The late-presenting HIV-infected patient 30 years after the introduction of HIV testing: spectrum of opportunistic diseases and missed opportunities for early diagnosis.

OBJECTIVES: The aim of the study was to describe the characteristics of HIV-infected late presenters, opportunistic diseases at diagnosis and missed opportunities to diagnose HIV infection earlier. METHODS: In a retrospective cohort study, we reviewed the medical records of all adults with newly diagnosed HIV infection admitted to the Department of Infectious Diseases of the Vivantes Auguste-Viktoria Hospital, Berlin, Germany. RESULTS: In the 5-year period from 2009 to 2013, 270 late presenters were identified. The most common AIDS-defining conditions were oesophageal candidiasis (n = 136; 51%), wasting syndrome (n = 106; 40%) and pneumocystis pneumonia (n = 91; 34%). Fifty-five patients (21%) had presented with at least one HIV indicator condition on prior contact with health care services without being offered testing for HIV. Female patients and heterosexual men [not men who have sex with men ('non-MSM')] had a significantly higher chance of being among patients previously presenting with indicator conditions and not being tested [odds ratio (OR) 4.7; 95% confidence interval (CI) 2.2-10.0; P < 0.001; and OR 2.4; 95% CI 1.2-5.1; P < 0.01, respectively]. The most commonly missed indicator conditions were leucocytopenia (n = 13; 24%), thrombocytopenia (n = 12; 22%), oral candidiasis (n = 9; 16%), unexplained weight loss (n = 7; 13%), herpes zoster (n = 5; 9%) and cervical dysplasia/cancer (n = 4; 20% of women). The median time between presentation with an indicator condition and the diagnosis of HIV infection was 158.5 days [interquartile range (IQR) 40-572 days]. Patients with oral candidiasis and unexplained weight loss had the shortest time between the "missed opportunity" and the diagnosis of HIV infection. Fifty-five hospital admissions with a total cost of over EUR 500 000 and - most importantly - six in-hospital deaths might have been prevented if HIV testing had been performed in patients with documented indicator conditions. CONCLUSIONS: Indicator conditions are still missed by clinicians. Women and 'non-MSM' are at highest risk of presenting with an indicator condition but not being tested for HIV infection.

Effects of clofibric acid alone and in combination with 17ß-estradiol on mRNA abundance in primary hepatocytes isolated from rainbow trout.

Clofibric acid (CA) is the active substance of lipid lowering drugs. It is resistant to degradation, polar in nature, and has been found ubiquitously in the aquatic environment. Though CA is classified as a peroxisomal proliferator in rodents and is considered as a potential endocrine disruptor, little information exists on the effects of CA in aquatic organisms, such as fish. In the present study, we examined the mRNA levels of peroxisome proliferator- and estrogen-sensitive genes on the exposure of primary rainbow trout (Oncorhynchus mykiss) hepatocytes to CA alone and in combination with the natural female sex hormone, 17ß-estradiol (E2). Our results demonstrate that rainbow trout hepatocytes are relatively refractory to the effects of CA on the PPAR signaling pathway and lipid metabolism. Moreover, CA did not show recognizable estrogenic activity, but after the induction of vitellogenesis by E2, CA significantly reduced vitellogenin (VTG) mRNA abundance. Apparently, the indirect repression of VTG transcription, independent of estrogen receptors, occurred. The mechanism is not yet clearly understood but may involve disruption of the stabilization of VTG mRNA known to be induced by E2.

Mechanical and metabolic functions in pig hearts after 4 days of chronic coronary stenosis.

OBJECTIVES: This study sought to evaluate the functional and metabolic consequences of imposing a chronic external coronary stenosis around the left anterior descending coronary artery for 4 days in an intact pig model. BACKGROUND: A clinical condition termed hibernating myocardium has been described wherein as a result of chronic sustained or intermittent coronary hypoperfusion, heart muscle minimizes energy demands by decreasing mechanical function and thus avoids cell death. The use of chronic animal models to stimulate this disorder may assist in establishing causative associations among determinants to explain this phenomenon. METHODS: A hydraulic cuff occluder was placed around the left anterior descending coronary artery in eight pigs. Coronary flow velocity was reduced by a mean (+/- SE) of 49 +/- 5% of prestenotic values, as estimated by a Doppler velocity probe. After 4 days the pigs were prepared with extracorporeal coronary circulation and evaluated at flow conditions dictated by the cuff occluder. Substrate utilizations were described using equilibrium labeling with [U-14C]palmitate and [5-3H]glucose. Results were compared with a combined group of 21 acute and chronic (4 day) sham animals. RESULTS: Four days of partial coronary stenosis significantly decreased regional systolic shortening by 54%. Myocardial oxygen consumption was maintained at aerobic levels, and rest coronary flows were normal. Fatty acid oxidation was decreased by 43% below composite sham values, and exogenous glucose utilization was increased severalfold. Alterations in myocardial metabolism were accompanied by a decline in tissue content of adenosine triphosphate. CONCLUSIONS: These data suggest that chronic coronary stenosis in the absence of macroscarring imparts an impairment in mechanical function, whereas coronary flow and myocardial oxygen consumption are preserved at rest. The increases in glycolytic flux of exogenous glucose are similar to observations on glucose uptake assessed by fluorine-18 2-deoxy-2-fluoro-D-glucose in patients with advanced coronary artery disease. We speculate that intermittent episodes of ischemia and reperfusion are the cause of this phenomenon.

Effects of moderate repetitive ischemia on myocardial substrate utilization.

The purpose of this report was to directly measure the influence of antecedent ischemia or repetitive ischemia on subsequent rates of intermediary metabolism, specifically exogenous glucose utilization and fatty acid oxidation, with the use of myocardial equilibrium labeling with [U-14C]palmitate and [5-3H]glucose. Twenty-one intact, working, extracorporeally perfused pig hearts were prepared and divided into three groups. These groups included 7 control hearts and 14 comparison hearts, which were exposed to either one cycle (cycle 1, n = 7) or four cycles (cycle 4, n = 7) of brief (5-10 min), moderate (70% decrease in flow below aerobic values) precursory ischemia to the left anterior descending (LAD) circulation followed by aerobic reperfusion. All groups then underwent a 40 min sustained LAD ischemia (60% decrease in flow below aerobic levels) and 40 min aerobic reperfusion. Treatment with one cycle of transient ischemia did not significantly modify the pattern of glycolytic flux from control values during sustained ischemia (over a ninefold increase in average control and cycle 1 values above aerobic levels). However, repetitive ischemia in cycle 4 hearts demonstrably attenuated glycolytic flux during the same interval (-45% from control hearts, P < 0.046). Glucose utilization rapidly returned to near-aerobic values in all three groups during reperfusion but was again appreciably lower (P < 0.004 from control values) in cycle 4 hearts. Fatty acid oxidation averaged 12.3 +/- 1.2 mumol.h-1.g dry wt-1 in all three groups during sustained ischemia and 21.3 +/- 2.0 mumol.h-1.g dry wt-1 during reperfusion (not significant among groups for either perfusion interval).(ABSTRACT TRUNCATED AT 250 WORDS)

Ischemia produces an increase in ammonia output in swine myocardium.

We have recently reported that ischemia causes myocardial ammonia production which is not due to amino acid breakdown. The purpose of this study was to identify the remaining possible sources of ammonia production. The prospects were either deamination of AMP to inosine monophosphate (IMP), or adenosine to inosine. Eight intact extracorporally perfused pig hearts were rendered regionally ischemic by reducing the left anterior descending coronary artery blood flow by 60% for 40 minutes. Adjacent myocardium supplied by the circumflex artery was held aerobic throughout the study. Myocardial oxygen consumption and regional systolic shortening in the left anterior descending perfusion bed fell by 50 and 32%, respectively. Myocardial ammonia production increased significantly (p = 0.008) and tissue ammonia concentration was 55% greater in the ischemic left anterior descending bed than in the aerobic circumflex bed (p = 0.003). Compared to the circumflex bed, ATP and creatine phosphate concentrations in the left anterior descending bed were decreased by 41 and 53%, respectively. There were no significant increases in AMP or IMP levels, however there were dramatic increases of 525 and 397% in adenosine and inosine levels in the ischemic tissue. Thus, myocardial ammonia production was stimulated by ischemia without an increase in IMP levels. Combined with the fact that adenylate deaminase levels in the swine myocardium are normally low, this leads to the likely conclusion that source of the increased myocardial ammonia production during ischemia is deamination of adenosine, not IMP formation from AMP.

Myocardial function and metabolism in pig hearts after relief from chronic partial coronary stenosis.

Metabolic behavior was compared during acute extracorporeal reperfusion after removal of a chronic 4-day partial coronary stenosis in eight pig hearts (RCS group) and during comparable extracorporeal perfusion in seven chronically prepared hearts (Sham group). Coronary stenosis in RCS hearts was induced in the left anterior descending (LAD) artery by partial inflation of a hydraulic occluder to restrict LAD peak phasic velocity by approximately 50%. Regional mechanical shortening was decreased in RCS compared with Sham hearts after 4 days of chronic coronary stenosis [diminished systolic shortening (P < 0.066) with systolic expansion (P < 0.015)] but was comparable to Sham hearts after relief from stenosis. At analogous workloads (left ventricular pressure and heart rate) during reperfusion, metabolic behavior was distinctive between groups. Specifically, compared with Sham hearts, myocardial O2 consumption was selectively increased in RCS hearts (+ 49 delta %, P < 0.026) as was fatty acid oxidation estimated from 14CO2 production from [U-14C]palmitate (+ 60 delta %, P < 0.061) and exogenous glucose utilization measured from the release of 3H2O from [5-3H]glucose (+ 517 delta %, P < 0.025). At the conclusion of the studies, triphenyltetrazolium chloride staining showed no gross evidence of macroinfarction in RCS or Sham hearts, and there was an essentially unremarkable histological survey of anterior myocardium for microscopic necrosis in either group. The level of O2 consumption and preservation of preferred fatty acid utilization indicate that metabolism remains or regains its aerobic pattern of activity in early recovery immediately after removal of chronic partial coronary stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial metabolism in chronic reperfusion after nontransmural infarction in pig hearts.

The purpose of these studies was to evaluate metabolic behavior in a 4-day reperfusion model in pigs after induction of subendocardial infarction. Two groups of swine [sham and intervention (Int) groups, n = 7) and 10 hearts per group, respectively] were prepared comparably with two surgical procedures separated over 4 days. In the Int group at the time of the first surgery, coronary flow in the left anterior descending (LAD) circulation was partially restricted (by 60%) for 60 min and was then reperfused. LAD myocardium at the time of the second surgery in both groups was extracorporeally perfused aerobically (5.9 +/- 0.2 ml.min-1.g dry wt-1) for 60 min and infused by equilibrium labeling with [U-14C]-palmitate and [5-3H]glucose to estimate fatty acid oxidation and exogenous glucose utilization. During extracorporeal perfusion, regional myocardial shortening and oxygen consumption were comparable between groups despite a marginal impairment in ATP resynthesis by mitochondria (26% decrease, P < 0.071) in Int hearts and a significant decline in mitochondrial respiration (45% decrease in respiratory control rate, P < 0.008; and 41% decrease in state 3 respiration, P < 0.032) as compared with sham hearts. Fatty acid oxidation described by 14CO2 production was 34.00 +/- 4.72 mumol.h-1.g dry wt-1 (averaged from 30-60 min of perfusion) in sham hearts but was decreased (by 48%, P < 0.004) in Int hearts. This reduction in fatty acid utilization may in part be explained by declines in the observed activity of the mitochondrial membrane transporter enzyme, carnitine palmitoyltransferase.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of pantothenic acid, cysteine and dithiothreitol in intact, reperfused pig hearts.

The objective of this study was to augment myocardial tissue levels of amphiphiles using a treatment protocol of pantothenic acid, cysteine and dithiothreitol (DTT) in 24 hr fasted pigs and to test their influence on mechanical recovery in reperfusion. Eighteen pig hearts were extracorporeally perfused aerobically, subjected to regionally reversible ischemia in the left anterior descending perfusion system and reperfused. Nine hearts served as a placebo group; nine hearts were treated. All hearts received trace-labeled palmitate to measure fatty acid oxidation and were perfused with an infusion of 20% Intralipid to augment perfusate levels of fatty acids. Fasting alone in the presence of carbon substrates in the coronary perfusate was not sufficient to de-inhibit pantothenic acid kinase such that CoA synthesis was not enhanced. Tissue contents of triacylglycerols and phospholipids in reperfused myocardium were no different than in aerobic heart muscle but free CoA and free and total carnitine were reduced, suggesting a leakage of cytosolic contents across injured sarcolemma. Treatment significantly impaired mechanical recovery during reflow, presumable due to the noxious properties of DTT whose reported effects in heart muscle are wide ranging, difficult to predict in intact hearts and may be harmful.

Clinical assessment of the surgical patient with heart disease.

This article is a review of available data describing those identifying features that should prospectively alert surgeons, anesthesiologists, and their medical consultants to a subpopulation of cardiac patients most likely to tolerate noncardiac surgery poorly. Appropriate management decisions are discussed also.

Effects of carnitine in ischemic and fatty acid supplemented swine hearts.

FREE FATTY ACIDS (FFA) IN EXCESS FFA: albumin molar ratios have been determined to additionally compromise mechanical performance in ischemic hearts. Carnitine, an intracellular carrier of FFA and an agent which is lost to the heart during ischemia, has been postulated to in part restore function with its replacement. To test whether its benefits are also operative in a setting of excess FFA, these studies were performed. In the main protocol, four groups of perfused swine hearts (n = 45) were compared during 50 min of control flow (179.7 ml/min) and 40 min of global ischemia (106.1 ml/min). Initial base-line serum FFA:albumin molar ratios and carnitine levels in all groups were 1.3:1 and 8.5 nmol/ml, respectively. In two of these groups FFA:albumin ratios were increased to 5.9:1 with constant infusions of Intralipid. In two alternate groups (one with and one without extra FFA supplements) dl-carnitine was supplied, sufficient to increase serum levels nearly 200-fold. Ischemia per se in 14 hearts significantly decreased several parameters of global and regional mechanical function including left ventricular (LV) and mean aortic pressures, LV isovolumetric pressure development (max dp/dt), LV epicardial motion, and LV work, together with concomitant decreases in myocardial oxygen consumption. Elevated FFA in 12 hearts rendered similarly ischemic further decreased mechanical function (LV pressure: -20.8%, P < 0.05; mean aortic pressure -26.9%, P < 0.05; LV max dp/dt: -39%, P < 0.05; regional LV shortening: -51.1%, P < 0.05; and LV work: -50.3%, P < 0.05) as compared with nonsupplemented hearts. dl-Carnitine treatments in nine hearts, not supplemented with extra FFA were without apparent effect in improving overall hemodynamic performance. However, dl-carnitine in 10 high FFA-ischemic hearts effected several improvements as compared with the untreated group: LV pressure was increased 25.6%, P < 0.025; mean aortic pressure: +43.5%, P < 0.05; LV max dp/dt: +41.5%, P < 0.05; regional LV shortening: +241.3%, P < 0.001; and LV work: +76.2%, P < 0.05 at comparable levels of myocardial oxygen consumption. In a separate protocol, the effects of stereospecificity were also studied by comparing l- with dl-carnitine in globally perfused, palmitate-supplemented hearts (five hearts in each treatment group). At similar conditions of flow and serum FFA, changes in mechanical function were comparable, except for a tendency to perform greater LV work at reduced flows in the l-carnitine-treated hearts. Thus, it was demonstrated that carnitine in ischemic hearts is capable of preserving mechanical function under conditions of excess FFA, presumably by modifying the toxic effects of FFA intermediates. The major therapeutic actions appeared to derive from the l-isomer of carnitine.

Ischemic injury to the conducting system of the heart. Involvement of myocardial lysosomes.

The conducting system was studied in an in situ perfused swine heart preparation with reduced coronary flow (ischemia) using perfusate containing high and low levels of glucose (26.6 versus 8.6mM) with and without insulin. Coronary flow was maintained at normal levels for 60 minutes in control hearts. In ischemic hearts flow was reduced to about 50 percent of control levels for 30 minutes. Ultrastructural studies documented only subtle modifications of Purkinje fibers in ischemic hearts. Glycogen depletion and disruption of cell junctions were observed in some fibers. One consistent finding was the activation of the lysosomal system. The outer membranes of primary lysosomes appeared herniated and in some cases disrupted, and small vesicles containing hydrolytic enzymes were seen in association with the Golgi apparatus and larger primary lysosomes. Specimens prepared for the demonstration of acid phosphatase indicated a redistribution of hydrolytic enzymes in Purkinje fibers with a depostion of acid hydrolases in smaller lysosomal vesicles, the transverse and side-to-side junctions between cells, and occasionally in the sarcoplasmic reticulum. Enriched perfusate containing high levels of glucose with insulin appeared to have no therapeutic effects in terms of the structure of the Purkinje fibers. The results suggest that alterations in the lysosomal system may be one of the earliest structural changes which occur in oxygen-deficient hearts.

The role of coronary artery injury and perfusion in the development of cardiac contusion secondary to nonpenetrating chest trauma.

Myocardial contusion secondary to nonpenetrating chest trauma can occur in the absence of any identifiable large vessel coronary artery occlusion or injury. It has also been reported in association with coronary artery atheromata, thrombosis, rupture, and fistula formation. After reviewing the clinical and experimental research literature, we conclude that myocardial contusion necrosis results from changes in perfusion of small vessels and the coronary microvasculature. Coronary arteriography and emergency coronary artery bypass surgery do not appear promising as therapeutic modalities to reduce myocardial necrosis in this condition. More appropriate therapeutic emphasis may result from research efforts to develop pharmacologic interventions to preserve contused myocardium similar to those currently being evaluated in the management of patients with ischemic myocardium secondary to coronary artery disease.

Diffuse coronary artery disease in diabetic patients: fact or fiction?

To compare angiographically-determined coronary artery disease in diabetic patients with controls, 1,653 patients coming to cardiac catheterization were reviewed retrospectively to find 37 diabetic and 79 control patients matched for sex, age (+/- 3 years), and risk factors (hypertension, hyperlipidemia, and smoking). The severity of coronary artery disease was assessed using an angiographic grading system. The following results were obtained: 16 of 37 diabetic patients (43%) had three-vessel disease compared to 20 of 79 controls (25%). Seventy-six of 111 (68%) diabetic vessels were diseased compared to 110 of 237 control vessels (46%) (P less than 0.005). The total coronary score reflecting total extent of disease for diabetic patients was 371 (mean 10.0 +/- (SEM) compared to 594 for controls (mean 7.5 +/- 0.7, (P less than 0.01). Diabetic patients had a statistically similar number of diffusely diseased vessels as controls (28% vs 22%). There were only three of 76 diabetic vessels (4%) considered inoperable compared to seven of 110 (6%) control vessels. We conclude that diabetic patients with chest pain have more coronary artery disease than nondiabetics, but no more diffuse or inoperable disease.

Consequences of intramyocardial arterial lesions in aortic valvular stenosis.

Proliferative lesions, which included collagen deposition, developed with age in intramyocardial arteries of 27 patients with aortic stenosis and matched controls. Those with the most extensive intramyocardial artery lesions developed massive subendocardial infarcts during surgery. Using histologic quantitation, the percent of intramyocardial arteries with lesions in a patient was correlated with decreases in the amount of muscle in arterioles between the subepicardial and subendocardial zones of the left ventricle. The mean decrease in arteriolar muscle was 43% in patients with aortic stenosis and 19% in controls. Blood pressures correlate with the amount of muscle in arterioles, so subendocardial perfusing pressures were presumably low in those with aortic stenosis. Patients with the greatest decrease in arteriolar muscle across the myocardium had the most impaired left ventricular function, i.e., highest end diastolic pressures, lowest ejection fractions, and lowest mean fiber shortening rates.

Effects of coronary perfusion during myocardial hypoxia. Comparison of metabolic and hemodynamic events with global ischemia and hypoxemia.

The effects of metabolic accumulation on myocardial metabolism during global heart oxygen deprivation were evaluated in a working in situ swine heart preparation with controlled total coronary blood flow. Myocardial oxygen consumption was depressed to a similar extent by either reducing total coronary flow 60 per cent (ischemia, low coronary perfusion) in 10 swine or by decreasing coronary perfusate PO2 to 30 mm. Hg at normal flows (hypoxemia, high coronary perfusion) in 13 swine. Compared with findings in 13 control hearts, ischemia significantly (p less than 0.05) decreased myocardial oxygen consumption (640 to 390 mumole per hour per gram), glucose uptake (185 to 16 mumole per hour per gram), and free fatty acid consumption (32 to 17 mumole per hour per gram). ttissue levels of glycogen, creatine phosphate, and adenosine triphosphate (tatp) were significantly reduced (p less than 0.005), and tissue lactate, adenosine diphosphate (ADP), and adenosine monophosphate (AMP) were increased (p less than 0.001). During hypoxemia, glucose uptake was increased (240 mumole per hour per gram) and free fatty acid consumption was somewhat less depressed (19 mumole per hour per gram). Creatine phosphate and ATP were higher than with ischemia (p less than 0.01), and lactate, ADP, and AMP accumulations were less (p less than 0.01). Thus, in the period immediately following myocardial oxygen deprivation, inadequate coronary perfusion caused greater metabolic buildup which inhibited myocardial substrate utilization and energy production. High coronary perfusion, even though the perfusate was unoxygenated, was associated with greater preservation of substrate utilization, higher levels of high-energy phosphates, less accumulation of metabolic products, and a longer survival. These data suggest a critical role of coronary perfusion in protecting myocardial metabolism in the immediate period following global heart hypoxia.

Functional reductions in left ventricular volume. Minimum chamber size consonant with effective hemodynamic performance.

A heart model in dogs was developed to evaluate quantitatively the extent to which left ventricular chamber size could be reduced and yet retain residual mechanical function to perform adequately as a pump. In 9 animals placed on right heart bypass perfusion to control systemic flows; left ventricular performance was estimated from high-fidelity left ventricular pressure and aortic flowmeter recordings and from lateral plane left ventricular angiograms. Studies were made during unrestricted left ventricular filling at varying cardiac outputs and with inflation of a balloon in the left ventricular cavity at a physiological cardiac output. As compared with control data (cardiac output 1.4 L. per minute), balloon inflation to 18.7 ml. caused an increase in total left ventricular end-diastolic volume (from 35.4 to 44.3 ml., p less than 0.001) and left atrial pressure (from 7.8 to 21.2 mm. Hg; p less than 0.001); it also caused a reduction in left ventricular stroke work (from 12.5 to 8.1 Gm.-M., P LESS THAN 0.005) ANd max. dp/dt (from 2,487 to 1,320 mm. Hg per second, p less than 0.05). Importantly, left ventricular stroke volume was unchanged. When compared with preload augmentation (with the balloon deflated), the magnitude of depression of cardiac performance caused by balloon inflation was more fully appreciated (left ventricular stroke work, max. dp/dt, and ejection fraction reduced 69, 61, and 45 per cent, respectively). Even so, with appropriate compensations, principally by the Frank-Starling mechanism, up to 42 per cent of the left ventricular cavity volume could be functionally eliminated with retention of adequate mechanical performance. Such data may have implications regarding the extent of resections possible in patients undergoing surgery for left ventricular aneurysm.

Metabolic responses to varying restrictions of coronary blood flow in swine.

An in situ working swine heart preparation is described in which total coronary perfusion was controlled. At normal rates of coronary flow, oxygen, glucose, and fatty acid utilization were stable for at least a 60-min perfusion period. With a 50% reduction in coronary flow, oxygen and glucose consumption were reduced during 30 min of perfusion and fatty acid extraction was lower at the end of 30 min. Glycogen utilization was increased, but tissue levels of creatine phosphate, ATP, and lactate were similar to those in hearts receiving normal flow. With a 60% reduction in coronary flow, uptake of oxygen, glucose, and fatty acids were further decreased. Tissue levels of high-energy phosphates and glycogen were decreased and ADP, AMP, and lactate increased. Mechanical performance progressively deteriorated in these hearts, and ventricular fibrillation developed after about 20 min (19.8 plus or minus 3.0 min). The data indicate that this preparation is suitable for the study of myocardial metabolism during mild and severe ischemia and may be useful for the evaluation of pharmacological interventions designed for the treatment of myocardial ischemia.

An experimental model for studying myocardial ischemia. Correlation of hemodynamic performance and metabolism in the working swine heart.

An intact, working swine heart preparation with controlled coronary perfusion is described. In this model, hemodynamic and metabolic functions were correlated in control and ischemic myocardium. A closed-loop, extracorporeal coronary perfusion circuit in series with a perfusion pump and oxygenator was designed to return reoxygenated coronary venous blood at controlled flow rates to the left and right coronary arteries. In 9 swine at normal flows (232 plus or minus 17 ml. per minute), the preparation maintained stable hemodynamic performance and oxygen consumption for a 1 hour period, after which ischemia was induced by reducing coronary flow by 50 per cent. As a result, left ventricular end-diastolic pressure (LVEDP) rose by 227 per cent, whereas heart rate (-17 per cent), aortic pressure (-9 per cent), pressure time/minute (PTM) (-28 per cent), left ventricular work (-47 per cent), and oxygen consumption (-39 per cent) all decreased. The ischemic myocardium shifted from lactate extraction to production. With this model, we can define, over a period of time, several mechanical and metabolic collations as a function of total coronary blood flow in an intact, large animal. We can also test interventions during the acute phases of ischemia in an effort to reduce myocardial damage.

Relationship between coronary flow and adenosine triphosphate production from glycolysis and oxidative metabolism.

The relationship between coronary flow and adenosine triphosphate ATP production was determined in isolated rat hearts and in situ pigs hearts. The major source of ATP in ischemic hearts was oxidative phosphorylation. Oxidation of glucose accounted for most of the residual oxygen consumption in ischemic hearts when the concentration of fatty acids was low, but at 1.2 mM palmitate fatty acids were oxidized in preference to carbohydrate, as in aerobic hearts. The rates of ATP production from both glycolysis and oxidative metabolism were decreased in proportion to the reduction in coronary flow in oxygen-deficient hearts. Glycolysis was reduced to below aerobic rates when coronary flow was about 0.5 ml/min/g tissue in both rat hearts perfused with bicarbonate buffer and blood-perfused pig hearts. Tissue level of high energy phosphates reflected the rates of ATP production and declined in proportion to the reduction in coronary flow. In addition, tissue lactate and H+ accumulated in proportion to the restriction in flow.