Use of cytosolic triacylglycerol hydrolysis products and of exogenous fatty acid for the synthesis of triacylglycerol secreted by cultured rat hepatocytes

In this study, we examined whether chronic severe diabetes may affect ischaemic and post-ischaemic regional myocardial dysfunction in vivo in the dog. Diabetes was chemically induced in randomized animals and major metabolic alterations were observed confirming the severity and chronicity of the diabetes. After 70 days, halothane-anaesthetized dogs underwent a 20-min coronary occlusion, followed by reperfusion. During ischaemia, global left ventricle function (dP/dtmax) was more altered (P<0.005) in diabetics ( n=10) than in controls (n=10), whereas area-at-risk (29+/-2.5% of the left ventricle in diabetics v 32.4+/-1.9% in controls) and ischaemic subendocardial myocardial blood flow (radioactive microsphere technique, 0.11+/-0.02 v 0.10+/-0.03 ml/min/g) were similar. During reperfusion, both groups developed significant (P<0.05) regional myocardial dysfunction (somomicrometry, 41+/-14% of baseline in controls and 66+/-8% in diabetics), whereas the difference between groups was not significant. No dog of either group developed myocardial cell necrosis on tissue histology. Multivariate analyses, including the severity of prior ischaemia and the occurrence of ventricular fibrillation as covariables, confirmed that myocardial stunning was not increased in diabetics, although ischaemia was clearly less-well-tolerated in diabetic dogs as global (dP/dtmax) as well as regional myocardial function were significantly (P<0.05) more altered in diabetics during ischaemia. Whilst alteration of arachidonate and cholesterol metabolism may partly explain this apparent paradox, further studies are required to resolve this issue.     

Early cardiac allograft rejection is independent of regional myocardial blood flow

Noninvasive telemetric monitoring of canine heterotopic cardiac allograft unipolar peak-to-peak amplitude (UPPA) has permitted prospective surveillance for rejection; moreover, this technique is able to reliably detect rejection before the development of histologic evidence of myocyte necrosis. This study was performed to determine whether early cardiac allograft rejection and the accompanying decline in allograft UPPA were associated with alterations in regional myocardial blood flow (RMBF). Seven heterotopic, intrathoracic canine cardiac transplantations were performed using triple-drug immunosuppression. Native hearts and allografts were instrumented with right ventricular and left ventricular epicardial screw-in electrodes connected to subcutaneous telemeters. Daily measurement of native and graft UPPA was performed; using radioactive microspheres, native and graft RMBF were determined during the control period and when UPPA had declined by 15%, 30%, and 45%. Graft histologic status was determined by endomyocardial biopsy at the time of RMBF determination. Mean duration of the study was 19.7 +/- 3.9 days. Rejection was documented in all animals. The UPPA was stable in native hearts; UPPA declined in the allografts after the onset of rejection. A biphasic change in allograft blood flow was seen. Initially RMBF increased as UPPA declined; a 30% to 45% reduction in UPPA was associated with a 41% increase in RMBF (p = 0.028 versus allograft control). Subsequently, a significant decline in blood flow was observed for reductions in UPPA greater than 45% (0.68 +/- 0.44 versus 1.07 +/- 0.47 mL.g-1 x min-1 for a 30% to 45% decline in UPPA; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of short-term treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reverse

BACKGROUND: We tested the hypothesis that correction of hyperlipidemia improves coronary vasodilator response and maximal perfusion in myocardial regions having substantial impairment of pretreatment vasodilator capacity. METHODS AND RESULTS: Measurements of myocardial blood flow were made with PET [13N]ammonia in 12 patients with ischemic heart disease (11 men; age, 65+/-8 years [mean+/-SD]) at rest and during adenosine at 70 and then 140 microg . kg-1 . min-1 for 5 minutes each before and approximately 4 months after simvastatin treatment (40 mg daily). Simvastatin reduced LDL (171+/-13 before versus 99+/-18 mg/dL after simvastatin, P<0.001) and increased HDL (39+/-8 versus 45+/-9 mg/dL, P<0.05). Myocardial segments were classified on the basis of pretreatment blood flow response to 140 microg . kg-1 . min-1 adenosine as normal (flow >/=2 mL . min-1 . g-1) or abnormal (flow <2 mL . min-1 . g-1). In normal segments, baseline myocardial blood flow (0.95+/-0.32) increased (P<0.001) at both low- (1.62+/-0.81) and high- (2.63+/-0.41) dose adenosine and was unchanged both at rest and with adenosine after simvastatin. In abnormal segments, myocardial blood flow at rest (0. 73+/-0.19) increased at low- (1.06+/-0.59, P<0.02) and high- (1. 29+/-0.33, P<0.01) dose adenosine. After simvastatin, myocardial blood flow increased more compared with pretreatment at both low- (1. 37+/-0.66, P<0.05 versus pretreatment) and high- (1.89+/-0.79, P<0. 01 versus pretreatment) dose adenosine. CONCLUSIONS: Short-term lipid-lowering therapy increases stenotic segment maximal myocardial blood flow by approximately 45%. The mechanism involves enhanced, flow-mediated dilation of stenotic epicardial conduit vessels and may account at least in part for the efficacy of lipid lowering in secondary prevention trials and in reducing ischemic episodes in ambulatory patients.     

Preconditioning improves myocardial function and reflow, but not vasodilator reactivity, after ischaemia and reperfusion in anaesthetized dogs

1. The present study examines whether three cycles of brief coronary artery occlusion and reperfusion (i.e. ischaemic preconditioning; PC) can prevent vasodilator dysfunction and the impairment of myocardial reflow caused by prolonged ischaemia. Coronary blood flow, left ventricular dP/dt, systemic arterial blood pressure and heart rate were measured in open-chest anaesthetized dogs. 2. Sixty minute occlusion of the left circumflex coronary artery (LCx) and 60 min LCx reperfusion (ISC/REP; group 1) significantly reduced resting coronary blood flow (CBF, initial 29 +/- 3 mL/min; ISC/REP 20 +/- 3 mL/min, P < 0.05 vs initial) and increased coronary vascular resistance (CVR, initial 4.1 +/- 0.6 mmHg/min per mL; ISC/REP 5.8 +/- 1.0 mmHg/min per mL, P < 0.05 vs initial). By contrast CBF and CVR were not affected in dogs subjected to preconditioning before ischaemia (group 2: CBF, initial 24 +/- 4 mL/min; PC+ISC/REP 23 +/- 4 mL/min; CVR, initial 4.7 +/- 0.6 mmHg/min per mL; PC+ ISC/REP 5.3 +/- 1.0 mmHg/min per mL). These data suggest that ischaemic preconditioning prevents the ischaemia-induced impairment of myocardial reflow. 3. Ischaemia and reperfusion impaired coronary dilator responses to the endothelium-dependent dilator acetylcholine (delta CBF, after ISC/REP: 50 +/- 6% of initial) and the endothelium-independent dilator glyceryl trinitrate (delta CBF, ISC/REP: 46 +/- 6% of initial). Despite the improvement in reperfusion in the preconditioned group, there was no significant improvement in responses to acetylcholine (PC+ISC/REP 52 +/- 6% of initial) or glyceryl trinitrate (PC+ISC/REP 59 +/- 6% of initial) after ischaemia and reperfusion. 4. The reduction in left ventricular dP/dt after ischaemia and reperfusion was significantly smaller in the preconditioned group indicating a lower level of impairment of cardiac contractility. In addition, we confirmed that preconditioning caused a significant reduction in infarct size and a reduction in the release of lactate dehydrogenase indicating less cardiac injury. 5. These results suggest that although ischaemic preconditioning was able to improve both myocardial reperfusion and contractility, it was not able to preserve vasodilator function. Such a reduction in vasodilator reserve could prevent adequate myocardial perfusion under conditions of elevated oxygen demand.     

Myocsrdial uptake of technetium-99m stannous pyrophosphate following direct current transthoracic countershock

The effect of direct current (DC) countershock upon myocardial technetium-99m stannous pyrophosphate (PYP) uptake was studied in 22 dogs. All eight dogs imaged had positive abnormal PYP scintigrams that were usually indistinguishable from experimental infarction. In three animals, additional areas of radionuclide uptake were seen in overlying noncardiac tissue. Left and right ventricular myocardial PYP uptake averaged (+/- SEM) 23 +/- 5 times control and 24 +/- 6 times control, respectively. These activity ratios occurred without reduction in regional myocardial blood flow (RMBF), and were associated with histologic evidence of necrosis. The necrosis was usually epicardial, corresponding to the transmural site of greatest PYP uptake. The magnitude of PYP accumulation and the weight of damaged tissue increased with increasing applied energy. Thus, PYP uptake following DC countershock could result in false-positive interpretation of acute ischemic myocardial infarction. Since RMBF is normal in regions of PYP uptake, the major determinant of radionuclide accumulation is the extent of cellular damage.     

The effect of CY1503, a sialyl Lewisx analog blocker of the selectin adhesion molecules, on infarct size and "no-reflow" in the rabbit model of acute myocardial infarction/reperfusion

CY1503, an analogue of sialyl-Lewisx, is an inhibitor of the selectin adhesion molecules. CY1503 has been found to limit myocardial infarct size in canine and feline models. However, the effect of CY1503 on the "no-reflow" phenomenon is still unknown. Anesthetised rabbits were subjected to 30 min of coronary artery occlusion and 4 h of reperfusion. Protocol 1: after 27 min of ischemia, rabbits were randomised to an iv bolus of either CY1503 (30 mg/kg) (n=9) or saline (n=9). Protocol 2: rabbits were randomly given two iv boluses of CY1503 (30 mg/kg) (n=6) or saline (n=6), administered after 10 and 25 min of ischemia. Protocol 3: after 27 min of ischemia rabbits were randomly given an iv bolus of CY1503 (30 mg/kg) (n=6) and infusion of 20 mg/kg over 4 h or saline bolus+infusion (n=6). Regional myocardial blood flow (RMBF) was assessed after 30 min and 4 h of reperfusion. The risk zone (RZ) was assessed by blue dye and the necrotic zone (NZ) by tetrazolium staining. RMBF: protocol 1: RMBF in the RZ was 2.19+/-0.33 v 2. 34+/-0.34 ml/g/min in CY1503 and controls at 30 min (P=0.75), and 0. 43+/-0.07 v 0.41+/-0.08 at 4 h of reperfusion (P=0.85). The corresponding results for protocol 2 were 1.77+/-0.29 v 1.53+/-0.34 at 30 min (P=0.61) and 0.53+/-0.16 v 0.91+/-0.55 at 4 h (P=0.53). RMBF in RZ in protocol 3 were 1.52+/-0.25 v 1.32+/-0.20 at 30 min (P=0.56) and 0.30+/-0.05 v 0.29+/-0.09 (P=0.90) after 4 h of reperfusion. The RZ was similar in both groups in all protocols. The NZ/RZ ratio was comparable in the CY1503 and control group in all three protocols (0.32+/-0.04 v 0.37+/-0.06, 0.37+/-0.08 v 0.33+/-0. 07, and 0.51+/-0.05 v 0.38+/-0.05 in protocols 1, 2, and 3, respectively). CY1503 did not limit infarct size or prevent the "no-reflow" phenomenon in the rabbit.     

Assessment of blood flow distal to coronary artery stenoses. Correlations between myocardial positron emission tomography and poststenotic intracoronary Doppler flow reserve

BACKGROUND: Previous studies have correlated quantitative coronary angiographic stenosis severity with positron emission tomography (PET) myocardial perfusion and proximal measurements of intracoronary flow velocities in normal and diseased coronary arteries. The aim of this study was to correlate regional myocardial blood flow (RMBF) derived from [15O]H2O PET with directly measured poststenotic intracoronary Doppler flow velocity data acquired under basal conditions and dipyridamole-induced hyperemia. METHODS AND RESULTS: Eleven consecutive patients 53 +/- 13 years old with ischemic chest pain and isolated proximal left coronary artery stenoses (left anterior descending, 9; left circumflex, 2; mean, 59 +/- 23% diameter stenosis) underwent [15O]H2O myocardial PET and intracoronary Doppler flow velocity studies within 1 week. PET RMBF (mL.g-1.min-1) and myocardial perfusion reserve (MPR) were calculated in poststenotic and normal reference vascular beds. Poststenotic Doppler average peak flow velocities (APV; cm/s) and coronary flow velocity reserve (CFR) were compared with corresponding PET data and quantitative angiographic lesional parameters. PET RMBF and Doppler APV were linearly correlated (r = .60; P < .001), as were poststenotic PET MPR and Doppler CFR (r = .76; P < .0002). Relative coronary flow velocity and MPR ratios between poststenotic and angiographically normal vascular beds were comparably reduced (0.83 +/- 0.25 versus 0.86 +/- 0.21, respectively; P = NS). CONCLUSIONS: Intracoronary Doppler flow velocities acquired distal to isolated left coronary artery stenoses correlated with [15O]H2O PET regional myocardial perfusion and are useful for assessment of the physiological significance of coronary stenoses in humans.     

Myocardial viability. The concept of myocardial viability

MYOCARDIAL VIABILITY: Certain zones of ischemic, akinetic or severely hypokinetic myocardium are capable of recovering normal contractile function. This is termed myocardial viability and occurs in two different situations: myocardial stunning and myocardial hibernation. MYOCARDIAL STUNNING: This term designates temporary but prolonged impairment of myocardial function resulting from a brief episode of ischemia before reperfusion. MYOCARDIAL HIBERNATION: Hibernation designates prolonged but potentially reversible myocardial contractile dysfunction caused by chronic myocardial ischemia and persisting at least until blood flow is restored. CLINICAL CONSEQUENCES: Theoretically reversible, myocardial stunning or hibernation can have devastating effects if they persist too long. Revascularization with angioplasty or bypass surgery is indicated. DIAGNOSIS: The degree of myocardial viability in akinetic zones can be determined by assessing preserved inotropic capacity with stress echocardiography and/or evidencing metabolic activity with isotopic techniques (myocardial scintigraphy, positron emission tomography).     

Hibernating myocardium

Decreased myocardial contraction occurs as a consequence of a reduction in blood flow. The concept of hibernation implies a downregulation of contractile function as an adaptation to a reduction in myocardial blood flow that serves to maintain myocardial integrity and viability during persistent ischemia. Unequivocal evidence for this concept exists in scenarios of myocardial ischemia that lasts for several hours, and sustained perfusion-contraction matching, recovery of energy and substrate metabolism, the potential for recruitment of inotropic reserve at the expense of metabolic recovery, and lack of necrosis are established criteria of short-term hibernation. The mechanisms of short-term hibernation, apart from reduced calcium responsiveness, are not clear at present. Experimental studies with chronic coronary stenosis lasting more than several hours have failed to continuously monitor flow and function. Nevertheless, a number of studies in chronic animal models and patients have demonstrated regional myocardial dysfunction at reduced resting blood flow that recovered upon reperfusion, consistent with chronic hibernation. Further studies are required to distinguish chronic hibernation from cumulative stunning. With a better understanding of the mechanisms underlying short-term hibernation, it is hoped that these adaptive responses can be recruited and reinforced to minimize the consequences of acute myocardial ischemia and delay impending infarction. Patients with chronic hibernation must be identified and undergo adequate reperfusion therapy.     

Chemical, physical, and sensory characteristics of mozzarella cheese fortified using protein-chelated iron or ferric chloride

OBJECTIVE: Short-term myocardial hibernation is characterized by an adaptation of contractile function to the reduced blood flow, the recovery of creatine phosphate content and lactate balance back towards normal, whereas ATP content remains reduced at a constant level. We examined the hypothesis that, despite the absence of ATP recovery, the short-term hibernating myocardium regains an energetic balance. METHODS: An enzymatic method was modified for the measurement of inorganic phosphate (Pi) in transmural myocardial drill biopsies (about 5 mg). In 12 anaesthetized swine, moderate ischemia was induced by reduction of coronary inflow into the cannulated left anterior descending coronary artery to decrease regional myocardial function (sonomicrometry) by 50%. RESULTS: The development of short-term hibernation was verified by the recovery of creatine phosphate content, the persistence of inotropic reserve in response to dobutamine and the absence of necrosis (triphenyl tetrazolium chloride). At 5-min ischemia, Pi was increased from 3.6 +/- 0.3 (SD) to 8.1 +/- 1.1 mumol/gwet wt (p < 0.05). The free energy of ATP hydrolysis (delta GATP) was decreased from -57.8 +/- 0.8 to -52.2 +/- 1.4 kJ/mol (p < 0.05). The relationships between function and Pi (r = -0.81) and delta GATP (r = -0.83), respectively, during control and at 5-min ischemia became invalid at 90-min ischemia, as myocardial blood flow and function remained reduced at a constant level, but Pi decreased back to 4.9 +/- 0.9 mumol/g (p < 0.05 vs. control and 5-min ischemia), and delta GATP fully recovered back to -57.2 +/- 1.3 kJ/mol (p < 0.05 vs. 5-min ischemia). CONCLUSIONS: In short-term hibernating myocardium, myocardial inorganic phosphate content recovers partially and the free energy change of ATP hydrolysis returns to control values. Contractile function remains reduced by mechanisms other than an energetic deficit.     

Myocardial protection after monophosphoryl lipid A: studies of delayed anti-ischaemic properties in rabbit heart

1. Monophosphoryl lipid A (MLA) is a non-pyrogenic derivative of Salmonella lipopolysaccharide. Administration of this agent at high doses to rats and at low doses to dogs was previously shown to confer marked protection against ischaemia-reperfusion 24 h later, although the cellular mechanisms of this delayed protection are obscure. We hypothesized that MLA pretreatment causes the induction of the 70 kDa cytoprotective stress protein HSP70i in the myocardium. If this were the case, protection against ischaemia-reperfusion injury would be observed both in vitro and in vivo. 2. Rabbits were pretreated with MLA 0.035 mg kg-1, i.v. or vehicle solution. For the in vitro study, hearts were isolated 24 h later and Langendorff-perfused with Krebs-Henseleit buffer at 37 degrees C. Global ischaemia was induced for 20 min followed by 120 min reperfusion. Recovery of post-ischaemic left ventricular function and lactate dehydrogenase efflux was similar in MLA and vehicle pretreated hearts and there was no significant difference in the percentage of infarction of the left ventricle determined by triphenyltetrazolium staining (MLA 22.4 +/- 5.2%, vehicle 24.8 +/- 5.1%). 3. When 30 min regional ischaemia and 120 min reperfusion was instituted in pentobarbitone-anaesthetized rabbits 24 h after pretreatment with MLA or vehicle, the percentage infarction within the risk zone was reduced from 42.6 +/- 5.7% in vehicle pretreated animals to 19.6 +/- 4.4% in MLA pretreated animals (P < 0.01). 4. Determination of myocardial HSP70i content by Western blot analysis showed that MLA treatment did not increase HSP70i immunoreactivity. 5. We conclude that MLA at this dose confers protection only against ischaemia-reperfusion injury in vivo and that this protection is not related to induction of HSP70i. Because protection was observed only in vivo it seems possible that the delayed protection conferred by MLA is mediated by effects on humoral or blood-borne factors.     

Effect of nitrovasodilators and inhibitors of nitric oxide synthase on ischaemic and reperfusion function of rat isolated hearts

1. The functional role of the nitric oxide (NO)/guanosine 3':5'-cyclic monophosphate (cyclic GMP) pathway in experimental myocardial ischaemia and reperfusion was studied in rat isolated hearts. 2. Rat isolated hearts were perfused at constant pressure with Krebs-Henseleit buffer for 25 min (baseline), then made ischaemic by reducing coronary flow to 0.2 ml min(-1) for 25 or 40 min, and reperfused at constant pressure for 25 min. Drugs inhibiting or stimulating the NO/cyclic GMP pathway were infused during the ischaemic phase only. Ischaemic contracture, myocardial cyclic GMP and cyclic AMP levels during ischaemia, and recovery of reperfusion mechanical function were monitored. 3. At baseline, heart rate was 287+/-12 beats min(-1), coronary flow was 12.8+/-0.6 ml min(-1), left ventricular developed pressure (LVDevP) was 105+/-4 mmHg and left ventricular end-diastolic pressure 4.6+/-0.2 mmHg in vehicle-treated hearts (control; n=12). Baseline values were similar in all treatment groups (P>0.05). 4. In normoxic perfused hearts, 1 microM N(G)-nitro-L-arginine (L-NOARG) significantly reduced coronary flow from 13.5+/-0.2 to 12.1+/-0.1 ml min(-1) (10%) and LVDevP from 97+/-1 to 92+/-1 mmHg (5%; P<0.05, n=5). 5. Ischaemic contracture was 46+/-2 mmHg, i.e. 44% of LVDevP in control hearts (n=12), unaffected by low concentrations of nitroprusside (1 and 10 microM) but reduced to approximately 30 mmHg (approximately 25%) at higher concentrations (100 or 1000 microM; P<0.05 vs control, n=6). Conversely, the NO synthase inhibitor L-NOARG reduced contracture at 1 microM to 26+/-3 mmHg (23%), but increased it to 63+/-4 mmHg (59%) at 1000 microM (n=6). Dobutamine (10 microM) exacerbated ischaemic contracture (81+/-3 mmHg; n = 7) and the cyclic GMP analogue Sp-8-(4-p-chlorophenylthio)-3',5'-monophosphorothioate (Sp-8-pCPT-cGMPS; 10 microM) blocked this effect (63+/-11 mmHg; P<0.05 vs dobutamine alone, n=5). 6. At the end of reperfusion, LVDevP was 58+/-5 mmHg, i.e. 55% of pre-ischaemic value in control hearts, significantly increased to approximately 80% by high concentrations of nitroprusside (100 or 1000 microM) or L-NOARG at 1 microM, while a high concentration of L-NOARG (1000 microM) reduced LVDevP to approximately 35% (P<0.05 vs control; n=6). 7. Ischaemia increased tissue cyclic GMP levels 1.8 fold in control hearts (P<0.05; n=12); nitroprusside at 1 microM had no sustained effect, but increased cyclic GMP approximately 6 fold at 1000 microM; L-NOARG (1 or 1000 microM) was without effect (n=6). Nitroprusside (1 or 1000 microM) marginally increased cyclic AMP levels whereas NO synthase inhibitors had no effect (n=6). 8. In conclusion, the cardioprotective effect of NO donors, but not of low concentrations of NO synthase inhibitors may be due to their ability to elevate cyclic GMP levels. Because myocardial cyclic GMP levels were not affected by low concentrations of NO synthase inhibitors, their beneficial effect on ischaemic and reperfusion function is probably not accompanied by reduced formation of NO and peroxynitrite in this model.     

Effects of dobutamine stress on myocardial blood flow, 99mTc sestamibi uptake, and systolic wall thickening in the presence of coronary artery stenoses: implications for dobutamine stress testing

BACKGROUND: Although dobutamine stress is used with both 99mTc sestamibi (sestamibi) myocardial perfusion imaging and echocardiography for detecting coronary artery stenoses, the impact of stenosis severity on test end points (myocardial sestamibi uptake and systolic thickening, respectively) has not been clearly defined. METHODS AND RESULTS: In 15 open-chest dogs, dobutamine (2.5 to 30 microg x kg(-1) x min(-1)) was infused after placement of an LAD stenosis that reduced (n=8) or abolished (n=7) flow reserve. In dogs with reduced flow reserve, the stenotic-to-normal sestamibi activity ratio (0.86+/-0.03) significantly underestimated the approximately 2-to-1 dobutamine-induced flow disparity at the time of sestamibi injection (flow ratio, 0.53+/-0.04; P<.001). Stenotic-zone thickening increased at low but not at higher doses of dobutamine (2.9+/-0.4 versus 4.2+/-0.4 mm in normal zone at peak dobutamine; P=.055) but did not fall below baseline (2.7+/-0.3 mm). Similarly, in dogs with absent flow reserve, the sestamibi activity ratio (0.78+/-0.02) underestimated the approximately 2.5-to-1 dobutamine-induced flow disparity (flow ratio, 0.41+/-0.05; P<.001), and failure to increase systolic thickening was observed in the stenotic zone (2.7+/-0.4 versus 4.6+/-0.3 mm in the normal zone at peak stress, P<.01). In both groups of dogs, myocardial sestamibi uptake and image defect magnitudes were less than expected for the dobutamine-induced hyperemia, suggesting that dobutamine adversely affects myocardial sestamibi binding. Finally, a significant reduction in stenotic-zone thickening was seen during postdobutamine recovery, consistent with myocardial stunning. CONCLUSIONS: In the presence of stenoses that reduced or abolished regional flow reserve, (1) myocardial sestamibi uptake significantly underestimated the dobutamine-induced flow heterogeneity, (2) a "failure to increase systolic thickening" rather than a reduction in thickening was observed during dobutamine stress, and (3) myocardial stunning was observed during postdobutamine recovery.     

Preconditioning enhances myocardial resistance to postischaemic myocardial stunning via adenosine receptor activation

OBJECTIVE: The aim was to test a hypothesis that ischaemic preconditioning attenuates myocardial stunning via adenosine receptor activation. METHODS: Myocardial stunning was induced in male rabbits by a transient 5 or 10 min coronary artery occlusion, and alteration of regional systolic thickening fraction (TF) was measured by using an epicardial Doppler sensor before and after the regional ischaemia. Rabbits were either untreated, preconditioned with 1 min ischaemia, given 8-phenyltheophylline (8-PT, 10 mg.kg-1 intravenously), or given 8-PT plus 1 min ischaemic preconditioning. Preconditioning and 8-PT were given 5 min and 20 min before stunning the heart, respectively. RESULTS: Postischaemic recovery of the thickening fraction was significantly improved by preconditioning with 1 min ischaemia. TF (% baseline) after 10 min ischaemia/30 min reperfusion was 84.3(SEM 5.0)% in the preconditioned group, which was significantly higher than the value of 51.3(8.1)% in the control rabbits. Treatment with 8-PT alone did not significantly alter the recovery of TF from 10 min ischaemia [TF = 45.0(7.4)%,], but 8-PT treatment completely abolished the effect of 1 min preconditioning [TF = 51.3(6.4)%]. Attenuation of myocardial stunning by 1 min preconditioning was also observed when the stunning was induced by 5 min ischaemia [92.2(1.3)% in preconditioned group v 75.9(3.2)% in controls]. CONCLUSIONS: These findings suggest that preconditioning protects the myocardium against stunning through activation of the adenosine receptors.     

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INTRODUCTION: In vitro studies have suggested that human atrial natriuretic peptide (ANP) modulates the electrophysiologic properties of myocardial cells. This study assessed whether ANP could influence defibrillation efficacy. METHODS AND RESULTS: In 35 anesthetized dogs, the transcardiac defibrillation threshold (DFT) as well as hemodynamic and electrophysiologic variables were determined before and during treatment with ANP (n = 11), hydralazine (n = 11), or saline (n = 13). ANP (1.5 microg/kg + 0.2 microg/kg per min) increased the plasma concentration of cyclic GMP (a second messenger for ANP) and significantly decreased aortic blood pressure (mean 100+/-11 mmHg to 83+/-15 mmHg). ANP also prolonged ventricular repolarization (effective refractory period 157+/-7 msec to 165+/-11 msec) and markedly reduced DFT (5.4+/-1.2 J to 3.8+/-0.7 J [P < 0.01]) without changing pulmonary artery pressure or sinus cycle length. Neither saline nor hydralazine (1.5 mg/kg) had a significant effect on DFT (saline 4.7+/-2.1 J to 4.6+/-2.4 J; hydralazine 4.3+/-2.0 J to 4.2+/-1.9 J), although hydralazine caused pronounced hypotension (mean aortic pressure 103+/-9 mmHg to 74+/-13 mmHg). CONCLUSION: These results suggest that ANP increases defibrillation efficacy, and that this effect is not necessarily shared by other vasodilating agents.     

The neuroprotective effect of the glycine site antagonist 3R-(+)-cis-4-methyl-HA966 (L-687,414) in a rat model of focal ischaemia

BACKGROUND: Cardiovascular conditioning reduces resting myocardial oxygen demand by lowering systolic blood pressure and heart rate. Lower myocardial oxygen demand at rest would be expected to be associated with a decrease in resting myocardial blood flow and, consequently, an increase in myocardial flow reserve as the ratio of hyperemic to resting blood flow. However, the effect of controlled exercise together with a low-lipid diet on myocardial blood flow and flow reserve has not been examined in humans. METHODS AND RESULTS: Myocardial blood flow at rest and after dipyridamole-induced hyperemia (0.56 mg/kg i.v.) was quantified with [13N]ammonia and positron emission tomography in 13 volunteers before and upon completion of a 6-week program of cardiovascular conditioning and a low-fat diet. Exercise capacity and serum lipid profiles were also assessed at the start and finish of the program. Eight normal volunteers of similar age not participating in the conditioning program served as a control group. Cardiovascular conditioning lowered the resting rate-pressure product (8859 +/- 2128 versus 7450 +/- 1496, P < .001), serum cholesterol (217 +/- 36 versus 181 +/- 26 mg/dL), LDL cholesterol (140 +/- 32 versus 114 +/- 24 mg/dL), and triglycerides (145 +/- 53 versus 116 +/- 33 mg/dL, all P < .05). Exercise tolerance (metabolic equivalent of the task, METs) improved significantly from 10.0 +/- 3.0 to 14.4 +/- 3.6 (P < .01). Resting blood flow decreased (0.78 +/- 0.18 versus 0.69 +/- 0.14 mL.g-1.min-1, P < .05), whereas hyperemic blood flow increased (2.06 +/- 0.35 versus 2.25 +/- 0.40 mL.g-1.min-1, P < .05), resulting in an improved myocardial flow reserve (2.82 +/- 1.07 versus 3.39 +/- 0.91, P < .05). Overall, the myocardial flow reserve was significantly related to exercise performance (METs). In the control group, no changes in resting rate-pressure product, serum cholesterol levels, exercise performance, resting or hyperemic myocardial blood flow, or flow reserve were observed. CONCLUSIONS: Short-term cardiovascular conditioning together with a low-fat diet results in an improved myocardial flow reserve by lowering resting blood flow and increasing coronary vasodilatory capacity. These changes are associated with an improved exercise capacity and may offer a protective effect in patients with coronary artery disease.     

Isometric and dynamic contractile properties of porcine skinned cardiac myocytes after stunning

The purpose of this study was to investigate myofibrillar mechanisms of depressed contractile function associated with myocardial stunning. We first tested whether the degree of stunning was directly related to changes in myofilament Ca2+ sensitivity. Variable degrees and durations of low-flow ischemia were followed by 30 minutes of reperfusion in an open-chest porcine model of regional myocardial stunning (n = 27). Ca2+ sensitivity of isometric tension was measured in skinned myocytes obtained from endocardial biopsies taken during control aerobic flow and after 30 minutes of reperfusion. The degree of stunning, as assessed by percent systolic wall thickening, ranged from -3% to 75% of control but did not correlate (r = .11) with changes in pCa50, ie, pCa for half-maximal tension. Only in the group (n = 10) with the most severe level of ischemia was there a significant decrease in pCa50 (from 5.97 +/- 0.06 in the control condition to 5.86 +/- 0.07 after ischemia, P < .05). Less severe levels of ischemia (n = 17) resulted in significant stunning (percent systolic wall thickening, 38 +/- 4% of control) but no change in pCa50. To investigate the possibility that alterations in myofibrillar cross-bridge kinetics contribute to depressed function in stunning, maximum velocity of shortening (Vo) was measured in postischemic myocytes. Vo in postischemic myocytes was reduced to 56 +/- 4% of Vo in control myocytes and was independent both of the degree of stunning (r = .26) and changes in Ca2+ sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term antihypertensive therapy with isradipine. Improvement of coronary flow reserve in patients with arterial hypertension and microvascular angina

Antihypertensive Long-term Therapy with Isradipine/Improvement of coronary flow reserve in patients with arterial and microvascular angina In patients with arterial hypertension coronary flow reserve is often impaired due to left ventricular (LV) hypertrophy and alterations of the coronary microcirculation. Experimental and clinical studies have shown that calcium channel blockers can induce regression of myocardial hypertrophy. Objective of the present study was to see whether chronic antihypertensive treatment with calcium channel blockers can improve the diminished coronary reserve in patients with arterial hypertension and microvascular angina pectoris. Fifteen hypertensive patients with microvascular angina (61 +/- 7 years, normal coronary angiogram, mild LV-hypertrophy) were treated with isradipine (CAS 75695-93-1) (5.3 +/- 0.9 mg/d) for 12 +/- 2 months. Before and after therapy (after a washout period of 1 week) coronary flow was quantitatively measured by the gas chromatographic Argon method. Coronary reserve was calculated as the quotient of coronary resistance under baseline conditions and after dipyridamole (0.5 mg/kg i.v.). Under isradipine therapy systolic blood pressure was lowered from 165 +/- 20 to 140 +/- 13 mmHg (p < 0.01) and diastolic blood pressure from 98 +/- 8 to 88 +/- 6 mmHg (p < 0.01). The LV muscle mass index decreased by 10% from 154 +/- 33 to 139 +/- 28 g/m2 (p < 0.05). Baseline coronary blood flow (81 +/- 13 versus 83 +/- 16 ml/min x 100 g, n.s.) was identical before and after therapy. There were also no differences in coronary perfusion pressure, heart rate, myocardial oxygen consumption and arterio-coronary venous oxygen difference before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular basis of type III hyperlipoproteinemia in Germany

1. The aim of the present investigation was to evaluate the effect of cloricromene on myocardial infarct size, regional myocardial blood flow and neutrophil accumulation in a canine model of ischaemia-reperfusion. 2. Dogs were instrumented to measure blood pressure, left anterior descending (LAD) coronary flow (flow probe) and regional myocardial blood flow (coloured microspheres). Two groups were studied: (i) CLO (n = 8) received an infusion of cloricromene (15 micrograms/kg per min); and (ii) VEH (n = 8) received saline. Infusions began at the onset of ischaemia (60 min) and continued through reperfusion (180 min). 3. Haemodynamic responses were not different between groups. Cloricromene reduced the area of necrosis expressed as a percentage of the area at risk from 35 +/- 3% in the VEH group to 23 +/- 4% in the CLO group (P < 0.05). Regional myocardial blood flow in the ischaemic region was different between groups; VEH dogs showed an early reperfusion hyperaemia followed by a progressive reduction in flow, while CLO dogs exhibited a gradual increase in reflow in the absence of an early hyperaemic response (P < 0.05). Left anterior descending flow was enhanced during the reperfusion period in the CLO group compared with VEH (P < 0.05). Cloricromene reduced polymorphonuclear neutrophil (PMN) infiltration (myeloperuxidase activity) in all myocardial regions when compared with VEH (non-ischaemic zone, 0.34 +/- 0.54 vs 0.05 +/- 0.01 IU/100 mg; ischaemic zone, 2.03 +/- 0.80 vs 0.24 +/- 0.08 IU/100 mg; and necrotic zone, 0.56 +/- 0.04 vs 3.59 +/- 1.09 IU/100 mg for VEH vs CLO groups, respectively; P < 0.01). In a separate in vitro preparation, cloricromene reduced adherence of platelet-activating factor (PAF)-stimulated PMN to canine coronary endothelium. Stimulation of PMN by 100 nmol/L PAF resulted in adherence of 176 +/- 36 compared with 48 +/- 12 cells/mm2 in PAF-stimulated PMN treated with 100 mumol cloricromene (P < 0.001). 4. These data indicate that cloricromene reduces myocardial infarct size in a canine model of ischaemia-reperfusion injury. Postischaemic blood flow patterns are significantly different in cloricromene-treated dogs. Cloricromene-mediated reductions in infarct size, neutrophil accumulation and adherence may play a role in this effect.     

Coronary surgery on the beating heart under extracorporeal circulation in high-risk patients. An acceptable compromise?

Coronary artery surgery with cardioplegia in high risk patients carries a risk of myocardial ischaemia and, without cardiopulmonary bypass, is not always technically feasible. The authors assessed an alternative, surgery on the beating heart with haemodynamic assist by cardiopulmonary bypass in 43 consecutive patients with poor left ventricular function (mean ejection fraction: 0.26), evolving myocardial ischaemia or acute myocardial infarction, old age (mean: 79.5 years) and comorbid conditions. Results were assessed mainly on clinical criteria. In addition, 9 patients had pre- and post-cardiopulmonary bypass measurements of markers of myocardial ischaemia (troponine Ic) and systemic inflammation (interleukines 6 and 10, elastase). In 6 cases, right atrial biopsy was analysed for expression of messenger ribonucleic acid coding for heat shock protein (HSP) 70; the data were compared with those of patients operated under warm blood cardioplegia. There was one cardiac death and one myocardial infarction. Myocardial conservation was confirmed by the minimal increase in troponine Ic levels and the significant increase in HSP 70 in RNA suggesting myocardial adaptation to stress. On the other hand, the minimal concentrations of mediators of inflammation were not significantly changed. In selected high risk patients, coronary revascularisation on the beating heart under cardiopulmonary bypass could be a valuable alternative. It conserves the potentially deleterious effects of cardiopulmonary bypass but peroperative global myocardial ischaemia, an important factor in the aggressivity of cardiac surgery, is eliminated.