A no-reflow phenomenon (NRP) develops in hearts subjected to global ischemia and prevents reperfusion of the subendocardial myocardium upon restoration of arterial supply. In the present study the transmural progression of the NRP across the left ventricular wall in globally ischemic rat hearts was quantitatively defined by using autoradiographic nuclear track emulsion (NTE) as an indicator of microvascular competence. Rat hearts were isolated and perfused for 10 min with oxygenated Krebs-Henseleit buffer, then were made completely globally ischemic for from 0 to 60 min and were maintained at 37 degrees C. They were then fixed by perfusion with glutaraldehyde after which NTE was injected into the coronary arteries. Transverse sections through the left ventricles were examined by scanning electron microscopy using back-scattered electron imaging and the vessels in a standard transmural contiguous series of photomicrographs were classified according to whether they did or did not permit the flow of NTE. Non-ischemic control myocardium showed a mean proportion of filled vessels of 99.4 +/- 0.5% SD, and those subjected to 15 min of ischemia showed only a slight overall reduction. After 30 min of ischemia 96 +/- 3% of vessels in the subepicardial third could be reperfused, but the proportion progressively diminished across the myocardium to total no-reflow near the endocardium. From 45-60 min of ischemia the totally non-reperfusible region remained confined to the subendocardial third but there was a significant reduction in the proportion of reperfusible vessels in the subepicardial third to 40% +/- 27%. Ischemia thus progressively reduces the capacity of myocardium to be reperfused.(ABSTRACT TRUNCATED AT 250 WORDS)

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Morphological changes in endocardium subjected to global ischaemia.

To provide insight into the effects of severe ischaemia on endocardium, the sequence of morphological changes which develop in the endocardium of the isolated rat heart subjected to 0-12 hours of global ischaemia at 37 degrees C was examined. A progression of changes occurred. Following one or more hours of ischaemia crater-like depressions and blebs appeared on the luminal surfaces of ventricular endothelial cells, with margination and clumping of nuclear chromatin, loss of glycogen granules, swelling of mitochondria, and the development of subendothelial membrane-bound dilatations of myocytes. Following two or more hours of ischaemia there was progressive separation of endothelial cells along their intercellular boundaries and desquamation of an increasing proportion of these cells. In regions of desquamation the surface was initially smooth due to persistence of the lamina densa of the basal lamina, but after longer periods of ischaemia the surface became rough with exposure first of the subendothelial connective tissue fibres (4 hours) and eventually of cardiac muscle cells (12 hours).

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The effect of coronary pressure on contracture and vascular perfusion in the hypoxic isolated rat heart.

The relationships among coronary perfusion pressure (0-150 cm H2O), ventricular contracture, vascular resistance, and loss of perfusion of subendocardial myocardium were studied in anoxic isolated rat hearts. Coronary flow and myocardial pH and lactate concentrations were measured during 60 minutes, and the perfusable proportion of the ventricular wall determined after 15 and 60 minutes of global, substrate-free anoxic perfusion. Myocardial contracture in similarly treated hearts was indicated by the pressure exerted on left intraventricular balloons. Decreased perfusion pressure proportionately decreased both coronary flow and the extent of perfusion, and delayed the onset of contracture. The slower development of contracture was associated with a measured increase in lactate content and fall in pH within the ventricular wall. During anoxia the subendocardial myocardium progressively lost its capacity to be perfused, commencing at the onset of ventricular contracture, and continuing to extend even after maximum contracture pressures had been developed. Increased coronary perfusion pressures accelerated the rate of development of contracture but significantly reduced the extent of the perfusion defect, probably by opposing vascular compression.

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The role of post-ischaemic reperfusion in the development of microvascular incompetence and ultrastructural damage in the myocardium.

To determine the contribution of oxygenated reperfusion to the development of myocardial microvascular incompetence and ultrastructural damage following ischaemia, isolated buffer perfused rat hearts were subjected to either temporary (n = 15) or permanent (n = 15) ischaemia for 15, 30 or 45 minutes. The temporarily ischaemic hearts were reperfused for 5 min with oxygenated Krebs Henseleit buffer. All hearts were then fixed by perfusion fixation with nitrogen-bubbled glutaraldehyde. The transmural development of microvascular incompetence was determined quantitatively by scanning electron microscopy using nuclear track photographic emulsion as an intravascular marker of competent capillaries, and ultrastructural damage was examined by transmission electron microscopy. Thirty or more minutes of ischaemia where required to significantly reduce the mean density of competent capillaries in the subendocardial third of the left-ventricular wall. Such ischaemic myocardium contained relatively normal, open unobstructed vessels, indicating that the microvascular incompetence arising during ischaemia per se was not due to ultrastructural change in the capillaries. Subendocardial myocardium reperfused following 15 min ischaemia also showed little ultrastructural change, but did show a significant reduction in the density of competent capillaries. However, reperfusion of more severely ischaemic myocardium resulted in obvious ultrastructural damage as well as significant further reduction in capillary competence. These findings demonstrate that oxygenated reperfusion of ischaemic myocardium paradoxically results in the further development of microvascular incompetence and, in severely ischaemic myocardium, also to additional ultrastructural damage.

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Changing relationships between structure and function in the cochlea during recovery from intense sound exposure.

This study examines the relationship between the morphological and electrophysiological changes in the guinea pig cochlea at intervals following exposure to intense sound (5 kHz, 125 dB SPL, 30 minutes). The cochlear compound action potential (N1) audiogram (2-30 kHz) was determined within one hour or 1, 7, 14, or 28 days after exposure. When these organs of Corti were examined by scanning electron microscopy, most (92%) showed damage to hair cells and supporting cells around the 5-kHz region. The number of damaged hair cells increased significantly (p less than 0.01) in the first 24 hours following exposure, but there was no significant change thereafter. In contrast, the initial extensive loss of function (maximum at 8-12 kHz) recovered partially during the first 24 hours but also showed no significant further change. All morphological lesions occurred within regions corresponding tonotopically to the N1 threshold losses, but only the larger lesions, which were observed seven or more days after exposure, fully reflected the extent of the loss of N1 thresholds. This indicates that functionally important damage to the cochlea is usually more extensive than indicated by topographical abnormalities in the organ of Corti.

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A quantitative study of the sequence of topographical changes in the organ of Corti following acoustic trauma.

The organs of Corti of 30 guinea pigs were examined quantitatively by scanning electron microscopy either immediately or 1, 3, 7 or 14 days after exposure to 3 kHz at 125 dB SPL for 30 min. Lesions (0.1-4.15 mm in length) were observed in 70% of the organs of Corti. There was no significant change in lesion length with recovery from the exposure. Early changes in hair cells consisted of stereocilia abnormalities, predominantly amongst inner hair cells and the first row of outer hair cells. The proportion of affected cells increased towards the centre of lesions, where supporting cells were affected also. Subsequent to exposure, affected hair cells were either lost or remained with stereocilia abnormalities but did not recover. Regions showing supporting cell damage were replaced within 3 days by inner sulcus and Claudius cells. Despite similar changes to stereocilia, inner hair cells were more resistant to necrosis than outer hair cells, suggesting that the nature of stereocilia damage does not necessarily indicate the fate of hair cells.

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Functional recovery of hearts after cardioplegia and storage in University of Wisconsin and in St. Thomas' Hospital solutions.

There are conflicting reports of the beneficial effects of University of Wisconsin (UW) cardioplegic solution used in heart preservation techniques. Therefore we investigated the efficacy of myocardial protection in adult rat hearts subjected to single-dose infusion (3 minutes) of nonoxygenated cardioplegic solutions (UW or St. Thomas' Hospital solution No. 2 [STH]) and stored at 4 degrees C by immersion in the same solution or in saline solution. Isolated working-heart preparations (n = 8 per group) were used to assess the prearrest (20 minutes' normothermic perfusion) and postischemic left ventricular functions. Four groups of hearts underwent 5, 8, 10, and 20 hours of cold ischemia (4 degrees C) in UW solution. Hearts stored for 8 to 20 hours showed no postischemic recovery of cardiac pump function (aortic flow, 0%), had decreased levels of myocardial high-energy phosphates, and were highly edematous (50% to 70% increased). After 5 hours of storage there was also poor recovery of aortic flow, coronary flow, and aortic pressure (55.0% +/- 19.4%, 67.1% +/- 5.1%, and 58.1% +/- 11.7%, respectively) but good recovery of adenosine triphosphate, creatine phosphate, and guanosine triphosphate (18.54 +/- 1.42, 29.99 +/- 2.05, and 1.64 +/- 0.14 mumol/gm dry weight, respectively). In contrast, hearts arrested and stored in STH solution for 5 hours rapidly established normal left ventricular functions (aortic flow, 111.5% +/- 2.5%; cardiac output, 99.1% +/- 1.2%; coronary flow, 85.0% +/- 3.4%; heart rate, 95.8% +/- 2.7%; and aortic pressure, 94.6%). A group of hearts arrested with STH solution but stored in saline solution recovered more slowly, had only partial return of function (aortic flow, 73.6% +/- 14.8%; p less than 0.01 vs STH/STH group), and had significantly greater tissue water content (8.020 +/- 0.080 vs 6.870 +/- 0.126 ml/gm dry wt; p less than 0.01). These results demonstrate the superior preservation of explanted hearts at 4 degrees C obtained by STH cardioplegic solution compared with UW solution under conditions used for transplantation.

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The Commonwealth doctor of medicine: a degree of uncertainty.

The degree of doctor of medicine (MD) is awarded by many universities in the British Commonwealth as a senior, postgraduate, research thesis-based degree. Some of its features are that it is limited to medical graduates of the same university, but that the research on which the thesis is based need not be conducted at the university awarding the degree and that there is no requirement for formal supervision of candidates. These characteristics, and its close similarities with the master of surgery (ChM) degree, may be responsible for the confusion that exists about its quality and status in relation to the doctorate of philosophy (PhD) and the 'higher' doctorates like doctor of science (DSc). There is also uncertainty about its role in the training and selection of clinical consultants and physician scientists.

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