Postischemic Myocardium Research Articles

Positron emission tomography. Diagnostic and therapeutic implications in human myocardial ischemia.

Positron emission tomography and tracers of blood flow and of metabolism offer a most unique capability: The noninvasive study of regional myocardial metabolism and its derangements as a result of regional or global myocardial disease. Research with PET not only has confirmed the existence of metabolic fluxes and reactions as established previously through highly invasive or even destructive investigational techniques but has provided new insights into pathophysiologic processes, especially in ischemic and post-ischemic myocardium. From these investigations in both animal experiments and in humans, observations have emerged which indicate a place for PET in clinical cardiology. PET is likely to contribute to detection of disease, to characterizing its extent and severity as well as to decide upon the most appropriate therapeutic strategy and assessing its results. It is recognized that many of these observations with clinical implications await confirmation through larger clinical trials, follow-up studies as well as independent confirmation. Besides exploring ischemic heart disease, PET is equally suitable for examining substrate fluxes and interactions in other disorders as for example in intrinsic myocardial disease like primary and secondary cardiomyopathies. While derangements of metabolism in these disorders may be an expression of the consequences of the disease process or its underlying mechanisms itself, findings on PET will allow formulation of new hypotheses on disease mechanisms that conversely can then be tested. In addition to F-18 2-deoxyglucose and C-11 palmitate, the number of tracers for substrate metabolism is likely to increase. An example is C-11 acetate currently intensely investigated as a tool for measuring overall myocardial oxidative metabolism. Others as for example C-11 labeled short chain fatty acids are on the horizon. The study of cardiac receptors is similarly possible. Thus, a set of tools will soon be available for dissection of entire metabolic pathways and for determination of rate limiting steps in health and disease and to more clearly define specific defects in biochemical reaction steps that critically contribute to or even ae the specific cause of disease.

Relation between reversal of diastolic creep and recovery of systolic function after ischemic myocardial injury in conscious dogs.

Although prolonged functional abnormalities after transient myocardial ischemia have been well described, the interrelationship between postischemic systolic and diastolic alterations remains controversial. Therefore, 24 chronically instrumented conscious dogs were studied with left ventricular and pleural micromanometers, ultrasonic dimension transducers in the left anterior descending (LAD) coronary distribution, and vena caval and coronary artery occluders. The LAD was occluded for 15 minutes and reperfused for 24 hours while vena caval occlusions were performed at intervals to measure myocardial segment length at 0 mm Hg transmural diastolic left ventricular pressure (L0). Coronary occlusion produced an immediate fall in systolic function as assessed by ejection shortening and stroke work and also induced a 16 +/- 4% increase in L0, which was termed diastolic creep. Throughout reperfusion, reversal of diastolic abnormalities correlated strongly with recovery of segmental shortening and stroke work (p less than 0.001). Correlation between systolic dysfunction and diastolic creep was also observed during alteration of inotropic state by dopamine, during initial reperfusion hyperfunction, and during pharmacologic manipulation of afterload. In 5 additional dog hearts fixed in diastole by rapid glutaraldehyde infusion after coronary occlusion, myocardial creep measured by the segment length transducers paralleled sarcomere elongation measured by electron microscopy. Thus, the direct correlation between diastolic creep and systolic dysfunction throughout reperfusion and during hemodynamic alterations suggests that diastolic properties of postischemic myocardium may not be entirely passive and that systolic and diastolic dysfunction induced by ischemia may have a common basis at the cellular level.

Dissociation between early recovery of regional function and purine nucleotide content in postischaemic myocardium in the conscious dog.

Since abnormalities in regional myocardial function and nucleotide metabolism persist for a prolonged period after a brief coronary occlusion the temporal relation between the resolution of myocardial dysfunction and repletion of nucleotide pools in postischaemic myocardium was studied in conscious mildly sedated animals. In a second experiment 5-amino-4-imidazolecarboxamide riboside (AICAriboside) was infused in an attempt to influence myocardial function by altering the rate of adenine nucleotide synthesis. Conscious dogs mildly sedated with morphine underwent coronary occlusion for 15 min followed by reperfusion for 30 min or 12 h, at which time a myocardial sample was obtained for nucleotide analysis. Segment shortening averaged 62% of control values at 15 min of reperfusion and increased to 81% of control by 12 h of reperfusion (p less than 0.05). Adenine nucleotide content was 75(5)% of control after 30 min of reperfusion and did not change significantly over the next 12 h of reperfusion. Thus the early return of systolic function was not accompanied by a detectable increase in total adenine nucleotide content. In the second experiment a pronounced stimulation of the proximal purine nucleotide synthetic pathway occurred as evidenced by a 13-fold to 25-fold increase in inosine monophosphate content. One branch of the distal purine pathway was also stimulated as evidenced by complete repletion of guanine nucleotide pools, but the product of the other branch (adenine nucleotides) did not increase significantly. These results indicate a selective limitation of the distal adenine nucleotide synthetic pathway in postischaemic myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of pulsatile reperfusion on postischemic recovery of myocardial function after global hypothermic cardiac arrest

It has been postulated that pulsatile blood flow helps to preserve the myocardium after ischemia. However, its effect on postischemic myocardium during cardiopulmonary bypass has not been clearly defined. To determine if pulsatile reperfusion improves postischemic recovery of cardiac metabolism and performance, we subjected 20 dogs to 60 minutes of aortic cross-clamping followed by 45 minutes of pulsatile (P group; 10 dogs) or nonpulsatile (NP group; 10 dogs) reperfusion. Left ventricular function was measured at a controlled preload in both groups before induction of global ischemia and after termination of bypass. Segmental length (assessed by sonomicrometry) was used to determine dimensional changes. Ventricular pressures were measured with solid-state micromanometers. Percent recovery of left ventricular peak systolic pressure, its first derivative, and stroke work were 66%, 59%, and 38%, respectively in the NP group and 82%, 76%, and 65% in the P group. The postarrest decrease in segmental shortening was minimized in the P group; left ventricular function curves and the slope of the end-systolic pressure-length relationship also indicated better performance after pulsatile reperfusion than after nonpulsatile reperfusion. Myocardial lactate extraction was transiently improved during the early pulsatile reperfusion period. We conclude that pulsatile reperfusion provides better myocardial preservation than nonpulsatile perfusion after 60 minutes of induced global ischemia.

Calcium-accentuated ischemic damage during reperfusion: The time course of the reperfusion injury in the isolated working rat heart model

The purpose of this study was to determine the time course of calcium-induced postischemic reperfusion injury to the myocardium, using an initial short-term calcium-enriched reperfusion solution. The isolated rat heart model was subjected to 30 min of normothermic potassium cardioplegia-induced ischemic arrest. Control hearts received normal calcium Krebs-Henseliet buffer (KHB) reperfusion. Experimental hearts were challenged with 10 min of calcium-enriched (KHB) reperfusion starting at 0, 1, 2, 5, 15, and 30 min after the beginning of reperfusion. Aortic flow recovery 60 min after reperfusion was used to determine functional recovery. Control hearts recovered 82 ± 3% of preischemic aortic flow. Hearts which received calcium challenge at 0 and 1 min after the start of reperfusion recovered 43 ± 4 and 69 ± 3% of preischemic aortic flow, respectively ( P < 0.01 and P < 0.05, respectively). Hearts which received calcium challenge 2, 5, 15, and 30 min after reperfusion recovered 75 ± 2, 80 ± 2, 85 ± 2, and 83 ± 2% of preischemic aortic flow, respectively. Our results indicate that the postischemic myocardium is very susceptible to calcium-accentuated ischemic damage during the initial period of reperfusion. The post-ischemic heart, however, quickly recovers its ability to withstand a calcium challenge. Five minutes after the start of reperfusion the heart is not influenced by calcium challenge.

Effect of nifedipine on the myocardial and vascular response to myocardial ischemia.

Nifedipine reduces reactive hyperemia following brief coronary artery occlusions. To determine whether this is related to improvement in collateral blood flow to ischemic myocardium or alterations in myocardial oxygen consumption, ten chloralose anesthetized dogs were instrumented with coronary sinus catheters, circumflex artery flowmeters, and ultrasonic microcrystals for measurement of myocardial segment shortening. Myocardial oxygen consumption and circumflex coronary artery flow were determined at rest and during incremental infusions of isoproterenol. Myocardial blood flow measured with microspheres and segmental function were assessed during and following 30- and 60-second coronary artery occlusions. Thirty minutes after the intravenous administration of nifedipine, 10 micrograms/kg iv, all measurements were repeated. Nifedipine did not alter myocardial oxygen consumption or the relationship between oxygen consumption and circumflex coronary artery flow either at rest or during isoproterenol infusion. Following 60-second coronary occlusions, nifedipine reduced peak circumflex coronary artery flow (176 +/- 99 vs. 128 +/- 68 cc/min) and reactive hyperemia debt repayment (221 +/- 84 vs. 158 +/- 66%; p less than 0.01). Nifedipine did not alter flow to ischemic segments during coronary artery occlusions (0.16 +/- 0.10 vs. 0.19 +/- 0.13 ml/min/g mean transmural flow). Furthermore, nifedipine did not affect the severity of ischemic segment dysfunction, nor the rate of recovery of ischemic segment function following release of coronary artery occlusion. We conclude that the reduction in reactive hyperemia induced by nifedipine was not related to alterations in the severity of hypoperfusion in ischemic areas, or alterations in myocardial oxygen consumption. Reductions in reactive hyperemia produced by nifedipine did not impair recovery of mechanical function in postischemic myocardium.

Increased uptake of 18F-fluorodeoxyglucose in postischemic myocardium of patients with exercise-induced angina.

Regional myocardial perfusion and exogenous glucose uptake were assessed with rubidium-82 (82Rb) and 18F-2-fluoro-2-deoxyglucose (FDG) in 10 normal volunteers and 12 patients with coronary artery disease and stable angina pectoris by means of positron emission tomography. In patients at rest, the myocardial uptake of 82Rb and FDG did not differ significantly from that measured in normal subjects. The exercise test performed within the positron camera in eight patients produced typical chest pain and ischemic electrocardiographic changes in all. In each of the eight patients a region of reduced cation uptake was demonstrated in the 82Rb scan recorded at peak exercise, after which uptake of 82Rb returned to the control value 5 to 14 min after the end of the exercise. In these patients, FDG was injected in the recovery phase when all the variables that were altered during exercise, including regional myocardial 82Rb uptake, had returned to control values. In all but one patient, FDG accumulation in the regions of reduced 82Rb uptake during exercise was significantly higher than that in the nonischemic regions, i.e., the ones with a normal increment of 82Rb uptake on exercise. In the nonischemic areas, FDG uptake was not significantly different from that found in normal subjects after exercise. In conclusion, myocardial glucose transport and phosphorylation seem to be enhanced in the postischemic myocardium of patients with exercise-induced ischemia.

Adenine nucleotide synthesis de novo in mature rat cardiac myocytes

Inadequate oxygenation of cardiac muscle leads to rapid loss of high energy compounds essential for contractile function. ATP can be regenerated by synthesis de novo, a route operating at a relatively slow rate in the heart. Myocytes isolated from mature rat heart have been used to measure the rate of ATP synthesis de novo from both [ 14C]glycine and [ 14C]ribose. Incorporation of glycine into ATP is accelerated 10-fold in the presence of 1 mM ribose. Myocytes also accumulate both precursors into IMP and four other metabolites on the de novo synthesis pathway. These metabolites represent 80% of the glycine entering the pathway. The potential of de novo synthesis for restoration of adenine nucleotides appears to be limited by the rates of early reactions, adenylosuccinate synthetase being only one of the enzymes operating at a sufficiently slow rate to make this pathway an inherently weak route for the restoration of normal energy status in post-ischemic myocardium. Interventions are being sought to alleviate these apparent metabolic delays.

Accumulation and salvage of adenosine and inosine by isolated mature cardiac myocytes

Reoxygenation of ischaemic, energy-depleted heart does not result in sufficiently rapid regeneration of normal adenine nucleotide concentrations for preservation of cardiac function and structure. Salvage of nucleoside as a mechanism for restoration of ATP in the post-ischaemic myocardium is limited by efflux of adenosine during ischaemia. Isolated cardiac myocytes have been used to establish the kinetics of uptake and salvage of adenosine and inosine, measuring the distribution of radioactive nucleoside incorporated into ATP, ADP and AMP. Maximum rates of catalysis of reactions on the salvage pathway, and of enzymes competing for substrates on the pathway, have been established in myocyte extracts. Myocytes have little capacity to salvage or catabolise inosine. Enzyme measurements indicate that salvage of adenosine should proceed at 7–8-times the rate exhibited by intact myocytes dependent upon extracellular adenosine as substrate. The data indicate that the rate of transport of adenosine is not determined by its metabolic utilization, but is the rate-limiting step in the salvage of adenosine.

Protective effects of AICAriboside in the globally ischemic isolated cat heart.

The effects of a purine precursor, AICAriboside (5-aminoimidazole-4-carboxamide riboside), on postischemic recovery of myocardial function and adenine nucleotides have been studied in the isolated blood-perfused cat heart. The isolated hearts received either AICAriboside or saline prior to 60 min of global ischemia and during 60 min of subsequent reperfusion. After 60 min of global ischemia and reperfusion, left ventricular function of the AICAriboside-treated hearts approached preischemic values, whereas contractile function of the saline-treated hearts remained depressed. At 60 min postischemia, recovery of left ventricular developed pressure (LVDP) was 62 +/- 10% for the saline-treated hearts as compared to 93 +/- 8% for the AICAriboside-treated hearts. Left ventricular compliance of the saline-treated hearts was decreased slightly at 60 min postischemia. In contrast, left ventricular compliance was increased in the isolated hearts which received AICAriboside. Myocardial ATP concentrations were decreased significantly at 60 min postischemia in both the saline-treated hearts and in the AICAriboside-treated hearts relative to nonischemic hearts. Similarly, total adenine nucleotides (TAN = ATP + ADP + AMP) were decreased significantly in both the saline-treated hearts and AICAriboside-treated hearts relative to nonischemic hearts. The present study demonstrates that AICAriboside protected globally ischemic hearts from the mechanical dysfunction associated with an ischemic insult but did not restore ATP or the total adenine nucleotide pool of the postischemic myocardium.

Myocardial pyruvate, lactate, and orthophosphate contents under different postischemic conditions. A study in a paracorporeal rat heart model.

The myocardial contents of pyruvate, lactate and orthophosphate after ischemia were investigated in a paracorporeal rat heart model under different conditions. The arterial blood was supplemented with phosphoenolpyruvate (PEP) and adenosine triphosphate early during reperfusion of excised hearts subjected to 15 min of complete global ischemia at 37 degrees C. The increase in myocardial pyruvate was significant after 4 min of reperfusion compared with the content in non-supplemented hearts subjected to the same ischemic trauma. Such dynamic changes were not observed for lactate and orthophosphate under corresponding conditions. The distinct increase in myocardial pyruvate content on supplementation with PEP and adenosine triphosphate was most probably due to an adenosine triphosphate-mediated PEP translocation into myocardial cells, with rapid metabolization of translocated PEP into adenosine triphosphate (in the presence of cellular adenosine diphosphate) and pyruvate. The pyruvate and lactate relationship varied, depending on the postischemic conditions. The postischemic myocardial orthophosphate content was stable, with only minor fluctuations. This possibility to supply the postischemic myocardium with substrate for immediate intracellular energy production is of clinical interest and merits further studies.

The influence of infused calcium on the postischemic myocardium

Despite evidence for calcium-induced damage in the postischemic myocardium, calcium remains a frequently used inotropic agent following cardiopulmonary bypass surgery with cardioplegic arrest. The purpose of this study was (1) to challenge the postischemic myocardium with incremental doses of ionized calcium, and (2) to relate postischemic calcium reperfusion concentration to final recovery of left ventricular contractile function. Rabbit hearts ( N = 38) were perfused and equipped with a ventricular balloon to monitor developed pressure (DP) ±dp/dt, and left ventricular end diastolic pressure (LVEDP). Hearts underwent 40 min of global ischemia. Hearts were then assigned to one of four groups to receive a variable calcium concentration (0.6, 1.2, 2.5, 5.0 m M) for the initial 5 min of reperfusion followed by 55 min of reperfusion (Ca +2 = 1.25 m M). No differences were found between groups for final recovery of DP ±dp/dt, or final LVEDP. It was concluded that: (1) within the physiologic range, variable calcium infusions during the first 5 min of postischemic reperfusion do not impair final recovery of LV contractile function, (2) irreversible partial recovery of left ventricular function appears due to mechanisms other than mitochondrial or myofibrillar calcium loading during reperfusion, and (3) infused calcium is a safe inotropic agent even in the postischemic myocardium.

Accelerated repletion of ATP and GTP pools in postischemic canine myocardium using a precursor of purine de novo synthesis.

During ischemia, the myocardial content of the purine nucleotides ATP and GTP falls and remains depressed for hours to days. Prolonged depletion of ATP in the postischemic state is accompanied by functional and ultrastructural abnormalities. This report describes the successful use of the purine precursor 5-aminoimidazole-4-carboxamide riboside to selectively enhance the rate of repletion of the ATP and GTP pools in postischemic myocardium.

Prolonged abnormalities of myocardium salvaged by reperfusion.

The purpose of this study was to determine if biochemical, functional, and ultrastructural abnormalities persist in nonnecrotic postischemic myocardium salvaged by coronary reperfusion. Anesthetized dogs were subjected to 15 min of occlusion of the left anterior descending (LAD) coronary artery followed by 3 days of reperfusion. Biopsies were obtained for measurement of adenosine 5'-triphosphate (ATP) and creatine phosphate (CP) nmol/mg protein), and regional function was evaluated using sonomicrometry. Myocardial ATP concentration after 15 min of occlusion was 37 +/- 1 nmol/mg cardiac protein in nonischemic subendocardium and 19 +/- 2 nmol/mg in ischemic subendocardium. After the hearts underwent 90 min and 72 h of reperfusion, ATP remained significantly depressed in reperfused subendocardium with values of 25 +/- 5 and 29 +/- 2 nmol/mg, respectively (P less than 0.05 and P less than 0.01 compared with the nonischemic zone in which ATP remained normal). CP levels fell during ischemia but returned to normal by 90 min of reperfusion. Percent systolic shortening of myocardial segments fell from +18 +/- 1% (active shortening) to -13 +/- 2% (passive lengthening) during ischemia and was still significantly depressed at +11 +/- 1% (P less than 0.05 vs. preocclusion) at 72 h of reperfusion. Histological examination showed no necrosis, but ultrastructural abnormalities were present. Therefore brief periods of myocardial ischemia are not associated with necrosis but result in functional, biochemical, and ultrastructural abnormalities, which are present for at lest 3 days after coronary reperfusion.

Relationship between hemodynamics and cardiac metabolism in the reperfusion period following hypothermic global ischemia.

Ten mongrel dogs were subjected to hypothermic ischemic cardioplegia for two hours followed by 30 minutes of reperfusion to characterize the relationship between hemodynamic parameters during reperfusion and the recovery of high energy store of the post-ischemic left ventricular myocardium. Dogs were anesthetized with intravenous pentobarbital 30 mg/kg, and standard cardiopulmonary bypass was instituted with the flow rate of 80 ml/min/kg and perfusion pressure around 80 mmHg. Ischemic cardioplegia was obtained by cross-clamping of the aorta for 2 hours under 20 degrees C of myocardial temperature. After termination of cardioplegia, the heart was rewarmed by the support of cardiopulmonary bypass with the flow rate of 80 ml/min/kg until the myocardial temperature was reached 36 degrees C. Hemodynamic parameters were measured throughout the experiment and myocardial adenosine triphosphate (ATP) and creatine phosphate (CP) were measured at the end of experiment. Correlation was significant between myocardial ATP and coronary blood flow and myocardial oxygen consumption. However, myocardial creatine phosphate correlated poorly to coronary blood flow, myocardial oxygen consumption and other hemodynamic parameters. These results indicate that the recovery of myocardial high energy store is partly related to coronary blood flow and myocardial oxygen consumption, but other parameters are probably involved in the process of early recovery of the myocardium from ischemic cardioplegia.

Relationship of ischemic contracture to high energy phosphate content and mitochondrial function in hypertrophied myocardium

Relationship of ischemic contracture to high energy phosphate content and mitochondrial function in hypertrophied myocardium

Effects of pulsatile and nonpulsatile reperfusion on the post-ischemic myocardium

Effects of pulsatile and nonpulsatile reperfusion on the post-ischemic myocardium

Beneficial effects of alkalotic reperfusion following ischemic cardiac arrest

The results of the present study indicate that exposure of ischemic myocardium to a solution with a low hydrogen ion concentration (pH 7.70) during the immediate post-ischemic period provides for better myocardial functional recovery and less myocardial water accumulation than does exposure to solutions with a normal hydrogen ion concentration (pH 7.40). Furthermore, exposure of the postischemic myocardium to a solution with a high hydrogen ion concentration (pH 7.10) results in poor recovery of ventricular function and significant myocardial water accumulation following reperfusion. Neither the beneficial effect of alkalotic reperfusion nor the harmful effect of acidotic reperfusion is associated with alterations in intramyocardial pCO 2 concentrations.

Effects of exercise and conditioning on rat heart glycogen and glycogen synthase

ARTICLESEffects of exercise and conditioning on rat heart glycogen and glycogen synthaseL. D. Segel, and D. T. MasonL. D. Segel, and D. T. MasonPublished Online:01 Feb 1978https://doi.org/10.1152/jappl.1978.44.2.183MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByCocaine does not alter cardiac glycogen content at rest or during exerciseMetabolism, Vol. 38, No. 11Increased uptake of 18F-fluorodeoxyglucose in postischemic myocardium of patients with exercise-induced angina.Circulation, Vol. 74, No. 1 More from this issue > Volume 44Issue 2February 1978Pages 183-189 Copyright & PermissionsCopyright © 1978 the American Physiological Societyhttps://doi.org/10.1152/jappl.1978.44.2.183PubMed416010History Published online 1 February 1978 Published in print 1 February 1978 Metrics

Effects of adenine nucleotides on contractility of normal and postischemic myocardium

Effects of adenine nucleotides on contractile force of normal and postischemic ventricular muscle were studied. Experiments were performed at room temperature on Langendorff perfused feline right ventricular papillary muscle preparation remaining in situ. Peak systolic force developed by normal muscles was not significantly altered by adenine nucleotides in the concentrations used. Complete cessation of coronary perfusion (“ischemia”) for 30 minutes caused severe contractile failure which was not completely reversed on resumption of perfusion with oxygenated Tyrode solution. ATP (0.5 mM) and ADP (2.0 mM) caused significant recovery of force of failing postischemic muscles while 0.5 mM ADP, 0.5 mM AMP, 2.5 mM AMP, 0.5 mM adenosine, and 2.5 mM adenosine did not. These findings show that the contractile failure of ventricular muscle subjected to acute ischemia can be reversed by administration of high-energy phosphates. The recovery, however, is not sustained after nucleotide perfusion is stopped. There is suggestive evidence that ATP does not enter the cell intact but may enter the cell in the form of ADP.