Towards a Canadian national cardiovascular database.
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Canada↗
Biomedical subjects
P M Olley
Publications and source records attributed to P M Olley.
CACH (Canadian Adult Congenital Heart): meeting an emerging need.
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Adult↗
The Canadian Cardiovascular Society and reference-based drug pricing.
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Canada↗
Evaluation of the Heart and Stroke Foundation of Canada Research Scholarship Program: research productivity and impact.
OBJECTIVE: To compare the research productivity, and its impact, of individuals awarded research scholarships from the Heart and Stroke Foundation of Canada (HSFC) with that of a parallel group of unsuccessful applicants during the funding years 1980/81 to 1989/90 inclusive. Research productivity was defined as the number of peer reviewed publications, and impact was evaluated from the number of publications cited; the number of citations per publication; the number of citations per individual; and the impact score. STUDY SELECTION: Data were collected on 192 individuals. Cohorts were defined as successful and unsuccessful individuals entering the system in the same year. The study comprised 10 separate cohorts. Data were collected on yearly publications and citation counts for each individual. These data, along with journal impact factors, were obtained from the Institute for Scientific Information. CONCLUSIONS: During the 10 years of the study, individuals funded by the HSFC published more papers, more of their papers were cited, and they received more citations per individual than the unfunded comparison group. This consistency in multiple indicators provides strong evidence that funded individuals are more productive and that their work has a greater impact on the body of knowledge in this area. Although this study cannot unequivocally show a direct causal relation between funding and research success, the trend as shown by the indicators studied suggests a beneficial effect.
Analysis of Variance↗
Pharmacokinetic-pharmacodynamic modelling for captopril in healthy anaesthetized piglets.
The use of the angiotensin converting enzyme inhibitor, captopril, specially in children, has been empirical. This is because the relationship between the pharmacokinetics and pharmacodynamics of captopril has not been clearly defined. It is not usually feasible to obtain the serial kinetic-dynamic data necessary to study this relationship in infants. The piglet was therefore investigated as an animal model in which to study the relationship between the kinetics and dynamics of captopril. The standard pharmacokinetic parameters for captopril in healthy anaesthetized piglets were found to be within the range reported for humans. ClTB was estimated to be 1.42 +/- 0.33 L h-1 kg(-1); t1/2 was 0.44 +/- 0.08 h; Vdss was calculated to be 0.64 +/- 0.13 L kg(-1); t1/2 and AUC0-infinity was estimated to be 145 +/- 27 ng h mL(-1). The observed haemodynamic response was qualitatively similar to that in humans. Aortic pressure was reduced by 42 +/- 18%; heart rate was reduced by 21 +/- 11%. A parametric pharmacokinetic (two-compartment)-pharmacodynamic (linear) model has been established to describe plasma captopril concentration and aortic pressure relationship. Based on the observed results, the piglet was considered to be a viable model for our purpose.
Angiotensin-Converting Enzyme Inhibitors↗
Synergism between prostaglandin E2 and isoproterenol in stimulating glucose oxidation in the heart.
The increase in cardiac contractile function following adrenergic stimulation is accompanied by increased glucose metabolism. Since prostaglandin E2 (PGE2) can internalize beta-receptors, we determined what effects PGE2 and isoproterenol have on glycolysis and glucose oxidation in the isolated working rat heart. All hearts were perfused with Krebs-Henseleit buffer containing 11 mM [5-3H, 14C(U)]glucose, 100 microU/mL insulin, and 3% albumin. In the presence of 0.4 mM palmitate and 1.25 mM free Ca2+, isoproterenol (3 x 10(-8) M) increased the heart rate x peak systolic pressure product from 27 +/- 1 to 43 +/- 1 mmHg.beats.min-1.10(3) (1 mmHg = 133.3 Pa). This was accompanied by an increase in glycolytic rates from 3564 +/- 231 to 7775 +/- 475 nmol.g-1 dry weight min-1 and an increase in glucose oxidation from 930 +/- 72 to 2591 +/- 239 nmol.g-1 dry weight.min-1. Addition of PGE2 (10(-9) M) did not affect the isoproterenol stimulation of glycolysis, but caused a further increase in glucose oxidation (to 3863 +/- 495 nmol.g-1 dry weight.min-1). In the absence of isoproterenol, 10(-9) M PGE2 had no effect on either glycolysis or glucose oxidation. When perfusate [Ca2+] was raised to 2.5 mM, a significant increase in glycolysis was seen in control hearts (from 3564 +/- 231 to 5679 +/- 374 nmol.g-1 dry weight.min-1). The effects of isoproterenol and PGE2 on glucose metabolism remained, although the synergistic effects of PGE2 on glucose oxidation were less dramatic. When 1.2 mM palmitate was present in hearts perfused with 2.5 mM Ca2+, a decrease was seen in both glycolysis (from 5679 +/- 374 to 3027 +/- 346 nmol.g-1 dry weight.min-1) and glucose oxidation (from 1056 +/- 170 to 221 +/- 29 nmol.g-1 dry weight.min-1). Even at this high concentration of fatty acid, isoproterenol stimulated glucose oxidation (from 221 +/- 29 to 859 +/- 69 nmol.g-1 dry weight min-1), and addition of PGE2 resulted in a significant further increase (1021 +/- 139 nmol.g-1 dry weight.min-1). These data demonstrate that concentrations of PGE2 that bind to the high affinity cardiac PGE2 receptor have no effect on glucose metabolism in the absence of beta-agonists. In the presence of isoproterenol, which dramatically stimulates both glycolysis and glucose oxidation, PGE2 has a synergistic effect on glucose oxidation at lower fatty acid concentrations. These findings suggest that PGE2 receptors in the heart function to potentiate rather than decrease beta-adrenergic stimulation of glucose metabolism.
Adrenergic beta-Antagonists↗
Basic research: a continuing imperative for clinical practice.
Basic biomedical research is essential to progress in prevention and treatment of disease and often results in massive economic benefits to society. Despite this, the financial and institutional bases that support basic scientists is under threat in our rapidly changing society. Polio vaccination is cited as an outstanding example of both an unexpected outcome of basic research and an enormous economic return to society on the original research investment. Interventional catheterization and the potential of successful gene therapy for cystic fibrosis are further examples of great potential economics benefits flowing from fundamental research. One great impediment to adequate investment in basic research is the lack of understanding of its nature. Canadian scientists need to be much more active in bridging the cultural gap between science and society and especially in educating national policy makers about the major economic benefits resulting from previous investments in basic biomedical research.
Canada↗
The role of nitric oxide in cardiac depression induced by interleukin-1 beta and tumour necrosis factor-alpha.
1. Myocardial dysfunction during septic shock is associated with enhanced production of cytokines such as interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha). These cytokines depress cardiac mechanical function by a mechanism which is not well defined. 2. Bacterial endotoxin or cytokines cause the expression of Ca(2+)-independent nitric oxide (NO) synthase in cardiac myocytes, vascular endothelial cells and endocardial endothelial cells, causing enhanced production of NO. As NO has negative inotropic actions on cardiac muscle, we tested the sum effects of IL-1 beta plus TNF-alpha in the intact heart to determine whether enhanced expression of NO synthase activity in the cells that comprise the heart is involved in cardiac depression associated with cytokine stimulation. 3. Rat isolated working hearts perfused with IL-1 beta plus TNF-alpha showed a markedly greater depression in contractile function, measured as cardiac work, after 2 h of perfusion compared with time-matched control hearts. The depressant action of IL-1 beta plus TNF-alpha was first apparent after 1 h of perfusion; no early (15 min) cardiac depressant actions were seen. 4. The competitive inhibitor of Ca(2+)-dependent and Ca(2+)-independent NO synthases, NG-nitro-L-arginine methyl ester (L-NAME, 3 microM) when given concurrently with IL-1 beta plus TNF-alpha prevented the loss in contractile function such that these hearts after 2 h of perfusion had similar function to time-matched controls. L-NAME did not acutely reverse the loss of contractile function in hearts exposed for 2 h to IL-1 beta plus TNF-alpha. The protective action of L-NAME in the presence of cytokines was concentration-dependent and was not seen at a higher concentration (10 micro M) due to the significant reduction in coronary flow observed at this concentration.5. In contrast, when L-NAME (3 micro M) was given in the absence of IL-l beta plus TNF-alpha it depressed contractile function over the 2 h perfusion period by significantly reducing coronary flow.6. Inhibition of protein synthesis with cycloheximide (Cx) abolished the loss in function that occurred over 2h in both control and IL-1 beta plus TNF-a-treated hearts.7. Inducible, Ca2+-independent NO synthase activity was not observed in freshly isolated hearts but was observed in control hearts perfused for 2 h in vitro and was doubled in hearts perfused with IL-1 beta plus TNF-a. Cx prevented the expression of Ca2+-independent NO synthase in both control and cytokine-treated hearts.8. In summary, these results suggest that the depression of myocardial function by IL-l beta plus TNF-alpha is mediated, at least in part, by induction of Ca2+-independent NO synthase activity in the heart.
Amino Acid Oxidoreductases↗
Plasma fatty acid levels in infants and adults after myocardial ischemia.
High levels of fatty acids are detrimental during reperfusion of ischemic hearts in part because of an inhibition of myocardial glucose use. We therefore measured plasma fatty acids during and after myocardial ischemia in both adult and pediatric patients. In adult patients undergoing thrombolytic therapy after an acute myocardial infarction, plasma fatty acids levels were elevated on admission to hospital (0.96 +/- 0.06 vs 0.40 +/- 0.01 mmol/L in healthy control subjects) and remained elevated throughout the initial 48 hours of hospitalization. In adult patients undergoing cardiac surgery, plasma fatty acids were markedly increased during surgery and at the time of the release of the aortic cross clamp (2.21 +/- 0.54 and 1.61 +/- 0.32 mmol/L, respectively). In children and infants (mean age 4.33 +/- 0.44 years) who had surgery to correct congenital heart defects, fatty acid levels during surgery increased to 3.27 +/- 0.26 mmol/L and remained elevated during immediate reperfusion (1.91 +/- 0.15 mmol/L) and for 24 hours after surgery (1.67 +/- 0.22 mmol/L). Because experimental studies have shown that high levels of fatty acids are detrimental to recovery of adult animal hearts, we determined the effect of high fatty acid levels on reperfusion recovery of isolated working hearts from 1-day-old rabbits perfused with 0.4 mmol/L palmitate (normal fat) or 1.2 mmol/L palmitate (high fat) and subjected to 50 minutes of global ischemia followed by aerobic reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Analysis of myocardial plasmalogen and diacyl phospholipids and their arachidonic acid content using high-performance liquid chromatography.
A high-performance liquid chromatographic method for the assay of diacyl and plasmalogen (alk-1-enyl) phospholipid content and the determination of their fatty acid content from tissue homogenates is described. Myocardial phospholipids are rich in plasmalogens and have a high content of unsaturated fatty acids, including arachidonic acid, esterified in the sn-2 position. Using a three-stage HPLC assay we have analyzed the phospholipid subclass content and the amount of arachidonic acid esterified to these fractions extracted from isolated perfused rat hearts. After HPLC separation of total myocardial phospholipids, the phosphatidylcholine and phosphatidylethanolamine peak fractions are treated with phospholipase C to remove polar head groups and ultraviolet-absorbing benzoate derivatives are made. Separation and quantification of diacyl and plasmalogen content of the total phospholipids with nanomolar sensitivity is then achieved using isocratic elution with a silicic acid HPLC column. The separated plasmalogen and diacyl glycerobenzoates are then subjected to alkaline hydrolysis to remove fatty acids from the sn-2 position. The 2-(2,3-napthalimino)ethyltrifluoromethanesulfonate esters of the free fatty acids are then prepared and analyzed with subnanomolar sensitivity using reverse-phase chromatography with gradient elution. As plasmalogen-specific phospholipase A2 is activated during myocardial ischemia and comprises the majority of total phospholipase A2 activity in the heart, this methodology allows for a sensitive and complete determination of the changes in the mass of these phospholipids and their arachidonic acid content.
Animals↗
Solubilization and purification of the prostaglandin E2 receptor from cardiac sarcolemma.
A prostaglandin E2 (PGE2) receptor was solubilized and isolated from cardiac sarcolemma membranes. Its binding characteristics are almost identical to those of the membrane bound receptor. [3H]PGE2 binding to solubilized and membrane bound receptor was sensitive to elevated temperature and no binding was observed in the absence of NaCl. No significant effects of DTT, ATP, Mg2+, Ca2+ or of changes in buffer pH were observed on [3H]PGE2 binding to either solubilized or membrane-bound receptor. Unlabelled PGE1 displaced over 90% of [3H]PGE2 from the CHAPS-solubilized receptor. PGD2, PGI2, PGF2 alpha and 6-keto-PGF1 alpha were not effective in displacing [3H]PGE2 from the receptor. Scatchard analysis of [3H]PGE2 binding to CHAPS-solubilized receptor revealed the presence of two types of PGE2 binding sites with Kd of 0.33 +/- 0.05 nM and 3.00 +/- 0.27 nM and Bmax of 0.5 +/- 0.04 and 2.0 +/- 0.1 pmol/mg of protein. The functional PGE2 receptor was isolated from CHAPS-solubilized SL membrane using two independent methods: first by a WGA-Sepharose chromatography and second by sucrose gradient density centrifugation. Receptor isolated by these two methods bound [3H]PGE2. Unlabelled PGE1 and PGE2 displaced [3H]PGE2 from the purified receptor. Scatchard analysis of [3H]PGE2 binding to purified receptor revealed the presence of the two binding sites as observed for the membrane bound and CHAPS-solubilized receptor. SDS-polyacrylamide gel electrophoresis of the purified receptor fractions revealed the presence of a protein band of M(r) of approx. 100,000. This 100-kDa was photolabelled with [3H]azido-PGE2, a photoactive derivative of PGE2. We propose that this 100-kDa protein is a cardiac PGE2 receptor.
Affinity Labels↗
[3H]iloprost and prostaglandin E2 compete for the same receptor site on cardiac sarcolemmal membranes.
We have previously demonstrated that high-affinity PGE receptors are present on purified cardiac sarcolemmal (SL) membrane from bovine heart (Lopaschuk et al. (1989) Circ. Res. 65, 538-545). In this study we determined whether PGI2 receptors are also present on the cardiac SL membrane. Due to the extreme lability of prostacyclin (PGI2) under physiological conditions, the PGI2 analogue, Iloprost was substituted for PGI2. 3H-Iloprost specifically bound to two sites on the SL membrane; one of high affinity (Kd = 0.3 nM, Bmax = 97.0 fmol/mg SL), and one of lower affinity (Kd = 20.6 nM, Bmax = 1589 fmol/mg SL). Competition studies demonstrated that the concentrations of PGE2 and PGE1 necessary to displace 50% of the specific binding of 20 nM [3H]Iloprost on cardiac SL were 15-fold lower than the concentrations of unlabelled Iloprost necessary to displace 50% of binding. In contrast, a 15-fold higher concentration of unlabelled Iloprost was needed to displaced 50% of specific binding of 2 nM [3H]PGE2 compared to the concentrations of PGE1 or PGE2 required to displace 50% of [3H]PGE2 binding. In summary, our results indicate that a prostacyclin receptor is present on the cardiac sarcolemmal membrane, and that PGI2 competes for the same receptor site as PGE2.
Animals↗
Circulatory effects of denopamine in newborn piglets.
Denopamine is an orally active beta 1 agonist whose cardiovascular action in the newborn is unknown. We evaluated its circulatory effects during normoxia in newborn piglets less than 7 days of age. The piglets were acutely instrumented under general anesthesia with an electromagnetic flow probe around the main pulmonary artery and catheters in the main pulmonary artery, aorta, left ventricle, and the right and left atria. A Millar high-fidelity catheter was used to measure left ventricular dp/dt. The ductus arteriosus was ligated. Denopamine was administered in the right atrium as a continuous infusion of 2, 4, and 8 micrograms/kg per min for 10 min each. Although cardiac index, heart rate and left ventricular dp/dt increased dose-dependently by 46.0 +/- 18.2%, 87.1 +/- 34.9% and 159.9 +/- 42.4%, respectively, stroke index was not significantly altered. Unlike pulmonary artery pressure (which increased dose-dependently), aortic pressure increased with 2 and 4 micrograms/kg per min denopamine, respectively, it fell with 8 micrograms/kg per min denopamine. Similarly, the systemic vascular resistance decreased with the high dose (8 micrograms/kg per min). There was no significant change in pulmonary vascular resistance. Denopamine is potently inotropic in the adult. However, its circulatory effect in the neonate is dependent on its chronotropic action. Furthermore, denopamine is a systemic vasodilator at high doses in the neonatal circulation.
Adrenergic beta-Agonists↗
Prostaglandin E2 receptors in the heart are coupled to inhibition of adenylyl cyclase via a pertussis toxin sensitive G protein.
In previous studies we have identified and isolated a prostaglandin E2 (PGE2) receptor from cardiac sarcolemmal (SL) membranes. Binding of PGE2 to this receptor in permeabilized SL vesicles inhibits adenylyl cyclase activity. The purpose of this study was to determine if the cardiac PGE2 receptor is coupled to adenylyl cyclase via a pertussis toxin sensitive guanine nucleotide binding inhibitory (Gi) protein. Incubation of permeabilized SL vesicles in the presence of 100 microM 5'-guanylamidiophosphate, Gpp(NH)p, a nonhydrolyzable analogue of GTP, resulted in a shift in [3H]PGE2 binding from two sites, one of high affinity (KD = 0.018 +/- 0.003 nM) comprising 7.7% of the total available binding sites and one of lower affinity (KD = 1.9 +/- 0.7 nM) to one site of intermediate affinity (KD = 0.52 +/- 0.01 nM) without a significant change in the total number of PGE2 binding sites. A shift from two binding sites to one binding site in the presence of Gpp(NH)p was also observed for [3H]dihydroalprenolol binding to permeabilized cardiac SL. When permeabilized SL vesicles were pretreated with activated pertussis toxin, ADP-ribosylation of a 40- to 41-kDa protein corresponding to Gi was observed. ADP-ribosylation of SL resulted in a shift in [3H]PGE2 binding to one site of intermediate affinity without significantly changing the number of binding sites. In alamethicin permeabilized SL vesicles, 1 nM PGE2 significantly decreased (30%) adenylyl cyclase activity. Pretreatment with activated pertussis toxin overcame the inhibitory effects of PGE2. These results demonstrate that the cardiac PGE2 receptor is coupled to adenylyl cyclase via a pertussis toxin sensitive Gi protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Diphosphate Ribose↗
Lysoplasmenylethanolamine accumulation in ischemic/reperfused isolated fatty acid-perfused hearts.
Lysophospholipid accumulation has been implicated in the pathogenesis of irreversible injury during myocardial ischemia and reperfusion. Plasmalogens (phospholipids with a vinyl-ether bond in the sn-1 position) account for more than 50% of total myocardial sarcolemmal and sarcoplasmic reticulum phospholipids. Accumulation of plasmalogen choline and ethanolamine lysophospholipids (lysoplasmenylcholine and lysoplasmenylethanolamine) or the effects of exogenous fatty acids on lysoplasmalogen accumulation during ischemia and reperfusion have not been examined. Isolated working rat hearts perfused with buffer containing either 11 mM glucose or 11 mM glucose plus 1.2 mM palmitate were subjected to aerobic, ischemic, or ischemia/reperfusion protocols. Levels of lysoplasmenylcholine and lysoplasmenylethanolamine were quantified using a two-stage high-performance liquid chromatographic technique. In hearts perfused with glucose alone, no significant differences in levels of lysoplasmenylcholine or lysoplasmenylethanolamine were seen during ischemia or reperfusion. In fatty acid-perfused hearts, however, significant accumulation of lysoplasmenylethanolamine occurred during reperfusion but not during ischemia (723 +/- 112, 734 +/- 83, and 1,394 +/- 193 nmol/g dry wt for aerobic, ischemic, and ischemic/reperfused hearts, respectively; p less than 0.05 for ischemic/reperfused hearts versus aerobic or ischemic hearts). Lysoplasmenylcholine levels after ischemia and reperfusion did not differ significantly from aerobic values, regardless of whether fatty acids were present or absent from the perfusate. Aerobic and ischemic/reperfused rabbit hearts, in the presence of fatty acid, showed a similar profile in their lysoplasmalogen content. We conclude that differential lysoplasmenylethanolamine accumulation occurs during myocardial reperfusion when exogenous fatty acid concentrations are high. This may reflect the selective action of fatty acid intermediates on the metabolism of lysoplasmenylethanolamines.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparison of ion-exchange chromatography, isoelectric precipitation and reversed-phase high-performance liquid chromatography for the separation of individual cardiac myosin light chains.
Three modified procedures for the separation of cardiac myosin light chains are carefully compared. Ion-exchange chromatography gives a purified cardiac myosin light chain 1, whereas light chain 2 is always contaminated by light chain 1. Reversed-phase high-performance liquid chromatography gives the best resolution of these light chains and needs only 20 min for each run. However, it requires pure preparation of myosin light chains before separation. Isoelectric precipitation is the simplest procedure and suitable for large quantities of material. Although it gives the highest yield the separation is not adequate. A modified and rapid procedure for the isolation of cardiac and skeletal total myosin light chains is also presented.
Chromatography, Ion Exchange↗
A novel method to maintain ductus arteriosus patency.
Survival of patients with certain ductal-dependent congenital heart diseases depends on continued patency of the ductus arteriosus or the surgical creation of an aortopulmonary shunt. The latter may be difficult in the presence of hypoplastic pulmonary arteries. Long-term prostaglandin therapy may be used to maintain ductal patency but is not without limitation and side effects. This experimental study describes a novel approach to maintain ductal patency with a stainless steel stent. Six newborn lambs less than or equal to 48-h old had a ductal stent placed during right heart catheterization. Two lambs less than 36-h old had a stent delivered by the arterial route. The stent was delivered and released at the target with relative ease and no incidence of embolization. Continued ductal patency up to 3 months was demonstrated by repeat cardiac catheterization and angiography, two-dimensional color Doppler echocardiography and postmortem examination. The experimental model provides a left to right shunt model in which the size may be increased as the animal grows. More important, a ductal stent could be used to maintain ductal blood flow in neonates and infants with ductal-dependent cardiac malformations, thereby avoiding a thoracotomy.
Angioplasty, Balloon, Coronary↗
Photolabelling of the prostaglandin E2 receptor in cardiac sarcolemmal vesicles.
A [3H]azidophenacyl ester of PGE2 ([3H]azido-PGE2) was synthesized and used to photoaffinity label the protein component of the high affinity PGE2 binding site in cardiac sarcolemma membrane. Photolysis of the isolated cardiac sarcolemmal vesicles in the presence of [3H]azido-PGE2 resulted in the covalent labelling of a protein component that migrated on sodium dodecyl sulfate-polyacrylamide gels with an apparent molecular weight of 100,000. Incorporation of the [3H]azido-PGE2 did not occur in the absence of photolysis. The photolabelling of the 100-kDa protein by [3H]azido-PGE2 was inhibited by excess unlabelled PGE2 and azido-PGE2. Specific binding of [3H]azido-PGE2 was displaced by excess unlabelled PGE2 or azido-PGE2, but not PGF2 alpha, 6-keto-PGF1 alpha or PGD2. These results indicate that the 100-kDa photoaffinity labelled [3H]azido-PGE2 binding protein contains the binding site for PGE2 in isolated cardiac sarcolemma membranes.
Affinity Labels↗