cerebral ischemia., Methods: Cerebral perfusion was assessed in 6 dogs subjected to craniotomy with CEU at the time of 0, 30, 60, 90 and 120 min after occlusion of the left common carotid artery (LCCA). The microvascular volume (A) and blood flow velocity (beta) in the brain were measured from the time-versus-acoustic intensity plots, and the value of Axbeta were calculated. 99mTc-ECD brain single photon emission computed tomography (SPECT) was performed on the day before the experiment and at 120 min after LCCA occlusion. The radioactive counts on both sides of the cerebral cortex were calculated., Results: A significant correlation was found between Axbeta from CEU and volume of the blood flow of the CCA from Doppler flowmetry. A, beta and Axbeta values varied significantly between the different time points (P>0.001). The ipsilateral hemisphere showed a low-perfusion state while the contralateral hemisphere showed a high-perfusion state immediately after the occlusion., Conclusions: The changes of beta is the main regulation mechanism during acute cerebral ischemia in dogs.

Objective: To investigate the drag-reducing effect of polyethylene oxide (PEO) on the velocity of red blood cells in rat cremaster microcirculation., Methods: Blood samples were collected from 6 Wistar male rats (100-110 g) via the post-orbital venous plexus. The red blood cells were separated by centrifugation and labeled by fluorescinisothiocyate (FITC). After successful establishment of cremaster model, the labeled red blood cells were injected into the jugular vein, and the microcirculation was observed and recorded under fluorescence microscope. The hemodynamic parameters and microcirculation video was recorded every 4 min since 4 min before PEO or normal saline injection. Both PEO (10 ppm) and normal saline was injected into the same rat in random sequence at a constant rate of 3.5 ml/h for 20 min followed by observation for another 20 min. The velocity of the labeled-red blood cells was determined by IPP 6.0 software., Results: Compared with normal saline, PEO significantly increased the velocity of the red blood cells in the rat cremaster microcirculation (498.7-/+182.89 microm/s vs 773.54-/+308.27 microm/s, P=0.012). No significant changes in the heart rate and arterial blood pressure were observed during the experiment (P=0.836, P=0.420)., Conclusion: PEO at an extremely low concentration can significantly increase the velocity of the red blood cells in rat cremaster microcirculation and produces no significant impact on heart rate and arterial blood pressure.

Objective: To assess the binding ability of microbubbles targeted to alphavbeta3-integrin (MBp) for thrombus-targeted contrast-enhanced ultrasound., Methods: Targeted microbubbles were prepared by conjugating the monoclonal antibody against alphavbeta3-integrin to lipid shell of the microbubble via the avidin-biotin bridges. Equivalent isotype control microbubbles (MB) or targeted ultrasound microbubbles (MBp) were randomly added into the flow chamber. After a 30-min incubation with the thrombus fixed in an agarose flow chamber model, the thrombus was washed with a continuous flow of PBS solution (15 cm/s) for 2, 4, 6, 8 and 10 min, followed by thrombus imaging using contrast-enhanced ultrasound and measurement of the video intensity (VI) values of the images., Results: The VI of the thrombus in MBp group was reduced by 28%-66%, while that in control MB group was decreased by 87%-94%, and the VI values of the thrombus group were significantly greater in former group at each of the time points (P<0.05)., Conclusion: MBP has good targeting ability to the thrombus with resistance to the shear stress after adhesion to the thrombus. In vitro evaluation of the thrombus-binding capability of the targeted microbubble (MBp) by simulating the shear stress in vivo can be helpful for predicting the in vivo effects of ultrasonic molecular imaging using MBp.

Objective: To evaluate the relationship between myocardial systolic, diastolic functions and perfusion in coronary artery stenosis using velocity vector imaging (VVI) and myocardial contrast echocardiography (MCE)., Methods: Stenoses in the anterior descending branch of the coronary artery were induced in 8 dogs. Before and after coronary artery stenosis, two-dimensional images of the left ventricular mastoid muscle section on the short axis at rest and in the peak dose of dobutamine were obtained for evaluation of VVI and MCE. The myocardial blood flow A.beta values, peak systolic strain rate (SRsys) and peak diastolic strain rate (SRdia) in the direction of the circumference of the short axis were measured., Results: At rest, only severe coronary stenosis resulted in significantly lowered SRsys, SRdia and A.beta value of the stenotic bed compared to the values before the stenosis (-1.1-/+0.50 vs -1.62-/+0.50, 1.19-/+0.48 vs 1.75-/+0.51, 0.4-/+0.21 vs 0.80-/+0.47, P<0.05). In stress, SRsys, SRdia and A.beta value of the stenotic bed gradually decreased as coronary stenosis worsened (-4.31-/+1.14 vs -3.20-/+0.98 vs -1.18-/+0.64, 4.51-/+1.13 vs 3.39-/+0.98 vs 1.37-/+0.64. 3.54-/+1.95 vs 1.81-/+0.89 vs 0.82-/+0.42, P<0.05). Both at rest and in stress, good correlations were noted between SRsys and SRdia (r(rest)=0.88, r(stress)=0.96, P<0.01), between SRsys and the standard A.beta values (r(rest)0.56, r(stress)=0.71, P<0.01), and between SRdia and A.beta (r(rest)=0.57, r(stress)=0.72, P<0.01) in the direction of the circumference of the short axis., Conclusions: Using VVI and MCE, the changes in myocardial perfusion and the systolic and diastolic functions in the direction of the circumference can be observed dynamically. VVI may help assess the condition of myocardial perfusion by evaluating the systolic and diastolic function.

Objective: To assess the feasibility of evaluating myocardial ischemia-reperfusion injury in mouse with targeted myocardial contrast echocardiography (MCE)., Methods: Phospholipid microbubbles targeted to P-selectin (MBp) and control microbubbles (MBc) were created by conjugating monoclonal antibody against murine P-selectin or isotype control antibody with the lipid shell via "avidin-biotin" bridging. Ten mice with myocardial ischemia-reperfusion were injected intravenously of MBp and MBc in a random order with a 30 min interval. After 5 min of intravenous injection of microbubble, targeted MCE imaging was performed in all mice. And then the video intensity (VI) was determined., Results: A significant ultrasonic enhancement was observed in ischemic region of MBp-group. Increment in VI value of ischemic region in MBp-group was great and it amounted to (26.0 +/- 6.2) U. However, increment in VI value of ischemic region in MBc-group was minor and it was merely (9.1 +/- 0.9) U. Difference was evident in ischemic region between of two groups (P < 0.05). In both MBp-group and MBc-group, the VI value of ischemic region was significantly greater than that of non-ischemic region (6.5 +/- 1.0) U vs (6.4 +/- 0.8) U (P < 0.05). There was no obvious difference in the VI of non-ischemic region between two groups., Conclusion: Molecular imaging of P-selectin with targeted contrast echocardiography can effectively evaluate myocardial ischemia-reperfusion injury.

Objective: To evaluate the effect of a phospholipid-coated microbubble contrast agent for myocardium opacification in comparison with a albumin-coated microbubble contrast agent (Quanfuxian)., Methods: In 10 dogs with single coronary artery stenosis involving the anterior descending branch or circumflex branch randomly received infusion of the two contrast agents through the femoral vein. The myocardial blood flow, heart rate and blood pressure were analyzed qualitatively and quantitatively. The concentration and the particle diameter of the two contrast agents were determined., Results: The concentration of the phospholipid-coated microbubbles was (1.06-/+0.22) x10(9)/ml, with a diameter of 3.04-/+0.34 microm, similar to the concentration and diameter of Quanfuxian ((1.31-/+0.33)x10(9)/ml and 2.88-/+0.58 microm, respectively, P>0.05). Both of the agents achieved grade three myocardium opacification, and produced no obvious effect on the heart rate and blood pressure. Quantitative analysis of myocardial opacification in terms of myocardial blood volume (A), blood velocity (beta), and blood flow (A x beta) revealed no significant difference between the two agents (P>0.05), and the parameters derived from the two agents showed good correlations (P<0.05, rA=0.809, r beta=0.932, rA.beta=0.925)., Conclusion: The phospholipid-coated microbubble contrast agent shows good effect for myocardial opacification without significant difference from Quanfuxian. Both of the agents are good ultrasound contrast agents for quantitative analysis of myocardium blood flow.

Objective: To investigate the effects of ultrasound mediated microbubble destruction on capillary permeability in rat skeletal muscles., Methods: Eighteen SD rats were randomized into 3 groups, namely the Evans blue (EB) group, EB+ultrasound (E+U) group and EB+microbubble+ultrasound (U+E+M) group with corresponding treatments, using EB injected into the carotid artery as the indicator for capillary permeability. The microbubbles were injected through the carotid artery with fixed ultrasound parameters. The spillover of EB was estimated under fluorescence microscope according to the visual staining scores. The contents of EB in the skeletal muscles were calculated according to the standard curve and spectrophotometry., Results: EB spillover was observed around the capillaries in E+U+M group, which had a significantly higher visual score than EB group and E+U group (0 and 0-1, respectively, P<0.05). The EB content was 51.57-/+3.89 microg/g in E+U+M group, also significantly higher than those in EB group (28.99-/+4.67 microg/g) and E+U group (30.99-/+4.11 microg/g) (P<0.05)., Conclusion: Exposure to both ultrasound and microbubble contrast agents results in increased capillary permeability of rat skeletal muscles, which might be an important mechanisms for gene delivery enhancement by ultrasound contrast agents.

Objective: To evaluate the direct effects of dobutamine as compared to adenosine on the coronary microcirculation in both normal and stenotic segments using myocardial contrast echocardiography (MCE)., Methods: Left anterior descending (LAD) coronary artery stenosis, which was not flow limiting at rest, was established in 9 dogs. At the baseline and during intracoronary infusion of dobutamine (2 mg.kg(-1).min(-1)) and adenosine (5 mg.kg(-1).min(-1)), the radiolabeled microsphere (RM)-derived myocardial blood flow (MBF) were determined, and the double product (DP) and myocardial vascular resistance (MVR) were calculated. MCE was performed to determine the myocardial blood volume (MBV, represented by A) and microbubble velocity (beta)., Results: As compared to the baseline level, the MBF increased and MVR decreased significantly in both the normal and abnormal beds during infusion of both drugs (P<0.05). In the normal bed, adenosine had no effect on MBV, the decrease in MVR was the result of decreased arteriolar (plus venular) resistance, and the increase in MBF was predominately due to the increase in b (deltabeta/ deltaA=13.6). Dobutamine caused a 28% increase in MBV, responsible for 32% of the decrease in the total MVR, but the increase in MBF arose mainly from the increase in b (deltabeta/deltaA=5.9). In the abnormal bed, both the drugs caused a similar increase in MBF entirely by increasing b, and 14% and 15% of the increases in capillary resistance were associated with the capillary derecruitment during administration of dobutamine and adenosine, respectively., Conclusion: The direct effects of intracoronary dobutamine infusion on the coronary microcirculation are similar to that of adenosine, and the increase in MBF occurs mostly as the result of increased myocardial blood velocity.

Objective: To investigate the effects of nitroglycerine (NTG) on myocardial oxygen metabolism and regional cardiac function in canine hearts with a stable systemic hemodynamics in situ., Methods: Eight anesthetized open-chest dogs with flow-limited left anterior descending branch of the coronary artery or left circumflex artery (LCx) stenosis were studied. The percentage of ventricular wall thickening (%WT) was measured with quantitative two-dimensional echocardiography (2DE), myocardial blood flow (MBF) with radiolabeled microspheres and tissue oxygen pressure (tPO(2).) with oxygen-dependent quenching of phosphorescence. 2DE was performed and radiolabeled microspheres and Pd-porphyrin injected in the dogs at rest during intracoronary infusion of 0.3-0.6 mg x kg(-1) x min(-1) of NTG. Myocardial oxygen consumption (MVO(2), ml x min(-1) x 100 g(-1)) was calculated as the multiplication product between the arterio-venous oxygen content difference and MBF, and myocardial O(2) delivery as the product between arterial oxygen content and MBF., Results: As compared with the baseline, NTG increased %WT and MBF significantly in both normal and ischemic beds (P<0.05). There was a significant increase in MVO(2) during NTG infusion in the ischemic bed (P<0.05) in comparison with that measured at rest. NTG, however, significantly increased the ability of myocardial O(2) delivery in both normal and ischemic beds (P<0.05), therefore tPO(2) was still higher in the ischemic bed during NTG infusion than that at rest (P<0.05). The percentage increment in tPO(2) was significantly greater in the ischemic bed than percentage MBF increment., Conclusions: NTG enhances myocardial oxygen concentration in normal and ischemic myocardium and may increase oxygen release to the ischemic myocardium in vivo. NTG may have a positive inotropic effect on regional cardiac function. In addition to direct effect on vascular tone, NTG plays important roles in the cardiovascular system by modulating myocardial oxygen metabolism and contractile function.

Background: The mechanism by which transmyocardial revascularization (TMR) offers clinical benefit is controversial. We hypothesized that TMR ameliorates ischemia by reversing paradoxical catecholamine-induced vasoconstriction., Methods and Results: Chronic ischemic cardiomyopathy was created in 11 dogs by placing ameroid constrictors on the proximal coronary arteries and their major branches. Six weeks later, 35 channels were created percutaneously in the left circumflex artery region, with the left anterior descending artery region serving as control. At rest, wall thickening and myocardial blood flow did not change in the treated region, whereas they deteriorated in the control bed. Contractile and myocardial blood flow reserve increased in the treated region but deteriorated in the control region. There was diminished iodine 123 metaiodobenzylguanidine uptake and a significant reduction in noradrenergic nerves in the treated region compared with the control region, with a corresponding reduction in tissue tyrosine hydroxylase activity., Conclusions: We conclude that the absence of a catecholamine-induced reduction in MBF reserve and contractile reserve in the TMR-treated region with associated evidence of neuronal injury indicates that the relief of exercise-induced ischemia after TMR most likely results from reversal of paradoxical catecholamine-induced vasoconstriction. These findings may have implications in selecting patients who would benefit from TMR.

Objective: To investigate the effect of therapeutic ultrasound-induced microbubble destruction on the microcirculation of rat skeletal muscle., Methods: Thirty SD rats were randomized into 5 groups (n=6), namely normal saline, microbubble, ultrasound, high-energy ultrasound microbubble and low-energy ultrasound microbubble groups. Before and after the treatments, the diameter and blood flow velocity in the microvessels in the skeletal muscle were measured, and the structural changes of the injured microvessels observed by electron microscopy., Results: Microbubble cavitation did not produce significant effect on the mean arterial pressure and diameter of microvessels in rat skeletal muscle (P>0.05), but the blood flow velocity was obviously lowered and blood flow volume reduced in the microvessels. The reduction of the flow velocity and blood flow volume and their subsequent recovery were associated with ultrasound energy, and in the low ultrasound energy group, the flow velocity and blood flow volume in the of venules recovered obviously after about 15 min, which, however, took approximately 1 h for the arterioles. In contrast, recovery of the flow velocity and blood flow volume in the microvessels took more than 2 h in the high ultrasound energy group. Cavitation resulted in endothelium cell rupture, widening of the endothelial interspace and entry of the red blood cells into the extravascular tissues as revealed by electron microscopy, but no rupture of the lining endothelium was observed 2 h after the treatment., Conclusions: Endothelium cell rupture induced by microbubble cavitation may affect the local microcirculation, and lower ultrasound energy exposure is associated with milder endothelial injury and more rapid recovery.

Background: We hypothesized that nitroglycerin improves O2 delivery to ischemic tissue by altering erythrocyte rheology and O2 unloading through an increase in bioactive nitric oxide (NO) content., Methods and Results: Twelve dogs with resting flow-reducing single-vessel stenosis were studied at rest and during intracoronary infusion of nitroglycerin (0.3 to 0.6 microg.kg(-1).min(-1)). Half the dogs also had occlusion of the remote coronary artery to remove any collateral effects. Systemic and coronary hemodynamics, myocardial blood flow (MBF), whole blood viscosity (WBeta), erythrocyte charge (EC) and mobility (EM), regional myocardial O2 delivery and consumption, and tissue O2 pressure (Po2) were measured. No changes in systemic hemodynamics were seen with nitroglycerin. Despite flow-limiting stenosis, MBF increased significantly in the central 25% of the ischemic bed, which was associated with an approximately 19% decrease in WBeta. There was a good correlation (r=0.87) between the two. The decrease in WBeta was associated with a decrease in EC and an increase in EM (r=0.83). The nitroglycerin-induced increase in tissue Po2 was disproportionate to the increase in MBF, indicating enhanced O2 unloading. Erythrocyte S-nitrosothiol content (reflecting mainly S-nitrosohemoglobin) was significantly higher for blood exposed in vitro to 0.1 micromol/L nitroglycerin or the NO donor SNAP, as compared with control (18.9+/-8.8 and 10.5+/-6.5 versus 2.6+/-0.5x10(-5), P<0.05)., Conclusions: The augmented MBF in the ischemic microcirculation during nitroglycerin administration occurs in tandem with increased erythrocyte S-nitrosothiol content, EM, and O2 unloading. These additional microvascular mechanisms may contribute to the powerful antiischemic effects of nitroglycerin, especially during low-flow states.

Objective: To study the characteristics of renal blood flow with contrast ultrasound., Methods: The examination of the renal ultrasonography was performed in 10 dogs after intravenous injection of Quanfuxian (a contrast agent consisting of C3F8 microbubbles)., Results: Contrast visualization appeared in the renal cortex and then in the outer to inner medulla at the baseline level after administration of the contrast agent. Notable differences in the values of microvascular volume (A, which was 120.3 in the corted vs 110.8 in the medulla, P>0.05), microcirculatory flow velocity (beta, which was 1.39 in the corted vs 0.54 in the medulla, P<0.05), and microcirculatory flow rate (A x beta, 167.4 in the corted vs 59.5 in the medulla, P<0.05) were found between the corted and the medulla, with also marked difference between the the corted-to-the medulla ratios of beta and A (0.612 vs 0.078, P<0.05)., Conclusion: Contrast ultrasound of the kidney provides a useful means of renal circulatory flow study.

Objective: To quantitatively evaluate the effects of dopamine (DA) and noradrenaline (NE) on renal medullary perfusion and the differences in perfusion in the outer and inner medulla using contrast-enhanced ultrasound., Methods and Results: Contrast-enhanced ultrasound was performed in 10 dogs with simultaneous renal artery flow (RAF) measurement at the baseline level and during application of 3 different doses of DA and NE. During treatment with the 3 doses of DA, the changes of ultrasound-derived parameters (A, beta and A*beta) in the medulla were similar to the changes in the cortex. As compared with the baseline level, the ratios between the cortex and medulla exhibited no significant difference in A, beta and A*beta during DA treatment (P>0.05). No significant difference in ultrasound-derived medullar parameters was noted in dogs with NE treatment from the baseline level (P>0.05). However, a progressive decrease in the ratios of A, beta and A*beta between the cortex and medulla was noted during NE treatment in comparison with the baseline level (P<0.05). The velocity (beta) and perfusion (A*beta) of blood flow in the medulla decreased progressively from the outer medulla to the inner medulla at baseline (P<0.05), while the blood volume (A) remained unchanged (P<0.05)., Conclusions: The changes of blood flow in both the cortex and medulla are identical during DA treatment but different in the presence of NE. The progressive decrease in perfusion from the outer medulla to the inner medulla is attributed to the decrease in the velocity of blood flow.

Objective: To investigate the changes and the effects of captopril on the renal blood flow and microvascular perfusion in dogs with acute cardiac insufficiency., Methods: Acute cardial insufficiency was induced by combining occlusion of the left anterior descending artery with right ventricular pacing in 12 mongrel dogs. The ascending aorta and left kidney were dissected and ultrasonic flow probes were placed on ascending aorta and renal artery to monitor cardiac output (CO) and renal blood flow (RBF). Contrast-enhanced ultrasound of the kidney was performed as CO was reduced to 25% (LCO25%) and 50% (LCO50%) from the basic measurement and microvascular flow velocity (beta), microvascular volume (A) and microvascular blood flow (renal cortex) were observed. After CO reduced to 50%, captopril 1 mg/kg and 2 mg/kg were injected successively and contrast-enhanced ultrasound of the kidney were performed again before and after injection., Results: At baseline, CO, RBF, CXbeta (beta of renal cortex), A and A x beta were (1.46 +/- 0.16) ml/min, (107.5 +/- 35.7) ml/min, 1.39 +/- 0.14, 120.3 +/- 14.8 and 167.4 +/- 25.0, respectively. After the LCO25% was reached, RAF, CXbeta, A and A x beta decreased to (72.50 +/- 32.4) ml/min, 0.87 +/- 0.082, 117.6 +/- 13.1, and 102.6 +/- 15.5, respectively. The corresponding values after the LCO50% was reached were (44.1 +/- 17.2) ml/min, 0.61 +/- 0.039, 106.9 +/- 12.0, and 64.7 +/- 8.83, respectively. It is suggested that the volume of the renal microvasculature remained stable until the LCO50% was reached. When captopril 1 mg/kg and 2 mg/kg were injected successively at LCO50%, MAP decreased from (85.4 +/- 7.8) mm Hg to (78.7 +/- 7.3) mm Hg and to (69.1 +/- 6.3) mm Hg (P < 0.05), respectively, while CO increased from 0.73 +/- 0.084 to 0.83 +/- 0.065 and to 0.9 +/- 0.054 (P < 0.05), respectively. RBF increased from (44.1 +/- 17.2) ml/min to 60.3 +/- 17.8 and to 79.4 +/- 17.8 (P < 0.05), respectively. After captopril 1 mg/kg and 2 mg/kg were injected, the increased flow ratios with CO were 0.15 +/- 0.084 and 0.31 +/- 0.011, respectively, and with RBF were 0.29 +/- 089 and 0.522 +/- 0.040, respectively. The increased renal blood flow ratio was higher than that of CO after captopril was used. The corresponding increases were from 0.61 +/- 0.039 to 0.75 +/- 0.020 and to 0.86 +/- 0.027 for CX beta, from 106.9 +/- 11.9 to 115.4 +/- 11.1 and to 116.6 +/- 8.9 for A, from 64.7 +/- 8.83 to 87.0 +/- 8.6 and to 100.6 +/- 8.9 for A x beta, respectively., Conclusion: The renal microvasculature plays a role by keeping its volume stable in the protection against renal ischemia when acute cardiac output decreases slightly. The role of captopril to improve renal microvascular perfusion is independent of increased total cardiac output or increased systemic blood pressure.

Background: The purpose of this study was to determine whether acoustic disruption of microbubbles in the left ventricular (LV) cavity prior to entry in the coronary circulation or their gradual destruction in the myocardium during myocardial contrast echocardiography (MCE) affects quantitative parameters of myocardial perfusion., Methods: MCE was performed in 12 open chest dogs with both intermittent high-power imaging (IHPI) and real-time low-power imaging (RLPI). To assess the affects of microbubble destruction in the LV cavity, MCE parameters of myocardial perfusion were compared for imaging planes that included versus avoided the LV cavity. To assess the effects of gradual disruption of microbubbles in the microcirculation during RLPI, MCE parameters from frames acquired continuously were compared to that from acquiring only end-systolic frames., Results: Destruction of microbubbles in the LV cavity did not alter perfusion data for either form of imaging unless RLPI was performed using long (6-frame) destructive pulse sequences. With RLPI, a gradual decay in microbubble signal occurred during their myocardial transit, the degree of which was related to the acoustic power. Signal decay during microbubble transit resulted in an overestimation of the microvascular blood velocity (beta-value) and an underestimation of the microvascular blood volume (A-value)., Conclusions: MCE parameters of perfusion at low power can be significantly altered by microbubble destruction in the LV cavity and in the myocardial microcirculation during RLPI. Short microbubble destruction pulse sequences and imaging only at end-systole can reduce these effects.

Objective: To examine the thrombus-targeting effect of platelet receptor-specific lipid microbubbles., Methods: The targeted microbubbles were prepared by coupling Arg-Gly-Asp-Ser (RGDS) with the lipid microbubbles, which were added to the microthrombus generated by platelet aggregation. The effects of the targeted microbubbles on the ultrasonic signal was observed in an artificial thrombus model., Results: The targeted microbubbles were adhesive to the microthrombus, while the non-targeted microbubbles did not possess this property. The ultrasonic signal of the thrombus border was enhanced significantly after the addition of the targeted microbubbles., Conclusions: Platelet receptor-specific microbubbles possess significant adhesive property to the thrombus and can improve signal-to-noise ratio of the thrombus, suggesting the potential value of the targeted microbubbles for clinical application in the diagnosis and treatment of thrombus.

Objective: To evaluate the accuracy of contrast-enhanced ultrasound (CEU) in renal blood flow quantification., Methods: Regional renal perfusion was quantified with CEU in 10 dogs at the baseline level and after treatment with 3 doses of dopamine (3, 8 and 16 mg.kg(-1).min(-1)), and renal arterial flow (RAF) was measured with ultrasonic flow probes deployed directly on the renal artery simultaneously. Normalized RAF was calculated as RAF divided by renal weight (ml.min(-1).g(-1))., Results: Compared with the baseline level, a progressive increase in RAF was induced by dopamine treatment at the doses of 3 and 8 mg.kg(-1).min(-1) (P<0.05), but at a higher dose of 16 mg.kg(-1).min(-1), the increment in RAF was reduced in comparison with that with the two lower doses (P<0.05). The same changes in cortical nutrient blood flow derived from CEU were observed. Significant positive correlation was found between normalized RAF and CEU-derived cortical nutrient blood flow (y=39.8x + 44.3, r=0.88, P<0.001)., Conclusion: CEU can be used to accurately quantify renal blood flow in dogs.

Objective: To further confirm the effect of nicorandil in reducing the area of myocardial infarct is through the mediation of activation of the KATP channel but not by its nitrate-like properties, and to determine whether the protective effect is the same or not when the drug is either given immediate after infarction or after reperfusion., Methods: Thirty-five dogs were randomly divided into five groups as follows. Ischemia/reperfusion (IR) group: the dogs were subjected to 90 minutes of left anterior descending coronary artery(LAD) occlusion followed by 120 minutes reperfusion. Pre-nicorandil (PNIC) group: nicorandil(NIC) 100 microg/kg was administrated by intravenous injection 10 minutes before occlusion, followed by infusion of 10 microg x kg(-1) x min (-1) of the drug till the end of reperfusion. Ischemia nicorandil(INIC) group: NIC 100 microg/kg was administered by intravenous injection 15 minutes after occlusion and 10 microg x kg(-1) x min (-1) of drug intravenously till the end of reperfusion. In the Onset reperfusion treated with nicorandil(RNIC) group: NIC 100 microg/kg was administered intravenously at the onset of reperfusion followed by 10 microg x kg(-1) x min (-1)of drug intravenously up to the end of reperfusion. Glibenclamide(GLIB)+INIC group: before NIC was administered, dogs were pretreated with GLIB 0.3 mg/kg for 10 minutes, and other treatment was the same as INIC group. Hemodynamics data were determined as baseline, 60 minutes post-occlusion, and 120 minutes post-reperfusion. By using 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, the infarct areas were analyzed with image analyzer., Results: The results showed that at 60 minutes post-occlusion, cardiac output (CO) was reduced in every group compared with baseline (all P<0.01), CO value recovered at 120 minutes after reperfusion in both PNIC and INIC group (P>0.05). There were no significant differences in heart rate (HR), mean artery pressure(MAP), mean pulmonary artery pressure(MPAP), pulmonary capillary wedge pressure(PCWP) values among all the groups. A marked reduction in the infarct area was found in PNIC group and INIC group (P<0.01) compared with IR group. Administration of GLIB before INIC shows to have no protective effect (P>0.05)., Conclusion: Our study shows that nicorandil which is a K ATP channel activator, could mimic the effect of ischemic pre-conditioning of the myocardium, by reducing the area of myocardial infarct.

Objective: To evaluate the efficacy of intravenous ultrasound microbubbles for thrombolysis of arterial thrombus without using thrombolytic drugs., Methods: Twelve rabbit models of acute bilateral femoral artery thrombosis were established and 6 of them received transcutaneous ultrasound and intravenous albumin microbubble treatment for thrombosis on one side while only microbubble treatment for the other side. The other 6 rabbits received ultrasound treatment on one side but no treatment on the other to serve as the control group., Results: None of the 6 arteries treated with microbubbles alone and only 2 arteries treated with ultrasound alone in the 6 control rabbits were recanalized. All the 6 femoral arteries treated with microbubbles together with ultrasound were recanalized (P=0.014), with significantly shorter patent time and smaller residual thrombus cross-sectional area than those of the arteries with only ultrasound treatment (P=0.004 and P=0.003, respectively)., Conclusion: Treatment with intravenous microbubbles assisted by transcutaneous ultrasound effectively promotes arterial thrombolysis in vivo, and this technique can be of significance in clinical treatment of acute thrombotic occlusions.

Objective: To identify the factors affecting ST-T segment in asymptomatic hypertensive patients., Methods: The asymptomatic patients with hypertension were divided into abnormal ST-T group (n=28) and normal ST-T group (n=20), in whom the serum levels of glucose, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), very-low-density lipoprotein cholesterol (VLDL) were measured., Results: Compared with patients with normal ST-T segment, patients with abnormal ST-T segment had significantly higher serum levels of TC, but significantly lower HDL. The serum levels of glucose, TG, LDL, VLDL differed little between the 2 groups of patients., Conclusion: In asymptomatic patients with hypertension, higher serum TC level may cause or worsen ischemic myocardial damage, for which HDL plays a protective role.

Objective: To investigate the effect of an echo-contrast agent on the proliferation of rat smooth muscle cells under different ultrasound conditions., Methods: The vascular smooth muscle cells of rats were cultured with echo-contrast agent in 96-well plates, followed by exposure to ultrasound of different conditions. Trypan blue staining was performed 48 h later, and the proliferation of the cells observed by MTT assay., Results: No cytotoxicity was found by trypan blue staining when the mechanical index of ultrasound was below 0.75. Compared with the control cells, the proliferation of the smooth muscle cells was decreased following the exposure as the mechanical index of ultrasound increased. The most obvious inhibition of cell proliferation was resulted when the microbubble concentration was 20% for a 60-second exposure., Conclusions: The inhibition of the vascular smooth muscle cell proliferation by echo-contrast agent destruction is correlated with the mechanical index of the ultrasound, concentration of the echo-contrast agent, and exposure time of ultrasound.

Objective: To observe the changes in the activity of platelet glycoprotein (GP) IIb/IIIa receptor following the occurrence of no-reflow after myocardial reperfusion, to explore the measures for clinical management of this condition., Methods: Nine canine models of no-reflow following myocardial ischemia verified by reperfusion myocardial contrast echocardiography were used in this investigation. The peripheral venous blood (PVB) and sinus venous blood (SVB) were sampled before myocardial reperfusion (after a 3-hour myocardial ischemia) and after a 3-hour reperfusion for determinating GP IIb/IIIa receptor activities by means of enzyme-linked immunosorbent assay (ELISA)., Results: The activity of platelet GP IIb/IIIa of PVB, either in 3-hour ischemic group or in 3-hour reperfusion group, was elevated significantly (P < 0.001), suggesting platelet activation. Elevated platelet GP IIb/IIIa receptor activity in SVB occurred only in 3-hour ischemic group, and the 3-hour reperfusion group (P < 0.001) and the no-reflow group had significantly decreased activities, which was more obvious in the latter group (P < 0.01). The findings signified the consumption of the platelet GP IIb/IIIa receptors in the myocardial microcirculation and the presence of platelet aggregation., Conclusions: Myocardial ischemia may activate the platelets to express GP IIb/IIIa receptors through stress response mechanism and damage the endothelia of the microvasculature to incur adhesion and aggregation of the platelets within the microcirculation, which may be one of the pathogeneses for myocardial no-reflow phenomenon.

The direct effects of dobutamine on capillary blood volume (VOL) and blood flow velocity (VEL) are not known. We hypothesized that these would be more similar to that of adenosine because of its effects on the beta(2) receptors on the coronary circulation. A total of 9 open-chest anesthetized dogs were studied after placement of 2 noncritical stenoses at rest and during separate intracoronary administrations of 5 microg/kg(-1)/min(-1) of adenosine and 2 microg/kg(-1)/min(-1) of dobutamine. VOL and VEL were measured using myocardial contrast echocardiography, wall thickening with 2-dimensional echocardiography, and myocardial blood flow (MBF) with radiolabeled microspheres. Dobutamine increased the rate-pressure product significantly, whereas adenosine had no effect on the rate-pressure product. In the normal myocardium, adenosine had no effect on VOL and increases in MBF were all a result of increases in VEL. Dobutamine also caused mostly an increase in VEL and only a 30% increase in VOL indicating modest capillary recruitment. In the bed with stenosis both drugs attenuated increase in MBF by the same amount, which was associated with an attenuation in the increase in VEL secondary to a 15% increase in capillary resistance because of capillary derecruitment. The MBF-wall thickening relation was described for both drugs by the same function: y = 1 - exp(x) with wall thickening being significantly higher for dobutamine compared with adenosine for each level of MBF. We conclude that the increase in MBF in the normal myocardium with intracoronary dobutamine occurs mostly from an increase in VEL rather than from an increase in VOL. In the bed with a noncritical stenosis, the increases in MBF and VEL are similar for both drugs. Similar to intracoronary adenosine, intracoronary dobutamine also caused capillary derecruitment distal to a noncritical coronary stenosis.

Diminished myocardial function can be seen in chronic coronary stenosis (CS) even in the presence of normal resting myocardial blood flow. We hypothesized that adenosine contributes to myocardial depression in this setting, predominantly through activation of the A(1) adenosine receptor. To test this hypothesis we used aminophylline, a nonselective adenosine receptor antagonist, and 8-cyclopentyl 1,3 dipropylxanthine, a selective A(1) adenosine receptor antagonist, in a canine model of chronic CS. Chronic CS was produced by placement of ameroid constrictors on the left anterior descending and left circumflex coronary arteries in 17 adult mongrel dogs, which resulted in severe left ventricular dysfunction 6 weeks later. Eight dogs without ameroid placement were used as controls (C). Closed-chest echocardiographic short-axis images at the low midpapillary level, hemodynamics, and radiolabeled microsphere-derived myocardial blood flow were obtained before and immediately after injection of either 5 mg/kg(-1) of aminophylline (7 left ventricular dysfunction and 4 C dogs) or 1 mg/kg(-1) of 8-cyclopentyl 1,3-dipropylxanthine (10 left ventricular dysfunction and 4 C dogs). Both 8-cyclopentyl 1,3-dipropylxanthine and aminophylline had no effect in C animals but resulted in a significant transient increase in regional percent wall thickening (P <.05) with a concomitant decrease in end-systolic wall stress (P <.05) in CS animals. There was no change in transmural myocardial blood flow or systemic hemodynamics to explain these results. Thus, adenosine plays a significant role in myocardial dysfunction in chronic ischemia by activation of the A(1) receptor. Aminophylline or a selective A(1) adenosine receptor antagonist can be used to detect viable myocardium and may be safer than dobutamine in severe chronic ischemic heart disease.

Objective: To investigate the hemodynamic changes in the epicardial coronary blood flow (ECBF) and myocardial microcirculation (MMC) during reactive hyperemia (RH) in response to reperfusion following 2-min ischemia in the left anterior descending coronary artery of canines., Methods: Twelve adult mongrel dogs were used, whose left anterior descending coronary artery was separated and ligated for 2 min twice below the first branch. The heart rate, systolic blood pressure, diastolic blood pressure, mean blood pressure, ECBF and MMC were measured respectively before and after the ligation and at 5, 10, 15, 30, 45, 60, 90 and 120 s after reperfusion. ECBF was determined with Doppler coronary flowmeter and MMC derived from the ultrasonic intensity measured by myocardial contrast echocardiography., Results: During the course of RH, ECBF and MMC both evinced responses to hyperperfusion but in manners different in view of their hemodynamic changes, demonstrating the mismatch between them in this condition. ECBF exhibited a much higher peak flow increase than MMC., Conclusions: RH occurs in response to reperfusion after short-term (2 min) myocardial ischemia, when the discrepancy arises between ECBF and MMC. The primary mechanism might involve the recruitment of the capillaries and the opening of the shunt through the capillaries, and as a consequence, the myocardial perfusion is increased at the cost of decreased reserve of the coronary microcirculation.

Myocardial blood volume (MBV) is the volume of blood residing in myocardial vessels, 90% of which is in capillaries. MBV can be measured in vivo using myocardial contrast echocardiography (MCE). It has been shown that when increases in coronary blood flow (CBF) are not associated with increase in myocardial oxygen consumption (MVO(2)), MBV does not increase. We hypothesized that MBV would increase when increases in CBF are associated with an increase in MVO(2). The atrioventricular node was ablated in 18 dogs and dual-chamber pacing was instituted. In group 1 dogs (n = 9), heart rate was altered from 50 to 150 bpm(-1) in increments of 20 bpm(-1) in random order. In group 2 dogs (n = 9), heart rate was kept constant, and dobutamine was infused at doses of 5, 10, 20, 30, and 40 microg/kg(-1)/min(-1). During each intervention, hemodynamic parameters and MVO(2) were measured, and MCE was performed. MVO(2) increased more (P <.01) with inotropic compared with chronotropic stimulation, resulting in a parallel increase in CBF. MBV fraction and MCE-derived myocardial blood flow increased significantly with increases in MVO(2) (P <.05 and P <.001, respectively) when dobutamine was infused, but remained unchanged when heart rate alone was increased. We conclude that when MVO(2) is increased substantially, the resulting increase in CBF and MCE-derived myocardial blood flow is mediated, in part, by an increase in MBV. Thus, capillary recruitment plays an important role in the physiologic regulation of CBF. Lack of increase in MBV during dobutamine stress may indicate the presence of coronary stenosis or microvascular disease.

Objectives: We hypothesized that, although the effects of dipyridamole and dobutamine on myocardial blood volume (MBV) and mean microbubble velocity (VEL) are different, the magnitude of perfusion deficit during both forms of stress is the same because both drugs unmask abnormal myocardial blood flow (MBF) reserve., Background: Both dipyridamole and dobutamine are used clinically as pharmacologic stress agents to induce reversible perfusion defects in patients with chronic coronary artery disease (CAD), but the basis for doing so for dobutamine is not clear., Methods: Eleven chronically instrumented closed-chest dogs with multivessel coronary stenosis were studied. Hemodynamics, radiolabeled microsphere-derived MBF, and myocardial contrast echocardiography (MCE)-derived myocardial perfusion were measured at rest, after dipyridamole infusion (0.56 mg x kg(-1)), and at peak dobutamine dose (either 30 or 40 microg x kg(-1) x min(-1)). Abnormal beds were defined as those demonstrating an MBF reserve <3 with dipyridamole., Results: In the presence of either drug, MBV increased more in the normal bed than in the abnormal bed, but the increase was higher in both beds with dobutamine than with dipyridamole. The slope of the relationship between MBF reserve and MBV reserve was greater during dobutamine than dipyridamole (p < 0.05). The converse was true for VEL reserve (p < 0.05). Consequently, the relationship between the ratios of either variable, or the product of the two, between the abnormal bed and normal bed was similar for both drugs., Conclusions: Although the effects of dipyridamole and dobutamine on MBV and VEL are different, both are equally effective in detecting physiologically relevant coronary stenoses on MCE. Both can therefore be used interchangeably with myocardial perfusion imaging for the detection of CAD.

Background: We hypothesized that increased myocardial oxygen demand resulting from hypotension and reflex tachycardia unmasking a reduced endocardial myocardial blood flow (MBF) reserve is the mechanism of dipyridamole-induced regional dysfunction in chronic coronary artery disease., Methods and Results: Ameroid constrictors were placed around the proximal coronary arteries and their major branches in 15 dogs to create chronic coronary stenosis. Seven days later, radiolabeled microsphere-derived MBF and 2-dimensional echocardiography-derived percent wall thickening (%WT) were measured at rest and after 0.56 mg/kg dipyridamole. Dipyridamole caused an increase (mean, 21%) in the rate-pressure product secondary to reflex tachycardia resulting from mild systemic hypotension. %WT in myocardial segments with an endocardial MBF reserve (dipyridamole/resting MBF) of 1.5 to 2.5 (n=35) did not change after dipyridamole, whereas it decreased in segments with an endocardial MBF reserve of <1.5 (n=30) and increased in those with an endocardial MBF reserve of > or =2.5 (n=45) (P<0.05). Most (80%) segments with endocardial MBF reserve of <1.5 and 14% with an endocardial MBF reserve of 1.5 to 2.5 showed inducible dysfunction after dipyridamole, whereas none of the segments with an endocardial MBF reserve of > or =2.5 showed this finding. A sigmoid relation (y=-6.74/[1+exp (19.9. [x-1.84])]+1.35. x, r=0.93, P<0.0001) was noted between endocardial MBF reserve and Delta%WT. In contrast, neither the epicardial MBF reserve nor the endocardial/epicardial MBF ratio during hyperemia was associated with inducible regional dysfunction., Conclusions: Increased myocardial oxygen demand resulting from hypotension and reflex tachycardia unmasking a reduced endocardial MBF reserve is the primary mechanism of dipyridamole-induced regional dysfunction in chronic coronary artery disease.

Objectives: The aim of the study was to determine whether coronary stenosis can be detected and myocardial viability assessed after myocardial infarction from a single venous bolus injection of BR14, a new ultrasound contrast agent., Background: BR14 is an ultrasound contrast agent that, like (201)Tl, demonstrates redistribution. Whether this principle can be used to determine myocardial viability is not known., Methods: Non-critical (n = 6) or flow-limiting (n = 4) stenoses were placed on coronary arteries of 10 open-chest dogs, which then underwent 2 h of coronary occlusion followed by reperfusion through the stenosis. Hyperemia was induced to create flow mismatch in the dogs with non-critical stenosis. Hyperemia was not induced in dogs with reduced resting coronary blood flow. All dogs were given 2 ml of BR14 as a bolus injection and serial images were obtained. Myocardial blood flow (MBF) was measured using radiolabeled microspheres. At the end of the experiment, tissue staining was performed to determine infarct size and topography., Results: Initial images demonstrated flow mismatch between the normal bed and that subtended by the stenosis (during hyperemia in dogs without critical stenosis and during rest in those with reduced resting MBF). The perfusion defect size correlated well with radiolabeled microsphere-derived hypoperfused zone (r = 0.89). Regions within the hypoperfused zone that had not undergone necrosis showed redistribution, whereas the necrotic regions showed a persistent defect, the size of which correlated well with infarct size (r = 0.80)., Conclusions: Because of its ability to redistribute, BR14 can define regions of relative hypoperfusion and also discriminate between infarcted and viable tissue within the hypoperfused zone after a single venous injection. This property lends itself to assessing myocardial perfusion during exercise stress.

Background: Currently, the detection of noncritical coronary stenoses requires some form of stress. We hypothesized that these stenoses can be detected at rest without recourse to stress by assessing adaptive changes that occur distally in the microcirculation., Methods and Results: Phasic changes in myocardial video intensity (VI) were measured at rest with continuous high-mechanical-index (MI) contrast echocardiography in 15 open-chest dogs. Data were acquired at baseline and in the presence of different degrees of noncritical coronary stenosis. In 6 of these dogs, capillary blood volume was also measured at baseline using high-MI intermittent imaging with triggering performed separately at both end diastole and end systole. During continuous high-MI imaging, a significant increase in systolic VI was noted with coronary stenoses that resulted in progressive increases in the systolic/diastolic VI ratio with greater degrees of stenosis (P=0.003), with a mildly quadratic relation noted between the two: y=1.3. 10(-6). x(2)+0.01x+0.32, P<0.001, r=0.76, SEE=0.14. There was no difference in capillary blood volume between end diastole and end systole at baseline., Conclusions: Capillary blood volume does not change between diastole and systole in vivo. Phasic changes in VI are noted at baseline during high-MI continuous imaging. The systolic component is negligible at baseline but increases with increasing levels of noncritical coronary stenosis because of adaptive changes in the microcirculation distal to the stenosis. Thus, the measurement of phasic changes in myocardial VI has the potential to detect coronary stenosis at rest without recourse to any form of stress.

In chronic coronary artery disease, resting myocardial dysfunction can exist despite normal resting transmural myocardial blood flow (MBF). We hypothesized that this phenomenon occurs because of diminished endocardial MBF reserve. MBF (measured with radiolabeled microspheres) and wall thickening (WT) (measured with echocardiography) were assessed in 7 dogs after the development of severe left ventricular dysfunction caused by placement of ameroid constrictors on the left anterior descending (LAD) and left circumflex arteries and 3 weeks after selective bypass surgery to the LAD. Before surgery, the mean transmural MBF at rest and at peak dobutamine dose in the LAD bed were 1.1 +/- 0.5 and 3.0 +/- 1.5 mL/min per gram, respectively, and were not significantly changed after LAD bypass. The resting endocardial-to-epicardial MBF ratio (EER) was also normal before bypass (1.5 +/- 0.6) and remained unchanged after surgery. The prebypass EER at peak dobutamine dose, however, was markedly diminished in the LAD bed (0.7 +/- 0.3) and improved significantly (1.3 +/- 0.8, P <.01) after surgery. Resting WT in the LAD bed also improved to normal levels (36% +/- 4% versus 13% +/- 6%, P =.0001) and no longer demonstrated a biphasic response to dobutamine. In comparison, the nonbypassed left circumflex bed continued to show reduced resting WT (12% +/- 6%), a biphasic response to dobutamine, and abnormal EER during rest and dobutamine (0.7 +/- 0.3). We conclude that persistent myocardial dysfunction in the presence of normal resting transmural MBF can occur as a result of diminished endocardial MBF reserve, with transmural MBF reserve remaining normal.

Reversible perfusion defects on (99m)Tc-sestamibi imaging during hyperemia are thought to occur due to myocardial blood flow (MBF) "mismatch" between regions with and without stenosis. We have recently shown that myocardial blood volume (MBV) distal to a stenosis decreases during hyperemia, resulting in a reversible perfusion defect on myocardial contrast echocardiography (MCE). In this study, we hypothesized that a reversible perfusion defect on (99m)Tc-sestamibi imaging during hyperemia results from the same mechanism. We tested our hypothesis under the following conditions: 1) increases in MBF in the absence of changes in MBV by using direct intracoronary infusion of adenosine (group I, n = 10 dogs); 2) decrease in MBV despite an increase in MBF by left main infusion of adenosine proximal to a noncritical coronary stenosis placed on either coronary artery (group II, n = 13 dogs); and 3) reduction in both resting MBF and MBV by placement of a severe stenosis (group III, n = 7 dogs). In group I dogs, no difference in MBV or (99m)Tc-sestamibi uptake was found between the two coronary beds despite an up to fourfold increase in MBF in one bed with adenosine. In group II dogs, MBV distal to the stenosis decreased during hyperemia despite a twofold increase in mean MBF. A good correlation was found between (99m)Tc-sestamibi uptake and MBV ratios from the stenosed versus normal bed (r = 0.91, P < 0.001). In group III dogs, both MBF and MBV were decreased in the stenosed bed at rest with a good correlation noted between (99m)Tc-sestamibi uptake and MBV ratios from the stenosed versus normal bed (r = 0.92, P = 0.004). We conclude that reversible defects on (99m)Tc-sestamibi during vasodilator stress imaging are related to decreases in MBV distal to a stenosis and not to "flow mismatch" between beds. The decrease in MBV results in reduced (99m)Tc-sestamibi uptake during hyperemia.

Objectives: The goal of this study was to determine the ability of contrast-enhanced ultrasound (CEU) to quantify renal tissue perfusion., Background: The kinetics of tracers used to assess renal perfusion are often complicated by countercurrent exchange, tubular transport or glomerular filtration. We hypothesized that, because gas-filled microbubbles are pure intravascular tracers with a rheology similar to that of red blood cells, CEU could be used to quantify renal tissue perfusion., Methods: During a continuous venous infusion of microbubbles (SonoVue), regional renal perfusion was quantified in nine dogs using CEU by destroying microbubbles and measuring their tissue replenishment with intermittent harmonic imaging. Both renal blood volume fraction and microbubble velocity were derived from pulsing-interval versus video-intensity plots. The product of the two was used to calculate renal nutrient blood flow. Renal arterial blood flow was independently measured with ultrasonic flow probes placed directly on the renal artery and was increased using dopamine and decreased by placement of a renal artery stenosis., Results: An excellent correlation was found between cortical nutrient blood flow using microbubbles and ultrasonic flow probe-derived renal blood flow (r = 0.82, p < 0.001) over a wide range (2.5 fold) of flows., Conclusions: Ultrasound examination during microbubble infusion can be used to quantify total organ as well as regional nutrient blood flow to the kidney.

OBJECTIVE: To evaluate the efficacy of myocardial contrast echocardiography (MCE) in the assessment of myocardial viability, with positron emission tomography (PET) as the golden standard. METHODS: Eleven patients with anterior wall Q wave myocardial infarction were enrolled in this study, who received successful percutaneous transluminal coronary angioplasty (PTCA) 3 to 19 months prior to the examinations by PET and MCE that were completed within 2 d. RESULTS: MCE score for the segments of necrotic myocardium, viable myocardium and normal myocardium was mostly 0, 0.5 and 1 respectively, and there was a significant difference between the grades of MCE score in identifying myocardial viability. In terms of diagnosing myocardium survival, MCE result was closely correlated with that of PET (with the correlation index rp of 0.78). CONCLUSION: Myocardial perfusion evaluation can be effectively accomplished by MCE, which might serve as a new approach to assess myocardial viability in clinical practice.

In the setting of chronic coronary stenoses, percent wall thickening (%WT) both at rest and during catecholamine stimulation can be abnormal despite normal resting myocardial blood flow (MBF). We hypothesized that this phenomenon is related to abnormal MBF reserve. Accordingly, 15 dogs were studied between 7 and 10 days after placement of Ameroid constrictors around the proximal coronary arteries and their major branches, at a time when collateral development had not yet occurred. %WT and MBF were measured at rest, after 0.56 mg/kg of dipyridamole, and at incremental doses of dobutamine (5-40 microgram. kg(-1). min(-1)). Resting %WT and MBF were normal in all four sham dogs. Resting transmural MBF was normal in all segments in the 11 study dogs, despite reduced (-2 SD of normal) %WT (<30%) in 40 of 82 segments. MBF reserve was reduced (<3) in segments with reduced %WT, and a close coupling was noted between resting %WT and MBF reserve. All segments showed an increase in %WT with dobutamine up to a dose of 20 microgram. kg(-1). min(-1), above which those with abnormal endocardial MBF reserve showed a "biphasic" response. It is concluded that, in the presence of chronic coronary stenoses, abnormalities in resting %WT as well as inducible reduction in %WT during pharmacological stress are related to the degree of abnormal MBF reserve.

To define the role of capillaries in the control of coronary blood flow (CBF) reserve, we developed a model of the coronary circulation and evaluated experimental data in its context. Our model comprised three compartments connected in series (arterial, capillary, and venous), each with its own resistance. The resistance in each vascular compartment was derived from the model based on hemodynamic data obtained in nine dogs during baseline and stenosis, both at rest and during hyperemia. The capillary hydrostatic pressure was assumed to be constant in all stages. Although in the absence of stenosis, the contribution of capillaries to total myocardial vascular resistance was only 25 +/- 5% at rest, it increased to 75 +/- 14% during hyperemia, despite the total myocardial vascular resistance decreasing by 51 +/- 13%. In the presence of a noncritical stenosis, total myocardial vascular resistance decreased by 22 +/- 10% at rest, with no change in capillary resistance. During hyperemia, total myocardial vascular resistance increased by 58 +/- 50% in the presence of the noncritical stenosis. In this situation, because arteriolar and venular resistances were already minimal, the increase in myocardial vascular resistance was due to increased capillary resistance, making it the predominant source (84 +/- 8%) of total myocardial vascular resistance. Myocardial video intensity (VI) on myocardial contrast echocardiography (MCE), which reflects capillary blood volume, decreased distal to the stenosis during hyperemia. In the presence of a flow-limiting stenosis at rest, myocardial VI also decreased, indicating that decrease in CBF was associated with an increase in capillary resistance. Our findings also provide an alternative explanation for the critical coronary closing pressure. Thus, contrary to previously held notions, capillaries play a vital role in the regulation of CBF.