Cardiac hypertrophy in early hypertension

Cardiac Hypertrophy in Early Hypertension

YUKIO YAMORI, MD* CHUZO MORI, MD+ TOSHIKAZU NISHIO, MD+ AKIRA OOSHIMA, MD’ RYOICHI HORIE, MD* MICHIYA OHTAKA, MD* TAKESHI SOEDA, MD+ MASAKAZU SAITO, MD+ KATSUTOSHI ABE, MD+ YASUO NARA, PhD” YASUJI NAKAO, MDt MASAHIRO KIHARA. MD’ lzumo, Japan

From the Departments of Pathology* and Pediatrics,+ Shimane Medical University, and The Department of Pediatrics,* Shimane Prefectural Central Hospital, Izumo, Japan. This study was supported by grants from the Science and Technology Agency of the Japanese Government, Ministry of Education and Welfare, the Mitsubishi Foundation and the Daiwa Health Foundation. Manuscript received August 7. 1979, accepted August 14, 1979. Address for reprints: Professor Y. Yamori, Department of Pathology, Shimane Medical University, Izumo, Japan 693.

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Studies of cardiac hypertrophy in spontaneously hypertensive rats have indicated that left ventricular hypertrophy occurred even in the prehypertensive stage. These findings suggested that other factors besides blood pressure levels, and including possibly a genetic predisposition to myocardial hypertrophy, could play a role in structural cardiovascular alterations in spontaneously hypertensive rats. More recent studies have confirmed these anatomic results; left ventricular hypertrophy was vectorcardiographically detected even in the prehypertensive stage in both young stroke-prone rats and stroke-resistant spontaneously hypertensive rats. Further, a close relation was found between degree of left ventricular hypertrophy and vascular hypertrophy or hyperplasia; this suggests that early detection of left ventricular hypertrophy may be a useful indicator of the incipient stage of structural vascular changes in genetic hypertension.

In spontaneously hypertensive rats,l which are widely used as animal models for essential hypertension,sJ not only hypertension but also its cardiovascular complications develop. Cardiac hypertrophy, nephrosclerosis and cerebrovascular lesions (cerebral hemorrhage and infarction) are the three major complications of spontaneous hypertension in rats as they are of essential hypertension in man. These complications, however, are not only the result of the increased arterial pressure, which plays a dominant but not the only role in the disorder. Our earlier studies4-7 pointed out the importance of genetic factors in the development of at least two complications, ventricular hypertrophy and cerebrovascular lesions. In 1974, stroke-prone spontaneously hypertensive rats were selectively bred from our strain of spontaneously hypertensive rats.5 In more than 90 percent of stroke-prone spontaneously hypertensive rat colonies strokes develop spontaneously, which indicates the importance of genetic selection in this hypertensive complication. Similar conclusions were reached regarding cardiac hypertrophy, which is the most common complication of hypertension. Various grades of hypertrophy can be found among spontaneously hypertensive rats at different stages of their development.6-s Although this hypertrophy is often considered only a secondary effect of the increased pressure load, findings in very young spontaneously hypertensive rata suggested again a more complex picture. Significant ventricular hypertrophy was reported in these rats in the absence of significant differences in arterial pressure.7,8Jo,11 One could relate this early hypertrophy, by analogy with cerebral lesions, to a possible genetic influence, but other factors could also play a significant role. In the present review, we have examined again the evidence for early cardiac hypertrophy in spontaneously hypertensive rats and its correlation with vascular changes. Early structural alterations of the heart

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in spontaneous hypertension are of particular importance not only because of their pathophysiologic aspects, but also because of their potential clinical implications. Recognition of ventricular hypertrophy in children or adolescents with borderline elevation of arterial pressure would, if documented, help the physician to make a more precise assessment of their status and possible need for therapy.

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Early Cardiac Hypertrophy in Young Spontaneously Hypertensive Rats Factors accounting for discrepancy between cardiac hypertrophy and level of blood pressure: The heart weight of the spontaneously hypertensive rat was significantly greater even at the age of 30 days than in age- and body weight-matched Wistar-Kyoto control rats7 (Fig. l), although no significant difference in blood pressure could be documented at this very young age. This early cardiac hypertrophy in prehypertensive rats was also reported independently by Sen et a1.s Not only was the heart weight clearly increased in these young spontaneously hypertensive rats, but there were also found biochemical alterations, such as increased myocardial incorporation of labeled amino acids10 and increased cardiac enzyme activity (monoamine oxidase).7 The discrepancy between the insignificant increase in arterial pressure and the early ventricular hypertrophy pointed to the possible intervention of factors other than the increased pressure. One possibility was that ventricular hypertrophy could be dependent in these animals on genetic factor(s) that were either related or merely linked to their genetic predisposition to hypertension. Cutilletta et al.” advanced the hypothesis of an independent myocardiopathy for which, however, there was no firm evidence either pathologically12 or hemodynamically.s Apart from these two possibilities, other possibilities that are not necessarily contradictory could also account for the discrepancy between cardiac hypertrophy and level of blood pressure.l3J4

Changes in VCG of Young W K 40-DAY-OLD BP 126ImNJ

840AY-OLD BP 116mnHe

AC {Days) FIGURE 1. Early cardiac alteration in young spontaneously hypertensive rats (SHR) compared with findings in normal Wistar-Kyoto (WK) rats. MAO = monamine oxidase; NE = norepinephrine; p = probability; SE = standard error; T$ = half-life.

Role of increased adrenergic activity: Of these possible mechanisms, increased adrenergic activity may be of particular importance in the early development of myocardial changes in the young spontaneously hypertensive rat. This hypothesis is supported by the prominence of neurogenic factors in the early stages of spontaneous hypertension3J3; moreover, we7 have documented an accelerated cardiac norepinephrine turnover at 30 and 60 days after birth. It is conceivable, therefore, that the early development of left ventricular hypertrophy in this model could be related to or influenced by increased sympathetic nervous activity. In fact, the increased cardioadrenergic drive might play an equally if not more important role than the small and often insignificant differences in blood pressure at this age. Although Cutilletta et a1.l’ reported persistance of left ventricular hypertrophy even after peripheral sympathectomy in the spontaneously hypertensive rat, their results do not necessarily contradict this hypoth-

Changesin VCG uf YoungSHR 71-DAY-OLD BP 178 mmHg

45-DAYOLD BP138mmHq

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FIGURE 2. Left, changes in vector cardiogram (VCG) of a young Wistar-Kyoto (WK) rat compared with findings in a young spontaneously hypertensive rat (SHR) (right). BP = blood pressure: H = horizontal; LS = left sagittal; p = P wave.

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Blmd Pressure

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100 %

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FIGURE 3. Incidence of the vectorcardiographic pattern of left ventricular hypertrophy in prehypertensive stage in spontaneously hypertensive rats (SHR) (both stroke-resistant [SRI and stroke-prone [SP] compared with that in normal Wistar-Kyoto [WK] rats. Max. = maximal; p = probability.

esis. ‘Adrenomedullary catecholamines are compensatorily activated after sympathectomy and their influence could replace the drive lost from attempts at denervation. Vectorcardiography to detect early left ventricular hypertrophy: In order to detect the earliest

signs of cardiac hypertrophy more easily than can be done by observation of morphologic and biochemical changes, a vectorcardiographic method was developed for small animals6 Reproducible vectorcardiograms could be obtained in young spontaneously hypertensive rats by using four large electrodes around the thorax and two small electrodes on the head and tail.15 This technique was applied to young stroke-prone and strokeresistant spontaneously hypertensive rats of various age groups, and results in these two strains were compared with findings in closely matched Wistar-Kyoto control rats. In normotensive Wistar-Kyoto rats the vectorcardiogram showed a left downward orientation of the maximal QRS vector at all ages. The basic normotensive

pattern of the vectorcardiogram was well maintained even in rats older than 1 year of age. In contrast, in adult stroke-prone spontaneously hypertensive rats there was a consistent typical left upward deviation of the maximal QRS vector (Fig. 2, right). Old spontaneously hypertensive rats also showed these deviations of the QRS loop with prolonged QRS duration and characteristic ST-T changes.laJ7 This deviation from the norm appeared to be the common sign of left ventricular hypertrophy, not only in spontaneously hypertensive rats but also in rats with renal hypertension. Because these vectorcardiographic recordings in rats were confirmed to be reproducible and reliable, detailed vectorcardiographic changes were studied in very young spontaneously hypertensive rats while their blood pressure course was carefully monitored.15 The typical left upward deviation of the maximal QRS vector’in hypertensive spontaneously hypertensive rats was already noted in prehypertensive stroke-prone rata at the age of 30 to 40 days, when the systolic blood pressure was still only 130 to 140 mm Hg. These vectorcardiographic patterns of left ventricular hypertrophy suggest that hypertrophy is developing quite early in life, especially in the stroke-prone spontaneously hypertensive rat with a genetic disposition to severe hypertension. The incidence of these patterns among 30 to 40 day old rats was 100,67, and 0 percent, respectively, in groups of stroke-prone spontaneously hypertensive rats, stroke-resistant spontaneously hypertensive rats and Wistar-Kyoto control rats (Fig. 3). In our experience, the presence of left ventricular hypertrophy in the prehypertensive stage has been a constant finding in stroke-prone rats. Of particular importance was the contrast among these three groups between the variation in incidence of left ventricular hypertrophy and the absence at that age of differences in blood pressure. The cardiac weight at that time was significantly greater both in stroke-prone and in stroke-resistant spontaneously hypertensive rats than in Wistar-Kyoto rats.

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FIGURE 4. Effect of antihypertensive therapy on cardiovascular hypertrophy in spontaneously hypertensive rats (SHR).

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TABLE I Blood Pressure, Heart Weight and Incorporation of 3H-Lysine into Mesenteric Arteries of Treated and Untreated Spontaneously Hypertensive Rats (SHR)* and Untreated Wistar-Kyoto Rats (WK) (mean f standard error) Blood Pressure (mm Hg)

Experimental Groups (no. of rats) I. Untreated SHR (no. = 10) II. Hydralazine-treated SHR (no. = 10) Ill. Hexamethonium-treated SHR (no. = 9) IV. Splanchnicotomized SHR (no. = 10) 2. Untreated WK, (no. = 8)

168 136 136 136 131

f f f f f

Mesenteric Arteries (dpm/ 100 g wet weight)

Heart Weight (g) 1.19 1.30 0.80 1.05 0.91

2 3+ 7+ 3+ 2

f f f f f

1374 1517 824 790 777

0.05 0.04 0.05+ 0.05 0.04+

f f f f f

23 152 95’ 29+ 48+

* From Yamori et al.*O + Probability [P]
In summary, the early incidence of cardiac hypertrophy seems well established in spontaneously hypertensive rats of different strains (stroke-prone and stroke-resistant). This structural alteration, which is evident in the absence of significant elevations in blood pressure, may be related to or merely linked with a genetic predisposition to hypertension or it could be evoked or accentuated by hypertensive mechanisms already active before the development of overt hypertension. Relation

Between Cardiac Hypertrophy

Wistar-Kyoto rats and in spontaneously hypertensive rats treated with various antihypertensive agents.20 Details of this study have been published previously20; one example of these experiments is reported in Figure 4. Both a vasodilator (hydralazine, 80 mg/liter in drinking water) and a ganglion-blocking agent (hexamethonium, 50 mg/kg, given subcutaneously two times daily) clearly reduced blood pressure in spontaneously hypertensive rats to normotensive levels. However, the

and Vascular

Accelerated vascular and cardiac protein synthesis: The importance of structural vascular changes in the pathogenesis of hypertension was stressed in both clinical and experimental forms of the disease.ls We have repeatedly shown that neurogenically induced vasoconstriction in the incipient stage of hypertension was rapidly followed by accelerated synthesis of vascular proteins, including both collagenous and noncollagenous types of protein.3y7J3Jg*20 This increased synthesis results in medial hypertrophy and thickening of the vessel wall. Noncollagen protein synthesis in peripheral vessels was particularly enhanced in early hypertension and this was demonstrable even in the “prehypertensive stage.“7.21 This early acceleration of vascular protein synthesis appears analogous to the early development of cardiac hypertrophy. It is possible that both are related to or dependent on similar mechanisms. The possible temporal relation between cardiac and vascular hypertrophy was further analyzed in vitro; the incorporation of labeled leucine was clearly accelerated in the mesenteric arteries and the aorta of spontaneously hypertensive rats and tended to be increased in the heart even at 4 weeks.22 These results were consistent with the reported increased incorporation of labeled lysine into cardiac myosin in spontaneously hypertensive rats as compared with age-matched Wistar-Kyoto ratslo Thus, protein synthesis appeared to be accelerated concomitantly in both the heart and the peripheral vessels of young spontaneously hypertensive rats. Effect of antihypertensive treatment: This coincidence between changes in heart weight and rate of vascular protein synthesis was further observed in

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FIGURE 5. Relation between heart weight and vascular protein synthesis in treated and untreated spontaneously hypertensive rats (SHR) and in normal untreated Wistar-Kyoto (WK) rats.

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vasodilator was not effective either for reducing heart weight or for attenuating noncollagen protein synthesis in mesenteric arteries. In contrast, pharmacologic denervation effectively reduced both heart weight and vascular noncollagen protein synthesis.20 Eventually, similar results were obtained in mesenteric vessels after surgical sympathectomy (that is, splanchnicotomy with complete denervation of mesenteric arteries).20 The increased incorporation of lysine into noncollagenous protein of mesenteric vessels in spontaneously hypertensive rats was consistently abolished by treatment with hexamethonium or by splanchnicotomy, but was not affected by treatment with hydralazine (Table I). Whether denervation was obtained pharmacologically or by surgery, a positive correlation was consistently found between heart weight and vascular protein synthesis in mesenteric arteries (Fig. 5). Many explanations could be advanced for this correlation; both changes could reflect the influence of the same factors, be they neurogenic or humoral. Another possibility is that the structural change in vessel walls and their thickening contributes to increased peripheral resistance and thus indirectly to cardiac load. In any event, an important practical result for studies of pathologic mechanisms or of drug effects was that left ventricular hypertrophy appeared to be a good indicator of the hypertrophy or hyperplasia of peripheral arterial walls. Coronary arterial changes: Histologic studies further demonstrated that thickening of small coronary arteries due to medial hypertrophy or hyperplasia and occlusive arterial changes with thrombosis were often observed in the hypertrophied heart of adult spontaneously hypertensive rats. In the advanced stage, intraluminal proliferative changes are so marked that the arterial lumen is almost occluded, and such arterial hyperplasia coexists with myocardial hypertrophy. The ratio of the lumen to the transectional area of small

coronary arteries (diameter of less than 100 and between 100 and 150 p) was determined histometrically in laboratories using a quantitative picture analysis (MOPAM, 3, Kontrone). The investigation involved strokeprone and stroke-resistant spontaneously hypertensive and Wistar-Kyoto rats from 1 to 12 months of age with 5 to 10 rats in each group. The normal ratio was clearly and significantly reduced even in young 1 month old spontaneously hypertensive rats as compared with their age-matched Wistar-Kyoto counterpart. Furthermore, there seemed to be an inverse correlation between heart weight and the lumen to transectional area ratios of coronary arteries in spontaneously hypertensive and Wistar-Kyoto rats from 1 to 6 months of age (Fig. 6). Again, cardiac weight hypertrophy seemed to be a good indicator of vascular hypertrophy or hyperplasia, that is, for those structural vascular changes that are important in the further development and maintenance of hypertension.

Clinical Echocardiographic Studies These experimental observations in spontaneously hypertensive rats suggested that cardiac hypertrophy might develop early in life in persons with borderline elevations in arterial pressure or some predisposition to hypertension. If documented, this early incidence of cardiac hypertrophy could prove of major significance in our understanding of the disease and approach to its control. An extensive survey of schoolchildren in Japan was therefore undertaken involving more than 350 children aged 6 to 15 years (Shimane Heart Study).2s,24 Details of the methods have been published previously; of special relevance to the subject of cardiac hypertrophy were the results obtained with echocardiography in the 22 children with borderline hypertension. The extensive analysis of echocardiography in 369 normotensive children allowed the development of normal values for different age groups. Viewed against this

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FIGURE 6. Correlation between cardiac and coronary vascular hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP) and in age-matched normal Wistar-Kyoto (WK) rats. Cor. = coronary.

Note:~SHRSP at the agesof 1,2 and 6 months 0 age-matchedW K (diameterof coronaryarteryoeo 100P-150~)

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background, 5 of 22 subjects with borderline hypertension had a left ventricular mass clearly above 2 standard deviations of normal for their age. The blood pressure in these subjects ranged from 126/80 to 134/86 mm Hg, and they showed no other evidence of cardiovascular disease. Similar results in juvenile hypertension were recently also reported by Culpepper et a1.25More

ET AL.

studies are obviously needed, particularly ones with long-term follow-up and correlation with personal and family history for complete correlation of the significance of early increases in left ventricular mass. If documented in man, “cardiac hypertrophy in prehypertension” would have important diagnostic and prognostic implications.

References 1. Okamoto K, Aoki K: Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27:282-293. 1963 2. Yamori Y, Okamoto K: Spontaneous hypertension in the rat: a model of human “essential” hypertension. Proc 80th Cong Germ Sot Int Med, 1974, p 168-170 3. Yamori Y: Pathogenesis of spontaneous hypertension as a model for essential hypertension. Jpn Circ J 41:259-266. 1977 4. Yamori Y, Nagaoka A, Okamoto K: Importance of genetic factors in hypertensive cerebrovascular lesions: evidence obtained by successive selective breeding of stroke-prone and -resistant SHR. Jpn Circ J 38:1095-1100, 1974 5. Okamoto K, Yamorl Y, Nagaoka A: Establishment of the strokeprone spontaneously hypertensive rat (SHR). Circ Res 34,35:Suppl 1:1-143-l-153, 1974 6. Yamori Y, Ohtaka M, Nara Y: Vectorcardiographic study on left ventricular hypertrophy in spontaneously hypertensive rats. Jpn Circ J:1315-1329. 1976 7. Yamorl Y: Contribution of cardiovascular factors to the development of hypertension in spontaneously hypertensive rats. Jpn Heart J 15:194-196, 1974 a. Sen S, Tarazl RC, Khairallah PA, Bumpus M: Cardiac hypettrophy in spontaneously hypertensive rats. Circ Res 35:775-781. 1974 9. Pfeffer MA, Frohlich ED, Pfeffer JM, Weiss AK: Pathophysiological implications of the increased output of young spontaneously hypertensive rats. Circ Res 22:Suppl l:l235-1242, 1974 10. Sen S, Tarazl RC, Bumpus FM: Age, hypertension and protein synthesis in SHR. In, Spontaneous Hypertension: Its Pathogenesis and Complications. Washington, DC. DHEW Publication no. (NIH) 77-l 179, 1979, p 59-63 11. Cutllletta AF, Erlnoff L, Heller A, Low J, Oparll S: Development of left ventricular hypetiophy in young spontaneously hypertensive rats after peripheral sympathectomy. Circ Res 40:428-434, 1977 12. Kashli C, Takatan T, Kawamura K, lmamura K: Further study on cardiac hypertrophy in spontaneously hypertensive rats. In Ref 10, p 31-50 13. Yamori Y: Neural and nonneural mechanisms in spontaneous hypertension. Clin Sci Mol Med 51:431s-434s. 1976 14 Frohlich ED, Tarazi RC: Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy? Am J Cardiol 441959-963, 1979

15. Yamori Y, Ohtaka M, Hori R, Nara Y: Vectocardiographic features in the young SHR. Jpn Heart J 19:581-582, 1978 16. Yamorl Y, Ohtaka M, Kihara M, Nara Y, Horie R, Ooshlma A: Vectorcardiographical studies on spontaneous and experimental “myocardial infarction” in rats. Jpn Heart J Suppl ll:20. 1979 17. Yamori Y, Ohtaka M, Horle R, Nara Y, Ooshima A: Significance of spontaneous hypertension for cardiac hypertrophy and myocardial lesions in stroke-prone SHR. In, Proceedings of The Third International Symposium on SHR and Related Studies. Jpn Heart J Suppll:267-269, 1979 ia. Folkow B, Hallback M, Lundgren Y, Sivertsson R, Weiss L: Importance of adaptive changes in vascular design for establishment of primary hypertension studied in man and in spontaneously hypertensive rats. Circ Res 32, 33:Suppl 1:1-2-l-16. 1973 19. Ooshlma A, Fuller GC, Cardinale GJ, Spector S, Udenfriend S: Increased collagen synthesis in blood vessels of hypertensive rats and its reversal by antihypertensive agents. Proc Natl Acad Sci USA 71: 3019-3023, 1974 20. Yamori Y, Nakada T, Lovenberg W: Effect of antihypertensive therapy on lysine incorporation into vascular protein of the spontaneously hypertensive rat. Eur J Pharmacol 38:349-355, 1976 21. Yamabe H, Love&erg W: Increased incorporation of 14C-lysine into vascular protein of the spontaneously hypertensive rat. Eur J Pharmacol29:109-116, 1974 22. Ooshima A, Yamori Y, Horie R, Ohtaka M, Fukase M: Vascular protein metabolism in hypertensive models in relation to the prevention of hypertensive diseases. In, Prophylactic Approach to Hypertensive Disease (Yamori Y. Lovenberg W, Freis E, ed). New York, Raven Press, 1979, in press 23. Saito M. Morl C, Nishio T, Soeda T, Abe K: Normal values of echocardiography in pediatrics. I. Left ventricular muscle volume (LVMV). Shimane Heart Study. Shimane J Med Sci 263-69, 1978 24. Nlshlo T, Mori C, Salto M, Soeda T, Abe K, Nakao Y: Left ventricular hypertrophy in early hypertensive children: its importance as a risk factor for hypertension. Shimane J Med Sci 3:71-79, 1978 25. Culpepper W, Hutcheon N, Arcllla R, Cutilletta A: Left ventricular hypertrophy in juvenile hypertension. Circulation 58:Suppl ll:ll-51, 1979

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