Subendocardial and subepicardial pressure-flow relations in the rat heart in diastolic and systolic arrest

Ischemic heart disease is more apparent in the subendocardial than in subepicardial layers. We investigated coronary pressure-flow relations in layers of the isolated rat left ventricle, using 15 microm microspheres during diastolic and systolic arrest in the vasodilated coronary circulation. A special cannula allowed for selective determination of left main stem pressure-flow relations. Arterio-venous shunt flow was derived from microspheres in the venous effluent. We quantitatively investigated the pressure-flow relations in diastolic arrest (n=8), systolic arrest at normal contractility (n=8) and low contractility (n=6). In all three groups normal and large ventricular volume was studied. In diastolic arrest, at a perfusion pressure of 90 mmHg, subendocardial flow is larger than subepicardial flow, i.e., the endo/epi ratio is approximately 1.2. In systolic arrest the endo/epi ratio is approximately 0.3, and subendocardial flow and subepicardial flow are approximately 12% and approximately 55% of their values during diastolic arrest. The endo/epi ratio in diastolic arrest decreases with increasing perfusion pressure, while in systole the ratio increases. The slope of the pressure-flow relations, i.e., inverse of resistance, changes by a factor of approximately 5.3 in the subendocardium and by a factor approximately 2.2 in the subepicardium from diastole to systole. Lowering contractility affects subendocardial flow more than subepicardial flow, but both contractility and ventricular volume changes have only a limited effect on both subendocardial and subepicardial flow. The resistance (inverse of slope) of the total left main stem pressure-flow relation changes by a factor of approximately 3.4 from diastolic to systolic arrest. The zero-flow pressure increases from diastole to systole. Thus, coronary perfusion flow in diastolic arrest is larger than systolic arrest, with the largest difference in the subendocardium, as a result of layer dependent increases in vascular resistance and intercept pressure. Shunt flow is larger in diastolic than in systolic arrest, and increases with perfusion pressure. We conclude that changes in contractility and ventricular volume have a smaller effect on pressure-flow relations than diastolic-systolic differences. A synthesis of models accounting for the effect of cardiac contraction on perfusion is suggested.     

Myocardial tissue pressure and blood flow during coronary sinus pressure modulation in anesthetized dogs.

To determine whether coronary sinus outflow pressure (Pcs) or intramyocardial tissue pressure (IMP) is the effective back pressure in the different layers of the left ventricular (LV) myocardium, we increased Pcs in 14 open-chest dogs under maximal coronary artery vasodilation. Circumflex arterial (flowmeter), LV total, and subendocardial and subepicardial (15-microns radioactive spheres) pressure-flow relationships (PFR) and IMP (needle-tip pressure transducers) were recorded during graded constriction of the artery at two diastolic Pcs levels (7 +/- 3 vs. 23 +/- 4 mmHg). At high Pcs, LV, aortic and diastolic circumflex arterial pressure, heart rate, myocardial oxygen consumption, and lactate extraction were unchanged; IMP in the subendocardium did not change (130/19 mmHg), whereas IMP in the subepicardium increased by 17 mmHg during systole and 10 mmHg during diastole (P < or = 0.001), independently of circumflex arterial pressure. Increasing Pcs did not change the slope of the PFR; however, coronary pressure at zero flow increased in the subepicardium (P < or = 0.008), whereas in the subendocardium it remained unchanged at 24 +/- 3 mmHg. Thus Pcs can regulate IMP independently of circumflex arterial pressure and consequently influence myocardial perfusion, especially in the subepicardial tissue layer of the LV.     

Intramyocardial pressure and coronary extravascular resistance

Intramyocardial pressure is an indicator of coronary extravascular resistance. During systole, pressure in the subendocardium exceeds left ventricular intracavitary pressure; whereas pressure in the subepicardium is lower than left ventricular intracavitary pressure. Conversely, during diastole, subepicardial pressure exceeds both subendocardial pressure and left ventricular pressure. These observations suggest that coronary flow during systole is possible only in the subepicardial layers. During diastolic, however, a greater driving pressure is available for perfusion of the subendocardial layers relative to the subepicardial layers. On this basis, measurements of intramyocardial pressure contribute to an understanding of the mechanisms of regulation of the phasic and transmural distribution of coronary blow flow.     

Transmural difference in coronary arteriolar dilation to adenosine: effect of luminal pressure and K(ATP) channels

Coronary blood flow in the subendocardium is preferentially increased by adenosine but is redistributed to the subepicardium during ischemia in association with coronary pressure reduction. The mechanism for this flow redistribution remains unclear. Since adenosine is released during ischemia, it is possible that the coronary microcirculation exhibits a transmural difference in vasomotor responsiveness to adenosine at various intraluminal pressures. Although the ATP-sensitive K(+) (K(ATP)) channel has been shown to be involved in coronary arteriolar dilation to adenosine, its role in the transmural adenosine response remains elusive. To address these issues, pig subepicardial and subendocardial arterioles (60-120 micrometer) were isolated, cannulated, and pressurized to 20, 40, 60, or 80 cmH(2)O without flow for in vitro study. At each of these pressures, vessels developed basal tone and dilated concentration dependently to adenosine and the K(ATP) channel opener pinacidil. Subepicardial and subendocardial arterioles dilated equally to adenosine and pinacidil at 60 and 80 cmH(2)O luminal pressure. At lower luminal pressures (i.e., 20 and 40 cmH(2)O), vasodilation in both vessel types was enhanced. Enhanced vasodilatory responses were not affected by removal of endothelium but were abolished by the K(ATP) channel inhibitor glibenclamide. In a manner similar to reducing pressure, a subthreshold dose of pinacidil potentiated vasodilation to adenosine. In contrast to adenosine, dilation of coronary arterioles to sodium nitroprusside was independent of pressure changes. These results indicate that coronary microvascular dilation to adenosine is enhanced at lower intraluminal pressures by selective activation of smooth muscle K(ATP) channels. Since microvascular pressure has been shown to be consistently lower in the subendocardium than in the subepicardium, it is likely that the inherent pressure gradient in the coronary microcirculation across the ventricular wall may be an important determinant of transmural flow in vivo during resting conditions or under metabolic stress with adenosine release.     

Progression of myocardial injury during coronary occlusion in the collateral-deficient heart: a non-wavefront phenomenon

It is widely accepted that, during acute coronary occlusion, ischemic cell death progresses from the subendocardium to the subepicardium in a wavefront fashion. This concept, which implies that the subendocardium is the most susceptible myocardial region to ischemic injury, was established using a canine model with an extensive system of subepicardial coronary collaterals. In humans, particularly in those with coronary artery disease, there is a wide range in the distribution and functional capacity of the collateral circulation, which may affect the pattern of infarct evolution. Using an ovine model with a limited system of preformed subendocardial coronary collaterals, we characterized the effect of increasing lengths of ischemia on regional blood flow and infarct size in three regions of the ventricular wall: subendocardium, midmyocardium, and subepicardium. Our results demonstrate that the myocardium and microvasculature in these three regions are equally susceptible to injury after 45 min of ischemia. When ischemic time is increased to 1 h, infarct size in the midmyocardium (90 +/- 2%) is greater than in the subendocardium (76 +/- 4%, P = 0.004) and subepicardium (84 +/- 3%, P = 0.13). Microvascular dysfunction as assessed as a percentage of baseline flow is also greater in the midmyocardium (14 +/- 5%) compared with the subendocardium (20 +/- 3%, P = 0.23) and subepicardium (51 +/- 9%, P = 0.007). These findings suggest that, in subjects with a limited system of coronary collateral circulation, the midmyocardium is the most susceptible myocardial region to ischemia and the subendocardium is the most resistant. Myocardial viability during coronary occlusion appears to be primarily determined by the distribution and functional capacity of the collateral circulation.     

Increased diastolic time fraction as beneficial adjunct of alpha1-adrenergic receptor blockade after percutaneous coronary intervention

The effect of alpha1-receptor blockade with urapidil on coronary blood flow and left ventricular function has been attributed to relief of diffuse coronary vasoconstriction following percutaneous coronary intervention (PCI). We hypothesized that an increase in diastolic time fraction (DTF) contributes to the beneficial action of urapidil. In eleven patients with a 63% (SD 13) diameter stenosis, ECG, aortic pressure (Pa) and distal intracoronary pressure (Pd), and blood flow velocity were recorded at baseline and throughout adenosine-induced hyperemia. Measurements were obtained before and after PCI and after subsequent alpha1-receptor blockade with urapidil (10 mg ic). DTF was determined from the ECG and the Pa waveform. Functional parameters such as coronary flow velocity reserve, fractional flow reserve, and an index of hyperemic microvascular resistance (HMR) were assessed. Urapidil administration after PCI induced an upward shift in the DTF-heart rate relationship, resulting in a 3.1% (SD 2.7) increase in hyperemic DTF at a constant heart rate (P < 0.005) due to a shorter duration of systole. Hyperemic Pa and Pd decreased, respectively, by 6.1% (SD 6.6; P < 0.05) and 5.7% (SD 5.8; P < 0.01) after alpha1-blockade. Although epicardially measured functional parameters were on average not altered by alpha1-blockade due to concurrent changes in pressure and heart rate, HMR decreased by urapidil in those patients where coronary pressure remained constant. In conclusion, alpha1-receptor blockade after PCI produced a modest but significant prolongation of DTF at a given heart rate, thereby providing an adjunctive beneficial mechanism for improving subendocardial perfusion, which critically depends on DTF.     

Effects of coronary sinus pressure elevation on coronary blood flow distribution in dogs with normal preload

Coronary sinus pressure (Pcs) elevation shifts the diastolic coronary pressure-flow relation (PFR) of the entire left ventricular myocardium to a higher pressure intercept. This finding suggests that Pcs is one determinant of zero-flow pressure (Pzf) and challenges the existence of a vascular waterfall mechanism in the coronary circulation. To determine whether coronary sinus or tissue pressure is the effective coronary back pressure in different layers of the left ventricular myocardium, the effect of increasing Pcs was studied while left ventricular preload was low. PFRs were determined experimentally by graded constriction of the circumflex coronary artery while measuring flow using a flowmeter. Transmural myocardial blood flow distribution was studied (15-micron radioactive spheres) at steady state, during maximal coronary artery vasodilatation at three points on the linear portion of the circumflex PFR both at low and high diastolic Pcs (7 +/- 3 vs. 22 +/- 5 mmHg; p less than 0.0001) (1 mmHg = 133.322 Pa). In the uninstrumented anterior wall the blood flow measurements were obtained in triplicate at the two Pcs levels. From low to high Pcs, mean aortic (98 +/- 23 mmHg) and left atrial (5 +/- 3 mmHg) pressure, percent diastolic time (49 +/- 7%), percent left ventricular wall thickening (32 +/- 4%), and percent myocardial lactate extraction (15 +/- 12%) were not significantly changed. Increasing Pcs did not alter the slope of the PFR; however, the Pzf increased in the subepicardial layer (p less than 0.0001), whereas in the subendocardial layer Pzf did not change significantly. Similar slopes and Pzf were observed for the PFR of both total myocardial mass and subepicardial region at low and high Pcs. Subendocardial:subepicardial blood flow ratios increased for each set of measurements when Pcs was elevated (p less than 0.0001), owing to a reduction of subepicardial blood flow; however, subendocardial blood flow remained unchanged, while starting in the subepicardium toward midmyocardium blood flow decreased at high Pcs. This pattern was similar for the uninstrumented anterior wall as well as in the posterior wall. Thus as Pcs increases it becomes the effective coronary back pressure with decreasing magnitude from the subepicardium toward the subendocardium of the left ventricle. Assuming that elevating Pcs results in transmural elevation in coronary venous pressure, these findings support the hypothesis of a differential intramyocardial waterfall mechanism with greater subendo- than subepi-cardial tissue pressure.     

Why is the subendocardium more vulnerable to ischemia? A new paradigm

Myocardial ischemia is transmurally heterogeneous where the subendocardium is at higher risk. Stenosis induces reduced perfusion pressure, blood flow redistribution away from the subendocardium, and consequent subendocardial vulnerability. We propose that the flow redistribution stems from the higher compliance of the subendocardial vasculature. This new paradigm was tested using network flow simulation based on measured coronary anatomy, vessel flow and mechanics, and myocardium-vessel interactions. Flow redistribution was quantified by the relative change in the subendocardial-to-subepicardial perfusion ratio under a 60-mmHg perfusion pressure reduction. Myocardial contraction was found to induce the following: 1) more compressive loading and subsequent lower transvascular pressure in deeper vessels, 2) consequent higher compliance of the subendocardial vasculature, and 3) substantial flow redistribution, i.e., a 20% drop in the subendocardial-to-subepicardial flow ratio under the prescribed reduction in perfusion pressure. This flow redistribution was found to occur primarily because the vessel compliance is nonlinear (pressure dependent). The observed thinner subendocardial vessel walls were predicted to induce a higher compliance of the subendocardial vasculature and greater flow redistribution. Subendocardial perfusion was predicted to improve with a reduction of either heart rate or left ventricular pressure under low perfusion pressure. In conclusion, subendocardial vulnerability to a acute reduction in perfusion pressure stems primarily from differences in vascular compliance induced by transmural differences in both extravascular loading and vessel wall thickness. Subendocardial ischemia can be improved by a reduction of heart rate and left ventricular pressure.     

Evaluation of transmural distribution of viable muscle by myocardial strain profile and dobutamine stress echocardiography

Transmural distribution of viable myocardium in the ischemic myocardium has not been quantified and fully elucidated. To address this issue, we evaluated transmural myocardial strain profile (TMSP) in dogs with myocardial infarction using a newly developed tissue strain imaging. TMSP was obtained from the posterior wall at the epicardial left ventricular short-axis view in 13 anesthetized open-chest dogs. After control measurements, the left circumflex coronary artery was occluded for 90 min to induce subendocardial infarction (SMI). Subsequently, latex microbeads (90 microm) were injected in the same artery to create transmural infarction (TMI). In each stage, measurements were done before and after dobutamine challenge (10 microg.kg(-1).min(-1) for 10 min) to estimate transmural myocardial viability. Strain in the subendocardium in the control stage increased by dobutamine (from 53.6 +/- 17.1 to 73.3 +/- 21.8%, P < 0.001), whereas that in SMI and TMI stages was almost zero at baseline and did not increase significantly by dobutamine [from 0.8 +/- 8.8 to 1.3 +/- 7.0%, P = not significant (NS) for SMI, from -3.9 +/- 5.6 to -1.9 +/- 6.0%, P = NS for TMI]. Strain in the subepicardium increased by dobutamine in the control stage (from 23.9 +/- 6.1 to 26.3 +/- 6.4%, P < 0.05) and in the SMI stage (from 12.4 +/- 7.3 to 27.1 +/- 8.8%, P < 0.005), whereas that in the TMI stage did not change (from -1.0 +/- 7.8 to -0.7 +/- 8.3%, P = NS). In SMI, the subendocardial contraction was lost, but the subepicardium showed a significant increase in contraction with dobutamine. However, in TMI, even the subepicardial increase was not seen. Assessment of transmural strain profile using tissue strain imaging was a new and useful method to estimate transmural distribution of the viable myocardium in myocardial infarction.     

Dynamics of flow velocities in endocardial and epicardial coronary arterioles

The subendocardium is the most vulnerable area of the left ventricle to the effects of hypoperfusion and ischemia. Despite this well-acknowledged observation, the mechanisms underlying this susceptibility are not elucidated, although numerous explanations including differences in transmural distribution of hemodynamics, metabolism, and wall stresses have been proposed. Our goal was to make dynamic measurements of endocardial and epicardial flow velocities, which reflect hemodynamic and wall stresses, to approach this problem. We measured blood flow velocities in subendocardial and subepicardial coronary arterioles of in vivo beating canine hearts using a high-speed, charge-coupled device, intravital videomicroscope with a rod-probe lens. Subendocardial flow was characterized by remarkable systolic flow-velocity reversal (systolic slosh ratio, 84%; measurable velocity of retrograde flow, faster than -40 mm/s), which contrasted to predominant forward-flow velocity during systole in the subepicardial arterioles (systolic slosh ratio, 25%; maximum velocity, approximately -20 mm/s; P < 0.0005 and 0.05 vs. subendocardial arterioles, respectively). We speculate that this retrograde flow is "wasteful," because this volume must be refilled during the subsequent diastole, which thereby detracts from the net perfusion as well as the time for perfusion. Accordingly, we also believe that the retrograde systolic blood flow contributes to the vulnerability of the subendocardium to ischemia.     

Effect of acute exercise stress in cardiac hypertrophy: I. correlation of regional blood flow and qualitative ultrastructural changes.

Ultrastructural myocardial cell changes were determined in eight miniswine after the development of pressure-overload hypertrophy induced by supra-valvular aortic constriction. Four miniswine served as control animals. Regional myocardial blood flows were measured at rest and during exercise stress with radioactive microspheres after two days and one month of aortic constriction. Exercise stress, causing the heart rate to increase to 85 percent of its maximum, was imposed twice weekly for 7 minutes on four pressure-overloaded animals and the four control animals to elicit differences between the control and experimental groups that might not occur at rest. After one month of pressure overload the swine were killed and myocardial samples were processed for electron microscopy. Ultrastructural changes similar to those in hypertrophied hearts were present throughout the left ventricular walls of the pressure-overloaded animals. Other changes consistent with ischemic injury were present in the subendocardial regions of pressure-overloaded animals subjected to exercise stress. These changes included disorganization of myofibrils, disintegration and broadening of Z-bands, swelling and aggregation of mitochondria, electron-dense deposits in mitochondria, decreased cristal density and vacuolization of mitochondria, intracellular edema, margination and clumping of nuclear chromatin, and a decrease of glycogen granules. Regional ischemia in the subendocardium of these animals was confirmed by functional studies which showed decreased regional myocardial blood flow to the subendocardium during exercise and S-T segment elevation for the first 2-10 days after inducing pressure overload. The ischemia, as shown by flow studies, during exercise stress persisted in the compensatory stage of hypertrophy although S-T segments returned to normal. Thus, the combined effect of pressure overload and exercise stress can produce focal subendocardial ischemia in the compensated, hypertrophied heart.     

Stenosis differentially affects subendocardial and subepicardial arterioles in vivo

The presence of a coronary stenosis results primarily in subendocardial ischemia. Apart from the decrease in coronary perfusion pressure, a stenosis also decreases coronary flow pulsations. Applying a coronary perfusion system, we compared the autoregulatory response of subendocardial (n = 10) and subepicardial (n = 12) arterioles (<120 microm) after stepwise decreases in coronary arterial pressure from 100 to 70, 50, and 30 mmHg in vivo in dogs (n = 9). Pressure steps were performed with and without stenosis on the perfusion line. Maximal arteriolar diameter during the cardiac cycle was determined and normalized to its value at 100 mmHg. The initial decrease in diameter during reductions in pressure was significantly larger at the subendocardium. Diameters of subendocardial and subepicardial arterioles were similar 10--15 s after the decrease in pressure without stenosis. However, stenosis decreased the dilatory response of the subendocardial arterioles significantly. This decreased dilatory response was also evidenced by a lower coronary inflow at similar average pressure in the presence of a stenosis. Inhibition of nitric oxide production with N(G)-monomethyl-L-arginine abrogated the effect of the stenosis on flow. We conclude that the decrease in pressure caused by a stenosis in vivo results in a larger decrease in diameter of the subendocardial arterioles than in the subepicardial arterioles, and furthermore stenosis selectively decreases the dilatory response of subendocardial arterioles. These two findings expand our understanding of subendocardial vulnerability to ischemia.     

Morphological characteristics of tissue components of different layers of the rat myocardium

The tissue components of the subendocardial, inner and outer intramural layers of the myocardium were examined by morphometry. There was no significant difference in the proportion of cardiomyocytes in the different layers of the myocardium (subendocardium 0.820 +/- 0.007; inner layer 0.713 +/- 0.100; outer intramural layers 0.727 +/- 0.008; subepicardium 0.699 +/- 0.009). The relative surface of cardiomyocytes was maximal in the subepicardium (58.62 +/- 1,18). The magnitudes of the volumetric density and surface of the capillaries decreased from the subepicardial toward the subendocardial layer. The diameter of myocytes in the test layers of the myocardium varied within a wide range.     

Transmural sheet strains in the lateral wall of the ovine left ventricle

In an attempt to provide a better understanding of our finding that regions with contracting left ventricular myofibers need not develop a significant transmural systolic wall thickening gradient, the analytic approach of Costa et al. was applied to the four-dimensional dynamic data obtained 1 and 8 wk after surgical implantation of transmural radiopaque beads in the lateral equatorial left ventricular wall in seven ovine hearts. Quantitative histology of tissue blocks demonstrated that fiber angles varied linearly across the wall in this region from -37 degrees in the subepicardium to +18 degrees in the subendocardium. Sheet angles exhibited a pleated-sheet behavior, alternating sign from subepicardium to subendocardium. From end diastole (reference configuration) to end systole (deformed configuration), fiber strain was uniformly negative, sheet extension and sheet thickening were uniformly positive, and sheet-normal shear contributed to wall thickening at all wall depths. Subepicardial radial wall thickening increased significantly from week 1 to week 8, with significant increases in the contributions from subepicardial sheet extension and sheet-normal shear. At 1 and 8 wk, the contribution of sheet-normal shear to wall thickening was substantial at all transmural depths; the contribution of sheet extension to wall thickening was greatest in the subepicardium and least in the subendocardium, and the contribution of sheet thickening to wall thickening was greatest in the subendocardium and least in the subepicardium. A mechanistic model is proposed that provides a working hypothesis that a selective decrease in subepicardial intercellular matrix stiffness is responsible for elimination of the transmural wall thickening gradient 1-8 wk after marker implantation surgery.     

Coronary sinus occlusion enhances coronary collateral flow and reduces subendocardial ischemia

On the hypothesis that coronary sinus occlusion (CSO) may reduce myocardial ischemia, we examined the effects of CSO on coronary collateral blood flow and on the distribution of regional myocardial blood flow (RMBF) in dogs. Thirty-eight anesthetized dogs underwent occlusion of the left anterior descending coronary artery with or without CSO and intact vasomotor tone. We measured RMBF and intramyocardial pressure (IMP) in the subendocardium (Endo) and subepicardium (Epi) separately. With intact vasomotor tone, CSO during ischemia significantly increased RMBF in the ischemic region (IR), particularly in Endo from 0.17 +/- 0.03 to 0.33 +/- 0.05 ml x min(-1) x g(-1) (P < 0.05), and increased the Endo/Epi from 0.59 +/- 0.10 to 1.15 +/- 0.15 (P < 0.01). These effects of CSO were partially abolished by adenosine. However, the Endo/Epi was still increased from 0.90 +/- 0.13 to 2.09 +/- 0.30 (P < 0.01). The changes in RMBF in IR were significantly correlated with the peak CS pressure during CSO. The Endo/Epi of IMP in IR was significantly decreased during CSO. In conclusion, CSO potentially enhances coronary collateral flow, and preserves the ischemic myocardium, especially in Endo.     

Decreased Ca2+ extrusion via Na+/Ca2+ exchange in epicardial left ventricular myocytes during compensated hypertrophy

Hypertension-induced cardiac hypertrophy alters the amplitude and time course of the systolic Ca2+ transient of subepicardial and subendocardial ventricular myocytes. The present study was designed to elucidate the mechanisms underlying these changes. Myocytes were isolated from the left ventricular subepicardium and subendocardium of 20-wk-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY; control). We monitored intracellular Ca2+ using fluo 3 or fura 2; caffeine (20 mmol/l) was used to release Ca2+ from the sarcoplasmic reticulum (SR), and Ni2+ (10 mM) was used to inhibit Na+/Ca2+ exchange (NCX) function. SHR myocytes were significantly larger than those from WKY hearts, consistent with cellular hypertrophy. Subepicardial myocytes from SHR hearts showed larger Ca2+ transient amplitude and SR Ca2+ content and less Ca2+ extrusion via NCX compared with subepicardial WKY myocytes. These parameters did not change in subendocardial myocytes. The time course of decline of the Ca2+ transient was the same in all groups of cells, but its time to peak was shorter in subepicardial cells than in subendocardial cells in WKY and SHR and was slightly prolonged in subendocardial SHR cells compared with WKY subendocardial myocytes. It is concluded that the major change in Ca2+ cycling during compensated hypertrophy in SHR is a decrease in NCX activity in subepicardial cells; this increases SR Ca2+ content and hence Ca2+ transient amplitude, thus helping to maintain the strength of contraction in the face of an increased afterload.     

Morphometric data on the lymph capillaries of the ventricles of the rabbit heart

A morphometric analysis was done on the lymph capillaries of both left and right ventricles from the rabbit heart. The measurements were made on the lymphatics identified in the subepicardium, myocardium and subendocardium of the ventricular walls. Quantitative evaluations were carried out on light and electron microscopic sections by a computerized image analysis system. The following parameters were selected and measured: (1) the diameter (of area-equivalent circle) of lymph capillaries, (2) the diameter of the uncoated micropinocytotic vesicles (located on the abluminal and adluminal side and in the cytoplasm of the endothelial cell) and the area occupied by the vesicles per unit area of cytoplasm. Differences in the size of the lymph capillaries were found in the three layers (subepicardium, myocardium and subendocardium) of the ventricular walls. The largest vessels were present in the subepicardium both in the left ventricle and in the right one. No significant variations were found in the lymphatics of corresponding regions on both ventricles. Little variations on the mean diameter of the uncoated micropinocytotic vesicles are present in the three regions of the endothelial wall. In the left ventricle only, the subendocardial vesicles are significantly larger than the subepicardial and the myocardial ones (p less than 0.05). The areal density occupied by vesicular system in the three layers of the ventricular wall showed significant differences in both ventricles (p less than 0.05). The vesicles present in the subepicardial vessels occupied the smallest areal density. No significant variations existed in the vesicular areal density between the two ventricles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Difference in the relation between infarct and occluded bed in pentobarbital-anesthetized and conscious dogs

The relationship between myocardial infarct size (IS) and occluded bed size (OBS) in pentobarbital-anesthetized (A, n = 16) and conscious (C, n = 20) dog models were compared. IS and OBS (postmortem coronary arteriography) were measured by computerized planimetry of weighed left ventricular (LV) rings 7 days after permanent left anterior descending (LAD, n = 19) or circumflex (LC, n = 17) coronary artery occlusion. For both A and C groups, IS was directly related to OBS (p less than 0.001) and no infarcts developed for small occluded beds. For either LAD or LC subgroups, infarcts were larger in A than C dogs (49 +/- 18 vs. 30 +/- 19% OBS, p less than 0.025), with greater slope of the linear regression between IS and OBS (p less than 0.001) and less epicardial sparing on topographic mapping (p less than 0.05). Although postocclusion mean arterial and left atrial pressures were similar in A and C groups, heart rates were greater in the A dogs, both pre- (125 vs. 88 beats/min, p less than 0.001) and post-occlusion (151 vs. 108 beats/min, p less than 0.001). Endocardial flows (radioactive microspheres) in infarct centers and margins were less in A than C dogs. Also, endocardial/epicardial (endo/epi) flow ratios in all regions were less in A than C dogs, both pre- and post-occlusion. Increasing heart rate in 10 other C dogs with LAD occlusion to that of the A group (151 beats/min) by right ventricular pacing resulted in larger infarcts with greater slope of the linear regression and less endo/epi flow ratios, as in the A group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of vitamin C and L-NMMA on the inotropic response to dobutamine in patients with heart failure

The positive effect of vitamin C on left ventricular (LV) inotropic responses to dobutamine, observed in patients with preserved LV function, is lost in heart failure (HF). We tested the hypothesis that in HF, endogenous nitric oxide (NO) opposes the positive effect of vitamin C on adrenergically stimulated contractility by examining the effects of vitamin C on dobutamine responses during NO synthase inhibition. In 11 HF patients, a micromanometer-tipped catheter was inserted into the LV and an infusion catheter was positioned in the left main coronary artery. The peak positive rate of change of LV pressure (LV +dP/dt) was measured in response to intravenous dobutamine (Dob-1). After recontrol, intracoronary N(G)-monomethyl-L-arginine (l-NMMA) was infused before reinfusion of dobutamine (L-NMMA + Dob-2). Finally, intracoronary vitamin C was infused in addition to intracoronary L-NMMA and dobutamine (L-NMMA + Dob-2 + vitamin C). Intracoronary L-NMMA alone had no effect on LV +dP/dt. After a stable inotropic response to intracoronary L-NMMA and dobutamine was established, the addition of intracoronary vitamin C resulted in a modest but significant increase in LV +dP/dt. The change in LV +dP/dt in response to dobutamine alone was 25 +/- 5%, with intracoronary L-NMMA, 27 +/- 6%, and with intracoronary L-NMMA plus vitamin C, 37 +/- 5% (P < 0.05 vs. Dob-1 and L-NMMA + Dob-2). These findings demonstrate that an interaction between endogenous NO and redox environment exists and exerts some influence on stimulated contractility in HF.     

Myocardial flow distribution. II : Empty beating heart, ventricular fibrillation and cardiac arrest

Myocardial oxygen consumption (MVO2) and coronary blood flow (CBF) distribution were studied in 21 isolated, metabolically supported dog hearts. Measurements of MVO2 and CBF distribution were carried out in three different experimental conditions : empty beating heart (EBH), ventricular fibrillation (VF) and high potassium-induced cardiac arrest (CA). MVO2 was approximately the same in EBH and VF (4.09 +/- 0.77 and 4.28 +/- 0.68 ml O2 min-1 100 g-1 respectively), and significantly lower in the group with CA (2.40 +/- 0.18 ml O2 min-1 100 g-1, P less than 0.05). Total CBF showed no significant differences among the three groups (84 +/- 7 ml/min in EBH; 78 +/- 7 ml/min in VF and 83 +/- 7 ml/min in CA). Subendocardial CBF per unit of tissue mass was significantly lower in hearts with VF (0.43 +/- 0.01 ml/min-1 g-1, P less than 0.05) when tested against the other two groups of experiments (0.69 +/- 0.03 ml min-1 g-1 in EBH and 0.65 +/- +/- 0.04 ml min-1 g-1 in CA). This was also reflected in the endo/epi ratio, that was significantly lower in VF (1.41 +/- 0.07, P less than 0.05) with respect to the other two groups (2 +/- 0.09 in EBH and 2.21 +/- 0.07 in CA). From data presented here we can conclude that cardioplegia, even in absence of hypothermia, is a method that will assure myocardial protection providing : (1) a lower subendocardial MVO2; (2) a higher subendocardial CBF, which helps for a prompt recovery during reperfusion.