Diastolic anisotropic properties of the left ventricle in the conscious dog.

The role of myocardial anisotropy in determining change in left ventricular shape during diastolic filling has not yet been demonstrated. Therefore, 11 conscious dogs were instrumented with global ultrasonic dimension transducers to measure left ventricular major and minor axis diameters and equatorial wall thickness. Myocardial geometry was represented as a three-dimensional ellipsoidal shell. Left ventricular transmural pressure was measured with micromanometers, and ventricular volume was varied by inflation of vena caval occluders. Left ventricular wall strains and stresses calculated from the ellipsoidal shell model agreed closely with those measured directly by myocardial force and dimension transducers. Unequal normalized diastolic stress-strain relations were observed in the latitudinal, longitudinal, and wall thickness directions, reflecting anisotropic mechanical properties of the myocardium. Although a greater wall stress in the latitudinal versus longitudinal axis was predicted adequately from left ventricular geometry alone, the observed latitudinal strain exceeded longitudinal strain by an amount greater than was predicted by geometric considerations alone, suggesting that myocardial anisotropy contributes significantly to changes in ventricular shape during diastolic filling.

Hyperemic response to coronary occlusion during a single diastole in conscious dog.

This study determined whether the reactive hyperemic response to a 400-ms diastolic coronary occlusion is dependent on ventricular systole. Studies were obtained on 11 conscious dogs with complete heart block paced at 60 beats/min. A pressure catheter was chronically implanted in the aorta. An electromagnetic flow probe and pneumatic occluder were implanted on the circumflex coronary artery. Three interventions were employed: 1) interruption of pacing for a single beat generating a long diastolic period of 2,000 ms in duration (LDC); 2) introduction of a 400-ms diastolic coronary occlusion early in a long diastole (LD4); and 3) a 400-ms diastolic occlusion during uninterrupted pacing (400R). The rise in diastolic coronary vascular resistance index noted during LDC was inhibited significantly in the last 600 ms of diastole during LD4. Thus an intervening systole is not required for a reactive hyperemic response to a diastolic coronary occlusion. During 400R, the resistance index was lower than that found during LD4. The reactive hyperemic response may be caused by either a myogenic or metabolic mechanism or by both. The greater vasodilatation observed after the postocclusion systole in 400R probably reflects metabolic influences.

Carbamazepine in the treatment of aggression: a case report and a review of the literature.

Aggressive behaviour is an inescapable clinical problem confronting practitioners of medicine, neurology and psychiatry. Several drugs have been used to treat it, with limited success. Successful use of carbamazepine in the treatment of aggressive behaviour in a patient with limbic dysfunction is reported, and varieties of aggressive behaviour that respond to carbamazepine are examined. The authors suggest that carbamazepine may have a specific anti-aggressive effect perhaps due to an anti-kindling effect, but caution that double-blind studies are needed before firm conclusions are drawn.

Down's syndrome and its association with Alzheimer's disease.

The purpose of this study was to ascertain the frequency of Alzheimer's dementia in the relatives of Down's probands and to establish whether these two disorders cluster together. Out of 128 families of Down's probands, only 67 responded to the questionnaire. Twelve cases of Alzheimer's dementia were found in the eight families of 67 probands. There was a significant increase in the frequency of presenile dementia, but no significant increase in senile dementia among the first and second degree relatives of these probands. The methodological problems were discussed and future directions suggested.

Demonstration of coronary artery myogenic vasoconstriction in the awake dog.

The aim of this study was to determine whether or not coronary vasoconstriction occurs in response to a transient increase in coronary perfusion pressure. Eleven awake dogs with formalin-induced heart block, chronically instrumented with aortic and left ventricular catheters and left circumflex coronary and aortic electromagnetic flowprobes, were studied at a paced heart rate of 60 beats/min. A transient increase in aortic diastolic pressure of 17.3 +/- 1.5% for 330 +/- 20 ms and of 33.6 +/- 2.2% for 520 +/- 20 ms, via the inflation of an intra-aortic balloon, resulted in an increase in diastolic coronary vascular resistance index in the first response beat of 6 +/- 1% and 11 +/- 1%, respectively. An identical increase in diastolic coronary flow produced by the omission of a single paced beat resulted in no significant change in diastolic coronary vascular resistance index in the first response beat. Thus, the increase in diastolic coronary vascular resistance index following diastolic pressure augmentation is related to the increase in aortic diastolic pressure and not to the increase in diastolic coronary flow. These data are consistent with that of a brief myogenic response.

Metabolic mediation of single brief diastolic occlusion reactive hyperemic responses.

We tested the hypothesis that coronary reactive hyperemia following a single brief diastolic occlusion and subsequent systole is coupled to myocardial metabolic activity and myocardial O2 consumption (MVO2). Sixteen conscious dogs with Formalin-induced heart block were studied. A 400-ms diastolic occlusion was introduced during normal ventricular pacing, resulting in a reactive hyperemic repayment of 216 +/- 22%. A 400-ms diastolic occlusion was also introduced during a higher level of myocardial metabolic activity induced by ventricular paired pacing. MVO2 and mean coronary blood flow were significantly increased relative to these parameters during normal pacing, but reactive hyperemic repayment (189 +/- 18%) was not significantly changed. A third set of conditions was designed to measure the response to a 400-ms occlusion during normal pacing while eliminating the difference in magnitudes of myogenic influences that may exist between paired pacing and normal pacing. Adenosine and phenylephrine were infused intravenously during normal pacing to maintain mean aortic pressure and mean coronary flow at paired pacing levels. MVO2 was similar to O2 consumption during normal pacing in the absence of drug infusion, but the reactive hyperemic repayment was significantly reduced (94 +/- 22%) relative to paired pacing. Thus the magnitude of reactive hyperemic response after a brief diastolic occlusion is related primarily to myocardial metabolic activity.

Origin of atrial coving in canine phasic coronary artery blood flow.

The transient decrease in left circumflex coronary artery blood flow during atrial contraction (atrial coves) was examined in open-chest, heart-blocked dogs. Prominent atrial coves were observed in left circumflex flow during both diastole and systole as a result of the asynchrony of atrial and ventricular contractions. In eight open-chest dogs, atrial contractions decreased diastolic circumflex coronary flow by 0.016 +/- 0.002 ml and systolic flow by 0.014 +/- 0.001 ml compared with diastolic and systolic intervals during which no atrial contractions occurred. The diastolic and systolic flow reductions in this vessel were not significantly different (P greater than 0.14). In five of the eight dogs no diastolic atrial coves were observed in left anterior descending coronary flow, and only minimal diastolic coving was present in the remaining three dogs; no systolic coves were present in this vessel in any of the eight dogs. In five additional open-chest dogs, brief inflation of a balloon in the left atrium produced elevations of left ventricular diastolic pressure comparable to those produced by atrial contraction. Only minimal atrial coves were associated with these balloon inflations. These data are consistent with the hypothesis that atrial contraction limits flow through the atrial blood vessels and results in a transient decrease in flow in the atrial arteries that arise from the left circumflex coronary artery. Although increases in ventricular diastolic pressure may be partially responsible for the appearance of atrial coves in the left circumflex coronary artery, mechanical contraction of the atrial musculature appears to be of significant importance.

Regulation of stroke volume during submaximal and maximal upright exercise in normal man.

To characterize the hemodynamic factors that regulate stroke volume during upright exercise in normal man, 24 asymptomatic male volunteers were evaluated by simultaneous right heart catheterization, radionuclide angiography, and expired gas analysis during staged upright bicycle exercise to exhaustion. From rest to peak exercise, oxygen consumption increased from 0.33 to 2.55 liters/min (7.7-fold), cardiac index increased from 3.0 to 9.7 liters/min per m2 (3.2-fold), and arteriovenous oxygen difference increased from 5.8 to 14.1 vol% (2.5-fold). The increase in cardiac index resulted from an increase in heart rate from 73 to 167 beats/min (2.5-fold), and an increase in left ventricular stroke volume index from 41 to 58 ml/m2 (1.4-fold). During low levels of exercise, there was a linear increase in cardiac index due to an increase in both heart rate and stroke volume index; stroke volume index increased as a result of an increase in left ventricular filling pressure and end-diastolic volume index and, to a much smaller extent, a decrease in end-systolic volume index. During high levels of exercise, further increases in cardiac index resulted entirely from an increase in heart rate, since stroke volume index increased no further. Left ventricular end-diastolic volume index decreased despite a linear increase in pulmonary artery wedge pressure; stroke volume index was maintained by a further decrease in end-systolic volume index. The degree to which stroke volume index increased during exercise in individuals correlated with the change in end-diastolic volume index (r = 0.66) but not with the change in end-systolic volume index (r = 0.07). Thus, the mechanism by which left ventricular stroke volume increases during upright exercise in man is dependent upon the changing relationship between heart rate, left ventricular filling, and left ventricular contractility. At low levels of exertion, an increase in left ventricular filling pressure and end-diastolic volume are important determinants of the stroke volume response through the Starling mechanism. At high levels of exertion, the exercise tachycardia is accompanied by a decrease in end-diastolic volume despite a progressive increase in filling pressure, so that stroke volume must be maintained by a decrease in end-systolic volume.

Regional cerebral blood flow in normal blood circulated and perfluorocarbon transfused rats.

Perfluorocarbon blood substitutes have been shown to exert a protective effect in animal models of cerebral ischemia. The mechanisms by which PFCs improve cerebral hemodynamics are uncertain, however decreased viscosity, small particle size and high oxygen solubility relative to plasma are important factors. Extensive perfluorocarbon exchange transfusion (FC-43) in the rat to a hematocrit of 1%, produces a 100% increase in total cerebral blood flow (FIO2 = 1.0, CaO2 = 6 vol%). Similar increases were seen in normal blood circulated animals breathing 12% O2 (CaO2 = 12 vol%). Therefore, immediately following PFC exchange and the resulting decrease in CaO2, oxygen delivery to the brain is maintained by increasing total blood flow in a manner similar to hypoxic hypoxia.

Functional and reactive hyperemia are unaltered by homocysteine in conscious dogs.

The purpose of this study was to test the hypothesis that L-homocysteine thiolactone (L-HCTL), through its reaction with adenosine to form S-adenosylhomocysteine, may modulate myocardial functional and reactive hyperemic responses. Reactive hyperemic responses to 10-sec occlusions or 400-msec diastolic occlusions of the circumflex coronary artery and functional hyperemic responses to ventricular extra-activations were studied in a chronic heart-blocked dog preparation during a control period and following L-HCTL (40 mg/kg). In two additional dogs multiple venous blood samples and left ventricular myocardial biopsies were obtained following L-HCTL to measure changes in plasma homocysteine and tissue S-adenosylhomocysteine. Despite a 75-fold increase in peak plasma homocysteine and a 26-fold increase in tissue S-adenosylhomocysteine, L-HCTL did not alter myocardial functional and reactive hyperemic responses. The rapid increase in myocardial S-adenosylhomocysteine confirmed cellular entry of homocysteine and its reaction with endogenous adenosine. The failure of L-HCTL to alter functional and reactive hyperemic responses suggests that either such treatment does not affect myocardial release of adenosine or that adenosine is not an important regulator of coronary flow.

Effect of aminophylline on coronary reactive and functional hyperaemic response in conscious dogs.

This study was undertaken to determine whether adenosine release from myocardial cells plays a role in coronary reactive and functional vasomotion. Reactive hyperaemic blood flow responses to 10 s complete occlusions and 400 ms diastolic occlusions of the left circumflex coronary artery and to the vasomotor responses to the increased cardiac demand following ventricular extra-activation were examined in a chronic, heart-blocked dog preparation during a control period and following intravenous bolus administration of aminophylline (5 mg X kg-1). Aminophylline administration resulted in a 19% decrease in the blood flow debt repayment ratio of 10 s reactive hyperaemic responses compared with the control period. However, administration of aminophylline had no effect on the coronary vascular response to 400 ms diastolic occlusions or to ventricular extra-activations. These observations indicate that adenosine may play a role in the coronary vascular response to prolonged interventions but that other factors, as yet unidentified, may be implicated in the beat-to-beat regulation of coronary vascular resistance.

Effect of atrial fibrillation on atrial blood flow in conscious dogs.

This study was undertaken to examine the independent effects of atrial tachycardia, ventricular tachycardia, and atrial fibrillation (AF) on atrial and ventricular blood flow in conscious, heart-blocked dogs using radioactive microspheres. Atrial blood flow averaged 0.54 +/- 0.08 ml/min/g during the control period at an atrial rate of 124 beats/min and a ventricular rate of 90 beats/min. Atrial flow increased to 0.72 +/- 0.12 ml/min/g during atrial pacing at 236 beats/min, but was not significantly altered by ventricular pacing at 200 beats/min. AF at a ventricular rate of 90 beats/min resulted in atrial flow values of 0.91 +/- 0.08 ml/min/g. The ratio of atrial flow to left ventricular flow during AF averaged 1.18 +/- 0.08. Administration of a maximal vasodilating dose of adenosine during AF further increased atrial flow to 2.18 +/- 0.16 ml/min/g. Atrial tachycardia or AF did not significantly affect ventricular blood flow. These data indicate (1) that atrial blood flow increases significantly during AF, reaching flow values per gram of tissue comparable to those of the left ventricle, and (2) that this flow is regulated by the metabolic needs of the atrial tissue and does not represent maximal vasodilation.

The effects of airway pressure on cardiac function in intact dogs and man.

Ventilation with positive end-expiratory pressure (PEEP) is associated with reduced cardiac output, but the mechanisms involved are controversial. Possible explanations include increased intrathoracic pressure, reflex changes in myocardial inotropism, pulmonary vascular obstruction and abnormal ventricular interaction. Three types of conscious canine preparations were developed to examine simultaneously each of these factors during ventilation with PEEP. In addition, similar measurements were obtained in patients after cardiac surgical procedures and compared with the results of animal experiments. The primary cause of reduced cardiac output during PEEP appeared to be a diminished end-diastolic volume of the left ventricle, and this appeared to be the result of elevated intrathoracic pressure and increased impedance to blood flow through the lungs. Abnormal interventricular septal shifting and reflex autonomic alterations did not appear to be significant in the normal cardiovascular system. These data provide insight into the cardiac effects of PEEP and emphasize the importance of simultaneous quantification of biventricular performance when assessing cardiopulmonary function.

Prolonged myocardial nucleotide depletion after brief ischemia in the open-chest dog.

Purine and pyrimidine nucleotides are essential energy sources for basic metabolic reactions and play important roles in protein, glycogen, and nucleic acid synthesis, cyclic nucleotide metabolism, and energy transfer reactions. Brief coronary occlusions (12 min) were produced in seven open-chest dogs, and repetitive myocardial samples were taken in order to determine the response of the nucleotide pool to ischemia and reperfusion. During ischemia adenosine 5'-triphosphate (ATP) decreased to 57% of control, and similar decreases occurred in the guanosine 5'-triphosphate (GTP), cytidine 5'-triphosphate (CTP), uridine 5'-triphosphate (UTP), and nicotinamide adenine dinucleotide (NAD+) pools. The decrease in nucleotides was accompanied by an increase in nucleosides and bases. After 60 min of reperfusion the content of all nucleotides had increased but was still significantly less than nonischemic values. The content of nucleosides and bases decreased immediately upon reperfusion. In contrast, creatine phosphate (CP) fell to 10% of control during ischemia but rebounded to above control values immediately upon reperfusion. Thus depletion of all nucleotide pools occurs during ischemia, and with reperfusion nucleotide content is restored only slowly. Delayed repletion is not caused by a defect in mitochondrial synthesis of ATP because CP content is restored rapidly. The slow repletion of nucleotides may be secondary to loss of nucleotide precursors during reperfusion and may result in widespread alterations in myocardial metabolism.

Hyperemic response of the coronary circulation to brief diastolic occlusion in the conscious dog.

This study was undertaken to determine whether coronary blood flow can be regulated in response to coronary arterial occlusions briefer than a single diastole. The possible involvement of metabolic vs. myogenic mechanisms in such regulation was investigated. Eleven conscious dogs with experimentally produced complete heart block, chronically implanted electromagnetic flow probes, and pneumatic occluders on the left circumflex coronary artery were studied. Diastolic coronary occlusions lasting 100 to 400 msec were performed at paced heart rates of 40, 60, and 120 beats/min. At a heart rate of 60 beats/min, a 200-msec occlusion was sufficiently long to produce a significant reactive hyperemic response; 400-mec occlusions resulted in larger responses, while 100-msec occlusions did not generate a discernible response. The onset of reactive hyperemia was delayed from the end of the occlusion until the first post-occlusion systole. The length of this delay could be altered by changing the heart rate or occlusion duration, but no significant response was detected before the first post-occlusion systole. This characteristic of the data is more consistent with a metabolic than with a myogenic mechanism. If the response is metabolic, the data demonstrate that autoregulation of coronary flow by such a mechanism is very rapid, occurring during the first systole in which a flow deficit is detected by the myocardium.

Coronary vasodilation after a single ventricular extra-activation in the conscious dog.

This study was undertaken to determine if coronary blood flow can be regulated in response to a transient increase in cardiac metabolic demand. Eight conscious dogs with experimentally produced complete heart block, a chronically implanted electromagnetic flow probe on the left circumflex coronary artery, and fluid-filled catheters for measurement of left ventricular and aortic pressures were studied. At a paced heart rate of 60 beats/min, a single ventricular extra-stimulus was introduced with a delay of 150-200 msec from the preceding R-wave. The extra-stimulus produced a ventricular extra-activation, but not a discrete mechanical extra-systole. The ensuing beats exhibited systolic potentiation, manifest by a 50 +/- 8% increase from control in maximum left ventricular dp/dt in the first potentiated beat, presumably accompanied by increased myocardial oxygen demand. In the diastole immediately following the first potentiated systole, the coronary vascular resistance index (mean aortic pressure/mean coronary flow in that diastole) fell significantly from control by 12 +/- 2%. The results indicate that a transient increase in cardiac metabolic demand is followed immediately by a compensatory coronary vasodilation that occurs within the same cardiac cycle.

The deformational characteristics of the left ventricle in the conscious dog.

We studied left ventricular minor and major axis diameters and equatorial wall thickness in eleven conscious dogs with chronically implanted pulse-transit ultrasonic dimension transducers. Left ventricular transmural pressure was measured with micromanometers. Left ventricular volume was varied by inflation of implanted vena caval or aortic occluders. The geometry of the left ventricle was represented as a three-dimensioal ellipsoidal shell. Left ventricular eccentricity was found to be a linear function of ventricular volume during both diastole and ejection. However, the relationship was not the same for diastole and ejection, and during diastole the left ventricle was mre spherical at large volumes and more elliptical at small volumes than during ejection. The rearrangements in geometry observed during isovolumic contraction appeared to be transitional stages from the diastolic to the ejection-phase relationship. Thus, during isovolumic contraction, the left ventricle became more elliptical at large volumes and more spherical at small volumes. These relationships were not altered significantly by increased afterload or inotropic interventions. We also observed that the diastolic deformation of the ventricular chamber occurred in a set and predictable manner that seemed to be determined by the three-dimensional mechanical properties of the myocardium. The geometric inter-relationships of the ventricular wall determined the relationship between diastolic transmural pressure and mural stress. These findings probably reflect basic structural characteristics of the myocardium and provide a convenient method for quantitatively representing the dynamic geometry of the left ventricle.