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Concepts of “primary hypertension” and their epidemiological significance
Annotations
Concepts and
their
of “primary epidemiological
There are probably only three major views on the pathogenesis of primary or essential hypertension. At some time, with varying enthusiasm, I may have defended each. What I now propose as accessible to potentially productive epidemiologic analysis is largely a matter of emphasis with regard to one of these. The basic premises are that it is fruitless to approach an array or even a pair of problems with a single hypothesis, and that it is likely that there are several kinds of, or at least more than one, “primary hypert.ension.” The first view is that this is an entity, a specific disease, that has its origin in some more or less imposed, unphysiologic mechanism. This is reminiscent of the systems of pathogenesis that ascribed disease to worms in the blood or to a devil and is the sort of concept that would extend its credence were manometers more widely available to witch doctors. It is disconcerting to realize that something along this line is fairly widely held by those who have manometers and know how to use them. It is what Sir George Pickering’ called “the old idea. that the disease represents a qualitative deviation from the norm . . . a unique fault (with) . . a unique and specific cause.” The second view, which he terms “the new idea” is that essential hypertension is “a quantitative deviation from the norm,” and that it is an ageconditioned, graded characteristic in the distribution of arterial pressure. It is still a dis-ease, since those who have it often find it troublesome and need treatment to relieve or prevent the vascular disease that it engenders and accelerates. However, unlike the secondary hypertensions, in this there is no single primary disturbance. The evidence for this view derives from the somewhat skewed, but unimodal frequency distributions of pressure by age. Those who oppose the view look for bimodality in distribution curves and, with some selection, find them. In part, Pickering’s position is philosophic, since he suggests, in a footnote, that “the greatest contribution in the sanitation of the mind would be the abolition of the terms normal and Dhvsioloeical and their ormosites.” This mav have-merit! bit the concept lea& no clear direction for epidemiologic study directed to an understanding of mechanisms. The third major view is Page’s “mosaic” theory.2 This describes kssential hypertension as a multifactorial process that “results from a constellation
137
hypertension” significance
of facets,” among which “one or even none . . (may be) . more or less dominant.” As Pickering has pointed out, this resembles his view in several respects, notably in that it does not postulate a single or even an abnormal mechanism. It takes into account the whole tessellated array of factors, intrinsic and extrinsic, that have to do with regulation of arterial pressure. Because it is based on physiologic considerations, it would seem at the outset to be more realistic than a view based on an array of pressures in outpatients, some of which may have been disturbed by apprehension, tuberculosis, or renal arterial stenosis. Unfortunately, the mosaic theory involves so many organs and systems, and so many biologic disciplines, that it has been criticized as more of an unanswerable rhetorical device than a hypothesis. This criticism overlooks the fact that what is under consideration is established and not incipient hypertension, and that it is very likely that in primary, as in secondary, hypertensions the established disease involves all or most pressure-regulating mechanisms. From the aspect of epidemiologic study, the concept offers little unless attention is concentrated on those early stages of the process, when some dominant disturbance may still be recognizable. The first or “devil” approach can be discarded, except in the secondary hypertensions, where it also has to be qualified. The “quantitative” concept tends to lump all primary hypertensions into one, which is somewhat defeating. The “mosaic” theory recognizes that hypertensions may be different at the start, but has given some the impression that, by the time the condition is recognizable, there are so many powerful secondary overlays that it would be useless to try to sort out a primary disturbance. Actually, this sorting goes on all the time. Some 10 to 15 per cent of hypertension that was “primary” until 1940 is now “secondary”; about 5 per cent of the “primary” hypertension of 1950 is now attributed to renal arterial stenosis. On the basis of a series of serial renal angiograms-a penetrating epidemiologic expedient-it has been suggested that common anatomic variations, such as having two renal arteries, predispose to hypertension in some people. Actually, the proportion of renal arterial cases is not large and is still less (perhaps 1 per cent) in a Negro group,” so that this is not a problem in public health, nor, except as tech-
138
A motutions
niques such as radioisotope renography’ are rcfinctl, can it be evaluated by a lield survey. The various other “es-primar>.,” now secondar> hypertensions are grouped as follows: endocrine (aldosteronism, pheochromocytoma--both quite rare) ; neurogenic (some cases of poliomyelitis, porphyria, and neural injury from other causes5these are uurommon and the hypertension usually incidental); renal (noted above and reviewed elsewheree); and cardiovascular (aortic coarctation, again uncommon, and aortic arteriosclerosis with loss of elasticity and systolic hypertension, which is quite common). This last, except as it may be complicated by diastolic hypertension, is a mechanical problem, quite different from the hypertensions with which we are here concerned. It has contributed a measure of statistical confusion when means of pressure are considered without reference to clinical characteristics. We can perhaps accept it as an age-conditioned, graded, and quantitative characteristic, and one that is fairly benign. Epidemiologically, it may be useful to consider the possibility that the residual mass of some 80 to 90 per cent of diastolic, apparently “primary” hypertension is, as implied in the mosaic theory, sometimes discrete in its initial mechanisms, and to sort these as neural, humoral, and those intrinsic in vascular and cardiac muscle. Russian interest has centered on the neurogenic concept. The bases for the Pavlov-Bykov view were developed in several aspects and criticallq examined at the Prague Conference ou Pathogenesis of Essential Hypertension.’ In essence, this view supposes a disturbance of higher neural mechanisms. conditioned by external forces, that ultimateI> disturb centers in the mid-brain and medulla and upset the regulation of arterial pressure. This has been exemplified by the high prevalence of hvpertension during the siege of I.eningrad, h!; transient hypertension in those exposed to the Texas Cit, disaster, by that which was found in members of the Armored Brigade during the battles in the \2:estern Desert of Africa, bs- that in some primate experiments, and by that 111 strains of half-wild rats exposed to repetitive, intense auditory stimuli. The concept might even gain some support from the fact that all but one or two antihypertensive drugs in effective current use act on some part of the nervous system. In brief, this is an attracti\.-e notion; it is unproven but, since it postulates definable en\-ironmental factors that act, possibly, on some definable hereditary substrate, it is accessible to critical epidemiologic analysis that has )-et to be done. One reason for the deficit of information in this area is the lack of an applicable and specific way of recognizing what one might term “neurogenic prehypertension.” Sokolow’s7 psychodramas would be impractical in the field; Brad’s’ hemodynamic responses to mental arithmetic postulate a considerable laboratory and a willing subject who knows and dislikes the multiplication tables more than he does arterial puncture. Still, ingeunity and persistence should resolve this impasse. If we need a test badly enough, we shall doubtless turn one up. ~~nfortunately, a “therapeutic test” would be unavailing, since every hypertension seems sooner
or later to ;tcquirc a llcural txxllponeut which, ill the view of Page, McCubbin and Green, nlay, ;Ifter a while, overshadow the causal mechanism and cause hypertension to persist even after the cause is removed. If it can be shown that “salt hvpertension” is indeed more common in Djegro than in white hypertensive patients, this may bear on the fact that hypertension as such is more common in Negro than in white populations, even when lixring in the same environment,* and the one fact may underlie the other. Dahl’O has recently established inbred strains of rats; some of these lap up salt without noticeable harm, whereas others-those with the salt-hypertension trait-rapidly become hypertensive. It is possible that a similar trait occurs in people, and in some people more than in others. To persist, a trait should have some survival value, and it may be that the ability to restrict the loss of salt would have such value in a people living in the tropics and away from the sea. Dr. James Grainger seems to have recognized something like this during his years in St. Kitts, West Indies, where he composed his poem, in four books, called “The Sugar Cane” (London, 1764). The last book concerns the care of slaves and their selection. It is notably humanitarian, and Dr. Grainger seems to have been not only a good versifier, but an acute observer. Hc characterized one slave group as “Congas” and indicated their origin in North Angola; these he described as tractable, intelligent, suitable for domestic employment or trade, but not for the fields. The restriction is because of their great tendency to drops?-, which, I suppose, can be equated with hypertensive heart disease. Could it be that the trait for hypertension, perhaps a salt hl-pertension, was then more or less deliberately bred, along with tractability and humor, into the ruder, sometimes melancholic slave groups of other origin? Might this account for some of the high prevalence of hypertension in American Negroes? This, then is an area for study. Characteristics should be recognizable that are independent of actual blood pressure, such as the responses of blood flow to heat or cold and the relative rates of acclimatization to heat of Segro and white “normal,” “prehypertensive,” and hypertensive persons. Such study might be difficult, since it would best be done in populations that are both homogeneous racially aud well organized in terms of public health, such as was the case in St. Kitts in 1958.1’.‘2 Parenthetically, our impression then, supported now by some new evidence from the Government Medical Service, suggests that, although hypertension is as common in St. Kitts as in U. S. Negroes, hypertensive disease in the former is not so severe. Of course the whole psychosocial environment is very different, and it may be that, given a hypertensive state with some degree of hyperresponse to stimuli, our unstable, competitive society creates impacts of pressure peaks that damage vessels more rapidly than does the steadier strain of a stable, albeit increased, resting pressure. A study of West Indian migrants now in the I’nited Kingdom might bear on this point. I,astly, the prohlenl of a defect in biochemistry of vascular must.1~ is hardly approachable in epi-
l’o111mc Nzrmber
69
Annotations
1
demiologic terms, except as these are primarily genetic. However, as suggested above, the muscle response may be in part a response to salt, and, if so, there should be some way to get at it. It may be that a plausible “therapeutic test” may be developed. For example, there is a small proportion of hypertensive patients who seem to respond very well to small doses of hydralazine, a myotropic and amine-releasing drug, and this fact may have a special meaning, as probably does the response to thiazide. To close, it seems possible that a very few etiologitally distinct modalities include the majority of cases of primary hypertension. Mechanisms overlap as the process continues, until pathogenesis becomes very complicated and perhaps inaccessible. Still, in the incipient phases, it would seem possible to apply epidemiologic methods to separation of major groups in what now passes for “primary hypertension.” This requires time and imagination, the development of reasonably specific and adequately practical techniques, and the conviction that such an analysis of the problem may further sort out the field of “primary hypertension” into subgroups that, once recognized, can sooner or later be understood. A. C. Corcoran, M.D., CM.* Department of Clinical Investigation St. Vincent Charity Hospital 2222 Central Ave. Cleveland, Ohio, 44115 *Formerly. Special Research Fellow, National Heart Institute. National Institutes of Health (HF 13,190). Present address: Chief, Hypertension Research, U. S. Veterans Administration Hospital, Ann Arbor, Mich.. 48105.
3.
4.
5.
6.
7.
8.
9.
10.
11.
REFERENCES 1. Pickering, Sir George: The nature of essential hypertension, London, 1961, J. & A. Churchill, Ltd. 2. Page, I. H., et al.: Essential hypertension, an International symposium, Berlin, 1960, SpringerV’erlag..
Cardiovascular
findings
In healthy children there is frequently a rather sharp pulse, a systolic murmur, and a loud third heart sound; and inspiratory splitting of the second sound is usually even more obvious than in adults. It is important to know the normal range of these physical signs in order to diagnose the abnormal, and in order to prevent unnecessary invalidism as has happened in the past when the combination of fever and. a systolic murmur sometimes resulted in a diagnosis of rheumatic carditis. In children, electromechanical intervals and isoelectric times are shorter than in adults, and a more rapid contraction of the heart may at least
12.
139
Nolan, T. R., Mullally, P. R., Hirakawa, A., Loyke, H. F., and Corcoran, A. C.: Prevalence of renal arterial occlusive disease, J. Ohio State Med. Assoc. 59:677, 1963. Hirakawa, A., and Corcoran, A. C.: 1’3r-Oiodohippurate excretion and a quantitative formulation of the radioisotope renogram as indices of bilateral and unilateral renal functions, J. Lab. & Clin. Med. 61:795, 1963. Corcoran, A. C., Imperial, E. S., and Smith, H. E.: Neurogenic hypertension. A sequel of kanamycin intoxication, J.A.M.A. 174:1838, 1960. Corcoran, A. C.: Unilateral renal disease (with arterial hypertension), Bull. Chicago Med. Sot. 67:629, 1964. Cort, J. H., Fenel, V., Heil, Z., and Jirka, J., editors: Symposium on the pathogenesis of essential hypertension, Prague, 1960. Prague, 1961, State Med. Publishing House. Comstock, G. W.: An epidemiologic study of blood pressure levels in a biracial community in the southern United States, Am. J. Hyg. 65:271, 1957. Corcoran, A. C.: Conference on epidemiology of hypertension, Carmel, California, June 18, 1962. Dahl, L. Ii., Heine, M., and Tassinari, L.: Effects of chronic excessive salt ingestion. Evidence that genetic factors play an important role in susceptibility to experimental hypertension, J. Exper. Med. 115:1173, 1962. Schneckloth, R. E., Corcoran, A. C., Stuart, K. L., and Moore, F. E.: Arterial pressure and hypertensive disease in a West Indian Negro population. Report of a survey in St. Kitts, West Indies, AM. HEART J. 63:607, 1962. Stuart, K. L., Schneckloth, R. E., Lewis, L., Moore, F. E., and Corcoran, A. C.: Diet, serum cholesterol, protein, blood haemoglobin, and glycosuria in a West Indian community (St. Kitts, W. I.). With observations on ischaemic heart disease, Brit. M. J. 2:1283, 1962.
in healthy
children
partly account for the sharp pulse, rapid ejection, and, thus, a systolic murmur, and rapid ventricular filling may explain the loud third sound. A thin chest wall may be another factor in increasing audibility of the normal sounds and murmurs. The physiologic ejection systolic murmur so often heard in children is Grade 2 or 3 (of 6) in intensity, often grunting in quality, widespread in distribution, but usually maximal internal to the apex and in the pulmonary area and soft in the aortic area; it is short, finishing well before both components of the second sound and is probably due to rapid ejection into both the aorta and
Concepts and
their
of “primary epidemiological
There are probably only three major views on the pathogenesis of primary or essential hypertension. At some time, with varying enthusiasm, I may have defended each. What I now propose as accessible to potentially productive epidemiologic analysis is largely a matter of emphasis with regard to one of these. The basic premises are that it is fruitless to approach an array or even a pair of problems with a single hypothesis, and that it is likely that there are several kinds of, or at least more than one, “primary hypert.ension.” The first view is that this is an entity, a specific disease, that has its origin in some more or less imposed, unphysiologic mechanism. This is reminiscent of the systems of pathogenesis that ascribed disease to worms in the blood or to a devil and is the sort of concept that would extend its credence were manometers more widely available to witch doctors. It is disconcerting to realize that something along this line is fairly widely held by those who have manometers and know how to use them. It is what Sir George Pickering’ called “the old idea. that the disease represents a qualitative deviation from the norm . . . a unique fault (with) . . a unique and specific cause.” The second view, which he terms “the new idea” is that essential hypertension is “a quantitative deviation from the norm,” and that it is an ageconditioned, graded characteristic in the distribution of arterial pressure. It is still a dis-ease, since those who have it often find it troublesome and need treatment to relieve or prevent the vascular disease that it engenders and accelerates. However, unlike the secondary hypertensions, in this there is no single primary disturbance. The evidence for this view derives from the somewhat skewed, but unimodal frequency distributions of pressure by age. Those who oppose the view look for bimodality in distribution curves and, with some selection, find them. In part, Pickering’s position is philosophic, since he suggests, in a footnote, that “the greatest contribution in the sanitation of the mind would be the abolition of the terms normal and Dhvsioloeical and their ormosites.” This mav have-merit! bit the concept lea& no clear direction for epidemiologic study directed to an understanding of mechanisms. The third major view is Page’s “mosaic” theory.2 This describes kssential hypertension as a multifactorial process that “results from a constellation
137
hypertension” significance
of facets,” among which “one or even none . . (may be) . more or less dominant.” As Pickering has pointed out, this resembles his view in several respects, notably in that it does not postulate a single or even an abnormal mechanism. It takes into account the whole tessellated array of factors, intrinsic and extrinsic, that have to do with regulation of arterial pressure. Because it is based on physiologic considerations, it would seem at the outset to be more realistic than a view based on an array of pressures in outpatients, some of which may have been disturbed by apprehension, tuberculosis, or renal arterial stenosis. Unfortunately, the mosaic theory involves so many organs and systems, and so many biologic disciplines, that it has been criticized as more of an unanswerable rhetorical device than a hypothesis. This criticism overlooks the fact that what is under consideration is established and not incipient hypertension, and that it is very likely that in primary, as in secondary, hypertensions the established disease involves all or most pressure-regulating mechanisms. From the aspect of epidemiologic study, the concept offers little unless attention is concentrated on those early stages of the process, when some dominant disturbance may still be recognizable. The first or “devil” approach can be discarded, except in the secondary hypertensions, where it also has to be qualified. The “quantitative” concept tends to lump all primary hypertensions into one, which is somewhat defeating. The “mosaic” theory recognizes that hypertensions may be different at the start, but has given some the impression that, by the time the condition is recognizable, there are so many powerful secondary overlays that it would be useless to try to sort out a primary disturbance. Actually, this sorting goes on all the time. Some 10 to 15 per cent of hypertension that was “primary” until 1940 is now “secondary”; about 5 per cent of the “primary” hypertension of 1950 is now attributed to renal arterial stenosis. On the basis of a series of serial renal angiograms-a penetrating epidemiologic expedient-it has been suggested that common anatomic variations, such as having two renal arteries, predispose to hypertension in some people. Actually, the proportion of renal arterial cases is not large and is still less (perhaps 1 per cent) in a Negro group,” so that this is not a problem in public health, nor, except as tech-
138
A motutions
niques such as radioisotope renography’ are rcfinctl, can it be evaluated by a lield survey. The various other “es-primar>.,” now secondar> hypertensions are grouped as follows: endocrine (aldosteronism, pheochromocytoma--both quite rare) ; neurogenic (some cases of poliomyelitis, porphyria, and neural injury from other causes5these are uurommon and the hypertension usually incidental); renal (noted above and reviewed elsewheree); and cardiovascular (aortic coarctation, again uncommon, and aortic arteriosclerosis with loss of elasticity and systolic hypertension, which is quite common). This last, except as it may be complicated by diastolic hypertension, is a mechanical problem, quite different from the hypertensions with which we are here concerned. It has contributed a measure of statistical confusion when means of pressure are considered without reference to clinical characteristics. We can perhaps accept it as an age-conditioned, graded, and quantitative characteristic, and one that is fairly benign. Epidemiologically, it may be useful to consider the possibility that the residual mass of some 80 to 90 per cent of diastolic, apparently “primary” hypertension is, as implied in the mosaic theory, sometimes discrete in its initial mechanisms, and to sort these as neural, humoral, and those intrinsic in vascular and cardiac muscle. Russian interest has centered on the neurogenic concept. The bases for the Pavlov-Bykov view were developed in several aspects and criticallq examined at the Prague Conference ou Pathogenesis of Essential Hypertension.’ In essence, this view supposes a disturbance of higher neural mechanisms. conditioned by external forces, that ultimateI> disturb centers in the mid-brain and medulla and upset the regulation of arterial pressure. This has been exemplified by the high prevalence of hvpertension during the siege of I.eningrad, h!; transient hypertension in those exposed to the Texas Cit, disaster, by that which was found in members of the Armored Brigade during the battles in the \2:estern Desert of Africa, bs- that in some primate experiments, and by that 111 strains of half-wild rats exposed to repetitive, intense auditory stimuli. The concept might even gain some support from the fact that all but one or two antihypertensive drugs in effective current use act on some part of the nervous system. In brief, this is an attracti\.-e notion; it is unproven but, since it postulates definable en\-ironmental factors that act, possibly, on some definable hereditary substrate, it is accessible to critical epidemiologic analysis that has )-et to be done. One reason for the deficit of information in this area is the lack of an applicable and specific way of recognizing what one might term “neurogenic prehypertension.” Sokolow’s7 psychodramas would be impractical in the field; Brad’s’ hemodynamic responses to mental arithmetic postulate a considerable laboratory and a willing subject who knows and dislikes the multiplication tables more than he does arterial puncture. Still, ingeunity and persistence should resolve this impasse. If we need a test badly enough, we shall doubtless turn one up. ~~nfortunately, a “therapeutic test” would be unavailing, since every hypertension seems sooner
or later to ;tcquirc a llcural txxllponeut which, ill the view of Page, McCubbin and Green, nlay, ;Ifter a while, overshadow the causal mechanism and cause hypertension to persist even after the cause is removed. If it can be shown that “salt hvpertension” is indeed more common in Djegro than in white hypertensive patients, this may bear on the fact that hypertension as such is more common in Negro than in white populations, even when lixring in the same environment,* and the one fact may underlie the other. Dahl’O has recently established inbred strains of rats; some of these lap up salt without noticeable harm, whereas others-those with the salt-hypertension trait-rapidly become hypertensive. It is possible that a similar trait occurs in people, and in some people more than in others. To persist, a trait should have some survival value, and it may be that the ability to restrict the loss of salt would have such value in a people living in the tropics and away from the sea. Dr. James Grainger seems to have recognized something like this during his years in St. Kitts, West Indies, where he composed his poem, in four books, called “The Sugar Cane” (London, 1764). The last book concerns the care of slaves and their selection. It is notably humanitarian, and Dr. Grainger seems to have been not only a good versifier, but an acute observer. Hc characterized one slave group as “Congas” and indicated their origin in North Angola; these he described as tractable, intelligent, suitable for domestic employment or trade, but not for the fields. The restriction is because of their great tendency to drops?-, which, I suppose, can be equated with hypertensive heart disease. Could it be that the trait for hypertension, perhaps a salt hl-pertension, was then more or less deliberately bred, along with tractability and humor, into the ruder, sometimes melancholic slave groups of other origin? Might this account for some of the high prevalence of hypertension in American Negroes? This, then is an area for study. Characteristics should be recognizable that are independent of actual blood pressure, such as the responses of blood flow to heat or cold and the relative rates of acclimatization to heat of Segro and white “normal,” “prehypertensive,” and hypertensive persons. Such study might be difficult, since it would best be done in populations that are both homogeneous racially aud well organized in terms of public health, such as was the case in St. Kitts in 1958.1’.‘2 Parenthetically, our impression then, supported now by some new evidence from the Government Medical Service, suggests that, although hypertension is as common in St. Kitts as in U. S. Negroes, hypertensive disease in the former is not so severe. Of course the whole psychosocial environment is very different, and it may be that, given a hypertensive state with some degree of hyperresponse to stimuli, our unstable, competitive society creates impacts of pressure peaks that damage vessels more rapidly than does the steadier strain of a stable, albeit increased, resting pressure. A study of West Indian migrants now in the I’nited Kingdom might bear on this point. I,astly, the prohlenl of a defect in biochemistry of vascular must.1~ is hardly approachable in epi-
l’o111mc Nzrmber
69
Annotations
1
demiologic terms, except as these are primarily genetic. However, as suggested above, the muscle response may be in part a response to salt, and, if so, there should be some way to get at it. It may be that a plausible “therapeutic test” may be developed. For example, there is a small proportion of hypertensive patients who seem to respond very well to small doses of hydralazine, a myotropic and amine-releasing drug, and this fact may have a special meaning, as probably does the response to thiazide. To close, it seems possible that a very few etiologitally distinct modalities include the majority of cases of primary hypertension. Mechanisms overlap as the process continues, until pathogenesis becomes very complicated and perhaps inaccessible. Still, in the incipient phases, it would seem possible to apply epidemiologic methods to separation of major groups in what now passes for “primary hypertension.” This requires time and imagination, the development of reasonably specific and adequately practical techniques, and the conviction that such an analysis of the problem may further sort out the field of “primary hypertension” into subgroups that, once recognized, can sooner or later be understood. A. C. Corcoran, M.D., CM.* Department of Clinical Investigation St. Vincent Charity Hospital 2222 Central Ave. Cleveland, Ohio, 44115 *Formerly. Special Research Fellow, National Heart Institute. National Institutes of Health (HF 13,190). Present address: Chief, Hypertension Research, U. S. Veterans Administration Hospital, Ann Arbor, Mich.. 48105.
3.
4.
5.
6.
7.
8.
9.
10.
11.
REFERENCES 1. Pickering, Sir George: The nature of essential hypertension, London, 1961, J. & A. Churchill, Ltd. 2. Page, I. H., et al.: Essential hypertension, an International symposium, Berlin, 1960, SpringerV’erlag..
Cardiovascular
findings
In healthy children there is frequently a rather sharp pulse, a systolic murmur, and a loud third heart sound; and inspiratory splitting of the second sound is usually even more obvious than in adults. It is important to know the normal range of these physical signs in order to diagnose the abnormal, and in order to prevent unnecessary invalidism as has happened in the past when the combination of fever and. a systolic murmur sometimes resulted in a diagnosis of rheumatic carditis. In children, electromechanical intervals and isoelectric times are shorter than in adults, and a more rapid contraction of the heart may at least
12.
139
Nolan, T. R., Mullally, P. R., Hirakawa, A., Loyke, H. F., and Corcoran, A. C.: Prevalence of renal arterial occlusive disease, J. Ohio State Med. Assoc. 59:677, 1963. Hirakawa, A., and Corcoran, A. C.: 1’3r-Oiodohippurate excretion and a quantitative formulation of the radioisotope renogram as indices of bilateral and unilateral renal functions, J. Lab. & Clin. Med. 61:795, 1963. Corcoran, A. C., Imperial, E. S., and Smith, H. E.: Neurogenic hypertension. A sequel of kanamycin intoxication, J.A.M.A. 174:1838, 1960. Corcoran, A. C.: Unilateral renal disease (with arterial hypertension), Bull. Chicago Med. Sot. 67:629, 1964. Cort, J. H., Fenel, V., Heil, Z., and Jirka, J., editors: Symposium on the pathogenesis of essential hypertension, Prague, 1960. Prague, 1961, State Med. Publishing House. Comstock, G. W.: An epidemiologic study of blood pressure levels in a biracial community in the southern United States, Am. J. Hyg. 65:271, 1957. Corcoran, A. C.: Conference on epidemiology of hypertension, Carmel, California, June 18, 1962. Dahl, L. Ii., Heine, M., and Tassinari, L.: Effects of chronic excessive salt ingestion. Evidence that genetic factors play an important role in susceptibility to experimental hypertension, J. Exper. Med. 115:1173, 1962. Schneckloth, R. E., Corcoran, A. C., Stuart, K. L., and Moore, F. E.: Arterial pressure and hypertensive disease in a West Indian Negro population. Report of a survey in St. Kitts, West Indies, AM. HEART J. 63:607, 1962. Stuart, K. L., Schneckloth, R. E., Lewis, L., Moore, F. E., and Corcoran, A. C.: Diet, serum cholesterol, protein, blood haemoglobin, and glycosuria in a West Indian community (St. Kitts, W. I.). With observations on ischaemic heart disease, Brit. M. J. 2:1283, 1962.
in healthy
children
partly account for the sharp pulse, rapid ejection, and, thus, a systolic murmur, and rapid ventricular filling may explain the loud third sound. A thin chest wall may be another factor in increasing audibility of the normal sounds and murmurs. The physiologic ejection systolic murmur so often heard in children is Grade 2 or 3 (of 6) in intensity, often grunting in quality, widespread in distribution, but usually maximal internal to the apex and in the pulmonary area and soft in the aortic area; it is short, finishing well before both components of the second sound and is probably due to rapid ejection into both the aorta and