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Progression of target organ damage from sustained diastolic hypertension
Progression
of Target
Sustained
Organ
Diastolic
Damage
from
Hypertension*
MILTON TELLEM, OLD. Philadelphia,
Pennsylvania
BENIGN ESSENTIAL HYPERTENSION
T
HE small muscular arteries and arterioles are the primary targets damaged in sustained diastolic hypertension. This process is generalized but intensified in vessels of the kidney. Morphologic change is generally considered secondary to sustained diastolic hypertension because vascular alterations are absent in cases of clinically early hypertension ; furthermore, vascular disease occurring in secondary hypertension is morphologically similar to A quantitative that in essential hypertension. relation exists between the arteriolar lesion and the level of blood pressure ; and mortality can be correlated with the degree of arteriolar pathologic change. Regardless of cause, arteriolar narrowing This deoccurs in diastolic hypertension.‘,? mands greater work of the arteriolar smooth muscle cells whereby energy is translated into Depending on the demuscle contraction. mand, the muscle cells may become hyperbasement membrane and connective trophic, tissue elements may increase, and the vessel wall may undergo hyalinization or acute arteriolar necrosis. Increased peripheral resistance is associated concomitantly with elevated blood pressure and smooth muscle alteration, which may result in organic vascular disease, leading to organ damage. A broad spectrum of expression is associated At one extreme with essential hypertension. the vascular response may be so gradual and progress so slowly that life span is not shortened. On the other hand, elevated pressure and smooth muscle alteration may be so extreme that vascular necrosis and renal failure or cerebral damage quickly ensue. Subsequent remarks will focus on the nature of the vascular alteration followed by discussion of specific organ damage.
The vascular changes have been studied in greatest detail in the kidney. Two types of lesions involve the small arteries: hyaline arteriolar sclerosis of the afferent arteriole and hyperplastic elastosis of the interlobular artery. Hyaline arteriolar sclerosis of the afferent arteriole consists of homogeneous hyalinization and diminished cellularity of the wall associated with narrowing of the lumen. Hyperplastic elastosis of the interlobular artery, an arterial branch just proximal to the afferent arteriole, consists of eosinophilic thickening of intima with persistence and duplication of the inner elastic lamina. There is loosely arranged thickening of the intima with an increase in spindle-shaped cells. Hyaline and collagen accumulate in the intima and media and elastic fibers permeate the media. This hyperplastic elastic lesion is very similar to that of atherosclerosis. Though this alteration occurs chiefly in the interlobular arteries, afferent arterioles may also be similarly affected. One or both types of vascular change may be seen in varying degrees in normotensive individuals of advanced age (Fig. 1 A and B). Hi~tochemistry: The origin and nature of vascular hyaline are not conclusively established. Wilens and Elster” as well as Baker and Kent4 have stressed the role of plasma lipids in the pathogenesis of hyaline. Duguid and Anderson5 and others” concluded that hyaline was of hematogeneous origin and represented incorporation and reorganization of plasma substances in the vascular wall. McKinney7 considered hyaline a mixture of fibrin and plasma protein, gradually deposited subintimally and in the media. Muscle degeneration was considered a secondary process but not a source for hyalinr. Montgomery and Light Microscopy:
* From the Department of Pathology, Hahnemann Medical College and Hospital, Philadelphia, Pa. 604
THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Arteriolar
Sclerosis
in Diastolic
Hypertension
605
FIG. 1. A, hyalincj nrterzolnr sclrrosis shows increased cellular proliferation and hyaline thickening of wall of afferent arteriole. (Hrmatoxylin and eosin, X 250, reduced by 24y&) B, hy$qt&zstrc dnstic lesion of intdohular artrry shows laminated thickening of arterial wall with incrrascd subintimal cellularity and marked narrowing of lumen. (Hematoxylin and e&n, X 250, reduced by 24:‘;..)
Muirheads proposed that hyaline was a byproduct of smooth nruscle. Histochemical reactions were similar in both benign and malignant vascular alterations except for the presence of acid phosphatase in the malignant phase. Electron Microscopy: McGee and Ashworth studied human arteriolar renal lesions of varying degrees of severity. They interpreted the hvaline arteriolar sclerotic change as a progressive thickening and accumulation of basement membrane material from endothelial and smooth muscle origin. In later stages of the lesion, muscle cells became sparse and disappeared. Occasional lipid droplets were noted in the intima and media. Their study of hyperplastic elastosis of the interlobular artery revealed a thickened intima associated with increased cellularity due to proliferation of fibrocytes and smooth muscle cells. Basement membrane material accumulated in the intima and media as it did in the hyaline arteriolar process. The arteriole elastic membrane was thickened. Biava et al.‘” in an electron microscopic study of human material confirmed the findings of McGee but thought that hyaline was intimately related with but entirely distinct from any normal structures of the vessel wall, including basement membranes of endothelial or sn-.ooth muscle cells. They concluded that the material VOLUME
17,
MAY
1966
represented an excess of plasma proteins which passed into the wall secondary to altered endothelial permeability. In the most recent electron microscopic study of experimental renal hypertension in rats, Spiro et al.” noted that the most striking feature of the arterioles was the abnormal presence of smooth muscle cells between endothelium and the inner elastic lamellae. Smooth muscle cells were also increased in the media. These features could account for progressive lumen narrowing and a further rise in peripheral resistance. Increased basement membrane material was also noted in the intima and media. In summery, in benign hypertension arteriolar narrowing, increased luminal pressure and concomitant increased work by smooth muscle cells provide stimuli which, if maintained, lead to an irreversible accumulation of hyaline in the vessel wall. From histochemical and electron microscopic observations on human material, hyaline is probably derived from plasma constituents and products of destruction and proliferation of the arteriolar wall itself, associated with progressive ablation of smooth muscle elements. Electron microscopic studies in experimental renal hypertension have shown an abnormal localization of smooth muscle cells between the intima and inner elastic lamellae as
Tellem
606
and fibrin valved
nccrmis FIG. 2. Aculrur/~z?iolnr
terizrd by an acrllular of the artrriolar wall. reducrd by 28?;.)
of ufJwm/ ur~rriolr is rhxracexudative and drstructivc process (Hrmatoxylin and cosin. X 250,
one phase of the process and probably vascular alteration.
an early
MALIGNANT HYPERTENSION The appearance of arterioles in malignant hypertension will vary with the severity and The duration of previous hypertensive disease. vascular wall exhibits necrosis of a fibrinoid Immature connective tissue elements in type. the intima and media rich in acid mucopolysaccharides are also seen. The pathogenesis may be acute destruction of smooth muscle elements consequent to their metabolic failure in response to the work load imposed by the extreme intraluminal pressure. The plasma protein constituents located in the lesion, especially fibrin, are considered as a transudation from the plasma through injured endothelium and associated basement membranes. The over-all histologic picture may simulate angiitis of hypersensitivity For reaor certain connective tissue diseases. sons unknown, inflammatory cell response is rarely seen in the necrotizing arteriolar lesions (Fig. 2). SPECIFIC ORGAN DAMAGE There is an increased rate of atherosclerosis in essential hypertension, particularly affecting the coronary and cerebral Hemodynamic forces play a role in vessels. pathogenesis of the lesions as suggested by location of the plaques at orifices of arterial branches The acceleration and at points of bifurcation. of the process may be related to change in subFacilitated transfer, depintimal mucoproteins. osition and organization of plasma lipoproteins, Atherosclerosis:
in the arterial
\vall may also be in-
The xcork of the myocardiulu is proHeart: portional to arterial pressure in essential hypertension. There is a quantitative relation between left ventricular hypertrophy and arterial blood pressure. The Framingham studyI revealed that coronary atherosclerosis was associated with higher blood pressure levels. Essential hypertension was associated with a greater risk of developing coronary artery disease in men of all ages and in women, particularly those 45 to 62 years of age. One or any combination of left ventricular hypertrophy, congestive cardiac failure, angina pectoris and myocardial infarction is seen more frequently in the hypertensive as compared to The patient with the normotensive individual. left ventricular hypertrophy is more prone to suffer the effects of coronary atherosclerosis with lesser degrees of luminal narrowing. It is interesting to note that the cardiac arterioles show little or no change in hypertension as compared to those of the kidney, brain or spleen. Brain: The small intracerebral muscular arteries and arterioles are less involved than those in the kidney. The vascular changes are noted mainly in patients past 60 years of age. Our autopsy experience reveals a quantitative relation between atherosclerosis of the arteries of the circle of Willis (particularly the basilar vertebral system) and the duration and severity of hypertension. The hypertensive patient, because of these vascular alterations, is more prone to cerebral thrombosis, infarction, hemorrhage and hypertensive encephalopathy. Cerebral hemorrhage represents bleeding from multiple small vascular probably arteriolar, capillary and channels, venous. The pathogenesis of hemorrhage may be related to fluctuating blood pressures in the cerebral circulation. Occasional drops in pressure too low to drive the blood through the diseased arterioles may result in ischemia of neural tissue and vascular walls, followed by multiple points of hemorrhage. With marked increases in pressure, and associated arteriolar spasm, necrosis of the vascular wall may result; and with subsequent relaxation, hemorrhage may occur under a high head of blood pressure. Hypertensive encejhalojathy is consequent to a sudden elevation of blood pressure, associated with headache, unconsciousness, convulsions and focal neurologic signs. The condition is characterized by cerebral swelling, petechiae THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Arteriolar
FIG. 3.
Sclerosis
jibrosis and hyalinization of arcuate nnrrowing of the lumen. (Hematoxylin and eosin, X 80, reduced by 28Cc.) Submtimol
branch with mwkcd
and small acute infarcts. Byrom13 performed experiments with rats to elucidate the pathoof encephalopathy. He showed by genesis open-window observation that the cerebral arterioles underwent spasm in response to increased arterial pressure. If pressure were maintained, the spasm was followed by cerebral edema, vascular necrosis and focal hemorrhage. Kidney : The luminal narrowing of the interlobular arteries and arterioles caused by the hyperplastic elastic and hyaline sclerosing processes leads to progressive ischemic atrophy with glomerular and interstitial fibrosis. There is a reduction of renal weight by 30 to 40 per cent at time of autopsy in the average hypertensive paRarely, however, does the kidney tient. atrophy and scar to the small size seen in chronic pyelonephritis or glomerulonephritis. Late in the disease, the interlobar, arcuate and main renal artery branches develop intimal mucoid plaques and classic atherosclerotic lesions which, depending on the rate of luminal narrowing and the amount of functional remaining renal tissue, may precipitate a sudden worsening and acceleration of the hypertensive disease (Fig. 3). In malignant hypertension associated with the renal necrotizing arteriolar process, one may see hemorrhage and infarction of the glomerular tufts. Proliferative glomerular changes, acute tubular necrosis and interstitial hemorrhage are also present. SUMMARY
Morphologic and experimental pathologic studies have yielded great insight into the nature of vascular changes associated with sustained VOLUME 17, MAY 1966
in Diastolic
Hypertension
607
diastolic hypertension. The main targets in this disease are the small muscular arteries and arterioles, and secondarily the larger arteries. Visceral organ damage is consequent to the gamut of systemic vascular pathologic changes. Experimental investigative work has not yet elucidated the nature of the initial vascular abnormality at the point of onset of the disease, a time difficult to define in clinical and pathologic terms. Essential hypertension is probably not a single disease in terms of etiology. Homeostasis as regards blood pressure is a complex phenomenon involving many factors. A change involving one or several factors may affect the nature of the arteriolar response, but it must be remembered that the primary defect may well lie in the response of the arteriole itself. REFERENCES 1. PAGE, 1. H. The mosaic theory of hypertension. In: Essential Hypertension, an International Symposium, p. 1. Berlin, 1960. Springer-Verlag. 2. PICKERING, G. The Nature of Essential Hypertension, p. 128. New York, 1961. Grune and Stratton. 3. WILENS, S. L. and ELSTER, S. K. The role of lipid deposition in renal arteriolar sclerosis. Am. J. M. SC., 219: 183, 1950. 4. BAKER, R. D. and KENT, S. P. Nature of the lipid of hyaline arteriosclerosis. Arch. Path., 49: 568, 1950. 5. Ducum, J. B. and ANDERSON,G. S. The pathogenesis of hyaline arteriosclerosis. J. Path. &’ Bat., 64: 519, 1952. 6. STILL, W. J. S. and HILL, K. R. The pathogenesis of hyaline arteriolar sclerosis. Arch. Path., 68: 42, 1959. 7. MCKINNEY, B. The pathogenesis of hyaline arteriosclerosis. J. Path. Bat., 83: 449, 1962. 8. MONTGOMERY, P. 0. and MUIRHEAD, E. E. A characterization of hyaline arteriolar sclerosis by histochemical procedures. Am. J. Path., 30: 521, 1954. 9. MCGEE, W. G. and ASHWORTH, C. T. Fine structure of chronic hypertensive arteriopathy in the human kidney. Am. J. Path., 43: 273, 1963. 10. BIAVA, C. G., DYRDA, I., GENEST, J. and BENCOSME, S. A. Renal hyaline arteriolosclerosis. An electron microscopic study. Am. J. Path., 44: 349, 1964. 11. SPIRO, D., LATTES, R. G. and WIENER, J. The cellular pathology of experimental hypertension. Am. J. Path., 47: 19, 1965. 12. KAGAN, _4., GORDON, T., KANNEI., W. B. and DAWBER, T. R. Blood pressure and its relation to coronary heart disease in the Framingham study. In: Hypertension, Proceedings of the Council for High Blood Pressure Research, p. 53. New York, 1958. American Heart Association. 13. BYROM, F.
B. The pathogenesis of hypertensive encephalopathy and its relation to the malignant phase of hypertension. Lam?, 2: 201, 1954.
of Target
Sustained
Organ
Diastolic
Damage
from
Hypertension*
MILTON TELLEM, OLD. Philadelphia,
Pennsylvania
BENIGN ESSENTIAL HYPERTENSION
T
HE small muscular arteries and arterioles are the primary targets damaged in sustained diastolic hypertension. This process is generalized but intensified in vessels of the kidney. Morphologic change is generally considered secondary to sustained diastolic hypertension because vascular alterations are absent in cases of clinically early hypertension ; furthermore, vascular disease occurring in secondary hypertension is morphologically similar to A quantitative that in essential hypertension. relation exists between the arteriolar lesion and the level of blood pressure ; and mortality can be correlated with the degree of arteriolar pathologic change. Regardless of cause, arteriolar narrowing This deoccurs in diastolic hypertension.‘,? mands greater work of the arteriolar smooth muscle cells whereby energy is translated into Depending on the demuscle contraction. mand, the muscle cells may become hyperbasement membrane and connective trophic, tissue elements may increase, and the vessel wall may undergo hyalinization or acute arteriolar necrosis. Increased peripheral resistance is associated concomitantly with elevated blood pressure and smooth muscle alteration, which may result in organic vascular disease, leading to organ damage. A broad spectrum of expression is associated At one extreme with essential hypertension. the vascular response may be so gradual and progress so slowly that life span is not shortened. On the other hand, elevated pressure and smooth muscle alteration may be so extreme that vascular necrosis and renal failure or cerebral damage quickly ensue. Subsequent remarks will focus on the nature of the vascular alteration followed by discussion of specific organ damage.
The vascular changes have been studied in greatest detail in the kidney. Two types of lesions involve the small arteries: hyaline arteriolar sclerosis of the afferent arteriole and hyperplastic elastosis of the interlobular artery. Hyaline arteriolar sclerosis of the afferent arteriole consists of homogeneous hyalinization and diminished cellularity of the wall associated with narrowing of the lumen. Hyperplastic elastosis of the interlobular artery, an arterial branch just proximal to the afferent arteriole, consists of eosinophilic thickening of intima with persistence and duplication of the inner elastic lamina. There is loosely arranged thickening of the intima with an increase in spindle-shaped cells. Hyaline and collagen accumulate in the intima and media and elastic fibers permeate the media. This hyperplastic elastic lesion is very similar to that of atherosclerosis. Though this alteration occurs chiefly in the interlobular arteries, afferent arterioles may also be similarly affected. One or both types of vascular change may be seen in varying degrees in normotensive individuals of advanced age (Fig. 1 A and B). Hi~tochemistry: The origin and nature of vascular hyaline are not conclusively established. Wilens and Elster” as well as Baker and Kent4 have stressed the role of plasma lipids in the pathogenesis of hyaline. Duguid and Anderson5 and others” concluded that hyaline was of hematogeneous origin and represented incorporation and reorganization of plasma substances in the vascular wall. McKinney7 considered hyaline a mixture of fibrin and plasma protein, gradually deposited subintimally and in the media. Muscle degeneration was considered a secondary process but not a source for hyalinr. Montgomery and Light Microscopy:
* From the Department of Pathology, Hahnemann Medical College and Hospital, Philadelphia, Pa. 604
THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Arteriolar
Sclerosis
in Diastolic
Hypertension
605
FIG. 1. A, hyalincj nrterzolnr sclrrosis shows increased cellular proliferation and hyaline thickening of wall of afferent arteriole. (Hrmatoxylin and eosin, X 250, reduced by 24y&) B, hy$qt&zstrc dnstic lesion of intdohular artrry shows laminated thickening of arterial wall with incrrascd subintimal cellularity and marked narrowing of lumen. (Hematoxylin and e&n, X 250, reduced by 24:‘;..)
Muirheads proposed that hyaline was a byproduct of smooth nruscle. Histochemical reactions were similar in both benign and malignant vascular alterations except for the presence of acid phosphatase in the malignant phase. Electron Microscopy: McGee and Ashworth studied human arteriolar renal lesions of varying degrees of severity. They interpreted the hvaline arteriolar sclerotic change as a progressive thickening and accumulation of basement membrane material from endothelial and smooth muscle origin. In later stages of the lesion, muscle cells became sparse and disappeared. Occasional lipid droplets were noted in the intima and media. Their study of hyperplastic elastosis of the interlobular artery revealed a thickened intima associated with increased cellularity due to proliferation of fibrocytes and smooth muscle cells. Basement membrane material accumulated in the intima and media as it did in the hyaline arteriolar process. The arteriole elastic membrane was thickened. Biava et al.‘” in an electron microscopic study of human material confirmed the findings of McGee but thought that hyaline was intimately related with but entirely distinct from any normal structures of the vessel wall, including basement membranes of endothelial or sn-.ooth muscle cells. They concluded that the material VOLUME
17,
MAY
1966
represented an excess of plasma proteins which passed into the wall secondary to altered endothelial permeability. In the most recent electron microscopic study of experimental renal hypertension in rats, Spiro et al.” noted that the most striking feature of the arterioles was the abnormal presence of smooth muscle cells between endothelium and the inner elastic lamellae. Smooth muscle cells were also increased in the media. These features could account for progressive lumen narrowing and a further rise in peripheral resistance. Increased basement membrane material was also noted in the intima and media. In summery, in benign hypertension arteriolar narrowing, increased luminal pressure and concomitant increased work by smooth muscle cells provide stimuli which, if maintained, lead to an irreversible accumulation of hyaline in the vessel wall. From histochemical and electron microscopic observations on human material, hyaline is probably derived from plasma constituents and products of destruction and proliferation of the arteriolar wall itself, associated with progressive ablation of smooth muscle elements. Electron microscopic studies in experimental renal hypertension have shown an abnormal localization of smooth muscle cells between the intima and inner elastic lamellae as
Tellem
606
and fibrin valved
nccrmis FIG. 2. Aculrur/~z?iolnr
terizrd by an acrllular of the artrriolar wall. reducrd by 28?;.)
of ufJwm/ ur~rriolr is rhxracexudative and drstructivc process (Hrmatoxylin and cosin. X 250,
one phase of the process and probably vascular alteration.
an early
MALIGNANT HYPERTENSION The appearance of arterioles in malignant hypertension will vary with the severity and The duration of previous hypertensive disease. vascular wall exhibits necrosis of a fibrinoid Immature connective tissue elements in type. the intima and media rich in acid mucopolysaccharides are also seen. The pathogenesis may be acute destruction of smooth muscle elements consequent to their metabolic failure in response to the work load imposed by the extreme intraluminal pressure. The plasma protein constituents located in the lesion, especially fibrin, are considered as a transudation from the plasma through injured endothelium and associated basement membranes. The over-all histologic picture may simulate angiitis of hypersensitivity For reaor certain connective tissue diseases. sons unknown, inflammatory cell response is rarely seen in the necrotizing arteriolar lesions (Fig. 2). SPECIFIC ORGAN DAMAGE There is an increased rate of atherosclerosis in essential hypertension, particularly affecting the coronary and cerebral Hemodynamic forces play a role in vessels. pathogenesis of the lesions as suggested by location of the plaques at orifices of arterial branches The acceleration and at points of bifurcation. of the process may be related to change in subFacilitated transfer, depintimal mucoproteins. osition and organization of plasma lipoproteins, Atherosclerosis:
in the arterial
\vall may also be in-
The xcork of the myocardiulu is proHeart: portional to arterial pressure in essential hypertension. There is a quantitative relation between left ventricular hypertrophy and arterial blood pressure. The Framingham studyI revealed that coronary atherosclerosis was associated with higher blood pressure levels. Essential hypertension was associated with a greater risk of developing coronary artery disease in men of all ages and in women, particularly those 45 to 62 years of age. One or any combination of left ventricular hypertrophy, congestive cardiac failure, angina pectoris and myocardial infarction is seen more frequently in the hypertensive as compared to The patient with the normotensive individual. left ventricular hypertrophy is more prone to suffer the effects of coronary atherosclerosis with lesser degrees of luminal narrowing. It is interesting to note that the cardiac arterioles show little or no change in hypertension as compared to those of the kidney, brain or spleen. Brain: The small intracerebral muscular arteries and arterioles are less involved than those in the kidney. The vascular changes are noted mainly in patients past 60 years of age. Our autopsy experience reveals a quantitative relation between atherosclerosis of the arteries of the circle of Willis (particularly the basilar vertebral system) and the duration and severity of hypertension. The hypertensive patient, because of these vascular alterations, is more prone to cerebral thrombosis, infarction, hemorrhage and hypertensive encephalopathy. Cerebral hemorrhage represents bleeding from multiple small vascular probably arteriolar, capillary and channels, venous. The pathogenesis of hemorrhage may be related to fluctuating blood pressures in the cerebral circulation. Occasional drops in pressure too low to drive the blood through the diseased arterioles may result in ischemia of neural tissue and vascular walls, followed by multiple points of hemorrhage. With marked increases in pressure, and associated arteriolar spasm, necrosis of the vascular wall may result; and with subsequent relaxation, hemorrhage may occur under a high head of blood pressure. Hypertensive encejhalojathy is consequent to a sudden elevation of blood pressure, associated with headache, unconsciousness, convulsions and focal neurologic signs. The condition is characterized by cerebral swelling, petechiae THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Arteriolar
FIG. 3.
Sclerosis
jibrosis and hyalinization of arcuate nnrrowing of the lumen. (Hematoxylin and eosin, X 80, reduced by 28Cc.) Submtimol
branch with mwkcd
and small acute infarcts. Byrom13 performed experiments with rats to elucidate the pathoof encephalopathy. He showed by genesis open-window observation that the cerebral arterioles underwent spasm in response to increased arterial pressure. If pressure were maintained, the spasm was followed by cerebral edema, vascular necrosis and focal hemorrhage. Kidney : The luminal narrowing of the interlobular arteries and arterioles caused by the hyperplastic elastic and hyaline sclerosing processes leads to progressive ischemic atrophy with glomerular and interstitial fibrosis. There is a reduction of renal weight by 30 to 40 per cent at time of autopsy in the average hypertensive paRarely, however, does the kidney tient. atrophy and scar to the small size seen in chronic pyelonephritis or glomerulonephritis. Late in the disease, the interlobar, arcuate and main renal artery branches develop intimal mucoid plaques and classic atherosclerotic lesions which, depending on the rate of luminal narrowing and the amount of functional remaining renal tissue, may precipitate a sudden worsening and acceleration of the hypertensive disease (Fig. 3). In malignant hypertension associated with the renal necrotizing arteriolar process, one may see hemorrhage and infarction of the glomerular tufts. Proliferative glomerular changes, acute tubular necrosis and interstitial hemorrhage are also present. SUMMARY
Morphologic and experimental pathologic studies have yielded great insight into the nature of vascular changes associated with sustained VOLUME 17, MAY 1966
in Diastolic
Hypertension
607
diastolic hypertension. The main targets in this disease are the small muscular arteries and arterioles, and secondarily the larger arteries. Visceral organ damage is consequent to the gamut of systemic vascular pathologic changes. Experimental investigative work has not yet elucidated the nature of the initial vascular abnormality at the point of onset of the disease, a time difficult to define in clinical and pathologic terms. Essential hypertension is probably not a single disease in terms of etiology. Homeostasis as regards blood pressure is a complex phenomenon involving many factors. A change involving one or several factors may affect the nature of the arteriolar response, but it must be remembered that the primary defect may well lie in the response of the arteriole itself. REFERENCES 1. PAGE, 1. H. The mosaic theory of hypertension. In: Essential Hypertension, an International Symposium, p. 1. Berlin, 1960. Springer-Verlag. 2. PICKERING, G. The Nature of Essential Hypertension, p. 128. New York, 1961. Grune and Stratton. 3. WILENS, S. L. and ELSTER, S. K. The role of lipid deposition in renal arteriolar sclerosis. Am. J. M. SC., 219: 183, 1950. 4. BAKER, R. D. and KENT, S. P. Nature of the lipid of hyaline arteriosclerosis. Arch. Path., 49: 568, 1950. 5. Ducum, J. B. and ANDERSON,G. S. The pathogenesis of hyaline arteriosclerosis. J. Path. &’ Bat., 64: 519, 1952. 6. STILL, W. J. S. and HILL, K. R. The pathogenesis of hyaline arteriolar sclerosis. Arch. Path., 68: 42, 1959. 7. MCKINNEY, B. The pathogenesis of hyaline arteriosclerosis. J. Path. Bat., 83: 449, 1962. 8. MONTGOMERY, P. 0. and MUIRHEAD, E. E. A characterization of hyaline arteriolar sclerosis by histochemical procedures. Am. J. Path., 30: 521, 1954. 9. MCGEE, W. G. and ASHWORTH, C. T. Fine structure of chronic hypertensive arteriopathy in the human kidney. Am. J. Path., 43: 273, 1963. 10. BIAVA, C. G., DYRDA, I., GENEST, J. and BENCOSME, S. A. Renal hyaline arteriolosclerosis. An electron microscopic study. Am. J. Path., 44: 349, 1964. 11. SPIRO, D., LATTES, R. G. and WIENER, J. The cellular pathology of experimental hypertension. Am. J. Path., 47: 19, 1965. 12. KAGAN, _4., GORDON, T., KANNEI., W. B. and DAWBER, T. R. Blood pressure and its relation to coronary heart disease in the Framingham study. In: Hypertension, Proceedings of the Council for High Blood Pressure Research, p. 53. New York, 1958. American Heart Association. 13. BYROM, F.
B. The pathogenesis of hypertensive encephalopathy and its relation to the malignant phase of hypertension. Lam?, 2: 201, 1954.