Role of vasa vasorum in transendothelial solute transport in the coronary vessel wall: a study with cryostatic micro-CT

Using cryostatic microscopic computed tomography (micro-CT), we sought to determine the role of coronary vasa vasorum (VV) in transendothelial solute transport in arteries with normal and increased permeability due to high plasma cholesterol levels. In 6-mo-old pigs on a normal (n=23) and 2% high cholesterol (HC) diet (n=8), 2-cm segments of the proximal left anterior descending coronary arteries were removed in vivo after a selective injection of X-ray contrast solution. Harvesting of the specimens occurred at 0, 15, 25, 35, or 45 s after completion of the contrast injection. Specimens were snap frozen and scanned in our cryostatic micro-CT. The spatial distribution of contrast in the coronary artery wall was quantified using the CT images. Right coronary arteries were infused with Microfil to determine VV density (VV/mm2) and the cumulative lumen surface area (mm2/mm3). Transendothelial diffusion of contrast into the coronary vessel wall is a dynamic process starting at both the subintima and the adventitia. The subintimal opacification moves as a wave toward the adventitia, whereas the adventitial wave resolves. The coronary vessel wall in animals on a HC diet shows higher opacification than in normal coronary arteries without an increase of VV total luminal surface area. The loss of endothelial integrity in hypercholesterolemia significantly alters VV solute washin to, and washout from, the coronary artery wall.     

Relationship between surface area of nonperfused myocardium and extravascular extraction of contrast agent following coronary microembolization

Myocardial microvascular permeability and coronary sinus concentration of muscle metabolites have been shown to increase after myocardial ischemia due to epicardial coronary artery occlusion and reperfusion. However, their association with coronary microembolization is not well defined. This study tested the hypothesis that acute coronary microembolization increases microvascular permeability in the porcine heart. The left anterior descending perfusion territories of 34 anesthetized pigs (32 ± 3 kg) were embolized with equal volumes of microspheres of one of three diameters (10, 30, or 100 μm) and at three different doses for each size. Electron beam computed tomography (EBCT) was used to assess in vivo, microvascular extraction of a nonionic contrast agent (an index of microvascular permeability) before and after microembolization with microspheres at baseline and during adenosine infusion. A high-resolution three-dimensional microcomputed tomography (micro-CT) scanner was subsequently used to obtain ex vivo, the volume and corresponding surface area of the embolized myocardial islands within the perfusion territories of the microembolized coronary artery. EBCT-derived microvascular extraction of contrast agent increased within minutes after coronary microembolization (P < 0.001 vs. baseline and vs. control values). The increase in coronary microvascular permeability was highly correlated to the micro-CT-derived total surface area of the nonperfused myocardium (r = 0.83, P < 0.001). In conclusion, myocardial extravascular accumulation of contrast agent is markedly increased after coronary microembolization and its magnitude is in proportion to the surface area of the interface between the nonperfused and perfused territories.     

Mild inflammatory activation of mammary arteries in patients with acute coronary syndromes

Acute coronary syndromes (ACS) are characterized by multiple unstable coronary plaques and elevated circulating levels of inflammatory biomarkers. The endothelium of internal mammary arteries (IMA), which are atherosclerosis resistant, is exposed to proinflammatory stimuli as vessels that develop atherosclerosis. Our study investigated the IMA endothelial expression of inflammatory molecules in patients with ACS or chronic stable angina (CSA). IMA demonstrated normal morphology, intact endothelial lining, and strong immunoreactivity for glucose transporter 1. E-selectin expression was observed more frequently in IMA of ACS patiention than CSA patients (ACS 61% vs. CSA 14%, P = 0.01). High fluorescence for major histocompatibility complex (MHC) was significantly more frequent on the luminal endothelium (ACS 66.7% vs. CSA 17.6%, P = 0.001 for class I; and ACS 66.7% vs. CSA 6.2%, P = 0.0003 for class II-DR) and on the vasa vasorum (ACS 92.9% vs. CSA 33.3% and 7.7%, P = 0.0007 and P < 0.0001 for class I and class II-DR, respectively) of ACS patients than CSA patients. ICAM-1, VCAM-1, Toll-like receptor 4, tissue factor, IL-6, inducible nitric oxide synthase, and TNF-alpha expression were not significantly different in ACS and CSA. Circulating C-reactive protein [ACS 4.8 (2.6-7.3) mg/l vs. CSA 1.8 (0.6-3.5) mg/l, P = 0.01] and IL-6 [ACS 4.0 (2.6-5.5) pg/ml vs. CSA 1.7 (1.4-4.0) pg/ml, P = 0.02] were higher in ACS than CSA, without a correlation with IMA inflammation. The higher E-selectin, MHC class I and MHC class II-DR on the endothelium and vasa vasorum of IMA from ACS patients suggests a mild, endothelial inflammatory activation in ACS, which can be unrelated to the presence of atherosclerotic coronary lesions. These findings indicated IMA as active vessels in coronary syndromes.     

Three-dimensional imaging and morphometric analysis of alveolar tissue from microfocal X-ray-computed tomography

We evaluated microfocal X-ray-computed tomography (micro-CT) as a method to visualize lung architecture two and three dimensionally and to obtain morphometric data. Inflated porcine lungs were fixed by formaldehyde ventilation. Tissue samples (8-mm diameter, 10-mm height) were stained with osmium tetroxide, and 400 projection images (1,024 x 1,024 pixel) were obtained. Continuous isometric micro-CT scans (voxel size 9 microm) were acquired to reconstruct two- and three-dimensional images. Tissue samples were sectioned (8-microm thickness) for histological analysis. Alveolar surface density and mean linear intercept were assessed by stereology-based morphometry in micro-CT scans and corresponding histological sections. Furthermore, stereology-based morphometry was compared with morphometric semi-automated micro-CT analysis within the same micro-CT scan. Agreement of methods was assessed by regression and Bland-Altman analysis. Comparing histology with micro-CT, alveolar surface densities (35.4 +/- 2.4 vs. 33.4 +/- 1.9/mm, P < 0.05) showed a correlation (r = 0.72; P = 0.018) with an agreement of 2 +/- 1.6/mm; the mean linear intercept (135.7 +/- 14.5 vs. 135.8 +/- 15 microm) correlated well (r = 0.97; P < 0.0001) with an agreement of -0.1 +/- 3.4 microm. Semi-automated micro-CT analysis resulted in smaller alveolar surface densities (33.4 +/- 1.9 vs. 30.5 +/- 1/mm; P < 0.01) with a correlation (r = 0.70; P = 0.023) and agreement of 2.9 +/- 1.4/mm. Non-destructive micro-CT scanning offers the advantage to visualize the spatial tissue architecture of small lung samples two and three dimensionally.     

Coupled oxygen transport analysis in the avascular wall of a post-angioplasty coronary artery stenosis

The coupled oxygen transport in the avascular wall of a coronary artery stenosis is studied by numerically solving the convection-diffusion equations. Geometry, replicating residual stenosis after percutaneous transluminal coronary angioplasty (PTCA), is used for the analysis. Important physiological aspects, such as oxygen consumption in the wall, oxygen carried by the hemoglobin, non-Newtonian viscosity of the blood, and supply of oxygen from the vasa vasorum are included. Mean blood flow rate in the lumen is varied from basal to hyperemic conditions. The results show that the P(O2) in the medial region of the arterial wall is approximately 10 mmHg. The oxygen flux to the wall increases in the flow acceleration region, whereas it decreases at the flow reattachment zone. Near the location of flow separation there is a small rise and a sharp fall in the oxygen flux. The minimum P(O2) in the avascular wall, P(O2, min ), at the point of flow reattachment reduces to approximately 6 mmHg for a 300 micron wall thickness. For a thinner wall of 200 micron, the P(O2, min ) at the location of flow reattachment increases to 6 times that of a 300 micron wall. The P(O2, min ) in the wall decreases by 60% when volumetric oxygen consumption is increased by 30% for the same avascular wall thickness.     

Vasa vasorum inside out/outside in communication: a potential role in the patency of saphenous vein coronary artery bypass grafts

The saphenous vein (SV) is the most commonly used conduit for revascularization in patients undergoing coronary artery bypass surgery (CABG). The patency rate of this vessel is inferior to the internal thoracic artery (ITA). In the majority of CABG procedures the ITA is removed with its outer pedicle intact whereas the (human) SV (hSV) is harvested with pedicle removed. The vasa vasorum, a microvessel network providing the adventitia and media with oxygen and nutrients, is more pronounced and penetrates deeper towards the lumen in veins than in arteries. When prepared in conventional CABG the vascular trauma caused when removing the hSV pedicle damages the vasa vasorum, a situation affecting transmural flow potentially impacting on graft performance. In patients, where the hSV is harvested with pedicle intact, the vasa vasorum is preserved and transmural blood flow restored at graft insertion and completion of CABG. By maintaining blood supply to the hSV wall, apart from oxygen and nutrients, the vasa vasorum may also transport factors potentially beneficial to graft performance. Studies, using either corrosion casts or India ink, have shown the course of vasa vasorum in animal SV as well as in hSV. In addition, there is some evidence that vasa vasorum of hSV terminate in the vessel lumen based on ex vivo perfusion, histological and ultrastructural studies. This review describes the preparation of the hSV as a bypass conduit in CABG and its performance compared with the ITA as well as how and why its patency might be improved by harvesting with minimal trauma in a way that preserves an intact vasa vasorum.     

Role of A1 adenosine receptor in the regulation of coronary flow

To determine whether A1 adenosine receptors (AR) participate in adenosine-induced changes of coronary flow, isolated hearts from A1AR(-/-) and A1AR(+/+) mice were perfused under constant pressure, and the effects of nonselective and selective agonists were examined. Adenosine, 5'-N-ethylcarboxamidoadenosine (NECA, nonselective), and the selective A2AAR agonist 2-2-carboxyethylphenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) augmented maximal coronary vasodilation in A1AR(-/-) hearts compared with A1AR(+/+) hearts. Basal coronary flow was increased (P < 0.05) in A1AR(-/-) hearts compared with A1AR(+/+) hearts: 2.548 +/- 0.1 vs. 2.059 +/- 0.17 ml/min. In addition, selective activation of A1AR with 2-chloro-N6-cyclopentyladenosine (CCPA) at nanomolar concentrations (1-100 nM) did not significantly change coronary flow; at higher concentrations, CCPA increased coronary flow in A1AR(-/-) and A1AR(+/+) hearts. Because deletion of A1AR increased basal coronary flow, it is speculated that this effect is due to removal of an inhibitory influence associated with A1AR. Adenosine and NECA at approximately EC50 (100 and 50 nM, respectively) increased coronary flow in A1AR(+/+) hearts to 177.86 +/- 8.75 and 172.72 +/- 17% of baseline, respectively. In the presence of the selective A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50 nM), the adenosine- and NECA-induced increase in coronary flow in A1AR(+/+) hearts was significantly augmented to 216.106 +/- 8.35 and 201.61 +/- 21.89% of normalized baseline values, respectively. The adenosine- and NECA-induced increase in coronary flow in A1AR(-/-) hearts was not altered by DPCPX. These data indicate that A1AR may inhibit or negatively modulate coronary flow mediated by other AR subtypes (A2A and A2B).     

Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation

A close relationship exists between regional myocardial blood flow (RMBF) and function during acute coronary inflow restriction (perfusion-contraction matching). However, the relationship of flow and function during coronary microvascular obstruction is unknown. In 12 anesthetized dogs, the left circumflex coronary artery was perfused from an extracorporeal circuit. After control measurements, 3,000 microspheres (42 micrometer diameter) per milliliter per minute inflow were injected to cause a microembolism (ME, n = 6). With unchanged systemic hemodynamics and RMBF, posterior systolic wall thickening (PWT) decreased from 19.8 +/- 1.9% SD at control to 13.3 +/- 4.0, 10.3 +/- 3.8, and 6.9 +/- 4.7% (P < 0.05 vs. control) at 1, 4, and 8 h, respectively. For comparison, inflow was progressively reduced to match PWT to that of the ME group at 1, 4, and 8 h (stenosis, STE, n = 6). RMBF in the STE group was reduced in proportion to PWT. Infarct size was not different among groups (6.5 +/- 4.5 vs. 3.4 +/- 3.2%). However, the number of leukocytes infiltrating the area at risk was significantly greater in the ME group than in the STE group. Coronary microembolization results in perfusion-contraction mismatch and is associated with an inflammatory response.     

Systemic nitric oxide synthase inhibition improves coronary flow reserve to adenosine in patients with significant stenoses

We studied the impact of systemic infusion of the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on coronary flow reserve (CFR) in patients with coronary artery disease (CAD). We have previously demonstrated that CFR to adenosine was significantly increased after systemic infusion of L-NMMA in normal volunteers but not in recently transplanted denervated hearts. At baseline, myocardial blood flow (MBF; ml x min(-1) x g(-1)) was measured at rest and during intravenous administration of adenosine (140 microg x kg(-1) x min(-1)) in 10 controls (47 +/- 5 yr) and 10 CAD patients (58 +/- 8 yr; P < 0.01 vs. controls) using positron emission tomography and (15)O-labeled water. Both MBF measurements were repeated during intravenous infusion of 10 mg/kg L-NMMA. CFR was calculated as the ratio of MBF during adenosine to MBF at rest. CFR was significantly higher in healthy volunteers than in CAD patients and increased significantly after L-NMMA in controls (4.00 +/- 1.10 to 6.15 +/- 1.35; P < 0.0001) and in patients, both in territories subtended by stenotic coronary arteries (>70% luminal diameter; 2.06 +/- 1.13 to 3.21 +/- 1.07; P < 0.01) and in remote segments (3.20 +/- 1.23 to 3.92 +/- 1.62; P < 0.05). In conclusion, CFR can be significantly increased in CAD by a systemic infusion of L-NMMA. Similarly to our previous findings in normal volunteers, this suggests that adenosine-induced hyperemia in CAD patients is constrained by a mechanism that can be relieved by systemic NOS inhibition with L-NMMA.     

Beneficial effects of perfluorochemical artificial blood on cardiac function following coronary occlusion

This study compares the effects of perfluorochemical artificial blood versus whole blood on the systolic and diastolic function of regionally ischemic myocardial preparations. Regional ischemia was produced by ligation of the circumflex coronary artery in isolated, blood-perfused rabbit hearts. Three minutes after occlusion, half the hearts were switched from the blood perfusate to perfluorochemical artificial blood; the other half continued to be perfused with blood. Isovolumic left ventricular (LV) developed pressure, dP/dt and resting pressure were monitored before, and for 2 hours after coronary occlusion. After 90 minutes of regional ischemia, perfluorochemical-treated hearts exhibited significantly greater developed pressure than those perfused with blood (78 +/- 6% versus 61 +/- 5% of preligation values; P less than 0.05). At the end of the experiment, LV dP/dt was 21% greater in the perfluorochemical-perfused group than in the blood-perfused group (74 +/- 8% versus 53 +/- 10%; P less than 0.01). Perfluorochemical perfusion also preserved diastolic function by preventing the 58% increase in left ventricular chamber stiffness (i.e., resting pressure; P less than 0.01) associated with circumflex ligation. Thus, in the present model of regional ischemia, perfluorochemical artificial blood is significantly better than blood at maintaining both systolic and diastolic myocardial function after a major coronary artery has been occluded.     

Scaling of myocardial mass to flow and morphometry of coronary arteries.

There is no doubt that scaling relations exist between myocardial mass and morphometry of coronary vasculature. The purpose of this study is to quantify several morphological (diameter, length, and volume) and functional (flow) parameters of the coronary arterial tree in relation to myocardial mass. Eight normal porcine hearts of 117-244 g (mean of 177.5 +/- 32.7) were used in this study. Various coronary subtrees of the left anterior descending, right coronary, and left circumflex arteries were perfused at pressure of 100 mmHg with different colors of a polymer (Microfil) to obtain rubber casts of arterial trees corresponding to different regions of myocardial mass. Volume, diameter, and cumulative length of coronary arteries were reconstructed from casts to analyze their relationship to the perfused myocardial mass. Volumetric flow was measured in relationship with perfused myocardial mass. Our results show that arterial volume is linearly related to regional myocardial mass, whereas the sum of coronary arterial branch lengths, vessel diameters, and volumetric flow show an approximately 3/4, 3/8, and 3/4 power-law relationship, respectively, in relation to myocardial mass. These scaling laws suggest fundamental design principles underlying the structure-function relationship of the coronary arterial tree that may facilitate diagnosis and management of diffuse coronary artery disease.     

Effect of passive myocardium on the compliance of porcine coronary arteries

The objective of this study was to determine the effect of passive myocardium on the coronary arteries under distension and compression. To simulate distension and compression, we placed a diastolic-arrested heart in a Lucite box, where both the intravascular pressure and external (box) pressure were varied independently and expressed as a pressure difference (DeltaP = intravascular pressure - box pressure). The DeltaP-cross-sectional area relationship of the first several generations of porcine coronary arteries and the DeltaP-volume relationship of the coronary arterial tree (vessels >0.5 mm in diameter) were determined using a video densitometric technique in the range of +150 to -150 mmHg. The vasodilated left anterior descending (LAD) coronary artery of six KCl-arrested hearts were perfused with iodine and 3% Cab-O-Sil. The intravascular pressure was varied in a triangular pattern, whereas the absolute cross-sectional area of each vessel and the total arterial volume were calculated using video densitometry under different box pressures (0, 50, 100, and 150 mmHg). In the range of positive DeltaP, we found that the compliance of the proximal LAD artery in situ (4.85 +/- 3.8 x 10-3 mm2/mmHg) is smaller than that of the same artery in vitro (16.5 +/- 6 x 10-3 mm2/mmHg; P = 0.009). Hence, the myocardium restricts the compliance of the epicardial artery under distension. In the negative DeltaP range, the LAD artery does not collapse, whereas the same vessel readily collapses when tested in vitro. Hence, we conclude that myocardial tethering prevents collapse of large blood vessel under compression.     

Compression induced by RV pressure overload decreases regional coronary blood flow in anesthetized dogs

Pulmonary artery constriction (PAC), a model of right ventricular (RV) pressure overload, flattens or inverts the septum and may flatten the left ventricular (LV) free wall. Finite element (FE) analysis predicts that such deformations may cause substantial compression. This study tests the hypothesis that deformation-induced myocardial compressive stress impedes coronary blood flow (CBF). Colored microspheres ( approximately 2 x 10(6)) were injected into the left atrium of 13 open-chest, anesthetized dogs under control conditions and during PAC, which decreased the end-diastolic transseptal pressure gradient (LV - RV) from 1.6 +/- 1.3 to -3.4 +/- 1.7 mmHg. Septal and LV deformation was assessed with the use of two-dimensional echocardiography, and by FE analysis, the hydrostatic component of stress was assessed. Postmortem, a 2.5-cm wide, LV equatorial ring was divided into 16 endocardial and epicardial samples. PAC decreased CBF in the FE-predicted compression zones, areas with the greatest compression having the greatest reductions in CBF. During PAC, compression reached a maximum of 25.3 +/- 1.8 mmHg on the (LV) endocardial sides of the RV insertion points, areas that saw CBF decrease from 1.05 +/- 0.08 to 0.68 +/- 0.05 ml.min(-1).g(-1) (P < 0.001), more than 30%. CBF decreased (from 1.08 +/- 0.07 to 0.81 +/- 0.07 ml.min(-1).g(-1); P < 0.001) on the RV side of the midseptum, an area with as much as 16.0 +/- 1.0 mmHg of compression. Overall, average compressions of 10 mmHg decreased CBF by approximately 30%. We conclude that acute RV pressure overload deforms the septum and LV and induces compressive stresses that reduce CBF substantially. This may help explain why some patients with pulmonary hypertension and no critical coronary disease have chest discomfort indistinguishable from angina pectoris.     

Chronic coronary artery stenosis induces impaired function of remote myocardium: MRI and spectroscopy study in rat

Our purpose was to study morphological, functional, and metabolic changes induced by chronic ischemia in myocardium supplied by the stenotic vessel and in the remote area by MR techniques. A new technique of image fusion is proposed for analysis of coronary artery stenosis involving coronary MR angiography and spectroscopic imaging. Cine-MRI was performed 2 wk after induction of coronary stenosis. Global heart function and regional wall thickening were determined in 11 Wistar rats with stenosis and compared with 7 control rats. Two weeks after stenosis was induced, spin-labeling MRI for measurement of perfusion was performed in 14 isolated hearts. In eight isolated hearts with coronary stenosis, MR spectroscopy was performed, followed by angiography. 31P metabolite maps were fused with three-dimensional coronary angiograms. Induction of stenosis led to reduced segmental wall thickening (control: 75 +/- 9%, ischemic region: 9 +/- 3%, P < 0.05 vs. control) but also to impaired function of the remote region and lower cardiac output. Perfusion was reduced by 74.9 +/- 4.0% within ischemic segments compared with a septal control region. The phosphocreatine (PCr)/ATP ratio as a marker of ischemia was reduced in the region associated with stenosis (1.09 +/- 0.09) compared with remote (1.27 +/- 0.08) and control hearts (1.43 +/- 0.08; P < 0.05). The histological fraction of fibrosis within the ischemic region (12.8 +/- 1.4%) correlated to ATP signal reduction from remote to the ischemic region (r = 0.71, P < 0.05), but not to reduced wall thickening. Coronary narrowing caused declining function accompanied by diminished PCr/ATP, indicating impaired energy metabolism. Neither decline of function nor PCr signal decline correlated to fraction of fibrosis in histology. In contrast, reduction of ATP correlated to fibrosis and therefore to loss of viability. Impaired function within the ischemic region is associated with decreased PCr. Function of the remote region was affected as well. The fusion of PCr metabolite maps and the coronary angiogram may help to assess coronary morphology and resulting metabolic changes simultaneously.     

Beta-adrenergic receptor blockade impairs NO-dependent dilation of large coronary arteries during exercise

Shear stress-dependent nitric oxide (NO) formation prevents immoderate vascular constriction. We examined whether shear stress-dependent NO formation limits exercise-induced coronary artery constriction after beta-adrenergic receptor blockade in dogs. Control exercise led to increases (P < 0.01) in coronary blood flow (CBF) by 38 +/- 5 ml/min from 41 +/- 5 ml/min and in the external diameter of epicardial coronary arteries (CD) by 0.24 +/- 0.03 mm from 3.33 +/- 0.20 mm. CD and shear stress were linearly related. After propranolol, CD fell (P < 0.01) during exercise (0.08 +/- 0.03 from 3.23 +/- 0.19 mm), and the slope of the relationship between CD and shear stress was reduced (P < 0.01). This slope was not further altered by the additional blockade of NO formation. In propranolol-treated resting dogs, flow-dependent effects of intracoronary adenosine to mimic exercise-induced increases in shear stress (after propranolol) led to increases (P < 0.01) in CD (0.09 +/- 0.02 from 3.68 +/- 0.27 mm). Thus both shear stress-dependent NO formation and beta-adrenergic receptor activation are required to cause CD dilation during exercise. Suppression of beta-adrenergic receptor activation leads to impaired shear stress-dependent NO formation and allows alpha-adrenergic constriction to become dominant.     

Acetaminophen in the post-ischemia reperfused myocardium

Acetaminophen was administered acutely at the onset of reperfusion after 20 min of low-flow, global myocardial ischemia in isolated, perfused guinea pig hearts (Langendorff) to evaluate its influence in the postischemia, reperfused myocardium. Similarly prepared hearts were treated with vehicle or with uric acid (another phenol for comparison). Functionally, acetaminophen-treated hearts (0.35 mM) achieved significantly greater recovery during reperfusion. For example, left ventricular developed pressures at 40 min reperfusion were 38 +/- 3, 27 +/- 3, and 20 +/- 2 in the presence of acetaminophen (P < 0.05, relative to the other two groups), vehicle, and uric acid, respectively. Coronary perfusion pressures and calculated coronary vascular resistances, in the acetaminophen-treated hearts, were significantly lower at the same time (e.g., coronary perfusion pressures in the three groups, respectively, were 40 +/- 2 [P < 0.05], 51 +/- 3, and 65 +/- 12 mm Hg). Under baseline, control conditions, creatine kinase ranged from 12-15 units/liter in the three groups. It increased to 35-40 units/liter (P < 0.05) during ischemia but was significantly reduced by acetaminophen during reperfusion (e.g., 5.3 +/- 0.8 units/liter at 40 min). Oxidant-mediated chemiluminescence in all three treatment groups during baseline conditions and ischemia was similar (i.e., approximately 1.5-2.0 min for peak luminescence to reach its half maximal value). It took significantly more time during reperfusion for the oxidation of luminol in the presence of acetaminophen (>20 min, P < 0.05) than in its absence (3-8 min in uric acid- and vehicle-treated hearts). These results suggest that administration of acetaminophen (0.35 mM), at the onset of reperfusion, provides anti-oxidant-mediated cardioprotection in the postischemia, reperfused myocardium.     

Effect of endurance training on coronary artery size and function in healthy men: an invasive followup study

In eight healthy male volunteers (cardiologists; age 36 +/- 5 yr), bicycle spiroergometry, Doppler echocardiography, and quantitative coronary angiography with intracoronary Doppler measurements before and after completion of a physical endurance exercise program of >5 mo duration were performed. Maximum oxygen uptake increased from 46 +/- 6 to 54 +/- 5 ml x kg(-1) x min(-1) (P = 0.04), maximum ergometric workload changed from 3.8 +/- 0.3 to 4.4 +/- 0.3 W/kg (P = 0.001), and left ventricular mass index increased from 82 +/- 18 to 108 +/- 29 g/m(2) (P = 0.001). The right, left main, and left anterior descending coronary artery cross-sectional area increased significantly in response to exercise. Before versus at the end of the exercise program, flow-induced left anterior descending coronary artery cross-sectional area was 10.1 +/- 3.5 and 11.0 +/- 3.9 mm(2), respectively (P = 0.03), nitroglycerin-induced left coronary calibers increased significantly, and coronary flow velocity reserve changed from 3.8 +/- 0.8 to 4.5 +/- 0.7 (P = 0.001). Left coronary artery correlated significantly with ventricular mass and maximum oxygen uptake, and coronary flow velocity reserve was significantly associated with maximum workload.     

Relationship between arterial diameter and perfused tissue volume in myocardial microcirculation: a micro-CT-based analysis

The volume of myocardial tissue that is perfused by an epicardial coronary artery has been shown to be predictably related to the diameter of the epicardial arterial lumen. However, to what extent the intramyocardial microvasculature follows the epicardial rules remains unclear. To explore the relationship between the diameter of coronary arterioles and their subsequent perfused myocardial volumes, we quantified the volume of nonperfused myocardium resulting from an embolized arteriole of a certain diameter. We injected a single dose of microspheres selected from one of nine possible microsphere combinations (10, 30, and 100 microm diameter, each at three possible doses) into the left anterior descending coronary and/or left circumflex arteries of seven anesthetized pigs. At postmortem, the coronary arteries were infused with a radiopaque silicon polymer. Embolized myocardium (1 cm(3)) was scanned with a microcomputerized tomography scanner and resulted in three-dimensional images that consisted of 20 microm/side cubic voxels and a subvolume of the specimen with 4 microm/side cubic voxels. Image analysis provided the number and volumes of myocardial perfusion defects for each size and dose of microspheres. The smallest individual myocardial perfusion defects, which correspond to the volume of myocardium perfused by a single embolized arteriole, were found to be 0.0004 +/- 0.0002, 0.02 +/- 0.004, and 0.62 +/- 0.099 mm(3) for the 10-, 30-, and 100-microm microspheres, respectively. The number of myocardial perfusion defects in the embolized myocardium was inversely related to the dose of the injected microspheres. This reflects a clustering behavior that is consistent with a random distribution process of the individual embolized perfusion defects.     

The low oxygen-carrying capacity of Krebs buffer causes a doubling in ventricular wall thickness in the isolated heart

The buffer-perfused Langendorff heart is significantly vasodilated compared with the in vivo heart. In this study, we employed ultrasound to determine if this vasodilation translated into changes in left ventricular wall thickness (LVWT), and if this effect persisted when these hearts were switched to the "working" mode. To investigate the effects of perfusion pressure, vascular tone, and oxygen availability on cardiac dimensions, we perfused hearts (from male Wistar rats) in the Langendorff mode at 80, 60, and 40 cm H2O pressure, and infused further groups of hearts with either the vasoconstrictor endothelin-1 (ET-1) or the blood substitute FC-43. Buffer perfusion induced a doubling in diastolic LVWT compared with the same hearts in vivo (5.4 +/- 0.2 mm vs. 2.6 +/- 0.2 mm, p < 0.05) that was not reversed by switching hearts to "working" mode. Perfusion pressures of 60 and 40 cm H2O resulted in an increase in diastolic LVWT. ET-1 infusion caused a dose-dependent decrease in diastolic LVWT (6.6 +/- 0.4 to 4.8 +/- 0.4 mm at a concentration of 10(-9) mol/L, p < 0.05), with a concurrent decrease in coronary flow. FC-43 decreased diastolic LVWT from 6.7 +/- 0.5 to 3.8 +/- 0.7 mm (p < 0.05), with coronary flow falling from 16.1 +/- 0.4 to 8.1 +/- 0.4 mL/min (p < 0.05). We conclude that the increased diastolic LVWT observed in buffer-perfused hearts is due to vasodilation induced by the low oxygen-carrying capacity of buffer compared with blood in vivo, and that the inotropic effect of ET-1 in the Langendorff heart may be the result of a reversal of this wall thickening. The implications of these findings are discussed.     

Exercise training preserves coronary flow and reduces infarct size after ischemia-reperfusion in rat heart.

The effect of endurance training on the resistance of the heart to left ventricular (LV) functional deficit and infarction after a transient regional ischemia and subsequent reperfusion was examined. Female Sprague-Dawley rats were randomly assigned to an endurance exercise training (Tr) group or a sedentary (Sed) control group. After 20 wk of training, hearts were excised, perfused, and instrumented for assessment of LV mechanical function, and the left anterior descending coronary artery was occluded to induce a transient regional ischemia (1 h) that was followed by 2 h of reperfusion. Throughout much of the regional ischemia-reperfusion protocol, coronary flow rates, diastolic function, and LV developed pressure were better preserved in hearts from Tr animals. During the regional ischemia, coronary flow to myocardium outside the ischemic zone at risk (ZAR) was maintained in Tr hearts, whereas it progressively fell in Sed hearts. On release of the coronary artery ligature, flow to the ZAR was greater in Tr than in Sed hearts. Infarct size, expressed as a percentage of the ischemic ZAR, was significantly smaller in hearts from Tr rats (24 +/- 3 vs. 32 +/- 2% of ZAR, P < 0.05). Mn- and CuZn-SOD protein expression were higher in the LV myocardium of Tr animals (P < 0.05 for both isoforms). Our data indicate that long-term exercise training leads to infarct sparing and better maintenance of coronary flow and mechanical function after ischemia-reperfusion.