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Myocardial supply-demand factors and metabolism in isoproterenol treated dogs
ABSTRACTS
PROTECTION OF BORDER ZONE ISCHEMIC MYOCARDIUM WITH GLUCOSE INSULIN: MECHANICAL, METABOLIC, MORPHOLOGIC CORRELATES Frank N. Gravino, MD; Carl S. Apstein, MD, FACC; Christian Haudenschild, MD; Jonathan Frazer; Catherine Kieler; Peggy Bissel; Cardiac Muscle Res. Lab, Boston U., Boston, Mass. Increased glucose (G) protects cardiac tissue during high flow hypoxia; with low flow ischemia its effects are unproven. Accordingly, isolated (37°C) working rabbit hearts (balloon~in LV) paced at 180/min underwent 3 hrs of ischemia modelled on flow rates in infarct border zones (coronary flow=20% of normal, 0.5 ml/min/gm for the rabbit). During ischemia, control (C) perfusate (n=27) with 100mg% glucose - no insulin was compared to high glucose (500mg%) and insulin 100mU/ml (G+l)(n=28). Post-ischemia recovery for 60 min used C perfusate. D u r i n g ischemia with C, contracture occurred to 27±3 vs 2±imm Hg with G+I (F<0.001). Post-ischemia recovery of developed pressure was 52±6% with C vs 67±4% with G+I (P<0.05); dP/dt recovery was 66±8% with C vs 92±9% with G+I (P<0.05). Metabolically, G+I increased glycolysis and ATP levels. With C, total ischemic lactate production (LP) was 177±7~moles/ gm; G+I increased LP by 114% to 379±30~moles/gm (P<0.O01). G+I did not increase LP until after 45 min of ischemia, suggesting that glycogen is adequate during this time and that increased exogenous G enhances glycolytic flux only with ischemia of longer duration. After 3 hrs of ischemia with C, tissue ATP was 5.3±0.7 vs 7.8±0.5mM/gm with G+I, a 47% increase (P<0.01). Mannitol, equiosmolar to the G+I, did not affect contracture, recovery of contractility, or metabolism. A "blinded" assessment of ultrastructural damage (20 blocks from 5 hearts per group) showed a "damage score" With C of 4.3±0.4 vs 2.6±0.5 with G+I (P<0.05). Conclusion: G+I, by a non-osmotic mechanism, protected cardiac muscle subjected to "border zone" ischemia for 3 hrs as assessed by prevention of contracture, recovery of contractility, stimulation of glycolysis, and preservation of tissue ATP and ultrastructure.
COMPARATIVE EFFECTS OF HYPOXIA, L A C T I C A C I D AND HYPOXIC LACTIC ACIDOSIS ON ISOLATED CARDIAC MUSCLE: EVIDENCE FOR OXYGEN DEPRIVATION AS PRINCIPAL DETERMINANT OF MYOCARDIAL DEPRESSION Tedd A. Brandon, BS; Lloyd H. Michael, PhD; James B. Young MD; Richard R. Miller, MD, FACC, Baylor College of Medicine, Houston, Texas.
LIMITATIONS OF LACTATE PRODUCTION AS AN INDEX OF ISCHEMIA Carl S. Apstein, MD, FACC; Frank N. Gravino, MD; Jonathan Frazer; Peggy Bissell; William B. Hood, Jr., MD, FACC, Cardiac Muscle Research Lab, BostOn University, Boston, MA
MYOCARDIAL SUPPLY-DEMAND FACTORS AND METABOLISM ISOPROTERENOL TREATED D O G S
+
The relationship between lactate production (LP) and the severity and duration of myocardial ischemia (I) was studied in isolated rat (n=24) and rabbit hearts (n=56) during severe to mild global I (3-60% normal coronary flow). The rate of LP was not constant at a constant degree of I; LP reached a peak value after 10-15 min of I; with subsequent I, LP decreased by 54±16% (P<0.025) with severe I in rats, by 28±11% (P<0.05) with moderate I in rats, by 36±6% (P<0.001) with severe I in rabbits and by 42±8% (P<0.001) with moderate I in rabbits. Thus a decreased rate of LP with serial measurements does not necessarily imply relief of I. When different degrees of I were imposed, the coronary venous L concentration was highest with the most severe I, but the mean rate of LP (concentration x flow rate) was inversely proportional to the degree of I. Maximum LP occurred with mild or moderate I. I n comparison to severe I, mild I in the rat heart increased LP by 833% from 0.3±0.1 to 2.5±0.2~M/gm/min (P< 0.001), and by 300% in the rabbit heart from 0.4±0.3 to 1.2±0.1uM/gm/min (P<0.001). Thus partial relief of I increased LP, consistent with an inhibition of glycolysis during more severe I due to higher tissue L levels. These data were applied to a model of regional I, assessed by coronary sinus sampling, and show that partial relief of severeregional I will result in an increased coronary Sinus L concentration reflecting the increased rate of LP in the I region. Conclusion: Although net myocardial LP may qualitatively indicate the presence of tissue hypoxia, relative changes in the amount of LP or in the coronary sinus L concentration may reflect opposite changes in the relative degree of I.
Although prior studies have assessed hemodynamic effects of acidosis and hypoxia, in most, left ventricular(LV) function was subject to altered loading. This study assessed the isolated and direct effects on myocardial mechanics of hypoxia(HYPOX), lactic acid(LA), and HYPOX+LA in constant loaded isolated supported rat left ventricular papillary muscles. After achieving stable Lmax during normoxia in 28 muscles of uniform (p>.05) cross sectional area(CSA) (mean O.62mm2), LA was added incrementally to lower bath pH to 6.6 in 7 muscles; in 14 the bath w a s made HYPOX(10% 02, 5% C02, 85% N2); and 7 had combined HYPOX and LA. Peak tension (T,~Gm/mm2), first derivative of T(dT/dt), time to peak T(TPT, msec) and -dT/dt were measured. In NORMOX, pH lowered by LA from 7.4 to 7.2, 7.0 and 6.8 decreased T from C by 4, ii and 15%; dT/dt by 3, 15, and 18%; -dT/dt by 7, 17 and 22%; and prolonged TPT by 8, 14 and 18%,(ali p<.02 vs C). HYPOX lowered T from C by 52%; dT/dt 46%,-dT/dt, 44%, and increased TPT 16%, (all p <.01 vs LA). HYPOX + LA at pH 7.2, 7.0 and 6.8 respectively, decreased T from C by 39, 56 and 69%; dT/dt 42, 59 and 73%; -dT/dt + 51, 66 and 76% and prolonged TPT by ii, 28 and 39%;(ali p<,001) (all p<.01 vs LA alone; all p<.01 vs HYPOX alone). Thus, in constant loaded, isolated muscle, unaffected by pH or HYPOX-induced alterations in LV loading, lactic acid alone has modest depressive effect on mechanical function to pH of 6.8. In contrast, hypoxia alone, markedly depresses all mechanical indices. Combined LA and HYPOX exhibit potentiated inhibitory action on myocardial function.
IN
Tada yipintsoi , MB, PhD; Somsong Penpargkul, MD, PhD; Alan Schwartz, BS, MBA; Joel Rosenkrantz, BS; James Scheuer, MD, FACC, Montefiore Hosp.-Albert Einstein Col. of Med., Bronx, N.Y. A decline in the ratio of diastolic pressure time index (DPTI) to ejection pressure time (EPT) has been used to predict myocardial ischemia, but this has not been validated by metabolic studies, The relation of energy supply/demand (S/D) factors to myocardial energy levels (EL.) was studied during severe cardiac stress with isoproterenol. EL and perfusion were studied using biopsies and microspheres. In 9 dogs (Group A), heart rate (HR) and aortic diastolic pressure (DP) were not controlled but they were controlled in 7 dogs (Group B) with pacing and methoxamine. Factors related to energy demand were higher in Group B: HR* (224 in B vs 193 in A), max LV dP/dt* (5621 vs 3972), EPT* (3065 vs 2394). Factors related to energy supply were lower in Group A: DP* (46 in A vs 88 in B), DPTI* (1409 vs 2805) and LV flow (1.88 vs 2.60 ml/min/g). Indirect indices of S/D were lower in A: DPTI/EPT* (0.58 in A vs 0.89 in B), oxygen utilization/LV work (0.35 vs 0.46) and inner/ Outer LV flow* (0.67 vs 0.83). Despite the above differences, endocardial creatine phosphate, umoles/g dry (40.1 for A and 44.1 for B), was decreased below 40 in only 4 hearts in A and 1 in B with the lowest value being 30 and did not correlate with low DPTI/EPT. Endocardial adenosine triphosphate averaged 25.5 for A and 28.2 for B. Therefore, indices of S/D did not consistently predict subendocardial biochemical deficits in these severely stressed hearts. * = statistically significant difference unpaired data at p < 0.05.
February 1979
The American Journal of CARDIOLOGY
for the
Volume 43
435
PROTECTION OF BORDER ZONE ISCHEMIC MYOCARDIUM WITH GLUCOSE INSULIN: MECHANICAL, METABOLIC, MORPHOLOGIC CORRELATES Frank N. Gravino, MD; Carl S. Apstein, MD, FACC; Christian Haudenschild, MD; Jonathan Frazer; Catherine Kieler; Peggy Bissel; Cardiac Muscle Res. Lab, Boston U., Boston, Mass. Increased glucose (G) protects cardiac tissue during high flow hypoxia; with low flow ischemia its effects are unproven. Accordingly, isolated (37°C) working rabbit hearts (balloon~in LV) paced at 180/min underwent 3 hrs of ischemia modelled on flow rates in infarct border zones (coronary flow=20% of normal, 0.5 ml/min/gm for the rabbit). During ischemia, control (C) perfusate (n=27) with 100mg% glucose - no insulin was compared to high glucose (500mg%) and insulin 100mU/ml (G+l)(n=28). Post-ischemia recovery for 60 min used C perfusate. D u r i n g ischemia with C, contracture occurred to 27±3 vs 2±imm Hg with G+I (F<0.001). Post-ischemia recovery of developed pressure was 52±6% with C vs 67±4% with G+I (P<0.05); dP/dt recovery was 66±8% with C vs 92±9% with G+I (P<0.05). Metabolically, G+I increased glycolysis and ATP levels. With C, total ischemic lactate production (LP) was 177±7~moles/ gm; G+I increased LP by 114% to 379±30~moles/gm (P<0.O01). G+I did not increase LP until after 45 min of ischemia, suggesting that glycogen is adequate during this time and that increased exogenous G enhances glycolytic flux only with ischemia of longer duration. After 3 hrs of ischemia with C, tissue ATP was 5.3±0.7 vs 7.8±0.5mM/gm with G+I, a 47% increase (P<0.01). Mannitol, equiosmolar to the G+I, did not affect contracture, recovery of contractility, or metabolism. A "blinded" assessment of ultrastructural damage (20 blocks from 5 hearts per group) showed a "damage score" With C of 4.3±0.4 vs 2.6±0.5 with G+I (P<0.05). Conclusion: G+I, by a non-osmotic mechanism, protected cardiac muscle subjected to "border zone" ischemia for 3 hrs as assessed by prevention of contracture, recovery of contractility, stimulation of glycolysis, and preservation of tissue ATP and ultrastructure.
COMPARATIVE EFFECTS OF HYPOXIA, L A C T I C A C I D AND HYPOXIC LACTIC ACIDOSIS ON ISOLATED CARDIAC MUSCLE: EVIDENCE FOR OXYGEN DEPRIVATION AS PRINCIPAL DETERMINANT OF MYOCARDIAL DEPRESSION Tedd A. Brandon, BS; Lloyd H. Michael, PhD; James B. Young MD; Richard R. Miller, MD, FACC, Baylor College of Medicine, Houston, Texas.
LIMITATIONS OF LACTATE PRODUCTION AS AN INDEX OF ISCHEMIA Carl S. Apstein, MD, FACC; Frank N. Gravino, MD; Jonathan Frazer; Peggy Bissell; William B. Hood, Jr., MD, FACC, Cardiac Muscle Research Lab, BostOn University, Boston, MA
MYOCARDIAL SUPPLY-DEMAND FACTORS AND METABOLISM ISOPROTERENOL TREATED D O G S
+
The relationship between lactate production (LP) and the severity and duration of myocardial ischemia (I) was studied in isolated rat (n=24) and rabbit hearts (n=56) during severe to mild global I (3-60% normal coronary flow). The rate of LP was not constant at a constant degree of I; LP reached a peak value after 10-15 min of I; with subsequent I, LP decreased by 54±16% (P<0.025) with severe I in rats, by 28±11% (P<0.05) with moderate I in rats, by 36±6% (P<0.001) with severe I in rabbits and by 42±8% (P<0.001) with moderate I in rabbits. Thus a decreased rate of LP with serial measurements does not necessarily imply relief of I. When different degrees of I were imposed, the coronary venous L concentration was highest with the most severe I, but the mean rate of LP (concentration x flow rate) was inversely proportional to the degree of I. Maximum LP occurred with mild or moderate I. I n comparison to severe I, mild I in the rat heart increased LP by 833% from 0.3±0.1 to 2.5±0.2~M/gm/min (P< 0.001), and by 300% in the rabbit heart from 0.4±0.3 to 1.2±0.1uM/gm/min (P<0.001). Thus partial relief of I increased LP, consistent with an inhibition of glycolysis during more severe I due to higher tissue L levels. These data were applied to a model of regional I, assessed by coronary sinus sampling, and show that partial relief of severeregional I will result in an increased coronary Sinus L concentration reflecting the increased rate of LP in the I region. Conclusion: Although net myocardial LP may qualitatively indicate the presence of tissue hypoxia, relative changes in the amount of LP or in the coronary sinus L concentration may reflect opposite changes in the relative degree of I.
Although prior studies have assessed hemodynamic effects of acidosis and hypoxia, in most, left ventricular(LV) function was subject to altered loading. This study assessed the isolated and direct effects on myocardial mechanics of hypoxia(HYPOX), lactic acid(LA), and HYPOX+LA in constant loaded isolated supported rat left ventricular papillary muscles. After achieving stable Lmax during normoxia in 28 muscles of uniform (p>.05) cross sectional area(CSA) (mean O.62mm2), LA was added incrementally to lower bath pH to 6.6 in 7 muscles; in 14 the bath w a s made HYPOX(10% 02, 5% C02, 85% N2); and 7 had combined HYPOX and LA. Peak tension (T,~Gm/mm2), first derivative of T(dT/dt), time to peak T(TPT, msec) and -dT/dt were measured. In NORMOX, pH lowered by LA from 7.4 to 7.2, 7.0 and 6.8 decreased T from C by 4, ii and 15%; dT/dt by 3, 15, and 18%; -dT/dt by 7, 17 and 22%; and prolonged TPT by 8, 14 and 18%,(ali p<.02 vs C). HYPOX lowered T from C by 52%; dT/dt 46%,-dT/dt, 44%, and increased TPT 16%, (all p <.01 vs LA). HYPOX + LA at pH 7.2, 7.0 and 6.8 respectively, decreased T from C by 39, 56 and 69%; dT/dt 42, 59 and 73%; -dT/dt + 51, 66 and 76% and prolonged TPT by ii, 28 and 39%;(ali p<,001) (all p<.01 vs LA alone; all p<.01 vs HYPOX alone). Thus, in constant loaded, isolated muscle, unaffected by pH or HYPOX-induced alterations in LV loading, lactic acid alone has modest depressive effect on mechanical function to pH of 6.8. In contrast, hypoxia alone, markedly depresses all mechanical indices. Combined LA and HYPOX exhibit potentiated inhibitory action on myocardial function.
IN
Tada yipintsoi , MB, PhD; Somsong Penpargkul, MD, PhD; Alan Schwartz, BS, MBA; Joel Rosenkrantz, BS; James Scheuer, MD, FACC, Montefiore Hosp.-Albert Einstein Col. of Med., Bronx, N.Y. A decline in the ratio of diastolic pressure time index (DPTI) to ejection pressure time (EPT) has been used to predict myocardial ischemia, but this has not been validated by metabolic studies, The relation of energy supply/demand (S/D) factors to myocardial energy levels (EL.) was studied during severe cardiac stress with isoproterenol. EL and perfusion were studied using biopsies and microspheres. In 9 dogs (Group A), heart rate (HR) and aortic diastolic pressure (DP) were not controlled but they were controlled in 7 dogs (Group B) with pacing and methoxamine. Factors related to energy demand were higher in Group B: HR* (224 in B vs 193 in A), max LV dP/dt* (5621 vs 3972), EPT* (3065 vs 2394). Factors related to energy supply were lower in Group A: DP* (46 in A vs 88 in B), DPTI* (1409 vs 2805) and LV flow (1.88 vs 2.60 ml/min/g). Indirect indices of S/D were lower in A: DPTI/EPT* (0.58 in A vs 0.89 in B), oxygen utilization/LV work (0.35 vs 0.46) and inner/ Outer LV flow* (0.67 vs 0.83). Despite the above differences, endocardial creatine phosphate, umoles/g dry (40.1 for A and 44.1 for B), was decreased below 40 in only 4 hearts in A and 1 in B with the lowest value being 30 and did not correlate with low DPTI/EPT. Endocardial adenosine triphosphate averaged 25.5 for A and 28.2 for B. Therefore, indices of S/D did not consistently predict subendocardial biochemical deficits in these severely stressed hearts. * = statistically significant difference unpaired data at p < 0.05.
February 1979
The American Journal of CARDIOLOGY
for the
Volume 43
435