Relationship of myocardial morphometry in aortic valve regurgitation to myocardial function and post-operative results

Summary In 24 patients with aortic insufficiency undergoing aortic valve replacement, a clinical and hemodynamic study was performed pre-operatively. Left ventricular biopsies were obtained perioperatively for morphometric study.No significant relations were found when morphometric data were compared to functional class, cardiothoracic radio and ECG findings.The percentage of interstitial fibrosis was not correlated with any of the measured hemodynamic parameters. Myocardial cell diameter was weakly correlated with left ventricular systolic function parameters. A decrease in the percentage of contractile material was strongly correlated with an impaired left ventricular function, assessed pre-operatively. During clinical follow-up, patients were divided into two groups: Group A (17 patients) included patients who were in class I or II of NYHA after surgery. Group B (seven patients) included patients who died or were in functional class III or IV. As compared with Group A, Group B patients had a significantly lower ejection fraction; their myocardial cell diameter was larger and the percentage of myofibrils, and the content of contractile material were significantly lower. This suggests that, in aortic regurgitation left ventricular dysfunction is correlated with contractile material loss and not with interstitial fibrosis, and that morphometric changes are good predictors of follow-up after surgery.     

The idiopathic dilated cardiomyopathy in man. A biochemical and molecular study on myosin

Summary We studied subunit composition and Ca⁺⁺-activated ATPase activity of myosin isolated from atria and ventricles of hearts explanted from patients suffering from idiopathic dilated cardiomyopathy. At variance with previously published data, we have been unable to detect in the ventricular subendocardial layers a significant amount of myosin atrial-like light chain 1 (ALC1), which has been reported to be related to some hemodynamic features of the hypertrophied and failing heart. Such a subunit was not visible in the septum and in the subepicardial layers either. On the contrary, in both atria a ventricular-like light chain 2 (VLC2) was found. The nature of this additional light chain was confirmed on the basis of two-dimensional electrophoresis and immunoblotting techniques with polyclonal antibodies reacting with VLC2. In these patients we also observed a depressed Ca⁺⁺-activated ATPase activity, both in atrial and ventricular myosin. The explanation for this finding in ventricles still remains obscure since neither myosin light chains, nor myosin heavy chains showed any difference between patients with dilated cardiomyopathy and controls. On the contrary, in atria we clearly identified changes consistent with the expression of myosin heavy chains of ventricular type and VLC2, which can account for the depressed Ca⁺⁺-activated ATPase activity.     

Effect of dopamine on regional myocardial function and oxygen consumption in experimental left ventricular hypertrophy

Summary We investigated the hypothesis that the capacity of left ventricular myocardium to respond to an inotropic challenge by dopamine would be diminished in left ventricular hypertrophy induced by plication of the aortic valve. Seven mongrel dogs (LVH group) aged 6–8 weeks and weighing 4–6 kg, were subjected to preliminary surgery in which the noncoronary sinus of Valsalva was plicated. Six months later these animals, as well as a control group of dogs, were subjected to acute experiments in which the effect of dopamine (7.5 and 15 g/kg/min) on regional and global myocardial function and oxygen consumption was studied. Myocardial segment length was measured with ultrasonic dimension transducers, and left ventricular and aortic blood pressures were recorded from catheter-tip transducers. Regional coronary blood flow was determined with radioactive microspheres, and regional oxygen saturation in small arteries and veins was measured using microspectrophotometry. Regional myocardial O₂ consumption was calculated from these parameters. Heart weights were significantly elevated in the LVH group, and a pressure gradient of about 25 mm Hg was observed across the aortic valve. In both groups, dopamine infusion produced a dose-dependent increase in heart rate, left ventricular pressure, and LV dP/dt_max. Prior to dopamine infusion, percent shortening per beat was greater in the LVH group (13.97 ± 1.2 %) than in the control group (9.49 ± 1.07 %). Although the maximum speed of segment shortening was elevated by dopamine in both groups, percent shortening was not elevated in the LVH group. Stimulation by the high dose of dopamine produced a threefold elevation in regional coronary blood flow in both groups. Oxygen extraction was unchanged; the proportion of small veins with low O₂ saturation was not elevated in LVH hearts, even during dopamine stimulation. Regional myocardial O₂ consumption was elevated by dopamine (15 g/kg/min) to about the same extent in both the control and LVH groups (19.1 ± 2.3 and 17.5 ± 2.3 ml O₂/min/100 g) respectively. It is concluded that, in dogs with six months of aortic stenosis, dopamine does not exhaust functional reserve and the relationship between O₂ supply and consumption is not significantly impaired.This study was supported in part by PHS research grant HL40320     

Mitochondrial respiration in myocardial biopsy samples as a criterion of postischemic recovery of the cardiac contractility

Summary Isolated perfused guinea pig hearts were arrested by a high K⁺ cardioplegic solution containing (PG group) or lacking (control group) 10 mM phosphocreatine +15 mM glutamate. Total normothermic ischemia lasted 45 min followed by 30 min reperfusion. Mitochondrial respiration in the absence and presence of different concentrations of ADP and creatine was studied in biopsy samples (6–8 mg) after saponin treatment. The samples were taken before and after ischemia, as well as after the reperfusion period. A slightly better relative recovery of developed pressure (RRDP) in PG group was associated with higher mitochondrial acceptor control ratio after reperfusion (5.74±0.32 vs. 4.54±0.21 in PG and control groups, resp., p<0.01). When the results obtained in both groups were treated together, tight correlations between the pre- or postischemic mitochondrial state and RRDP were revealed. Higher values of RRDP were found for the hearts with lower preischemic values of (low ADP+creatine)-stimulation of mitochondrial respiration (r=–0.57, p<0.01). Relative changes in this mitochondrial parameter during ischemic period were in a good correlation with the RRDP (r=0.82, p<0.001). The data suggest that the study of the mitochondrial function in myocardial biopsy samples before ischemia and reperfusion could provide a useful information for the prognosis of cardiac function recovery.     

Enhanced lipolysis of myocardial triglycerides during low-flow ischemia and anoxia in the isolated rat heart

Summary We studied lipolysis in the isolated rat heart, measured as glycerol release during anoxia, low-flow ischemia and subsequent reperfusion. It was found that the rate of lipolysis was enhanced during ischemia/anoxia while the lipase activities in tissue extracts involved in the myocardial lipolysis and the amount of triglycerides were not affected. This indicates the dominant occurrence of a lipolysisreesterification principle in ischemic and anoxic tissue. A common observation of ischemia/anoxia is an increase in the tissue NADH/NAD⁺ ratio. Therefore we investigated the effect of lactate and malate, both of which enhance the tissue redox state on myocardial lipolysis. Perfusion in the presence of lactate (10 mM) and malate (10 mM) both stimulated myocardial lipolysis by about five times. This suggests that the rate of reesterification of product fatty acids to triglycerides, which is determined by the NADH/NAD⁺ ratio, because of the increased formation of glycerol 3-phosphate from dihydroxy acetone phosphate, plays an important role in the regulation of lipolysis. The existence of triglyceridefatty acid-triglyceride cycle is discussed.     

Changes in ECG,plasma and myocardial lipids in experimental myocardial hypertrophy in rats

Summary ECG, systolic blood pressure (BP), the ratio (R) of grams of myocardial mass/100 g of body mass, total lipids, cholesterol, triglycerides and phospholipids in blood plasma and the left ventricular myocardium, as well as the plasma free fatty acids, were investigated in 58 male Wistar rats 3,30 and 180 days after operation, in a model of myocardial hypertrophy (MH) induced by experimental coarctation hypertension, after the method of Sclye.An attempt was made to correlate some functional and metabolic indices which characterize the development of this type of MH. On a background of progressively rising BP and parallel increasing R, ECG change were recorded. They were typical of the respective stage of arterial hypertension and MH and expressed mostly in a shifting of the electrical axis of the heart to the left and in essential repolarization disturbances. The most significant changes in the studied lipid fractions were found 30 days after the induction of hypertension. The pathological changes manifested on the 180th day are discussed in relation to age, the stage of hypertension and especially in relation to the developing hypoxic and ischaemic myocardial damage.     

Atrial and ventricular myosins from human hearts II. Isoenzyme distribution after myocardial infarction

Summary Human atrial and ventricular myosins were prepared from autopsy specimens from subjects with coronary heart disease. Cardiac myosin light chain isotypes were resolved using twodimensional gel electrophoresis, whereas myosin isozymes were detected by pyrophosphate gel electrophoresis.Myocardial infarction and associated work overload cause a transition in the light chain complements of the myosins. Thus ventricular myosin light chains were found in pressure overloaded atria and atrial light chains have also been identified in the infarct ventricle of the human heart.Two molecular isoenzymes of the human atrial myosin, the relative proportions of which are changed after infarction, were separated under non-dissociating conditions by gel electrophoresis. A decrease in HA-3 and a corresponding increase in HA-1 were observed. Ventricular hypertrophy in patients with coronary insufficiency induces a second ventricle isomyosin, called HV-1, with the same electrophoretic mobility as HA-1. The relative part of this myosin type amounts to 20%. Comparative peptide mapping studies were carried out on myosin subfragment-1 preparations from normal and infarct ventricles. In the primary structures, the chymotrypsic digestions produced slight differences.These data demonstrate the heterogeneity of human atrial and ventricular myosins in patients with coronary heart disease.     

Alterations in heart and serum lysosomal activities in streptozotocin-induced diabetes

Summary Alterations in the cardiac tissue and serum acid hydrolase activities were studied in chronic streptozotocin-induced diabetes in rats. No changes were observed in total cardiac tissue homogenate lysosomal enzyme activities at 4 weeks of diabetes but there were significant alterations in the distribution of selected enzymes. Significant decreases in nonsedimentable -N-acetylglucosaminidase (NAG) and -galactosidase (Gal) activities were observed at 4 weeks of diabetes. At 8 weeks of the disease, decreased activities of NAG and Gal were observed in heart homogenates but no changes were apparent in -mannosidase (Man) or acid phosphatase activities. Nonsedimentable activities of NAG and both sedimentable and nonsedimentable activities of Gal were decreased at 8 weeks. At 16 weeks of the diabetic condition, increased activities of NAG, Gal and acid phosphatase were observed. This increase at 16 weeks of the disease was due to an increase in sedimentable enzyme activity. At all times of diabetes, serum enzyme activities were significantly increased. Insulin treatment reversed all of the observed changes in tissue homogenates, but serum levels were not completely reversed. These results suggest that cardiac lysosomal hydrolases are probably only involved in the later stages of the diabetic cardiomyopathy when extensive ultrastructural derangements are evident. The present evidence also suggests that the heart may be a source of serum hydrolase activities.     

Open chest and open pericardium affect the distribution of myocardial blood flow in the right ventricle

Summary We have investigated the effects of open chest and open pericardium on the distribution of myocardial blood flow assessed with the radioactive microsphere technique (15 m). Five dogs with intact thorax served as controls (group I) and six dogs were studied after a right-sided thoracotomy and pericardiotomy (group II). Global myocardial blood flow (mean±S.D.) was 0.73±0.17 ml·min^–1·g^–1 in group I and 1.22±0.09 ml·min^–1·g^–1 in group II (p<0.05). Analysis of transmural blood flow distribution revealed that flow was 44% higher in the right and 60% higher in the left ventricular endocardial layers in the open-chest animals, whereas epicardial flow increased by 105% and 90%, respectively. As a result of the preferential blood flow to the epicardial layers of the right ventricle, the endo/epi ratio was reduced from 1.30±0.26 in group I to 0.86±0.11 in the open-chest group (p<0.05). Left ventricular endo/epi ratio was 1.27±0.16 and 1.06±0.11 (n.s.), respectively. External work and diastolic filling pressure of the right ventricle did not differ between the two groups and therefore cannot account for the redistribution of myocardial blood flow. It is concluded that the distribution of myocardial blood flow, particularly in the RV, is severely disturbed by thoracotomy and pericardiotomy. This is an important aspect for the planning and evaluation of studies under open-chest/open-pericardium conditions.Supported by Deutsche Forschungsgemeinschaft grant SFB 320     

Alcohol-induced congestive cardiomyopathy in adult turkeys: Effects on myocardial antioxidant defence systems

Summary The effects of chronic intake of dietary alcohol upon left ventricular function, activities of myocardial antioxidant enzymes, reduced glutathione (GSH) content and lipoperoxidation (measured as the formation of diene conjugates and lipid-soluble fluorescence) were studied in adult domestic Nicholas turkeys. The non-invasive evaluation of left ventricular function by echocardiography revealed an impaired contractile function (the calculated fractional shortening values were 31.1±4.1% in the alcoholic group and 38.8±4.4% in the controls) and dilatation of the heart in the alcoholic birds. The changes in the non-invasive parameters of the left ventricle indicate that the adult Nicholas turkey developed congestive cardiomyopathy secondary to the ingestion of ethanol.In the hearts of normal adult turkeys, high GSH content (2.39±0.25 mol/g wet weight) and superoxide dismutase activity were found, as compared to other animals, indicating the relatively higher development of antioxidant defence systems. Compared to the controls, significant increases were noted for all the antioxidant enzymes investigated (superoxide dismutase, catalase and glutathione peroxidase) and a moderately significant decrease in the GSH content was found in the left ventricle of alcoholic birds. The changes in GSH concentration and antioxidant enzyme activities might indirectly indicate some involvement of free radicals in the pathogenesis of ethanol-induced myocardial lesion. However, the levels of in vivo lipoperoxidation in the alcoholic birds did not significantly vary from those of control turkeys. Based on these findings, it appears that the reactive oxygen radicals may play a less important role in the pathogenesis of alcohol-induced cardiomyopathy in turkeys—probably due to the higher development of myocardial antioxidant defence systems.     

Recruitment of inotropic reserve in “stunned” myocardium by the cardiotonic agent AR-L 57

Summary Contractile dysfunction of reversibly injured, reperfused myocardium can be enhanced by inotropic interventions. A decrease in the Ca-sensitivity of contractile proteins with slow recovery during reperfusion has been suggested as a potential mechanism underlying this postischemic dysfunction. We therefore tested the effects of the cardiotonic agent AR-L 57 (1 mg/kg i.v.) in six anesthetized, vagotomized dogs during constant atrial pacing at 192±6 beats/min. Before ischemia, AR-L 57 increased left ventricular pressure from 131±22 to 138±21 mm Hg and maximum dP/dt from 3,022±1,427 to 4,337±2,608 mm Hg/s. Mean systolic thickening velocity of the posterior myocardium was increased from 8.9±1.1 to 11.7±1.1 mm/s. After release of a 15 min LCX-occlusion which caused complete regional akinesia, baseline function in the posterior myocardium was severely depressed and only gradually returned towards control values over 8 h of reperfusion. AR-L 57 increased systolic thickening velocity at 10 min, 4 and 8 h reperfusion to a similar extent as before ischemia. With reference to a purported Ca-sensitizing mechanism underlying the positive inotropic action of AR-L 57, our data suggest no change in the Ca-sensitivity of reperfused myocardium.     

Coronary autoregulation and optimal myocardial oxygen utilization

The complex relationship among myocardial contractility, preload, afterload, and coronary autoregulation was studied using both analytical and numerical methods. To study autoregulation and coronary reserve changes in response to changes in cardiac oxygen consumption and in arterial pressure generation, a new variable was introduced: myocardial resistance to oxygen flow ( ). This variable was defined as the ratio of the coronary driving pressure to left-ventricular oxygen uptake. High values for this variable indicate small consumption relative to the generated aortic pressure. Conditions which produce the highest obtainable value for are considered as optimal. An expression relating to ventricular hemodynamic variables was developed and studied using a mathematical model of the cardiovascular system. The model included a mechanism of local autoregulation based on the assumption that, in steady state, the amount of oxygen consumed equals the amount extracted from coronary blood. Heart rate, peripheral resistance, end-diastolic volume, and myocardial contractility were varied while the coronary circulation was adjusted to meet ventricular oxygen consumption at each state. The model predicts that, for each state of the circulation, there is an optimal level of cardiac contractility for which the coronary reserve is maximized.     

Left ventricular shape-luminal pressure relationship An open-chest study

Summary Left ventricular dimensions were measured in Cd²⁺ arrested (presumably diastolic), openchest rats. Aortic pressure was maintained at 137 cm H₂O (100 mm Hg) and left-ventricular (luminal) pressures were established and maintained at their chosen values, each by means of reservoir systems. The selected left-ventricular pressures were chosen to be within or to even broaden the range of conceivable diastolic pressures (–3 to 48 cm H₂O). After in situ fixation with 4 % formaldehyde and gelatin embedding, the hearts were serially sectioned in the apex base direction to obtain information at 11 levels (10, 20, ... 90, 100%). Tracings of selected sections were made along the edge of the left ventricular lumen and the pericardial surface. Volumes, surface areas, and mean external and internal radii of the left ventricle were derived. To quantify the circularity of sections a form factor (FF) was introduced (FF = 1 for a circular cross-section and less than one for other shapes). Ventricular lengths, radial dimensions, endocardial and epicardial surface areas, and total and luminal volumes increased with the increasing intraventricular pressures; as expected, the wall simultaneously thinned. Though its appearance was altered by the wall thinning, the curving muscle fascicular pattern was present over the entire pressure range examined. Endocardial surface areas increased more than did the epicardial surface areas. The endocardial FF value increased (more circular) at each section level as the pressure increased. The epicardial FF relationship was apparently constant (0.798 ± 0.014) for all section levels from 10 % through 90 %, regardless of luminal pressure. These results, when taken in conjunction with the results of our previous published studies, prompted the following speculation.The wall of the diastolic ventricle is a fluid-filled chamber with intramyocardial pressures that may be higher than ventricular pressures.     

Enhanced myocardial preservation by nicotinic acid,an antilipolytic compound: Mechanism of action

Summary The cardioprotective effects of an antilipolytic compound, nicotinic acid, on arrested-reperfused myocardium were investigated in the isolatedin situ pig heart preparation. Hearts were preperfused for 15 min in the presence of (5-³H)-glucose and (U-¹⁴C)-palmitic acid. Half of the hearts were then perfused with 0.08 mM nicotinic acid for an additional 15-min period, while the remaining control hearts received unmodified perfusion. Arrest was then induced in all animals for 2 h using hypothermic K⁺ cardioplegia, followed by 60 min of normothermic reperfusion. In control hearts, there were significantly greater levels of long-chain acyl Co-A and acyl carnitine and lower levels of membrane phospholipids than in the nicotinic acid group. While nicotinic acid inhibited -oxidation during pre-ischemia and reperfusion, it also prevented the degradation of membrane phospholipids. The net result was a reduction of free fatty acid accumulation during arrest and reperfusion in the nicotinic acid group. Glycolysis, as reflected in³H₂O production, was significantly increased by nicotinic acid administration. In the control heart as compared to the nicotinic acid group, the incorporation of¹⁴C-label from palmitate into triglyceride and cholesterol during arrest was enhanced, while incorporation into phospholipids was depressed. The cardioprotective effects of nicotinic acid were demonstrated by decreased release of creatine kinase and improved coronary blood flow, and cardiac contractility in the reperfused myocardium supplemented with nicotinic acid compared to the control group. These results suggest that nicotinic acid significantly protects the arrested-reperfused myocardium by a) preventing elevation of myocardial fatty acid levels, b) stimulating glycolysis by limiting fatty acid oxidation, c) inhibiting degradation of membrane phospholipids, and d) preventing accumulation of fatty acid metabolites with harmful detergent properties.Supported by NIH Grants HL22559-06, HL33889 and HL34360, and American Heart Association Grant 11-202-856.Presented at the 72nd Annual Clinical Congress, American College of Surgeons, Surgical Forum, New Orleans, October 1986.     

A genetic abnormality of cardiac myocytes from the blind mutant (RC) chick heart: Abnormalities of cardiac structure and choline transport

Summary A new genetic cardiomyopathy was identified in a blind mutant avian strain. Cardiac myocytes were cultured from 7-day-old chick embryos from Rhode Island Red chickens and from another strain of this species that has been identified to have several abnormalities, the most striking of which is blindness. Cardiac myocytes were maintained in tissue culture. Morphologically, in culture, the cardiac myocyte from the blind mutant strain assumed a spherical shape and showed abnormalities of sarcolemmal membrane compared to control myocytes from heterozygous animals. Choline uptake and metabolism were examined, using [methyl³ H] choline, because it is a sarcolemmal transport process and choline is metabolised to phosphatidylcholine, an important phospholipid for cellular structure and function. Choline uptake through the active transport process was markedly and significantly reduced in the mutant cells compared to control cells, while choline metabolism to phosphatidylcholine was not significantly altered. These results demonstrate a new abnormality of cardiac myocytes, a cardiomyopathy that can be studied in cell culture and one with abnormalities of cellular choline transport.Supported in part by a grant from the Canadian (British Columbia) Heart Foundation     

Protective activity of nifedipine and R 58735 upon damage caused by global ischemia in the guinea pig heart-lung preparation

Summary In the guinea pig heart-lung preparation, the protective effects of nifedipine and R 58735 on cardiovascular alterations following mild (35 min) and severe (60 min) ischemia and reperfusion (30 min) were studied. Nifedipine and R 58735 were equi-protective against the effects of mild ischemia with respect to functional (LVP, dp/dt, and cardiac output) and biochemical (ATP, CrP, and adenylate charge) parameters. A clear difference, however, was observed between nifedipine and R 58735 upon severe ischemia, where R 58735 produced a significantly greater protection of functional, but not of biochemical parameters. Since no significant differences between the two compounds were found with respect to the concentrations of high energy phosphates after 35 and 60 min of ischemia before reperfusion, an energy sparing effect is not likely to be responsible for the difference between nifedipine and R 58735 in severe ischemia. An additional protective effect of R 58735 upon reperfusion in severe ischemia experiments may explain the difference between the two compounds.     

Maturation of coronary responsiveness to exogenous adenosine in the rabbit

Summary Previous studies have indicated that some cardiac control systems, such as autonomic innervation, are incomplete in the newborn and undergo postnatal maturation. However, relatively little is known of maturational changes which will affect the ability of the coronary circulation to regulate blood flow during various interventions. We tested the hypothesis that the coronary circulation of the rabbit develops a progressive, age related increase in responsiveness to exogenous adenosine during the first 16 weeks of life. We examined the response of coronary circulation to exogenous adenosine in four age groups (6–10 days, 3–4 weeks, 7–8 weeks, 16 weeks) of rabbits by using an isolated heart preparation. Coronary flow was measured during an control period, during reactive hyperemia (following release of a 2 min coronary flow interruption), and during infusions of exogenous adenosine. All age groups had similar levels of control coronary blood flow, with a large increase in flow observed during reactive hyperemia. The volume of coronary flow was higher during reactive hyperemia (P<0.001) in the 6–10-day-old animals than in the other age groups. However, the 6–10-day-old age group showed a smaller (P<0.01) flow response to exogenous adenosine than the other age groups. In addition, the 6–10-day-old animals required higher adenosine concentrations to produce an initial detectable coronary flow increase and to produce the maximal flow response. Additional studies demonstrated a significant reduction in percentage flow debt repayment after theophylline administration in adult rabbit hearts. However, neonatal rabbit hearts showed no change in flow debt repayment following theophylline. We conclude that the rabbit heart requires a period of maturation after birth before demonstrating an adult level of coronary responsiveness to exogenous adenosine.Florida Agricultural Experiment Station Series No. 5943. This study was supported in part by American Heart Assn., Florida Affiliate, Central Florida Chapter, 7/85 AG, and NIH RO1 HL 35680.     

Cardiac ultrastructural abnormalities in Syrian hamsters with spontaneous cardiomyopathy or subjected to cardiac overloads

Summary Ultrastructural and morphometric abnormalities of Syrian hamster cardiomyopathy were compared to those observed in two different models of cardiac hypertrophy produced by mechanical overload (abdominal aortic stenosis, 60-day duration) or by isoproterenol injection during 15 days in normal Syrian hamsters of the same strain. Aspects of increased protein synthesis were observed in all three groups of animals. This was the only abnormality observed in the aortic stenosis group. Cardiomyopathy was different from the two other types of overload by the existence of large calcium deposits inside of the myocytes, by the presence of thin filaments and amorphous material accumulation suggesting abnormal synthesis and by a significant reduction of myofibrils at the heart-failure phase. Nuclear abnormalities with nuclear constrictions suggesting a division process and an increased number of myocytes with two nuclei were present in both spontaneous cardiomyopathy and isoproterenol-induced cardiopathy. Therefore, Syrian hamster cardiomyopathy appears to be different from cardiopathy induced by hemodynamic overload but, in spite of specific aspects, resembles that induced by isoproterenol injections, strengthening the hypothesis of a pathogenic role of catecholamines in the Syrian hamster cardiomyopathy.     

Ketone bodies maintain normal cardiac function and myocardial high energy phosphates during insulin-induced hypoglycemia in vivo

Summary It has been suggested that myocardial utilization of ketone bodies might cause deterioration of cardiac function. Therefore, the influence of ketonemia (mean: 1.3 and 3.3 mM) in the presence of hypoglycemia (mean: 33 mg/dl) on cardiac function, substrate utilization and myocardial high energy phosphate levels was studied in 10 mongrel dogs. Hypoglycemia alone led to a significant increase of mean aortic pressure, total peripheral resistance and myocardial oxygen consumption, but other hemodynamic parameters and regional myocardial function were not changed. Additional infusion of 3-hydroxybutyrate did not affect hemodynamic variables significantly. During both metabolic interventionsin vivo phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy showed stable levels of myocardial Pi, PCr, ATP, as well as PCr/Pi (3.2–3.4) and PCr/ATP (3.0–3.2) ratios. Biochemical measurements revealed that ketonemia led to significant alterations in arterial concentrations and arterio-coronary venous differences of selected citric acid cycle intermediates, thus confirming previous reports which suggested a blockade of the 2-oxoglutarate-dehydrogenase reaction induced by ketone body oxidation. However, despite this blockade, the energy supply to the heart was not impaired as shown by normal NMR spectroscopy and cardiac perfomance. It is speculated that the blockade might be due to an enhanced NADH/NAD ratio.     

Effects of dipyridamole on collateral flow and regional myocardial function in conscious dogs with newly developed collaterals

Summary Studies were conducted on six conscious dogs instrumented for measurement of subendocardial segment lengths in the area perfused by the left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCCA), LCCA flow, and left ventricular pressure. Externally inflatable occluders were placed around the proximal LAD and LCCA. Collateral channels sufficient for the resting metabolic demands in the occluded LCCA perfusion territory were induced by repeated, brief LCCA occlusions. Dogs were then subjected to two consecutive brief periods of LAD occlusion. Dipyridamole (0.25 mg/kg) was injected intravenously 3 min prior to the second LAD occlusion. The collateral blood flow from the LCCA to the occluded LAD area was measured as the stepwise decrease in LCCA flow upon release of the LAD occlusion. During LAD occlusion after dipyridamole treatment collateral blood flow velocity decreased to 3.8±1.1 cm/s (±standard error) compared with a value of 4.9±0.9 cm/s measured during LAD occlusion without dipyridamole treatment. Percentage systolic segment shortening in the collateral dependent zone significantly deteriorated from 14.3±5.2 to 9.7±5.0% (p<0.05). Electrocardiograms taken simultaneously from endocardial ultrasonic transducers in the ischemic segment revealed significant increases in ST-segment level from 4.2±0.6 to 5.4±0.6 mV. These findings indicate that dipyridamolc adverscly affects the extent of myocardial ischemia in the collateral-dependent zone.Supported by grant HL 32800 from the NHLBI