On the distribution of myocardial flow. Part II: Effects of arterial stenosis and vasodilation.
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Animals↗
Biomedical subjects
W Flameng
Publications and source records attributed to W Flameng.
Cardiac function in the chronically volume-overloaded canine heart.
In the chronically volume-overloaded canine heart due to AV-block evaluations of cardiac function were performed during the development of hypertrophy and at stable hypertrophy. In an early stage (1 and 2 weeks of AV-block) when no or only a slight increase of cardiac muscle occurred, contractility measured from dP/dtmax at comparable load is elevated, while later (10 weeks of AV-block) when stable hypertrophy is present, contractility becomes again normal, In the hypertrophied heart a non-depressed cardiac performance and contractility and functional reserve was established from insitu experiments and from evaluations in the isolated heart.
Animals↗
Influence of tachycardia on regional myocardial flow in chronic experimental coronary occlusion.
The influences of tachycardia on regional myocardial flow was studied in normal dogs and in dogs with chronic coronary artery occlusions. Coronary vasodilation was induced by coronary occlusion and subsequent release, i.e. by reactive hyperemia. Local myocardial blood flow was determined with the tracer microspheres technique. In normal hearts atrial pacing produced a slight but significant increase in coronary resistance in the subendocardial layers of the left ventricle. The coronary resistance of the subepicardium remained unaffected. In the right ventricle atrial pacing had no influence on the resistance to flow. In hearts with multiple coronary occlusions tachycardia-induced changes of coronary resistance were more pronounced. In the collateral dependent subendocardium coronary resistance increased from 0.4-2.2 resistance units when the heart rate was raised to 200 beats/min. Perfusion of the right ventricular myocardium became also rate-dependent when the right coronary artery was chronically occluded. We conclude that regional perfusion dependes upon the relationship between the effective perfusion pressure, which is reduced in chronic coronary occlusion, and the integral of effective tissue pressure, which is increased with tachycardia. The results cannot be explained by assuming excessive O2-demand but rather by a rate-induced lowered O2-supply.
Animals↗
Prevention of the "no reflow" phenomenon in the canine heart by mioflazine.
The effects of oral pretreatment with mioflazine (2.5 mg X kg-1) on regional myocardial reflow, infarct size reduction and hemodynamic recovery were studied in 24 anesthetized open-chest dogs undergoing 90 minutes of acute left anterior descending coronary artery (LAD) occlusion followed by 150 minutes of reperfusion. Regional myocardial blood flow was measured with tracer microspheres, and infarct size was determined by triphenyl tetrazolium chloride staining. Pretreatment with mioflazine resulted in a reduced diastolic aortic pressure (p less than 0.05) and an elevated cardiac output and LV dpdt max (p less than 0.05). These effects persisted throughout the experiment. In control animals (n = 12) a hyperemic reflow response was found in the perfusion area of the LAD during the first minutes of reperfusion. After 150 min of reperfusion, however, the viable myocardium of the LAD area became underperfused, and almost no reflow was found in the infarcted zones. In the animals pretreated with mioflazine (n = 12) the hyperemic response persisted throughout the reperfusion phase and the no-reflow phenomenon was prevented. Infarct size (expressed as percentage of perfusion area) tended to be smaller in this group: 23.7 +/- 12.4% versus 33.7 +/- 19.2% (p greater than 0.05). Left atrial pressure increased during LAD occlusion in both groups but normalized completely in the drug-pretreated animals (p less than 0.05). It is concluded that pretreatment with mioflazine prevents the no-reflow phenomenon after reperfusion of an evolving infarction, tends to reduce infarct size and improves hemodynamic recovery.
Animals↗
Tolerance to ischemia of hypertrophied human hearts during valve replacement.
This study evaluates the tolerance to ischemia during induced cardiac arrest in patients undergoing aortic valve replacement. In all patients cardiac standstill was of 45 minutes duration. Biopsies for electron microscopic study were taken from the left ventricle before induction of arrest, at the end of the ischemic period and 20 minutes after coronary perfusion had been reestablished. Structural ischemic damage was more pronounced in patients with severe hypertrophy and structural reconstitution was delayed. Degenerative changes of the myocardial cells, although observed frequency, apparently did not influence the tolerance to ischemia. It is concluded from this study that patients with severe hypertrophy represent a high-risk group in cardiac surgery because of their reduced tolerance to induced myocardial ischemia during cardiopulmonary bypass.
Adult↗
Functional significance of coronary collaterals in man.
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Blood Pressure↗
The ultrastructure of sarcomeres in hypertrophied canine myocardium in spontaneous subaortic stenosis.
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Animals↗
Determinants of infarct size in non-human primates.
To achieve a better understanding of the major factors that determine infarct size in non-human primates, a mathematical model was constructed using stepwise regression analysis. The model was developed on the basis of infarct size measurements, including the anatomical area at risk, regional myocardial blood flow measurements and hemodynamic determinants obtained in 23 control baboons undergoing up to 2 h of coronary artery thrombosis followed by thrombolysis. In this model, the size of the perfusion bed of the occluded coronary artery and the duration of coronary artery occlusion were found to be the only important predictors of infarct size (expressed as a percentage of left ventricular mass). R2 (square or the multiple correlation coefficient) was 70% in this model. Collateral blood flow and rate-pressure product were not identified as important predictors of infarct size. In a second group of eight baboons, atenolol (0.1 mg.kg-1) was administered intravenously 15 min after the onset of coronary artery thrombosis. Predicted infarct size (based on the mathematical model obtained in the control group) was larger than the observed infarct size in seven out of eight cases. In four instances observed infarct size was smaller than the 95% lower limit of the predicted value. It is concluded that the determinants of infarct size in non-human primates differ from those in canine models with respect to collateral flow and estimates of myocardial oxygen consumption (rate pressure product). The developed mathematical model of infarct size prediction allows the detection of cardioprotective drug effects with an acceptable efficacy.
Animals↗
A comparison of two methods for estimating the area at risk in experimental myocardial infarction.
In a canine model of coronary artery occlusion and reperfusion, we assessed the amount of myocardium at risk for necrosis using both post-mortem perfusion staining with triphenyltetrazolium-chloride (TTC) and autoradiography following in vivo injection of 141Ce microspheres. Twenty-four transverse slices of 5 dog hearts were analyzed. In the same heart slice planimetry was performed both on the calibrated colour picture taken after TTC staining (A) and on the autoradiogram (B). The values for the area at risk, as determined by both methods, were very closely correlated and almost identical: A = 0.977 B + 31.4 mm2, r = 0.99, p less than 0.001. This is in contrast to an earlier report where a different autoradiographic technique was used. In short-term experimental models of coronary artery occlusion, autoradiography delineates an area at risk, matching very closely the area at risk obtained after TTC staining.
Animals↗
Oral pretreatment with mioflazine completely changes the pattern and remarkably prolongs the accumulation of nucleosides in ischemic and reperfused myocardium.
In dog myocardium, the changes in the levels of creatine phosphate, inorganic phosphate, ATP, ADP, AMP, adenosine and inosine with 8 min of ischemia and subsequent reperfusion for 2, 4, 8, 16 and 32 min have been followed. Creatine phosphate and inorganic phosphate recovered completely within a few minutes as did the energy charge. However, total nucleotides remained depressed, the decrease being compensated for by the increase in inosine levels during ischemia. There was a rapid removal of the latter with reperfusion. Low oral doses of mioflazine (2.5 mg X kg-1), given 2.5 h before LAD occlusion, did not affect the pattern of changes seen in control animals, except for the nucleosides. The drug induced a complete reversal of the adenosine to inosine ratio during ischemia and a remarkable prolongation of the accumulation within the tissue of mainly adenosine during early reperfusion and inosine afterwards. Assuming that the main action of mioflazine is through inhibition of nucleoside transport, the present results provide interesting information about the mechanism of release, metabolism and final washout of adenosine.
Adenosine↗
Myocardial steal produced by coronary vasocilation in chronic coronary artery occlusion.
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Analysis of Variance↗
Normothermic ischemic cardiac arrest in the isolated working rabbit heart: effects of dl-nebivolol and atenolol.
The effect of pretreatment with selective beta 1-adrenoceptor blockers (dl-nebivolol or atenolol) on myocardial mechanical activity, mitochondrial function, morphology, and calcium cytochemistry was studied during normothermic ischemic arrest and reperfusion of isolated working rabbit hearts. The hearts subjected to 25 min of ischemia followed by 30 min of post-ischemic reperfusion showed typical signs of severe myocardial ischemic damage. The ultrastructural changes showed a good relation with the changes in mechanical activity and mitochondrial function. To determine whether these changes could be prevented or reduced by beta 1-adrenoceptor blockade, dl-nebivolol or atenolol (0.62 mg/liter) was added to the perfusate 30 min before the induction of ischemia. The results showed that dl-nebivolol exerted a protective effect on recovery of mechanical activity, on mitochondrial function during reperfusion as well as on the ultrastructure as examined at the end of the reperfusion period. On the other hand, atenolol failed to protect the myocardium against ischemia-reperfusion damage in the isolated working rabbit heart.
Adrenergic beta-Antagonists↗
Molecular and functional characterization of ovine cardiac valve-derived interstitial cells in primary isolates and cultures.
At present the involvement of cardiac valve interstitial cells (VICs) in growth, repair, and tissue engineering is understudied. Therefore, this study aims at characterizing ovine VICs in order to provide a solid base for tissue engineering of heart valves. Ovine ICs of the four heart valves were isolated by the explant outgrowth method and expanded in vitro up to passage 5. Vimentin and collagen I gene expression from freshly isolated or cultured ICs was measured by reverse transcriptase-polymerase chain reaction. Immunocytochemical stainings of vimentin, alpha-smooth muscle actin (ASMA), smooth muscle myosin, and procollagen I were performed on aortic VICs. In addition, migration and extracellular matrix deposition were studied in vitro in aortic VICs. ICs show stable vimentin and collagen I expression in culture. Expression is approximately doubled in cultured ICs compared with fresh isolates. More than 95% of ICs in each passage stain for vimentin and procollagen I. Freshly isolated ICs are ASMA and myosin negative, but ICs in culture partially stain for these contractile markers. ICs have stable matrix production for up to five passages, associated with stable migration of the cells. We conclude that ovine valve interstitial cells undergo phenotypic modulation to activated myofibroblasts under culture conditions but retain stable matrix production.
Animals↗
Pattern of AMP degradation in ischemic rabbit lung tissue.
Because adenine nucleotide catabolites may be important during postischemic lung reperfusion, we examined the pathway of adenosine monophosphate (AMP) degradation in ischemic lung tissue. Once the pattern of degradation is known, pharmacological interventions can be considered, offering new methods of reducing lung reperfusion injury. For this purpose we used the isolated rabbit lung. Rabbit lungs were flushed in situ with a modified Krebs Henseleit solution (60 ml/kg). The lungs were removed and stored deflated, immersed in saline solution at 37 degrees C. At regular times, biopsies were taken, and adenine nucleotides, nucleosides, and bases were measured in these biopsies using high performance liquid chromatography (HPLC). During lung ischemia, a very significant increase of inosine monophosphate (IMP) was found. Adenosine levels on the other hand did not increase. Hypoxanthine was the major end catabolite of ischemic lung tissue (constituting 92% of the nucleoside and purine base fraction at 4 hours ischemia). To further determine the pathway of AMP degradation, 400 mM of the adenosine deaminase inhibitor erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA) was added to the lung flush solution. During ischemia, adenosine triphosphate (ATP) breakdown was unaltered but adenosine became the major catabolite (2.8 times the concentration of hypoxanthine at 4 hours ischemia). These data suggest that: 1) in rabbit lung tissue, dephosphorylation of AMP to adenosine is more important than deamination to IMP; 2) hypoxanthine is the major end catabolite of ischemic lung tissue. By inhibiting the enzyme deaminase, reduced hypoxanthine levels and increased adenosine levels were obtained. Pharmacological interventions are now available to interfere with the formation of adenine nucleosides and bases in ischemic lung tissue. The importance of adenine nucleotide catabolites to postischemic lung reperfusion injury is discussed.
Adenine↗
Ischemic and reperfusive release of the endogenous purines and its influence on the myocardial viability during beta-adrenergic blockade.
The aim of this study was to estimate ischemic and reperfusive release of myocardial adenosine degradation products (MADP) during beta-adrenergic blockade and its relation to infarct size (IS) and viable myocardium size (VM). In a group of 24 shepherd-mongrel dogs, randomly assigned to a metoprolol (M-) and placebo-group (P-group), occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion with recombinant tissue plasminogen activator was performed. Regional myocardial blood flow (MBF) was measured by the radiolabelled microsphere technique. Blood samples from aorta and great cardiac vein were collected to evaluate the concentrations of MADP. The triphenyltetrazolium chloride perfusion and fixation technique was used for infarct size measurement. MBF in the area at risk decreased in both groups during ischemia, but it was significantly higher (p = 0.013) in M-group. Recanalization of LAD was associated with an increase in flow in postischemic vascular bed. MBF was significantly higher (p = 0.024) in P-group during late reperfusion. In M-group IS was smaller (p = 0.007) and VM was bigger (p = 0.007). The correlation between arterial adenosine concentration during early reperfusion and IS (p = 0.044, r = -0.588) or VM (p = 0.036, r = 0.607) in M-group was noted. Values of net MADP balances significantly increased during early reperfusion. The correlation between reperfusive net MADP balance and IS (p = 0.00005, r = 0.906) or VM (p = 0.016, r = -0.675) in M-group was observed. The amount of MADP released during reperfusion correlates with the IS and is inversely proportional to the area of VM. The endogenously released adenosine may have additional cardioprotective effect during beta-adrenergic blockade.
Adenosine↗
Tolerance to ischemia in the human heart.
The tolerance to ischemic cardiac arrest during open-heart surgery depends on the degree of hypertrophy and on the functional impairment of the heart. The angiographically determined muscle mass is a good indicator of the susceptibility of the myocardium to ischemic injury and of its ability to quickly restore myocardial structure upon reperfusion. Tissue from extremely hypertrophied hearts exhibited numerous degenerative alterations.
Adult↗
A new concept of long-term donor heart preservation: nucleoside transport inhibition.
Myocardial ischemia results in a breakdown of adenosine triphosphate (ATP), which is associated with an accumulation of its catabolites adenosine and inosine. Adenosine is a potent but ineffective cardioprotective agent because it is rapidly transported to the endothelium and irreversibly catabolized. With the use of specific nucleoside transport inhibition (NTI), however, endogenous adenosine may accumulate at its site of production, and its further breakdown and washout on reperfusion is prevented. In this study we tested this concept and assessed the effect of NTI drug administration on 24 hours' preservation of donor hearts for transplantation. Twelve dogs were randomly allocated to two groups. In the first group (group 1, n = 6) the hearts were arrested with a cold hyperkalemic cardioplegic solution, excised and stored for 24 hours at 0.5 degrees C. After 24 hours the hearts were transplanted orthotopically. In group 2 (n = 6) the same procedure was followed, but a specific NTI agent was added to the cardioplegic solution (1 mg/L) and administered intravenously to the recipient dog before reperfusion of the transplanted heart (0.1 mg/kg). Despite maximal positive inotropic support, none of the control animals (group 1) could be weaned from cardiopulmonary bypass: within 1 hour irreversible cardiogenic shock occurred in all animals. In group 2 all hearts could be weaned from cardiopulmonary bypass and were hemodynamically stable without positive inotropic support. Serial transmural left ventricular biopsies revealed in group 1 moderate catabolism of ATP during cold storage. On reperfusion a further decline of the ATP content was seen, and the accumulated nucleosides were washed out.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine↗
Catabolism of high energy phosphates during long-term cold storage of donor hearts: effects of extra- and intracellular fluid-type cardioplegic solutions and calcium channel blockers.
Dog hearts were harvested and stored cold (0.5 degree C) for 24-hours. Cardiac arrest was induced by means of low-sodium and calcium-free cardioplegic (n = 6) or hyperkalemic cardioplegic (n = 6) solution. Nifedipine (2 micrograms/gm estimated heart weight) was added to each cardioplegic solution in two additional groups (n = 6 each). High energy phosphates (creatine phosphate and adenosine triphosphate) and catabolites (adenosine diphosphate and monophosphate, adenosine, inosine, hypoxanthine, xanthine) were determined in the myocardium before and during 24 hours of cold storage. With use of the standard hyperkalemic cardioplegic solution, breakdown of high energy phosphates was less pronounced than after the use of a low sodium, calcium-free solution: after 24 hours of cold storage myocardial ATP content was 57% of control versus 32% (p less than 0.05). The addition of nifedipine to the hyperkalemic cardioplegic solution delayed ATP breakdown during the first hours of cold storage: at 5 hours of preservation the myocardial ATP level was significantly higher (p less than 0.05) than in hearts preserved without nifedipine. Addition of nifedipine to the low-sodium, calcium-free solution did not influence catabolism of high energy phosphates significantly. It is concluded that preservation of high energy phosphates during long-term cold storage of donor hearts can be best achieved by simultaneous myocardial metabolic blockade at two specific sites: at the "fast" sodium-potassium channels by hyperkalemic depolarization and at the "slow" channels by means of calcium channel blockers.
Adenosine Triphosphate↗