Showing papers in "Cardiovascular Research in 1980"

Preferential uptake of lactate by the normal myocardium in dogs

Abstract: This study was undertaken to investigate whether the normal dog heart would switch to lactate as the preferred substrate when the arterial lactate level was raised. Sodium L-Lactate (pH adjusted to 7.0) was infused intravenously in sufficient quantity to raise the arterial lactate levels to those found in moderate to severe exercise (over 4.5 mmol.litre−1). The dogs were studied under chloralose anaesthesia breathing spontaneously. Blood samples were obtained from a branch of the femoral artery and the coronary sinus, and analysed for lactate, glucose, fatty free acids (FFA) and oxygen content. The ratio of lactate consumption to oxygen consumption was used to express the amount of lactate oxidised as a percentage of total substrate. This ratio was found to be a function of arterial lactate and reached a maximum at an arterial lactate concentration of 4.5 mmol.litre−1; this was uninfluenced by raised arterial glucose or FFA — the myocardium preferred lactate to glucose or FFA. A direct measurement of lactate oxidised as a percentage of total fuel was obtained in experiments with L-Lactate-[14C(U)], these showed that when the arterial lactate concentration was above 4.5 mmol.litre−1, even in the presence of high glucose or FFA, 87% of the total substrate oxidised was lactate. These results show that when the normal dog heart is presented with a choice of substrates, lactate is the preferred substrate for energy production.

Review: Observations on experimental myocardial ischaemia

Abstract: Over the past decade major advances have been made in the understanding of myocardial infarction largely through the use of animal models of ischaemia and infarction. Ultrastructural and biochemical aspects of reversible versus irreversible ischaemic injury have helped to clarify the nature of ischaemic cell death. The presence of a border zone of cells which are in the reversible phase of myocardial injury following coronary artery occlusion allows for salvage of ischaemic myocardium by a number of interventions. These interventions include reperfusion a variety of pharmacological agents, and physical and haemodynamic interventions. Several clinical studies have shown that these interventions may be beneficial in the treatment of patients with acute myocardial infarction.

Prediction of severity of coronary artery disease using slope of submaximal ST segment/heart rate relationship.

Abstract: A new exercise electrocardiography test has been examined in patients with angina pectoris; the rate of development of ST segment depression with respect to increases in heart rate during exercise on a bicycle ergometer was measured during exercise using 13 leads in 64 patients. The steepest slope of regression lines relating displacement of ST segment to increases in heart rate (maximal ST/HR slope) was used as an index of myocardial ischaemia and was compared with the results of coronary angiography which were determined by the radiologists and the cardiologist responsible for the management of these patients. The maximal ST/HR slope could be derived consistently from a linear ST/HR relationship (r greater than 0.95) only in 50 patients with significant coronary artery disease (greater than or equal to 75% liminal narrowing). The ranges of the maximal ST/HR slope in 17 patients with single-vessel disease, in 18 patients with double-vessel disease and in 15 patients with triple-vessel disease were different from each other and the differences between the means were statistically significant (P less than 0.0005). The maximal ST/HR slopes for the patients with single-vessel disease were also different from those in the 14 patients in whom significant coronary disease could not be demonstrated. In contrast, the criteria of heart rate at which ST segment depression began, maximum ST segment depression, rate-pressure product and heart rate attained at the end of the test showed an overlap between the groups of the patients studied; using the usual exercise test criteria in the same population, there were three false negative results, one false positive result and the results in eight of the patients were indeterminate. It is concluded that the maximal ST/HR slope, used as an index of myocardial ischaemia, reliably predicted the presence and severity of coronary artery disease, as determined by coronary arteriography in each of the patients with anginal pain.

Cardiac involvement in secondary haemochromatosis: a catheter biopsy study and analysis of myocardium

Abstract: Although high blood transfusion regimens have improved the life expectancy of the patient with Thalassemia Major, cardiac failure and arrhythmias remain a cause of early death It is not certain whether the massive myocardial iron deposition found in such patients is preventable by intensive chelation therapy This study evaluates endomyocardial biopsy as a method of assessing myocardial iron deposition Of four patients with clinical and biochemical evidence of severe haemochromatosis, only one had a myocardial iron content comparable to that found in severe haemochromatotic myocardium The one patient with cardiac failure had an endomyocardial iron content within the normal range Studies of the iron distribution in haemochromatotic myocardium demonstrate that the subendocardial myocardium contains only half the iron content of the subepicardial layer, and there is a large sampling variation It is concluded that catheter endomyocardial biopsy is an insensitive method of determining early myocardial deposition because of the location of iron and the variability of the sampling Studies of the nature of the myocardial iron protein with CM32 cation exchange resin chromatography show that there is a large increase in the haemosiderin: ferritin ratio (5:1) in iron overload myocardium as compared with the normal heart (2:1) Similar results have been observed in the liver with iron overload, where the increase in hepatic haemosiderin was associated with greater lysosomal fragility It is possible that myocardial cell damage may also occur by the rupture of iron engorged lysosomes

Myocardial blood flow and capillary density in chronic pressure overload of the feline left ventricle

Abstract: The effects of chronic pressure overload hypertrophy on myocardial blood flow and capillary density was measured in the feline left ventricle. Myocardial hypertrophy was produced by and 84% banding constriction of the ascending aorta 2.8 +/- 1.2 months before the experiments. In seven cats with aortic constriction, cardiac hypertrophy produced a 40% increase in left ventricular mass. Seven cats served as normals. Our findings show that, in chronic pressure overload hypertrophy, coronary blood flow at control (resting) levels is increased compared with normals. In both normal and hypertrophy cats endocardial/epicardial flow ratios were equal at the control level. In the hypertrophied hearts, coronary reserve, measured as the percentage increase in myocardial blood flow from control to near maximal flow during adenosine infusion, was reduced. In the hypertrophy group a shift in the transmural distribution of blood flow in the left ventricle was noticed, as indicated by a reduced endo/epi flow ratio, during adenosine infusion. A decreased capillary density in hypertrophy, most marked in endocardial tissue regions, was demonstrated by this study. These findings indicate that capillary growth does not parallel myofibre growth in the endocardium of pressure overload hypertrophied left ventricles. The resultant anatomical imbalance causes a compromise of flow reserve in the endocardium, making this region vulnerable to ischaemia.

Protective effect of verapamil on vulnerability to ventricular fibrillation during myocardial ischaemia and reperfusion

Abstract: The effects of verapamil on vulnerability to ventricular fibrillation were studied in 55 chloralose-anaesthetised dogs. Ventricular fibrillation threshold was measured before and during a 10 min period of left anterior descending coronary artery occlusion and following abrupt release of occlusion.The action of intravenous verapamil (0.01 mg·kg−1·min−1, following a 0.1 mg·kg−1 bolus) on vulnerability to fibrillation was examined before and during coronary artery occlusion and reperfusion. While the infusion of verapamil did not alter the ventricular fibrillation threshold in the nonischaemic myocardium, the vulnerable period threshold was raised and the incidence of spontaneous ventricular fibrillation was reduced both after coronary artery occlusion and release. Since cardiocardiac sympathetic reflexes are elicited in response to coronary artery occlusion, the effect of verapamil on vulnerability during left stellate ganglion stimulation and during noradrenaline infusion was investigated. Verapamil completely prevented the reduction in vulnerable period threshold during sympathetic nerve stimulation or noradrenaline infusion. This study suggests that the antifibrillatory action of verapamil during coronary artery occlusion may be, in part, related to antagonism of enhanced adrenergic input to the heart, while the mechanism of protection during reperfusion is as yet uncertain.

Measurement of left ventricular wall stress

Abstract: Forces in the myocardial wall can be measured in several ways or calculated using certain simplifying assumptions. In this study we investigated the reliability of two measurement methods, one of which was introduced by Feigl et al (1967), whereas the other method was developed in our laboratory. Both methods were tested in actively contracting skeletal muscle and beating hearts of open-chest dogs by comparing the force transferred from the muscle to the transducer under various circumstances. It appeared that changes in muscle length, be it through initial length changes or through shortening during contractions, had a great influence on the transfer of force to the transducer, for both methods, in both preparations. In the heart a decrease in internal left ventricular diameter of 15% resulted in a 50% reduction of force transferred to the transducer, independent of whether the length took place as a change in filling or as a change in ejection volume. In skeletal muscle the length-dependent effects during shortening were larger and those resulting from initial length changes were more variable than in beating hearts. That the effects of muscle length changes are of such magnitude means that, if no other errors exist, they alone would invalidate that until principally different methods of measuring wall stress in the myocardium are discovered, attempts at accurate calculation of myocardial wall stress are a better approach than wall stress measurements.

Collagen content in different areas of normal and hypertrophied rat myocardium

Abstract: Hydroxyproline concentration, representing the collagen content, in different areas of hypertrophied hearts from spontaneously hypertensive rats aged 10 and 16 months and in similar areas of hearts from control rats of the same age was investigated. As was expected, the hydroxyproline concentration in the left ventricular free wall from normal rats was lower than in the right ventricle and septum. In different parts of the normal left ventricle (endomyocardial and epimyocardial areas, papillary muscles) the hydroxyproline concentration was approximately the same. In all myocardial parts from the 16-month-old normal rats, the hydroxyproline concentration was greater than in respective tissue from younger (10-month-old) rats. The hydroxyproline concentration was increased in all parts of the hypertrophied myocardium in spontaneously hypertensive rats. The increase was greatest in endomyocardial areas of the left ventricular wall. The difference in increase of hydroxyproline concentration between epimyocardial and endomyocardial areas was greater in 10, than in 16-month-old spontaneously hypertensive rats. In the hypertrophied left ventricular papillary muscles the hydroxyproline concentration was lower than the average hydroxyproline concentration in the hypertrophied left ventricle as a whole. The results of this study demonstrate that pathophysiological changes in the hypertrophied left myocardium of spontaneously hypertensive rats are not the same in all ventricular areas.

Circadian rhythm of baroreflex reactivity and adrenergic vascular response.

Abstract: Five healthy normotensive volunteers (mean ± SEM age 29.6 ± 4.6 years) were infused with l -noradrenaline for a 15 min period every 3 hours for 24 hours from 0900. The concentrations of l -noradrenaline used were 0.02. 0.03, 0.05 [μg·kg−1·min−1, preceded by a saline infusion, each step lasting 5 min. The lowest preinfusion blood pressures and heart rates were at 0300 and 0600, the range being 1.45 kPa (11.6 mmHg) systolic, 1.33 kPa (10.0 mmHg) diastolic pressure, and 12.2 beats·min−1, heart rate. The slope of the log-dose response curve relating systolic pressure to infused noradrenaline was significantly reduced at 0300 compared with 0900 (P <0.05) and at 1200 compared with 1500 (P < 0.05). Baroreflex sensitivity as measured by the regression of mean RR interval on systolic pressure, was maximal at 1200 and 0300. The circadian variation to tilt was studied in the same subjects on a separate occasion. Mean tilted minus mean lying systolic pressure was least at 1200 and 0300. Supine plasma noradrenaline did not differ with clock time, but on tilt to 70° head up, plasma noradrenaline was significantly lower at 1200 and 0300 than at 0900 and 1500 respectively (P <0.05). The slope of RR interval on systolic pressure in response to tilt is significantly increased at 1200 and 0300 compared with 0900 and 2100 (P <0.05). These results suggest a decline in adrenergic vascular reactivity and an increase in the gain of the baroreflex at 1200 and 0300.

Transient depolarisation and action potential alterations following mechanical changes in isolated myocardium

Abstract: The effects of induced changes in muscle length on the action potential of frog ventricular strips and cat papillary muscle have been studied. When the frog preparation was stretched near the onset of contraction, the action potential duration shortened whereas a stretch during peak activity produced minimal change. Action potentials of cat papillary muscle do not alter with stretch at any time. By contrast, release of both preparations at a time when tension was near its peak, prolonged repolarisation or produced a transient depolarisation. The ECG changes corrobrated the action potential changes. The release produced a deactivation of contraction which correlated with the transient depolarisation when the contraction and potential were expressed as ratios of the undisturbed measurements. Possible explanations for the results are discussed in terms of active and passive mechanisms that can relate to mechanical and electrical phenomena simultaneously. The mechanically induced transient depolarisations are clinically relevant, for regional ischaemia produces electrical and mechanical inhomogeneities which would cause contraction-excitation feedback interactions and thus electrophysiological abnormalities.

Furosemide-induced thiamine deficiency

Abstract: Male Wistar rats were separated into 4 groups: group 1, thiamine sufficient diet (control); group 2, thiamine sufficient diet with intraperitoneal administration of furosemide (20 mg . kg-1 of body weight); group 3, thiamine deficient diet; group 4, thiamine deficient diet within tra-peritoneal administration of furosemide. After 4 weeks, the rats were killed and the thiamine levels and activity of transketolase were assayed. Thiamine concentration and transketolase activity were significantly decreased and thiamine pyrophosphate effect was significantly increased in the blood, and various tissues in group 2 and 4 compared with group 1 and 3, respectively. The intraperitoneal administration of various concentrations of furosemide (20 mg, 10 mg, and 2 mg . kg-1 of body weight) resulted in a significant increase in urinary thiamine excretion. Thus, it is assumed that long-term administration of furosemide could induce a thiamine deficiency.

Spontaneous phasic activity of isolated human coronary arteries.

Abstract: The functional behaviour and pharmacological responses of ring segments of large coronary arteries removed from five patients undergoing cardiac transplantation were studied in vitro. All segments showed spontaneous rhythmic contractions which were markedly dependent on external calcium and were rapidly abolished in calcium-free solutions and by verapamil. The contractions were inhibited by cooling and by anoxia. Phasic activity was enhanced by increasing the external potassium concentration over the range 5 to 20 mmol.litre-1 but was abolished by 120 mmol.litre-1 potassium. Noradrenaline and ergonovine enhanced or induced phasic activity. The behaviour of human coronary arteries resembles that of the portal-mesenteric veins of many species and our results suggest that the activation mechanisms of these two tissues may be similar.

Mechanisms of tachycardia on standing: studies in normal individuals and in chronic Chagas' heart patients.

Abstract: The reflex tachycardia induced by change from the supine position to a 70 degree head-up tilt was studied in conscious normal individuals and in patients with chronic Chagas' heart disease, known to constitute a model of parasympathetic denervation of the sinus node, in the absence of cardiac failure. Chagas' patients showed markedly decreased heart rate responses during the initial 10 s following tilt to upright posture. A similar response was obtained in normals after parasympathetic blockade with atropine. beta-Adrenergic blockade failed to produce a significant effect on the initial heart rate response of normals, but heart rate increment, at 1 and 5 min of tilt, was significantly reduced in normals and abolished in patients. These results indicate a biphasic mode of tachycardia elicited by the upright posture; initially it depends on parasympathetic withdrawal, sympathetic stimulation becoming the predominant mechanism when stabilisation is attained in the orthostatic position.

Variability of the body surface distributions of QRS, ST-T and QRST deflection areas with varied activation sequence in dogs

Abstract: Distributions of QRS, ST-T and QRST areas of 192 lead body surface ECG's were measured in dogs for multiple activation orders. Qualitatively, the distributions of QRST area were found to be strikingly similar over all activation orders in contrast to the distributions of QRS or ST-T areas. Quantitative results showed that variability of the QRST areas over all activation orders was consistently less than those of either QRS or ST-T. The factor responsible for the QRS deflection is ventricular activation sequence while those responsible for the ST-T deflection are both activation sequence and ventricular recovery properties. Since the total QRST deflection area was largely independent of activation sequence it is likely the quantity is an index of ventricular recovery properties. The significance of this relation is that QRST deflection area may permit evaluation of intrinsic ventricular recovery properties in the presence of abnormal ventricular activation as occurs with intraventricular conduction disorders and ectopic origin of excitation. Evaluation of intrinsic ventricular recovery properties may also permit recognition of states at risk of ventricular arrhythmias due to increased disparity of these properties.

Attenuation of myocardial acidosis by propranolol during ischaemic arrest and reperfusion: evidence with 31P nuclear magnetic resonance

Abstract: 31P nuclear magnetic resonance (NMR) spectroscopy was used to ascertain whether propranolol could reduce the development of myocardial acidosis during periods of ischaemic arrest and reperfusion of isolated, perfused guinea pig hearts. Two groups (35 or 60 min) of global ischaemia and arrest were studied. Cardiac pH progressively declined during ischaemia from a normal of 6.97 ± 0.02 (n = 23) to 6.09 ± 0.04 or 5.96 ± 0.04, respectively. Normalisation of pH following reperfusion occurred only in the 35 min ischaemic hearts. Propranolol (1 mg·litre−1) given prior to arrest significantly reduced the magnitude of developing acidosis regardless of the length of ischaemia. Furthermore, it aided in the normalisation of intramyocardial pH upon reperfusion in both groups. Propranolol significantly reduced the magnitude of phosphocreatine (PCr) loss normally seen during ischaemic arrest alone, but it did not protect against the depletion of ATP. Restoration of PCr during reperfusion was virtually complete in all cases, while transient increases in ATP were seen only in those hearts protected by propranolol. In summary, this NMR study demonstrated the first direct evidence that a significant component of the myocardial acidosis caused by global ischaemia and arrest can be blocked by propranolol.

Identification and quantification of histochemical border zones during the evolution of myocardial infarction in the rat.

Abstract: Several interventions have been shown to preserve ischaemic myocardium after coronary artery occlusion; yet there is uncertainty concerning the location, extent and very existence of the potentially salvageable myocardium. This study was undertaken to identify and to quantify by planimetry, histochemically different zones of myocardium in evolving infarcts. Serial frozen sections of the left ventricle from 98 rats killed at different time intervals ranging from 5 min to 72 h after coronary artery occlusion were stained for glycogen, neutral lipids and oxidative enzyme activity. From 5 to 20 min after occlusion, the ischaemic area (measured as a percentage of the cross-sectional area at the midventricular level) showed progressive glycogen loss which was, paradoxically, more severe at the periphery than at the center. By 30 min glycogen loss was uniform and complete. Three hours after occlusion 3 abnormal zones were observed: (1) a central zone of severe glycogen loss and severe loss of enzyme activity comprising 21 ± 3% (mean ± SE) of the left ventricular cross-sectional area; (2) a peripheral zone showing severe glycogen loss but only mild loss of enzyme activity comprising 21 ± 4% of the ventricle; and (3) a surrounding lipid-containing, but otherwise normal, zone comprising 9 ± 1% of the ventricle. The zone of mild loss of enzyme activity was smaller but still present 6 h after occlusion, but disappeared by 9 h as the zone of more severe loss of enzyme activity enlarged to equal the size of the glycogen-depleted zone. The lipid-containing zone persisted for 72 h. Thus, 2 histochemical border zones were observed: an outer histochemical border zone which contained lipid but was otherwise normal which was present up to 72 h after coronary occlusion, and an inner histochemical border zone with severe glycogen loss but delayed loss of enzyme activity presented at 3 and 6 h but which disappeared 9 h after coronary artery occlusion. These data support the concept that a myocardial infarction is not a homogeneous, static structure, but rather a dynamic temporally-related phenomenon with different zones that change in size and character as the infarct evolves.

Calcium exchange in rabbit myocardium during and after hypoxia: effect of temperature and substrate

Abstract: Calcium influx and efflux were measured during hypoxia and on reoxygenation in the isolated arterially perfused septum of the rabbit heart. The uptake of 47Ca2+ was continuously followed with a NaI crystal and counter. The extracellular space (ECS) was measured in a similar manner with 51Cr-EDTA. Calcium efflux was recorded by collection of effluent drops after labelling with 45Ca2+. Hypoxia caused a rapid decline of developed tension followed by a rise in resting tension. The ECS increased initially but decreased as resting tension rose. 51Cr-EDTA did not have free access to the intracellular fluid. Calcium efflux did not change and calcium influx was either unchanged or reduced. On reoxygenation calcium influx increased immediately but efflux was unaltered and 51Cr-EDTA did not enter the cell. The effects of hypoxia were altered by manipulation of temperature and substrate. The recovery of mechanical function was related to the size of the calcium influx on reoxygenation. The experiments show that a rise of resting tension during hypoxia can occur in the absence of a net gain of calcium, calcium accumulation is closely associated with the extent of tissue damage, and that calcium influx on reoxygenation is probably due to a specific abnormality and not gross disruption of the cell membrane.

Physical conditioning and membrane receptors for cardioregulatory hormones.

Abstract: To seek possible mechanisms for the relative bradycardia induced by physical conditioning we studied the effects of an eight-week swimming programme upon cardiac β-adrenergic and muscarinic-cholinergic receptors in rats. A training effect was documented by an increase in the ratio of heart wet weight to body weight in the conditioned animals compared with sedentary controls. Cardiac β-adrenergic receptors as assessed in crude membrane fractions by the binding of (−) (3H) dihydroalprenolol did not differ significantly in either number or affinity in conditioned hearts (30 ± 2 fmol·mg1 protein; KD = 1.4 ± 0.1 nmol·litre−1) compared with sedentary hearts (33 ± 2 fmol·mg−1; KD = 1.5 ± 2 nmol·litre−1). Likewise cardiac muscarinic-cholinergic receptors as assessed by the binding of (3H) quinuclidinyl benzilate to crude cardiac membranes did not differ significantly in either number or affinity in conditioned hearts (116 ± 6 fmol·mg−1 protein; KD = 0.17 ± 0.03 nmol·litre−1) compared with sedentary hearts (125 ± 11 fmol·mg−1; KD = 0.19 ± 0.03 nmol·litre−1). We conclude that the bradycardia of physical training is probably mediated by mechanisms other than alterations in cardiac β-adrenergic or muscarinic-cholinergic receptors.

Pump function of the feline left heart: changes with heart rate and its bearing on the energy balance

Abstract: Pump function of the feline left heart was determined by measuring the relationship between mean left ventricular pressure and mean left ventricular output, obtained by changing the arterial load on a beat-to-beat basis. The effect of a change in heart rate from 120 to 160 beats·min−1 was studied and a parallel shift of the pump function graph was found. Care was taken to keep left ventricular end-diastolic pressure constant with the change in frequency. If the mean pressure and output values obtained at 160 beats·min−1 were multiplied by the ratio between the two frequencies (0.75), almost complete superposition of the two graphs was obtained. Changes in arterial load also caused changes in oxygen consumption, mean external power and external efficiency of the heart. We plotted these variables, altered them as a function of mean left ventricular output for easy comparison with the pump function graph. It was found that oxygen consumption decreases with increasing output. Mean external power and efficiency attain maxima for different values of mean output. If the left heart in the intact animal is controlled to function at its maximum power output, this can therefore not be achieved at the optimum efficiency level. The results of the present study and those obtained earlier1 were compared with the behaviour of a time varying compliance model.

Background of hyperkinetic circulatory state in young spontaneously hypertensive rats

Abstract: The present study explores the relationship between central hyperreactivity to alerting stimuli and the presence of a hyperkinetic circulatory state during “rest ” in very young spontaneously hypertensive rats (SHR). 6 week old SHR, ordinary normotensive Wistar rats (NCR) and normotensive Wistar rats of the Kyoto strain (WKR) were fitted with chronic catheters in the right carotid artery and jugular vein. The rats were habituated to the laboratory environment before the actual experiment, which included measurement of cardiac output (CO), mean arterial pressure (MAP) and heart rate (HR). CO was determined by a cardiogreen dye-dilution technique in microscale. Measurements were first performed when the rats were awake and at rest, thereafter when exposed to shortlasting “mental stress”, then during pentobarbitone anaesthesia, and finally during anaesthesia combined with pharmacological blockade of the neurogenic control of the heart. Thus, central haemodynamics could be followed over a wide range of neurogenic cardiac stimulation, from complete blockade over to intense physiological stimulation during mental stress. Young SHR with a 30% MAP elevation had a higher CO at rest than either of the controls, primarily because of increased HR. During “mental stress” the pattern of increased CO and HR in SHR was further accentuated. Elimination of mental excitatory stimuli by anaesthesia, and a subsequent cardiac neurogenic blockade, lowered CO and HR more in SHR than in the controls. Following these interventions CO was similar in all groups, but MAP remained elevated in SHR because of an increased total peripheral resistance (TPR). Further, for any given CO level both MAP and TPR were always higher in SHR than in either NCR or WKR, indicative that there are already structural vascular changes in 6 week old SHR. The results further suggest that the centrally mediated cardiovascular hyperreactivity to environmental stimuli also greatly influences basal haemodynamics in young SHR and are therefore of major importance in inducing this variant of primary hypertension.

Calculation of coronary vascular resistance

Abstract: A conscious, chronically instrumented canine model was used to investigate resistance changes in the distribution of the circumflex coronary artery as the artery was constricted. Several discrete constrictions were studied at two different levels of flow: resting and peak flow reactive hyperaemia. The resistance of the bed downstream from the constriction was calculated by formulae which defined the coronary back pressure as either venous pressure (Pv) or the arterial pressure at which coronary flow ceased (Pc). When Pv was taken as the back pressure, the resistance of the coronary bed during reactive hyperaemia progressively increased as the upstream artery was constricted. When Pc was taken as the back pressure, calculated coronary resistance for reactive hyperaemia showed little change. It is not known if elastic recoil of coronary resistance vessels, consequent to low poststenotic pressure, could occur to the extent required to be the physical basis for the calculated increase in resistance when Pv is taken to be the back pressure. Use of Pc as the back pressure implies that the coronary circulation contains a segment having the hydraulic characteristics of a collapsible tube.

Opposite transmural gradients of coronary resistance and extravascular pressure in the working dog's heart

Abstract: In order to investigate the factors determining flow to the subendocardium independently from functional adjustments of the resistance vessels, pressure-flow curves for the bypassed left circumflex coronary artery were obtained during maximal vasodilatation induced by intra-coronary adenosine infusion in eight anaesthetised mongrel dogs with systolic and diastolic left ventricular pressures of 14.5 ± 2.3 and 0.3 ± 0.2 kPa (109 ± 17 and 2 ± 1.4 mmHg) respectively. For each experiment three or four flow rates were selected in the linear portion of the pressure flow curve for the injection of 15 ± 5 (μm diameter labelled microspheres for the measurement of regional flow in the internal (ENDO) middle (MID) and external (EPI) one third of the perfused left ventricular wall. Linear pressure-flow relationships were obtained for each of the three layers of the left ventricle using the diastolic coronary perfusion pressure and regional flow rates. The slopes (P/F) of the ENDO were in each instance significantly lower than those of the EPI. The extrapolation of the regional pressure-flow curves to zero flow showed the highest value of pressure for the ENDO and the lowest for the EPI, suggesting a transmural gradient of extravascular pressure. The results of this study agree with a waterfall model of the coronary circulation, in which the extravascular pressure decreases from the ENDO to the EPI in contrast to the vascular resistance which decreases from the EPI to the ENDO. This model explains why the subendocardial layer receives an equal or greater blood flow than the subepicardium in normal haemodynamic conditions even in the absence of autoregulation and in spite of a higher extravascular pressure; it also explains why it becomes selectively ischaemic in the presence of a low perfusion pressure such as that produced by a coronary stenosis.

The arterial system characterised in the time domain

Abstract: When an impulse of flow is applied to the arterial system then the resulting pressure, the impulse response, is a characterisation of the arterial tree. The impulse is generated by means of an occluder around the ascending aorta. The impulse response shows an initial sharp peak followed by an exponential decay with two peaks superimposed on it. The exponential decay is due to diffuse reflection and is linked to the windkessel properties of the arterial tree.1 The superimposed peaks arise from two distinct reflection sites in the arterial tree. By means of the pulse wave velocity the location of these reflection sites may be calculated; one is found in the bed distal to the brachiocephalic and subclavian arteries and the other in the bed distal to the descending aorta. The distinct reflections are linked to the reflection sites in the asymmetric T-model of the arterial tree.2 Vasodilatation (nitroprusside) and vasoconstriction (angiotensin) mainly influence the diffuse reflections, while the locations of the distinct reflection sites appear to be unchanged. Inflation of a balloon in the descending aorta shows up as a sharp peak in the impulse response function. The results obtained are compared with the impulse response function computed from pressure and flow waves in the steady-state.3

Depressed contractile function in reperfused canine myocardium: metabolism and response to pharmacological agents.

Abstract: Regional myocardial function was measured with miniature ultrasonic crystals before, during, and after 10 min of coronary occlusion in anaesthetised open-chest dogs. In normal myocardium, intracoronary isoprenaline (0.1 micrograms . min-1) increased contraction velocity during the first third of systole (early systolic velocity) from 13.8 +/- 2.5 to 19.4 +/- 3.9 mm . s-1 . cm-1, (P < 0.01), and blood flow (microspheres) from 0.55 +/- 0.04 to 0.80 +/- 0.12 cm3 . min-1 . g-1 (P < 0.05); lactate extraction was unchanged. Coronary occlusion induced dyskinesia with a fall in early systolic velocity to -10.0 +/- 2.4 mm . s . -1 . cm-1 (P < 0.01). Abrupt reperfusion after 10 min of ischaemia permitted recovery towards normal, but regional function then deteriorated over 15 min. After a second infusion of isoprenaline, early systolic velocity increased from 0.8 +/- 2.2 to 14.2 +/- 2.5 mm . s-1 . cm-1 (P < 0.01), blood flow 0.44 +/- 0.03 to 0.73 +/- 0.14 cm3 . min-1 . g-1 (P < 0.01) and oxygen consumption 50 +/- 5 to 58 +/- 5 mm3 . min-1 . g-1 (P < 0.05). Lactate extraction was unchanged. In a further series of experiments, administration of nitroglycerin and methoxamine accelerated recovery from dyskinesia induced by coronary occlusion, but did not modify late deterioration during reperfusion. Similarly, neither propranolol nor hypertonic mannitol were found to modify reperfusion damage. Four agents which affect calcium ion movement were studied. Verapamil and isoprenaline, drugs which respectively diminish and enhance calcium slow current, had no effect on reperfusion damage. By contrast, ruthenium red, a non-specific calcium inhibitor reduced deterioration and calcium ionophore (A23187; Lilly) increased it. muDepressed function in reperfused myocardium is not the result of residual ischaemia per se, gut is consistent with calcium overload during the period of reperfusion.

Myocardial stiffness during hypoxic and reoxygenation contracture

Abstract: Isolated rat papillary muscle preparations were used to study hypoxic contracture, and cat papillary muscle preparations with ouabain to study reoxygenation contracture. Electronic analysis of the response to rapid small sinusoidal perturbations gave a continuous measurement of the elastic and viscous components of total stiffness. Increased resting force during hypoxic contracture was characterised by an increase in resting elastic and viscous stiffness relative to the control stiffness-active force relationships. During reoxygenation contracture the stiffness-force relationships followed those of active force development. The linear active force-elastic stiffness relationship (dt/dl=kT+c) was also reversibly altered during hypoxic contracture, predominantly by an increase in intercept c. These data imply that hypoxic contracture unlike reoxygenation contracture is not due solely to a rise in intracellular calcium, but is associated with a component of stiffness not participating an active force development, for example rigor.

Effects of amrinone on experimental acute myocardial ischaemic injury

Abstract: This study was performed to assess the effects of the promising new inotropic agent amrinone on acute myocardial ischaemic injury in the anaesthetised, non-failing canine heart. Eight dogs underwent serial 15 min coronary artery occlusion (CAO) with intervening periods of coronary reperfusion. Saline was infused during the control CAO and amrinone or isoprenaline was infused intravenously at rates necessary to raise left ventricular dP/dt (LV dP/dt) by equivalent amounts in the latter two CAOs. Summed epicardial ST segment elevation (ΣST) was 42.9 ± 14.9 mV in the control CAO, but increased significantly to 76.1 ± 14.4 mV during CAO with amrinone infusion and to 68.6 ± 16.4 mV during CAO with isoprenaline infusion (P<0.001). Acute ischaemic injury was further assessed by mass spectrometric measurement of intramyocardial P co2 ( P m,co2) during a control CAO (saline infusion) and CAO with amrinone or isoprenaline infused to raise LV dP/dt by equivalent amounts in seven dogs. The magnitude of P m,co2 rise from baseline(Δ P m,co2) was 6.0 ± 0.5 kPa (45.3 ± 3.9 mmHg) for the control CAO, and was significantly higher during CAO with amrinone or isoprenaline infusion (8.7 ± 0.7 and 8.5 ± 1.0 kPa (64.9 ± 5.0 and 63.7 ± 7.2 mmHg), P <0.01 and P <0.05, respectively). Reproducible changes for ΣST and Δ P m,co2 in consecutive CAO's without inotropic stimulation were documented in further studies. We conclude that amrinone, when infused to produce positive inotropic effects equivalent to those of isoprenaline, is equally detrimental in increasing acute myocardial ischaemic injury in the non-failing canine heart, as manifest by augmentation of epicardial ST segment elevation and intramyocardial Pco 2 with both agents during coronary occlusion.

Autonomous influence on sinus node and AY node function in the elderly without significant heart disease: assessment with electrophysiological and autonomic tests

Abstract: Eighteen volunteers with a mean age of 63.3 years, who were asymptomatic and without significant heart disease, were investigated with standard electrophysiological tests, performed before and after inhibition of autonomous neural tone with propranolol (0.1 mg·kg−1) and atropine (0.02 mg·kg−1). In addition heart rate responses to maximal exercise, carotid sinus pressure and a bolus injection of isoprenaline (0.01 μg·kg−1) were studied to evaluate the relation between different functional qualities of the cardiac conduction system. Autonomous tone inhibition (ATI) caused significant reductions in the mean PP-interval, sinus node recovery time (SNRT) and corrected sinus node recovery time (CSNRT). Furthermore, the precision of CSNRT determinations increased after ATI. In contrast, the AV-node effective refractory period and conduction time (AH-interval) did not change after ATI. A significant correlation existed between CSNRT and heart rate after ATI, both variables reflecting sinus node automaticity, while no covariation was found between CSNRT and the response to isoprenaline stimulation. AV-node refractoriness and conduction time showed covariation after, but not before, autonomous inhibition. As elderly asymptomatic non-patients were examined the use of the presented group characteristics as reference values for diagnostic investigations is suggested. For example pre-drug CSNRT above 545 ms (mean + 2 SD) or above 505 ms after ATI, indicates impaired sinus node automaticity.

Inhibition of adrenergic neurotransmission in ischaemic regions of the canine left ventricle

Abstract: To test hypothesis that adrenergic neurotransmission is impaired in acute myocardial ischaemia, we studied contractile function of normal and ischaemic myocardium after coronary artery occlusion. For each area we compared the contractile response to left sympathetic nerve stimulation (LSS) with the response to exogenous noradrenaline (NA). Contractile response was measured with intramyocardial sonomicrometers. LSS increased aortic pressure and heart rate. NA was infused to achieve an aortic pressure equivalent to LSS and simultaneous atrial pacing matched the heart rate during LSS. In normal zones both interventions produced increased shortening equivalently. In ischaemic zones systolic expansion was unchanged during LSS, while NA improved contractile function of the same zones by decreasing systolic expansion. These responses occurred during ischaemia produced by either anterior or posterior descending coronary occlusion. Changes in regional blood flow, measured by 8 μm radiolabelled microspheres, could not account for the difference between the ischaemic regional response to LSS or NA. We conclude that acute regional ischaemia impairs adrenergic nerve transmission.

Steady-state effects of preload and afterload on isovolumic indices of contractility in autonomically blocked dogs

Abstract: The steady-state effects of independently altering left atrial pressure (LAP), aortic pressure (AP), and heart rate (HR) on left ventricular isovolumic indices were studied in autonomically blocked open-chested dogs. With mean AP and HR constant (dP/dt)max and (dP/dt)DP40 (that is dP/dt at a developed LVP of 5.3 kPa [40 mmHg]) rose to an approximate plateau above LAP 1.6 kPa (12 mmHg) implying optimum diastolic LV fibre length above this LAP. However, the index (dP/dt/TP)max (TP = total LVP above atmospheric) fell progressively at LAP > 1.6 kPa (12 mmHg). Increasing HR (LAP constant) increased (dP/dt)max by 5.6 ± 0.7% of basal value for every 10 beats.min−1 over HR range 120 to 200 beats·min−1. With LAP and HR constant changing AP in the aortic diastolic pressures (ADP) range 6.7 to 20 kPa (50 to 150 mmHg) had no effect on (dP/dt)DP40 and (dP/dt/TP)max, which occur early in systole. (dP/dt)max was afterload independent at ADP > 12 kPa (90 mmHg), but fell by about 5% (P <0.005) in the ADP range 6.8 to 9.3 kPa (51 to 70 mmHg) (basal conditions) and by 12% (P < 0.005) in the range 9.5 to 12 kPa (71 to 90 mmHg) (enhanced contractility), probably due to aortic valve opening. Under the present steady-state conditions direct afterload-mediated modulation of inotropic state could not be demonstrated. During Ca2+-mediated enhanced contractility the relative increases in the three indices differed, with the effects on (dP/dt)max, (dP/dt)DP40 and (dP/dt/TP)max respectively 235%, 176%, and 148% of their basal value. These changes were inversely related to the timing of each index in isovolumic systole and may reflect differences in activation of muscle fibres.