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.     

Clinical evidence for myocardial derecruitment downstream from severe stenosis: pressure-flow control interaction

To verify the interaction between coronary pressure (CP) and blood flow (CBF) control, we studied nine candidates for angioplasty of an isolated lesion of the left anterior descending coronary artery [i.e. , percutaneous transluminal coronary angioplasty (PTCA)]. CBF (i.e., flow velocity x coronary cross-sectional area at the Doppler tip) and CP were monitored during washout of 2-5 mCi of (133)Xe after bolus injection into the left main artery before and after PTCA. Xe mean transit time (MTT) was calculated as the area under the time-activity curve, acquired by a gamma camera, divided by the dose obtained from a model fit of the Xe curve in the anterior wall. CBF response to intracoronary adenosine (2 mg) was also assessed. PTCA increased baseline CBF (from 14.5 +/- 9.4 to 20 +/- 8 ml/min, P < 0.01), coronary flow reserve (from 1.52 +/- 0.24 to 2.33 +/- 0.8, P < 0.01), and CP (from 64 +/- 9 to 100 +/- 10 mmHg, P < 0.05). MTT decreased from 89 +/- 32 to 70 +/- 19 s (P < 0.05) after PTCA; however, MTT and CBF changes were not correlated (r = -0.09, not significant). Inasmuch as MTT is the ratio of distribution volume to CBF, MTT x CBF was used as an index of perfused myocardial volume. Volume increased after PTCA from 23 +/- 18 to 56 +/- 30 ml. A direct correlation was observed between the percent increase in distal CP and percent increase in perfused volume (r = 0.91, P < 0.01). Thus low CP was not associated with exhaustion of flow reserve but, rather, with reduction of perfused myocardial volume. These data suggest that, in the presence of a severe coronary stenosis, derecruitment of vascular units occurs that is proportional to the decrease in driving pressure. Residual perfused units maintain a vasomotor tone, thus explaining the paradoxical persistence of coronary reserve.     

Influence of serotonin on myocardial blood flow in the presence and absence of a coronary arterial stenosis: observations in domestic swine

This study tested the hypothesis that 5-HT may impair coronary flow regulation by inappropriately increasing arteriolar tone in the coronary circulation. Ten closed chest, domestic swine were studied both in the presence and in the absence of a severe artificial intraluminal coronary stenosis. A 5-French micromanometer catheter with fluid lumen was placed in the left anterior descending coronary artery and used to record pressure and infuse 5-HT (40 and 100 micrograms/min) into the coronary circulation. For the stenosis phase of the protocol the catheter was embedded in the artificial stenosis. Hemodynamics, regional myocardial blood flow (microsphere technique), coronary vascular resistance, lactate consumption, and oxygen metabolism were measured at control and at 5 min of each 5-HT dose. In the absence of coronary artery stenosis (i.e., full vasodilatory reserve), there was no change in regional myocardial blood flow or coronary vascular resistance during 5-HT infusion. In the presence of a severe coronary stenosis (i.e., limited vasodilator reserve) 5-HT produced a significant (P less than 0.05) decrease versus control in the distal left anterior descending: circumflex zone endocardial blood flow ratio (0.63 +/- 0.19, mean +/- 1 SD, to 0.55 +/- 0.15) and a significant (P less than 0.05) increase versus control in endocardial (50.6 +/- 16.6 to 61.2 +/- 19.8 mm Hg/ml/min/g) and transmural (49.9 +/- 9.5 to 57.2 +/- 12.8) coronary vascular resistance. Thus, 5-HT does not impair coronary flow regulation when full vasodilatory reserve is present. When coronary vasodilatory reserve is impaired by the presence of a severe proximal stenosis, 5-HT causes modest impairment of endocardial flow regulation.     

The effect of surgery with cardiopulmonary bypass on oxygen transport in elderly patients with ischemic heart disease

In a clinical trial, 103 patients undergoing coronary artery bypass grafting from May, 1999, to December, 2001 with hypothermic cardiopulmonary bypass (CPB) were retrospectively assigned to one of two groups: group I (n = 45)--patients 65 years of age and older (68.0 +/- 0.5), group II (n = 58)--patients 45-50 years of age (48.2 +/- 0.2). The following parameters were recorded: haemodynamic--with thermodilution method (SMU--612, Hellige), blood gases (OMNI-6, Austria). Measurements were performed 7 times: (1) before surgery, (2) before CPB, (3) after CPB, (4, 5, 6, 7)--1, 3, 9, 12 hours after surgery. Indexes of oxygen delivery and consumption, oxygen utilization coefficient and anion gap were calculated. Obtained results were statistically analyzed using appropriate t-test and chi2-test for categorical variables. Data are expressed as mean +/- SE. There were no significant differences between the groups in all stages of examination, p > 0.05. In elderly group both oxygen delivery and consumption were lower then in younger one, thus the coefficient of oxygen utilization did not differ between groups. Therefore the surgery with CPB seems to be inrelated to adverse changes on oxygen transport in elderly patients, and its dynamic was similar in patients over 65 years of age and younger group.     

Oxidative stress precedes peak systemic inflammatory response in pediatric patients undergoing cardiopulmonary bypass operation

Oxidative stress seems to contribute to cardiopulmonary bypass (CPB)-related postoperative complications. Pediatric patients are particularly prone to these complications. With this in mind, we measured oxidative stress markers in blood plasma of 20 children undergoing elective heart surgery before, during, and up to 48 h after cessation of CPB, along with inflammatory parameters and full analysis of iron status. Ascorbate levels were decreased by approximately 50% (P < 0.001) at the time of aorta cross-clamp removal (or pump switch-off in 4 patients with partial CPB), and associated with corresponding increases in dehydroascorbate (P < 0.001, r = -0.80) and malondialdehyde (P < 0.01, r = -0.59). In contrast to the immediate oxidative response, peak levels of IL-6 and IL-8 were not observed until 3-12 h after CPB cessation. The early loss of ascorbate correlated with duration of CPB (P < 0.002, r = 0.72), plasma hemoglobin after cross-clamp removal (P < 0.001, r = 0.70), and IL-6 and IL-8 levels at 24 and 48 h after CPB (P < 0.01), but not with postoperative lactate levels, strongly suggesting that hemolysis, and not inflammation or ischemia, was the main cause of early oxidative stress. The correlation of ventilation time with early changes in ascorbate (P < 0.02, r = 0.55), plasma hemoglobin (P < 0.01, r = 0.60), and malondialdehyde (P < 0.02, r = 0.54) suggests that hemolysis-induced oxidative stress may be an underlying cause of CPB-associated pulmonary dysfunction. Optimization of surgical procedures or therapeutic intervention that minimize hemolysis (e.g., off-pump surgery) or the resultant oxidative stress (e.g., antioxidant treatment) should be considered as possible strategies to lower the rate of postoperative complications in pediatric CPB.     

Catheter-based antegrade intracoronary viral gene delivery with coronary venous blockade

The purpose of this study is to evaluate the feasibility of percutaneous antegrade myocardial gene transfer (PAMGT). A consistent and safe technique for in vivo gene transfer is required for clinical application of myocardial gene therapy. PAMGT with concomitant coronary venous blockade was performed in 12 swine. The myocardium was preconditioned with 1 min of occlusion of the left anterior descending and left circumflex arteries. The anterior interventricular vein was occluded during left anterior descending artery delivery, and the great cardiac vein at the entrance of the middle cardiac vein was occluded during left circumflex artery delivery. With arterial and venous balloons inflated (3 min) and after adenosine (25 mug) injection, PAMGT was performed by antegrade injection of an adenoviral solution (1 ml of 10(11) plaque-forming units in each coronary artery) carrying beta-galactosidase or saline through the center lumen of the angioplasty balloon. In one set of animals, PAMGT was performed with selective coronary vein blockade (n = 9); in another set of animals, PAMGT was performed without coronary vein blockade (n = 5). At 1 wk after gene delivery, the animals were killed. Quantitative beta-galactosidase analysis was performed in the left and right ventricular walls. PAMGT was successfully performed in all animals with and without concomitant occlusion of the coronary veins. Quantitative beta-galactosidase analysis showed that PAMGT with coronary blockade was superior to PAMGT without coronary blockade. beta-Galactosidase activity increased significantly in the beta-galactosidase group compared with the saline group: 1.34 +/- 0.18 vs. 0.81 +/- 0.1 ng (P 相似文献   

Coronary smooth muscle reactivity to muscarinic stimulation after ischemia-reperfusion in porcine myocardial infarction.

This study tested whether ischemia-reperfusion alters coronary smooth muscle reactivity to vasoconstrictor stimuli such as those elicited by an adventitial stimulation with methacholine. In vitro studies were performed to assess the reactivity of endothelium-denuded infarct-related coronary arteries to methacholine (n = 18). In addition, the vasoconstrictor effects of adventitial application of methacholine to left anterior descending (LAD) coronary artery was assessed in vivo in pigs submitted to 2 h of LAD occlusion followed by reperfusion (n = 12), LAD deendothelization (n = 11), or a sham operation (n = 6). Endothelial-dependent vasodilator capacity of infarct-related LAD was assessed by intracoronary injection of bradykinin (n = 13). In vitro, smooth muscle reactivity to methacholine was unaffected by ischemia-reperfusion. In vivo, baseline methacholine administration induced a transient and reversible drop in coronary blood flow (9.6 +/- 4.6 to 1.9 +/- 2.6 ml/min, P < 0.01), accompanied by severe left ventricular dysfunction. After ischemia-reperfusion, methacholine induced a prolonged and severe coronary blood flow drop (9.7 +/- 7.0 to 3.4 +/- 3.9 ml/min), with a significant delay in recovery (P < 0.001). Endothelial denudation mimics in part the effects of methacholine after ischemia-reperfusion, and intracoronary bradykinin confirmed the existence of endothelial dysfunction. Infarct-related epicardial coronary artery shows a delayed recovery after vasoconstrictor stimuli, because of appropriate smooth muscle reactivity and impairment of endothelial-dependent vasodilator capacity.     

Biventricular cardiac dysfunction after acute massive pulmonary embolism in the rat.

Cardiac dysfunction has been documented in vivo after acute massive pulmonary embolism (AMPE). The present study tests whether intrinsic ventricular dysfunction occurs in rat hearts isolated after AMPE. AMPE was induced in spontaneously breathing ketamine-xylazine-anesthetized rats by thrombus infusion until mean arterial blood pressure (MAP) was approximately 40% of basal measurement. A hypotensive control group underwent controlled blood withdrawal to produce MAP approximately 40% of basal levels. Shams underwent identical surgical and anesthesia preparation but without pulmonary embolization. Hearts were perfused in isovolumetric mode, and simultaneous right ventricular (RV) and left ventricular (LV) pressures were measured. AMPE caused arterial hypotension with hypoxemia (PO(2) = 50 +/- 14 Torr), acidemia (pH = 7.26 +/- 0.11), and high lactate concentration (6.9 +/- 1.7 mM). Starling curves from both ventricles demonstrated that AMPE significantly reduced ex vivo systolic contractile function in the RV (P = 0.031) and LV (P = 0.008) compared with both the hypotensive control and sham hearts. AMPE did not alter coronary flow or compliance in either ventricle. Soluble tumor necrosis factor-alpha decreased in the RV (P = 0.043) and LV (P = 0.005) tissue. These data support the hypothesis that AMPE produces intrinsic biventricular dysfunction and suggest that arterial hypotension is not the principal mechanism of this dysfunction.     

Myocardial O2 consumption in porcine left ventricle is heterogeneously distributed in parallel to heterogeneous O2 delivery

Myocardial blood flow is unevenly distributed, but the cause of this heterogeneity is unknown. Heterogeneous blood flow may reflect heterogeneity of oxygen demand. The aim of the present study was to assess the relation between oxygen consumption and blood flow in small tissue regions in porcine left ventricle. In seven male, anesthetized, open-chest pigs, local oxygen consumption was quantitated by computational model analysis of the incorporation of 13C in glutamate via the tricarboxylic acid cycle during timed infusion of [13C]acetate into the left anterior descending coronary artery. Blood flow was measured with radioactive microspheres before and during acetate infusion. High-resolution nuclear magnetic resonance 13C spectra were obtained from extracts of tissue samples (159 mg mean dry wt) taken at the end of the acetate infusion. Mean regional myocardial blood flow was stable [5.0 +/- 1.6 (SD) and 5.0 +/- 1.4 ml.min(-1).g dry wt(-1) before and after 30 min of acetate infusion, respectively]. Mean left ventricular oxygen consumption measured with the NMR method was 18.6 +/- 7.7 micromol.min(-1).g dry wt(-1) and correlated well (r = 0.85, P = 0.02, n = 7) with oxygen consumption calculated from blood flow, hemoglobin, and blood gas measurements (mean 22.8 +/- 4.7 micromol.min(-1).g dry wt(-1)). Local blood flow and oxygen consumption were significantly correlated (r = 0.63 for pooled normalized data, P < 0.0001, n = 60). We calculate that, in the heart at normal workload, the variance of left ventricular oxygen delivery at submilliliter resolution is explained for 43% by heterogeneity in oxygen demand.     

Effect of pulmonary perfusion on the slopes of single-breath test of CO2.

The objective of this study was to evaluate the effects of lung perfusion on the slopes of phases II (S(II)) and III (S(III)) of a single-breath test of CO(2) (SBT-CO(2)). Fourteen patients submitted to cardiac surgery were studied during weaning from cardiopulmonary bypass (CPB). Pump flow was decreased in 20% steps, from 100% (total CPB = 2.5 l.min(-1).m(-2)) to 0%. This maneuver resulted in a progressive and opposite increase in pulmonary blood flow (PBF) while maintaining ventilator settings constant. SBT-CO(2), respiratory, and hemodynamic variables remained unchanged before and after CPB, reflecting a constant condition at those stages. S(III) was similar before and after CPB (19.6 +/- 2.8 and 18.7 +/- 2.1 mmHg/l, respectively). S(III) was lowest during 20% PBF (8.6 +/- 1.9 mmHg/l) and increased in proportion to PBF until exit from CPB (15.6 +/- 2.2 mmHg/l; P < 0.05). Similarly, S(II) and the CO(2) area under the curve increased from 163 +/- 41 mmHg/l and 4.7 +/- 0.6 ml, respectively, at 20% PBF to 313 +/- 32 mmHg/l and 7.9 +/- 0.6 ml (P < 0.05) at CPB end. When S(II) and S(III) were normalized by the mean percent expired CO(2), they remained unchanged during the protocol. In summary, the changes in PBF affect the slopes of the SBT-CO(2). Normalizing S(II) and S(III) eliminated the effect of changes in the magnitude of PBF on the shape of the SBT-CO(2) curve.     

Splenic baroreceptors control splenic afferent nerve activity

Stenosis of either the portal or splenic vein increases splenic afferent nerve activity (SANA), which, through the splenorenal reflex, reduces renal blood flow. Because these maneuvers not only raise splenic venous pressure but also reduce splenic venous outflow, the question remained as to whether it is increased intrasplenic postcapillary pressure and/or reduced intrasplenic blood flow, which stimulates SANA. In anesthetized rats, we measured the changes in SANA in response to partial occlusion of either the splenic artery or vein. Splenic venous and arterial pressures and flows were simultaneously monitored. Splenic vein occlusion increased splenic venous pressure (9.5 +/- 0.5 to 22.9 +/- 0.8 mmHg, n = 6), reduced splenic arterial blood flow (1.7 +/- 0.1 to 0.9 +/- 0.1 ml/min, n = 6) and splenic venous blood flow (1.3 +/- 0.1 to 0.6 +/- 0.1 ml/min, n = 6), and increased SANA (1.7 +/- 0.4 to 2.2 +/- 0.5 spikes/s, n = 6). During splenic artery occlusion, we matched the reduction in either splenic arterial blood flow (1.7 +/- 0.1 to 0.7 +/- 0.05, n = 6) or splenic venous blood flow (1.2 +/- 0.1 to 0.5 +/- 0.04, n = 5) with that seen during splenic vein occlusion. In neither case was there any change in either splenic venous pressure (-0.4 +/- 0.9 mmHg, n = 6 and +0.1 +/- 0.3 mmHg, n = 5) or SANA (-0.11 +/- 0.15 spikes/s, n = 6 and -0.05 +/- 0.08 spikes/s, n = 5), respectively. Furthermore, there was a linear relationship between SANA and splenic venous pressure (r = 0.619, P = 0.008, n = 17). There was no such relationship with splenic venous (r = 0.371, P = 0.236, n = 12) or arterial (r = 0.275, P = 0.413, n = 11) blood flow. We conclude that it is splenic venous pressure, not flow, which stimulates splenic afferent nerve activity and activates the splenorenal reflex in portal and splenic venous hypertension.     

Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest

The aim of this study was to investigate effects of poly(ADP-ribose) polymerase (PARP) inhibition on mesenteric vascular function and metabolism in an experimental model of cardiopulmonary bypass (CPB) with cardiac arrest. Twelve anesthetized dogs underwent 90-min hypothermic CPB. After 60 min of cardiac arrest, reperfusion was started for 40 min following application of either saline vehicle (control, n = 6) or a potent PARP inhibitor, PJ-34 (10 mg/kg iv bolus and 0.5 mg.kg(-1).min(-1) infusion for 20 min, n = 6). PJ-34 led to better recovery of cardiac output (2.2 +/- 0.1 vs. 1.8 +/- 0.2 l/min in control) and mesenteric blood flow (175 +/- 38 vs. 83 +/- 4 ml/min, P < 0.05 vs. control) after reperfusion. The impaired vasodilator response of the superior mesenteric artery to acetylcholine, assessed in the control group after CPB (-32.8 +/- 3.3 vs. -57.6 +/- 6.6% at baseline, P < 0.05), was improved by PJ-34 (-50.3 +/- 3.6 vs. -54.3 +/- 4.1% at baseline, P < 0.05 vs. control). Although plasma nitrate/nitrite concentrations were not significantly different between groups, mesenteric nitric oxide synthase activity was increased in the PJ-34 group (P < 0.05). Moreover, the treated group showed a marked attenuation of mesenteric venous plasma myeloperoxidase levels after CPB compared with the control group (75 +/- 1 vs. 135 +/- 9 ng/ml, P < 0.05). Pharmacological PARP inhibition protects against development of post-CPB mesenteric vascular dysfunction by improving hemodynamics, restoring nitric oxide production, and reducing neutrophil adhesion.     

Effect of bronchial artery blood flow on cardiopulmonary bypass-induced lung injury

Cardiovascular surgery requiring cardiopulmonary bypass (CPB) is frequently complicated by postoperative lung injury. Bronchial artery (BA) blood flow has been hypothesized to attenuate this injury. The purpose of the present study was to determine the effect of BA blood flow on CPB-induced lung injury in anesthetized pigs. In eight pigs (BA ligated) the BA was ligated, whereas in six pigs (BA patent) the BA was identified but left intact. Warm (37 degrees C) CPB was then performed in all pigs with complete occlusion of the pulmonary artery and deflated lungs to maximize lung injury. BA ligation significantly exacerbated nearly all aspects of pulmonary function beginning at 5 min post-CPB. At 25 min, BA-ligated pigs had a lower arterial Po(2) at a fraction of inspired oxygen of 1.0 (52 +/- 5 vs. 312 +/- 58 mmHg) and greater peak tracheal pressure (39 +/- 6 vs. 15 +/- 4 mmHg), pulmonary vascular resistance (11 +/- 1 vs. 6 +/- 1 mmHg x l(-1) x min), plasma TNF-alpha (1.2 +/- 0.60 vs. 0.59 +/- 0.092 ng/ml), extravascular lung water (11.7 +/- 1.2 vs. 7.7 +/- 0.5 ml/g blood-free dry weight), and pulmonary vascular protein permeability, as assessed by a decreased reflection coefficient for albumin (sigma(alb); 0.53 +/- 0.1 vs. 0.82 +/- 0.05). There was a negative correlation (R = 0.95, P < 0.001) between sigma(alb) and the 25-min plasma TNF-alpha concentration. These results suggest that a severe decrease in BA blood flow during and after warm CPB causes increased pulmonary vascular permeability, edema formation, cytokine production, and severe arterial hypoxemia secondary to intrapulmonary shunt.     

Vasoconstriction seen in coronary bypass grafts during handgrip in humans.

In animal studies, sympathetically mediated coronary vasoconstriction has been demonstrated during exercise. Human studies examining coronary artery dynamics during exercise are technically difficult to perform. Recently, noninvasive transthoracic Duplex ultrasound studies demonstrated that 1) patients with left internal mammary artery (LIMA) grafts to the left anterior descending artery can be imaged and 2) the LIMA blood flow patterns are similar to those seen in normal coronary arteries. Accordingly, subjects with LIMA to the left anterior descending artery were studied during handgrip protocols as blood flow velocity in the LIMA was determined. Beat-by-beat analysis of changes in diastolic coronary blood flow velocity (CBV) was performed in six male clinically stable volunteers (60 +/- 2 yr) during two handgrip protocols. Arterial blood pressure (BP) and heart rate (HR) were also measured, and an index of coronary vascular resistance (CVR) was calculated as diastolic BP/CBV. Fatiguing handgrip performed at [40% of maximal voluntary contraction (MVC)] followed by circulatory arrest did not evoke an increase in CVR (P = not significant). In protocol 2, short bouts of handgrip (15 s) led to increases in CVR (18 +/- 3% at 50% MVC and 20 +/- 8% at 70% MVC). BP was also increased during handgrip. Our results reveal that in conscious humans, coronary vasoconstriction occurs within 15 s of onset of static handgrip at intensities at or greater than 50% MVC. These responses are likely to be due to sympathetic vasoconstriction of the coronary circulation.     

Preserved reflex cutaneous vasodilation in cystic fibrosis does not include an enhanced nitric oxide-dependent mechanism.

In humans, vasoactive intestinal peptide (VIP) may play a role in reflex cutaneous vasodilation during body heating. We tested the hypothesis that the nitric oxide (NO)-dependent contribution to active vasodilation is enhanced in the skin of subjects with cystic fibrosis (CF), compensating for sparse levels of VIP. In 2 parallel protocols, microdialysis fibers were placed in the skin of 11 subjects with CF and 12 controls. Lactated Ringer was perfused at one microdialysis site and NG-nitro-L-arginine methyl ester (2.7 mg/ml) was perfused at a second microdialysis site. Skin blood flow was monitored over each site with laser-Doppler flowmetry. In protocol 1, local skin temperature was increased 0.5 degrees C every 5 s to 42 degrees C, and then it maintained at 42 degrees C for approximately 45 min. In protocol 2, subjects wore a tube-lined suit perfused with water at 50 degrees C, sufficient to increase oral temperature (Tor) 0.8 degrees C. Cutaneous vascular conductance (CVC) was calculated (flux/mean arterial pressure) and scaled as percent maximal CVC (sodium nitroprusside; 8.3 mg/ml). Vasodilation to local heating was similar between groups. The change (Delta%CVCmax) in CVC with NO synthase inhibition on the peak (9+/-3 vs. 12+/-5%CVCmax; P=0.6) and the plateau (45+/-3 vs. 35+/-5%CVCmax; P=0.1) phase of the skin blood flow response to local heating was similar in CF subjects and controls, respectively. Reflex cutaneous vasodilation increased CVC in CF subjects (58+/-4%CVCmax) and controls (53+/-4%CVCmax; P=0.37) and NO synthase inhibition attenuated CVC in subjects with CF (37+/-6%CVCmax) and controls (35+/-5%CVCmax; P=0.8) to a similar degree. Thus the preservation of cutaneous active vasodilation in subjects with CF is not associated with an enhanced NO-dependent vasodilation.     

Rosuvastatin reduces experimental left ventricular infarct size after ischemia-reperfusion injury but not total coronary occlusion

This study compared the effects of rosuvastatin on left ventricular infarct size in mice after permanent coronary occlusion vs. 60 min of ischemia followed by 24 h of reperfusion. Statins can inhibit neutrophil adhesion, increase nitric oxide synthase (NOS) expression, and mobilize progenitor stem cells after ischemic injury. Mice received blinded and randomized administration of rosuvastatin (20 mg.kg(-1).day(-1)) or saline from 2 days before surgery until death. After 60 min of ischemia with reperfusion, infarct size was reduced by 18% (P = 0.03) in mice randomized to receive rosuvastatin (n = 18) vs. saline (n = 22) but was similar after permanent occlusion in rosuvastatin (n = 17) and saline (n = 20) groups (P = not significant). Myocardial infarct size after permanent left anterior descending coronary artery occlusion (n = 6) tended to be greater in NOS3-deficient mice than in the wild-type saline group (33 +/- 4 vs. 23 +/- 2%, P = 0.08). Infarct size in NOS3-deficient mice was not modified by treatment with rosuvastatin (34 +/- 5%, n = 6, P = not significant vs. NOS3-deficient saline group). After 60 min of ischemia-reperfusion, neutrophil infiltration was similar in rosuvastatin and saline groups as was the percentage of CD34(+), Sca-1(+), and c-Kit(+) cells. Left ventricular NOS3 mRNA and protein levels were unchanged by rosuvastatin. Rosuvastatin reduces infarct size after 60 min of ischemia-reperfusion but not after permanent coronary occlusion, suggesting a potential anti-inflammatory effect. Although we were unable to demonstrate that the myocardial protection was due to an effect on neutrophil infiltration, stem cell mobilization, or induction of NOS3, these data suggest that rosuvastatin may be particularly beneficial in myocardial protection after ischemia-reperfusion injury.     

Postsystolic shortening of ischemic myocardium: a mechanism of abnormal intraventricular filling

Acute myocardial ischemia has been associated with abnormal filling patterns in the left ventricular (LV) apex. We hypothesized that this may in part be due to postsystolic shortening of ischemic apical segments, which leads to reversal of early diastolic apical flow. Fourteen open-chest anesthetized dogs were instrumented with micromanometers in the LV apex and left atrium and myocardial sonomicrometers in the anterior apical LV wall. Intraventricular filling by color Doppler and wall motion by strain Doppler echocardiography (SDE) were assessed from an apical view. Measurements were taken before and after 5 min of left anterior descending coronary artery (LAD) occlusion. In four dogs, we measured the pressure difference between the LV apex and outflow tract. At baseline, peak early diastolic flow velocities in the distal one-third of the LV were directed toward apex (9.2 +/- 1.6 cm/s). After LAD occlusion, the velocities reversed (-2.3 +/- 0.4 cm/s, P < 0.01), indicating that blood was ejected from the apex toward the base during early filling. This interpretation was confirmed by wall motion analysis, which showed postsystolic shortening of apical myocardial segments. The postsystolic shortening represented 9.7 +/- 1.7% (P < 0.01) and 14.2 +/- 2.4% (P < 0.01) of end-diastolic segment length by SDE and sonomicrometry, respectively. Consistent with the velocity changes, we found reversal of the early diastolic pressure gradient from the LV apex to outflow tract. In the present model, acute LAD occlusion resulted in reversal of early diastolic apical flow, and this was attributed to postsystolic shortening of dyskinetic apical segments. The clinical diagnostic importance of this finding remains to be determined.     

Activation of p38 MAPK and increased glucose transport in chronic hibernating swine myocardium

In preconditioned myocardium, activation of the mitogen-activated protein kinase (MAPK) p38 leads to increased glucose uptake via enhanced GLUT-4 translocation. Glucose uptake is also increased in chronic hibernating myocardium, but the role of p38 MAPK and GLUT-4 translocation has not been studied. Nine swine underwent instrumentation of the proximal left anterior descending coronary artery (LAD) with a small, external constrictor. At 3 mo after instrumentation, myocardial glucose uptake by PET imaging was higher in the LAD than in the remote region under basal, fasted conditions (0.08 +/- 0.02 vs. 0.04 +/- 0.01 micromol.min(-1).g(-1), P < 0.05). Compared with the remote region, the LAD region demonstrated increased membrane-bound GLUT-4 relative to total content (61 +/- 04 vs. 45 +/- 06%, P < 0.05), higher glycogen (28.37 +/- 4.41 vs. 19.26 +/- 1.87 mg/g wet wt, P < 0.05), and increased inducible nitric oxide synthase (NOS) activity (1.43 +/- 0.34 vs. 0.51 +/- 0.21 activity/mg protein, P < 0.05). p38 MAPK was 47 +/- 14% higher in the LAD than in the remote region (P < 0.05) and correlated well with the absolute degree of GLUT-4 membrane-bound translocation (r = 0.81, P < 0.01), relative increase in glycogen (r = 0.70, P < 0.05), and total NOS activity (r = 0.68, P < 0.05). In chronic hibernating myocardial tissue, p38 MAPK activation is increased under basal fasted conditions and correlates well with the increased degree of GLUT-4 translocation, glycogen accumulation, and NOS activity. As in preconditioned myocardium, activation of p38 MAPK may play an important role in the metabolic adaptations that characterize chronic hibernating myocardium.     

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.     

Hyperglycemia reduces coronary collateral blood flow through a nitric oxide-mediated mechanism

We tested the hypothesis that hyperglycemia alters retrograde coronary collateral blood flow by a nitric oxide-mediated mechanism in a canine Ameriod constrictor model of enhanced collateral development. Administration of 15% dextrose to increase blood glucose concentration to 400 or 600 mg/dl decreased retrograde blood flow through the left anterior descending coronary artery to 78 +/- 9 and 82 +/- 8% of baseline values, respectively. In contrast, saline or L-arginine (400 mg x kg(-1) x h(-1)) had no effect on retrograde flow. Coronary hypoperfusion and 1 h of reperfusion decreased retrograde blood flow similarly in saline- or L-arginine-treated dogs (76 +/- 11 and 89 +/- 4% of baseline, respectively), but these decreases were more pronounced in hyperglycemic dogs (47 +/- 10%). L-arginine prevented decreases in retrograde coronary collateral blood flow during hyperglycemia (100 +/- 5 and 95 +/- 6% of baseline at blood glucose concentrations of 400 and 600 mg/dl, respectively) and after coronary hypoperfusion and reperfusion (84 +/- 14%). The results suggest that hyperglycemia decreases retrograde coronary collateral blood flow by adversely affecting nitric oxide availability.