1283 assay for
mycoplasma
was not
performed However,
if it was the cause of these abnormalities, then the skin controls would also have been affected. The
histological similarity
to
a stroked This strongly suggests that it is the raised blood-pressure itself which damages blood-vessels and causes
strokes.
fibrosarcoma has been
noted. Chromosome abnormalities have been recognised in cells cultured from experimental connective-tissue tumours,4 5 but there is no question of Dupuytren’s contracture being other than entirely benign. Recent reports? 8 have suggested that different acquired chromosome abnormalities may vary in their prognostic significance and Codish and Paul8 have described the appearance of a specific chromosome which suppresses malignancy. One may speculate that, within the broad range of fibromatoses, the existence and balance of chromosome abnormalities may influence the clinical course. Meanwhile, we suggest that chromosomally abnormal cell lines may arise in the development
of Dupuytren’s disease. We thank Rhona Bauld and Elizabeth Grace for assistance with case 1. Requests for reprints should be addressed to S. B-R., Pathology Department, Royal Hospital for Sick Children, Sciennes Road, Edinburgh EH9 1LF. REFERENCES
Ling, R. G. M. J. Bone Jt. Surg. 1963, 45B, 709. 2. Enzinger, M., Lattes, R., Torloni, H. Types Histologiques des 1.
Tumeurs des Tissue Mous; p. 28. Geneva, 1970. 3. Hueston, J. T. Dupuytren’s Disease; p. 61. Edinburgh, 1974. 4. Rasheed, S., Nelson-Rees, W. A., Toth, E. M., Arnstein, P., Gardner, M. B. Cancer, 1974, 33, 1027. 5. Benedict, W. F., Rucker, N., Mark, C., Kouri, R. E. J. natr. Cancer Inst. 1975, 54, 157. 6. Littlefield, L. G., Mailhes, J. B. Am. J. hum. Genet. 1975, 27, 190. 7. Rowley, J. D. Lancet, 1973, ii, 390. 8. Codish, S. D., Paul, B. Nature, 1974, 252, 610.
Hypothesis
PATHOLOGICAL CHANGES IN HYPERTENSIVE CEREBRAL VESSELS
Microaneurysms Related to Lipohyalinosis For many years pathologists have sought an underlying pathological process which can explain the increased liability of cerebral arteries both to rupture and to occlusion. It is generally agreed that the walls of the larger cerebral arteries from chronic hypertensive patients show an increased thickening and hyalinisation of the muscle coat when compared with those from normotensive patients. Furthermore, atheroma is more extensive and severe in large arteries.4 In addition, however, there is a distinct pathological change which affects small intracerebral arteries 50-200 m in diameter and consists of multiple microaneurysms arising on segments of dilated artery. In the wall of the microaneurysm the endothelium has ruptured and the media and elastic coats have disappeared and been entirely replaced by connective tissue. A single brain may contain many microaneurysms, and they have a characteristic distribution, being found most frequently in putamen, globus pallidus, external capsule, thalamus, pons, and subcortical white-matter.5 Some of these microaneurysms show a reaction variously known as "fibrinoid necrosis", "lipohyalinosis", or "angionecrosis" consisting in the accumulation within the wall of hyaline material which stains for fibrin and for fat. Around the aneurysm there is frequently evidence of leakage of blood usually in small quantities6 (figs. 1 and 2). Lacunar Infarction Related to Lipohyalinosis
HOW DOES BLOOD-PRESSURE CAUSE STROKE? R. W. Ross RUSSELL National Hospital, Queen Square, London WC1N 3BQ, and St Thomas’ Hospital, London SE1 7EH
In chronic hypertension the specific arterial lesions responsible for brain damage affect the small resistance arteries. The pathological characteristics of these lesions (notably the presence of microaneurysms, intramural fibrin, and lipid) and the location of lesions within the brain all suggest that they arise from mechanical distension, which destroys the integrity of the vessel and allows plasma insudation into the wall (lipohyalinosis), finally leading to occlusion or rupture. The process is analogous to the breakdown in vascular resistance and permeability which occurs in acute hypertension.
Summary
Fisher’ has convincingly shown that lacunes-small, deep cerebral infarcts often found in the brains of chronic hypertensives-are usually associated with occlusions of small intracerebral arteries. The pathological change at the point of occlusion consists of mural destruction, focal expansion, thrombotic occlusion, and fibrinoid deposition, and has progressed to the point of complete disorganisation of the artery and obliteration
EFFECTS OF HYPERTENSION ON THE BRAIN
EPIDEMIOLOGICAL studies have established an association between high blood-pressure and an increased incidence of cerebral vascular disease; this is true for both cerebral haemorrhage and cerebral infarction. Moreover, in severely hypertensive patients a reduction in blood-pressure by medical treatment lowers the incidence of future strokes both in those who have no cerebrovascular symptoms2 and in those who have survived
1—Cross-section of wall.
Fig.
(PTAH; x90.)
microaneurysm showing plasma
insudation of
1284
2—Cross-section of microaneurysm arising artery.
Fig.
The endothelium has the subintimal region.
ruptured
and
on
dilated segment of
hyaline material
has formed in
Fig. 3-Creas-aection of microaneurysm showing lipohyalinosis thrombosis, and haemorrhage.
of wall,
(Kindly supplied by Dr D. Tavcar.)
of the lumen. In 31 out of 40 arteries Fisher found dilatation at the point of occlusion up to two or three times the normal diameter of the vessel; there was also evidence of haemorrhagic extravasation within and outside the walls. Fisher considers the vascular change underlying lacunes to be identical with lipohyalinosis. Some support of this view comes from the distribution of lacunes in different regions of the brain which is similar to that of hyalinosis9 and also of microaneurysms6 although the latter tend to be more frequent in the subcortical region (table). Fisher emphasised that lipohyalinosis could sometimes be found without arterial dilatation, and for this reason suggested that aneurysms were the sequel to fibrinoid change. It seems equally possible, however, that since aneurysms are frequently seen with no evidence of hyalinosis dilatation of the artery is the first event.
hyalinosis. A microaneurysm was convincingly shown in one case (fig. 3).
Cerebral Haemorrhage Related to Lipohyalinosis
(a) The strong association with chronic hypertension. (b) The focal nature of the pathological change, affecting exclusively intracerebral "resistance vessels". (c) The frequent association with focal dilatation of the
The identification of a source of major bleeding within the brain is made difficult by secondary change and distortion produced by the haemorrhage itself. Many of the microaneurysms originally described by Charcot and Bouchard 10 were found on closer examination to represent small periarterial hoematomas.11 However, good evidence is now available to link cerebral haemorrhage to a vascular reaction identical with lipohyalinosis. Tavcar9 found lipohyalinosis constantly in brains showing haemorrhage, and the location of pathological change matched that of cerebral haemorrhage very closely. In two instances he was able to trace the artery giving rise to haemorrhage, and in both there was focal lipo-
PATHOGENESIS OF LIPOHYALINOSIS
Thus it seems likely that microaneurysms are an important initial result of raised pressure but that it requires the addition of lipohyalinosis to render the artery liable to rupture or occlusion. What then is the cause of lipohyalinosis? A variety of views have been expressed on this question.1 They vary from the action of a hypothetical vasoactive chemical’2 to the results of severe spasm.l3 Fisher1 favours the view that the pathological change is related to atheroma, based on the frequent coexistence and proximity of the two processes and the presence of fat in the lesions. Any theory on the origin of lipohyalinosis must explain the following:
artery. (d) The sites of predeliction within the brain. (e) The presence of fibrin, lipids, and red blood-cells in and around the artery at the site of lipohyalinosis.
The hypothesis which fits most closely with these facts is simply one of mechanical distension, and the sequence of events may be explained as follows: the increased cerebral vascular resistance necessary for the maintenance of normal blood-flow in the hypertensive brain is achieved by hypertonus and hypertrophy mainly of
PERCENTAGE DISTRIBUTION OF LACUNES, MICROANEURYSMS, HYALINOSIS
SEVERE, AND
INTRACEREBRAL HAEMORRHAGE
1285 the media of small intracerebral arteries. In chronic hypertension, as a result of fibrotic change in vascular smooth muscle the vascular resistance gives way, possibly during hypertensive crises, at those points where the mechanical stresses are greatest. This results in dilatation and the formation of microaneurysms. The collapse of vascular resistance exposes the more distal vessels which are normally protected from the higher pressure and this in turn leads to further distension. At certain points the process is carried a stage further; the fibrous vessel wall loses its structural integrity and becomes permeable to plasma and to other blood constituents including fat. These accumulate within the vessel wall which becomes thicker and saturated with plasma. Evidence of this comes from the demonstration of fibrin inside the walls of retinal arteries in the hypertensive monkey by electron microscopy. 14 Finally, the small artery may rupture or become completely occluded. The distribution of microaneurysms can also be visualised most clearly in terms of pressure; the lesions occur in those parts of the vascular tree situated close to high pressure arteries such as the middle cerebral artery and the basilar artery. Regions remote from high pressure such as the centrum semiovale and cerebellar hemispheres are relatively free from microaneurysms and
from lipohyalinosis.
occur in normal and hypertensive affect and particularly systolic pressures. 20 patients These constitute a possible threat to the integrity of all arteries, especially to those of the cerebral circulation.
pressure
commonly
The illustrations are reproduced Brain and Acta Medica Iugoslavica.
by permission of the editors of
REFERENCES 1.
Shurtleff, D. The Framingham Study: 16 year Follow up. U.S. Government
2. 3.
Breckenridge, A., Dollery, C. T., Parry, E. Q. Jl Med. 1970, 29, 411. Beevers, D. G., Fairman, M. J., Hamilton, M., Harpur, J. E. Lancet, 1973,
Printing Office, 1970. i, 1407. 4. Adams, R. D., Vander Eecken, H. M. A. Rev. Med. 1953, 4, 213. 5. Russell, R. W. R. Brain, 1963, 86, 426. 6. Cole, F. M., Yates, P. O. J. Path. Bact. 1967, 93, 393. 7. Fisher, C. M. Acta neuropath., Berlin, 1969, 12, 1. 8. Fisher, C. M. Neurology, Minneapolis, 1965, 15, 774. 9. Tavcar, D. Acta med. iugosl. 1974, 28, 403. 10. Charcot, J. M., Bouchard, C. Archs. Physiol. norm. path. 1868, 1, 110, 643. 11. Ellis, A. G. Proc. path. Soc. Philad. 1909, 12, 197. 12. Rosenblatt, Dt. Z. NervHeilk, 1918, 61, 10. 13. Spatz, H. Z. ges. Neurol. Psychiat. 1939, 167, 301. 14. Garner, A. Ashton, N. Tripathi. R. Kohner, E. M., Bulpitt, C. J., Dollery, C. T. Br. J. Ophthal. 1975, 59, 3. 15. Strandgaard, S., Olesen, J., Skinhøj, E., Lassen, N. A. Br. med. J. 1973, i, 507. 16. Skinhøj, E., Strandgaard, S. Lancet, 1973, i, 46. 17. Dinsdale, H. B., Robertson, D. M., Hass, R. A. Archs Neurol. 1974, 31, 80. 18. Byrom, F. B. The Hypertensive Vascular Crisis. London, 1969. 19. Johansson, B. Acta neurol. scand. 1974, 50, 573. 20. Littler, W. A., Honour, A. J., Carter, R. D., Sleight, P. Br. med. J. 1975,
iii, 346.
CEREBRAL BLOOD-FLOW IN HYPERTENSION
The hypothesis of mechanical distension is supported by recent work on the regulation of cerebral blood-flow in hypertension. Under normal circumstances within certain limits cerebral blood-flow is maintained independently of blood-pressure by an intrinsic autoregulatory mechanism which does not depend on vascular innervation. A transient rise in blood-pressure is immediately followed by corresponding increase in cerebral vascular resistance, situated mainly in the small intracerebral arteries. In patients with chronic hypertension total and regional cerebral blood-flow is usually normal under resting conditions. Autoregulation continues to compen-
for variations in pressure but the range of autoregulation is altered to a higher level. IWhen the upper limit of autoregulation is exceeded, in either normotensive or hypertensive patients, by an acute short-term rise in blood-pressure a transient increase in cerebral bloodflow results.16 This implies a collapse of the regulating mechanism in the face of rising blood-pressure. In the experimental hypertensive animal a similar breakdown in autoregulation had been demonstrated and shown to result in brain damage.17 In contrast to the original views of Byrom18 who attributed focal brain oedema of acute hypertension to vasospasm, recent work suggests that the regions of oedema are where blood-flow has increased rather than decreased.’9 Why the brain blood-vessels should be particularly vulnerable is still a matter for speculation. A possible explanation is that the brain arteries contain smaller amounts of muscle and elastic tissue and are less able to withstand distension. An additional factor may be related to the physiological properties of the intracranial arteries where vascular nerves, although present, appear to play a relatively minor role in the regulation of bloodflow. In consequence the cerebral vascular tree does not participate in any generalised vasoconstrictor response of neurogenic origin. Rapid and marked fluctuations in sate
IS EARLY DECLINE OF CARDIAC FUNCTION IN ISCHÆMIA DUE TO CARBON-DIOXIDE RETENTION? PHILIP A. POOLE-WILSON
Department of Medicine, St Thomas’s Hospital Medical School, London SE1 7EH
There is no satisfactory explanation for the early and rapid decline of cardiac muscle function in ischæmia. Reduction of the energy source for contraction, A.T.P., is insufficient in magnitude and too slow in onset to be the prime cause. It is proposed that a large part of the loss of function is directly attributable to an immediate fall of intracellular pH and results from the accumulation of carbon dioxide and lactic acid; the intracellular acidosis reduces myocardial function by inhibition of that part of the calcium-ion influx associated with contraction.
Summary
INTRODUCTION
AN important problem relevant to the clinical management of ischaemic heart-disease is the mechanism by which myocardial function is reduced rapidly in the first few minutes of ischaemia. At present, there is no satisfactory explanation. Alterations in calcium-ion (Ca++) binding, metabolic changes, and a reduction of highenergy phosphates are not big enough to account for the early loss of function, and they can only be detected many minutes after the major part of the decline in muscular tension is complete.1-6 I suggest that this early loss of function is caused by a fall of intracellular pH (pHi) attributable to a rise of tissue Pco2 and lactic acid, and that the acidosis causes a reduction of the influx of that Ca++ which is associated with contraction. Such a
mycoplasma
was not
performed However,
if it was the cause of these abnormalities, then the skin controls would also have been affected. The
histological similarity
to
a stroked This strongly suggests that it is the raised blood-pressure itself which damages blood-vessels and causes
strokes.
fibrosarcoma has been
noted. Chromosome abnormalities have been recognised in cells cultured from experimental connective-tissue tumours,4 5 but there is no question of Dupuytren’s contracture being other than entirely benign. Recent reports? 8 have suggested that different acquired chromosome abnormalities may vary in their prognostic significance and Codish and Paul8 have described the appearance of a specific chromosome which suppresses malignancy. One may speculate that, within the broad range of fibromatoses, the existence and balance of chromosome abnormalities may influence the clinical course. Meanwhile, we suggest that chromosomally abnormal cell lines may arise in the development
of Dupuytren’s disease. We thank Rhona Bauld and Elizabeth Grace for assistance with case 1. Requests for reprints should be addressed to S. B-R., Pathology Department, Royal Hospital for Sick Children, Sciennes Road, Edinburgh EH9 1LF. REFERENCES
Ling, R. G. M. J. Bone Jt. Surg. 1963, 45B, 709. 2. Enzinger, M., Lattes, R., Torloni, H. Types Histologiques des 1.
Tumeurs des Tissue Mous; p. 28. Geneva, 1970. 3. Hueston, J. T. Dupuytren’s Disease; p. 61. Edinburgh, 1974. 4. Rasheed, S., Nelson-Rees, W. A., Toth, E. M., Arnstein, P., Gardner, M. B. Cancer, 1974, 33, 1027. 5. Benedict, W. F., Rucker, N., Mark, C., Kouri, R. E. J. natr. Cancer Inst. 1975, 54, 157. 6. Littlefield, L. G., Mailhes, J. B. Am. J. hum. Genet. 1975, 27, 190. 7. Rowley, J. D. Lancet, 1973, ii, 390. 8. Codish, S. D., Paul, B. Nature, 1974, 252, 610.
Hypothesis
PATHOLOGICAL CHANGES IN HYPERTENSIVE CEREBRAL VESSELS
Microaneurysms Related to Lipohyalinosis For many years pathologists have sought an underlying pathological process which can explain the increased liability of cerebral arteries both to rupture and to occlusion. It is generally agreed that the walls of the larger cerebral arteries from chronic hypertensive patients show an increased thickening and hyalinisation of the muscle coat when compared with those from normotensive patients. Furthermore, atheroma is more extensive and severe in large arteries.4 In addition, however, there is a distinct pathological change which affects small intracerebral arteries 50-200 m in diameter and consists of multiple microaneurysms arising on segments of dilated artery. In the wall of the microaneurysm the endothelium has ruptured and the media and elastic coats have disappeared and been entirely replaced by connective tissue. A single brain may contain many microaneurysms, and they have a characteristic distribution, being found most frequently in putamen, globus pallidus, external capsule, thalamus, pons, and subcortical white-matter.5 Some of these microaneurysms show a reaction variously known as "fibrinoid necrosis", "lipohyalinosis", or "angionecrosis" consisting in the accumulation within the wall of hyaline material which stains for fibrin and for fat. Around the aneurysm there is frequently evidence of leakage of blood usually in small quantities6 (figs. 1 and 2). Lacunar Infarction Related to Lipohyalinosis
HOW DOES BLOOD-PRESSURE CAUSE STROKE? R. W. Ross RUSSELL National Hospital, Queen Square, London WC1N 3BQ, and St Thomas’ Hospital, London SE1 7EH
In chronic hypertension the specific arterial lesions responsible for brain damage affect the small resistance arteries. The pathological characteristics of these lesions (notably the presence of microaneurysms, intramural fibrin, and lipid) and the location of lesions within the brain all suggest that they arise from mechanical distension, which destroys the integrity of the vessel and allows plasma insudation into the wall (lipohyalinosis), finally leading to occlusion or rupture. The process is analogous to the breakdown in vascular resistance and permeability which occurs in acute hypertension.
Summary
Fisher’ has convincingly shown that lacunes-small, deep cerebral infarcts often found in the brains of chronic hypertensives-are usually associated with occlusions of small intracerebral arteries. The pathological change at the point of occlusion consists of mural destruction, focal expansion, thrombotic occlusion, and fibrinoid deposition, and has progressed to the point of complete disorganisation of the artery and obliteration
EFFECTS OF HYPERTENSION ON THE BRAIN
EPIDEMIOLOGICAL studies have established an association between high blood-pressure and an increased incidence of cerebral vascular disease; this is true for both cerebral haemorrhage and cerebral infarction. Moreover, in severely hypertensive patients a reduction in blood-pressure by medical treatment lowers the incidence of future strokes both in those who have no cerebrovascular symptoms2 and in those who have survived
1—Cross-section of wall.
Fig.
(PTAH; x90.)
microaneurysm showing plasma
insudation of
1284
2—Cross-section of microaneurysm arising artery.
Fig.
The endothelium has the subintimal region.
ruptured
and
on
dilated segment of
hyaline material
has formed in
Fig. 3-Creas-aection of microaneurysm showing lipohyalinosis thrombosis, and haemorrhage.
of wall,
(Kindly supplied by Dr D. Tavcar.)
of the lumen. In 31 out of 40 arteries Fisher found dilatation at the point of occlusion up to two or three times the normal diameter of the vessel; there was also evidence of haemorrhagic extravasation within and outside the walls. Fisher considers the vascular change underlying lacunes to be identical with lipohyalinosis. Some support of this view comes from the distribution of lacunes in different regions of the brain which is similar to that of hyalinosis9 and also of microaneurysms6 although the latter tend to be more frequent in the subcortical region (table). Fisher emphasised that lipohyalinosis could sometimes be found without arterial dilatation, and for this reason suggested that aneurysms were the sequel to fibrinoid change. It seems equally possible, however, that since aneurysms are frequently seen with no evidence of hyalinosis dilatation of the artery is the first event.
hyalinosis. A microaneurysm was convincingly shown in one case (fig. 3).
Cerebral Haemorrhage Related to Lipohyalinosis
(a) The strong association with chronic hypertension. (b) The focal nature of the pathological change, affecting exclusively intracerebral "resistance vessels". (c) The frequent association with focal dilatation of the
The identification of a source of major bleeding within the brain is made difficult by secondary change and distortion produced by the haemorrhage itself. Many of the microaneurysms originally described by Charcot and Bouchard 10 were found on closer examination to represent small periarterial hoematomas.11 However, good evidence is now available to link cerebral haemorrhage to a vascular reaction identical with lipohyalinosis. Tavcar9 found lipohyalinosis constantly in brains showing haemorrhage, and the location of pathological change matched that of cerebral haemorrhage very closely. In two instances he was able to trace the artery giving rise to haemorrhage, and in both there was focal lipo-
PATHOGENESIS OF LIPOHYALINOSIS
Thus it seems likely that microaneurysms are an important initial result of raised pressure but that it requires the addition of lipohyalinosis to render the artery liable to rupture or occlusion. What then is the cause of lipohyalinosis? A variety of views have been expressed on this question.1 They vary from the action of a hypothetical vasoactive chemical’2 to the results of severe spasm.l3 Fisher1 favours the view that the pathological change is related to atheroma, based on the frequent coexistence and proximity of the two processes and the presence of fat in the lesions. Any theory on the origin of lipohyalinosis must explain the following:
artery. (d) The sites of predeliction within the brain. (e) The presence of fibrin, lipids, and red blood-cells in and around the artery at the site of lipohyalinosis.
The hypothesis which fits most closely with these facts is simply one of mechanical distension, and the sequence of events may be explained as follows: the increased cerebral vascular resistance necessary for the maintenance of normal blood-flow in the hypertensive brain is achieved by hypertonus and hypertrophy mainly of
PERCENTAGE DISTRIBUTION OF LACUNES, MICROANEURYSMS, HYALINOSIS
SEVERE, AND
INTRACEREBRAL HAEMORRHAGE
1285 the media of small intracerebral arteries. In chronic hypertension, as a result of fibrotic change in vascular smooth muscle the vascular resistance gives way, possibly during hypertensive crises, at those points where the mechanical stresses are greatest. This results in dilatation and the formation of microaneurysms. The collapse of vascular resistance exposes the more distal vessels which are normally protected from the higher pressure and this in turn leads to further distension. At certain points the process is carried a stage further; the fibrous vessel wall loses its structural integrity and becomes permeable to plasma and to other blood constituents including fat. These accumulate within the vessel wall which becomes thicker and saturated with plasma. Evidence of this comes from the demonstration of fibrin inside the walls of retinal arteries in the hypertensive monkey by electron microscopy. 14 Finally, the small artery may rupture or become completely occluded. The distribution of microaneurysms can also be visualised most clearly in terms of pressure; the lesions occur in those parts of the vascular tree situated close to high pressure arteries such as the middle cerebral artery and the basilar artery. Regions remote from high pressure such as the centrum semiovale and cerebellar hemispheres are relatively free from microaneurysms and
from lipohyalinosis.
occur in normal and hypertensive affect and particularly systolic pressures. 20 patients These constitute a possible threat to the integrity of all arteries, especially to those of the cerebral circulation.
pressure
commonly
The illustrations are reproduced Brain and Acta Medica Iugoslavica.
by permission of the editors of
REFERENCES 1.
Shurtleff, D. The Framingham Study: 16 year Follow up. U.S. Government
2. 3.
Breckenridge, A., Dollery, C. T., Parry, E. Q. Jl Med. 1970, 29, 411. Beevers, D. G., Fairman, M. J., Hamilton, M., Harpur, J. E. Lancet, 1973,
Printing Office, 1970. i, 1407. 4. Adams, R. D., Vander Eecken, H. M. A. Rev. Med. 1953, 4, 213. 5. Russell, R. W. R. Brain, 1963, 86, 426. 6. Cole, F. M., Yates, P. O. J. Path. Bact. 1967, 93, 393. 7. Fisher, C. M. Acta neuropath., Berlin, 1969, 12, 1. 8. Fisher, C. M. Neurology, Minneapolis, 1965, 15, 774. 9. Tavcar, D. Acta med. iugosl. 1974, 28, 403. 10. Charcot, J. M., Bouchard, C. Archs. Physiol. norm. path. 1868, 1, 110, 643. 11. Ellis, A. G. Proc. path. Soc. Philad. 1909, 12, 197. 12. Rosenblatt, Dt. Z. NervHeilk, 1918, 61, 10. 13. Spatz, H. Z. ges. Neurol. Psychiat. 1939, 167, 301. 14. Garner, A. Ashton, N. Tripathi. R. Kohner, E. M., Bulpitt, C. J., Dollery, C. T. Br. J. Ophthal. 1975, 59, 3. 15. Strandgaard, S., Olesen, J., Skinhøj, E., Lassen, N. A. Br. med. J. 1973, i, 507. 16. Skinhøj, E., Strandgaard, S. Lancet, 1973, i, 46. 17. Dinsdale, H. B., Robertson, D. M., Hass, R. A. Archs Neurol. 1974, 31, 80. 18. Byrom, F. B. The Hypertensive Vascular Crisis. London, 1969. 19. Johansson, B. Acta neurol. scand. 1974, 50, 573. 20. Littler, W. A., Honour, A. J., Carter, R. D., Sleight, P. Br. med. J. 1975,
iii, 346.
CEREBRAL BLOOD-FLOW IN HYPERTENSION
The hypothesis of mechanical distension is supported by recent work on the regulation of cerebral blood-flow in hypertension. Under normal circumstances within certain limits cerebral blood-flow is maintained independently of blood-pressure by an intrinsic autoregulatory mechanism which does not depend on vascular innervation. A transient rise in blood-pressure is immediately followed by corresponding increase in cerebral vascular resistance, situated mainly in the small intracerebral arteries. In patients with chronic hypertension total and regional cerebral blood-flow is usually normal under resting conditions. Autoregulation continues to compen-
for variations in pressure but the range of autoregulation is altered to a higher level. IWhen the upper limit of autoregulation is exceeded, in either normotensive or hypertensive patients, by an acute short-term rise in blood-pressure a transient increase in cerebral bloodflow results.16 This implies a collapse of the regulating mechanism in the face of rising blood-pressure. In the experimental hypertensive animal a similar breakdown in autoregulation had been demonstrated and shown to result in brain damage.17 In contrast to the original views of Byrom18 who attributed focal brain oedema of acute hypertension to vasospasm, recent work suggests that the regions of oedema are where blood-flow has increased rather than decreased.’9 Why the brain blood-vessels should be particularly vulnerable is still a matter for speculation. A possible explanation is that the brain arteries contain smaller amounts of muscle and elastic tissue and are less able to withstand distension. An additional factor may be related to the physiological properties of the intracranial arteries where vascular nerves, although present, appear to play a relatively minor role in the regulation of bloodflow. In consequence the cerebral vascular tree does not participate in any generalised vasoconstrictor response of neurogenic origin. Rapid and marked fluctuations in sate
IS EARLY DECLINE OF CARDIAC FUNCTION IN ISCHÆMIA DUE TO CARBON-DIOXIDE RETENTION? PHILIP A. POOLE-WILSON
Department of Medicine, St Thomas’s Hospital Medical School, London SE1 7EH
There is no satisfactory explanation for the early and rapid decline of cardiac muscle function in ischæmia. Reduction of the energy source for contraction, A.T.P., is insufficient in magnitude and too slow in onset to be the prime cause. It is proposed that a large part of the loss of function is directly attributable to an immediate fall of intracellular pH and results from the accumulation of carbon dioxide and lactic acid; the intracellular acidosis reduces myocardial function by inhibition of that part of the calcium-ion influx associated with contraction.
Summary
INTRODUCTION
AN important problem relevant to the clinical management of ischaemic heart-disease is the mechanism by which myocardial function is reduced rapidly in the first few minutes of ischaemia. At present, there is no satisfactory explanation. Alterations in calcium-ion (Ca++) binding, metabolic changes, and a reduction of highenergy phosphates are not big enough to account for the early loss of function, and they can only be detected many minutes after the major part of the decline in muscular tension is complete.1-6 I suggest that this early loss of function is caused by a fall of intracellular pH (pHi) attributable to a rise of tissue Pco2 and lactic acid, and that the acidosis causes a reduction of the influx of that Ca++ which is associated with contraction. Such a
