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Plasma norepinephrine and left ventricular hypertrophy in systemic hypertension
SYSTEMIC HYPERTENSION
Plasma Norepinephrineand Left Ventricular Hypertrophy in Systemic Hypertension LUIGI COREA, MD, MAURIZIO BENTIVOGLIO, MD, PAOLO VERDECCHIA, MD, and MARIO MOTOLESE, MD
The relations between some pressure and humoral factors, and some echocardiographic indexes of left ventricular (LV) hypertrophy were studied in 64 patients with essential hypertension. Fifty-seven percent of these patients showed echocardiographic evidence of LV hypertrophy (LV mass >215 g). Multivariate stepwise regression analysis showed that only mean blood pressure (BP) and circulating norepinephrine (NE) levels were significantly related to LV mass index in the group of patients with LV hypertrophy. However, mean BP was the only factor related to LV mass index in the subgroup of patients with LV hypertrophy and plasma NE within the normal laboratory range, whereas NE was the sole factor related to LV mass index in the subgroup with LV hypertrophy and abnormally elevated NE levels (greater than mean + 2 standard deviations of the normal laboratory range). Correlation of LV mass index vs NE was -0.35 (not significant) in the for-
mer group of patients and 0.69 (p
Results of several investigations suggest an involvement of humoral factors in the pathogenesis of hypertensive cardiac hypertrophy in animals.14 Even in human hypertension there is some evidence that factors other than pressure overload could be involved.5-8 Catecholamines, thyroid hormones, pituitary growth hormone and the renin-angiotensin system have been considered,gl10 but knowledge about their role is still scanty. In this report we have tested the hypothesis of a positive relation between left ventricular (LV) wall thickness and some pressure and humoral factors in patients with untreated essential hypertension, with or without echocardiographic evidence of LV hypertrophy.
Methods
(Am J Cardiol 1964;53:1299-1303)
Patients: We studied 37 hypertensive patients with echocardiographic LV mass (Penn cube formulall) >215 g, suggesting LV hypertrophy at least of mild degree;12 27 hypertensive patients with echocardiographic LV mass <215 g; and 18 healthy control subjects. The hypertensive subjects were recently diagnosed and previously untreated. They were consecutively studied in our laboratory; 11 additional hypertensive patients who met study criteria were excluded because of poor-quality echocardiograms. In all patients, systolic and diastolic BPS were always found to be greater then 150 and 95 mm Hg, respectively, during a 3-month period of outpatient observation. The study group was hospitalized for at least 1 week before the study, which was performed the morning after an overnight fast. Sodium (100 mmol/day) and potassium (80 mmol/day) were kept constant during hospitalization. Experimental procedures: BP was recorded with a conventional mercury sphygmomanometer after 10 minutes of supine rest. The first and fifth Korotkoff phases were con-
From the II Clinica Medica, University of Perugia, Perugia, Italy. Manuscript received September 29, 1983; revised manuscript received January 12, 1984, accepted January 16, 1984. Address for reprints: Professor Luigi Corea, MD, Associate Professor of Cardtology, Via degli Olivetani, 8 06100-Perugia PG, Italy. 1299
1300
NOREPINEPHRINE AND CARDIAC HYPERTROPHY
sidered for systolic and diastolic BP. The echocardiographic study was performed using an ATL MK 500 ultrasound system (Advanced Technology Laboratories) with M-mode examination under cross-sectional control, and standard recording and measurement t.echniques.i3 Tracings were coded and read by 2 independent observers who were unaware of the subjects’ blood pressure status. Differences in wall thickness I1 mm were averaged; greater differences were resolved in conference. Before beginning the echocardiographic study, venous blood samples for norepinephrine (NE),14 epinephrine14 and plasma renin activity15 determination were collected, after the subject rested for at least 60 minutes supine with an indwelling butterfly needle in an arm vein. The day-to-day variability in plasma NE concentration was assessed in the hypertensive subjects by performing 2 additional determinations 1 and 2 days before that of the echocardiographic study, under similar experimental conditions. NE values measured just before beginning the echocardiographic study were used in the statistical analysis, similar to the BP values. Statistical analysis: Statistical analysis was performed using the Statistical Analysis System package.16 In each of the 3 study groups the independent relation of systolic BP, diastolic BP, mean BP (diastolic BP + l/3 pulse pressure), heart rate, NE, E and plasma renin activity with ventricular septum thickness index (ventricular septum divided by body surface area17), posterior wall thickness index or LV mass index was assessed by the stepwise multiple regression procedure. This
includes 1 X 1 in the model all the independent variables contributing to the model with a significance level of at least 0.05. Analysis of covariance (age as covariate) was used in the comparison between the groups.
Results A representative echocardiographic healthy subject is shown in Figure 1.
--._._
- *-- -\_-.
“_‘li ,’
-
_x -..
‘----J
;’
;’
-,)_
.“. _e--+
from a
Hypertensive patients with left ventricular hypertrophy: The day-to-day variability of plasma NE concentration (Fig. 2) was not statistically significant (F = 0.40). Multiple regression analysis showed that the 3 sole independent factors related to septal thickness index were diastolic BP (F = 13.6; p = 0.0008), NE (F = 16.9; p = 0.0002) and body surface area (F = 19.8; p = 0.0001); no other variable was significant. The 2 independent factors related to posterior wall thickness index were mean BP (F = 21.6; p = 0.0001) and body surface area (F = 10.3; p = 0.002). LV mass index results were related only to mean BP (F = 9.1; p = 0.004) and NE (F = 14.8; p = 0.0005). The hypertensive patients with LV hypertrophy were separated in 2 subgroups according to circulating NE levels. Because our laboratory method for NE reports normal values of 174 f 24 ng/liter (mean f standard deviation),14 NE values >222 ng/liter (i.e., more than
-
-_.--.
tracing
fi
”
“--w-n_.i
1ooL
I FIGURE 1. Echocardiographic tracing from a healthy subject. The Mmode tracing, obtained under cross-sectional control at or just below the tips of the mitral valve leaflets, shows continuous endocardial echoes of both septum and posterior wall. A control phonocardiogram (lop), carotid pulse (mlddle) and electrocardiogram (bottom) are included.
clay 1
I
& day 2
day 3
FIGURE 2. The day-today variability of plasma norepinephrine concentration in hypertensive subjects with an echocardiographic suggestion of left ventricular hypertrophy (left ventricular mass >215 g). There is no significant day-today variability of the norepinephrine levels.
May 1.1984
mean + 2 standard deviations above the mean) should be considered as abnormally elevated; they are typical in only 2.28% of subjects in a normally distributed population.18 Sixteen of 37 hypertensive patients with LV hypertrophy showed plasma NE levels greater than 222 ng/liter. The correlation coefficient of septal thickness index vs NE was -0.17 (NS) in patients with NE levels less than 222 ng/liter, and 0.55 (p = 0.024) in the patients with NE levels above 222 ng/liter. The correlation coefficient of posterior wall thickness index vs NE was -0.29 (NS) in the group with NE <222 ng/liter, and 0.18 (NS) in the group with NE above such limit. LV mass index showed a positive relationship with NE in the group with NE of greater than 222 ng/liter (r = 0.89; p = O.OOOl),(Fig. 3) but not in the other group (r = -0.35; NS). Although limited by the small number of subjects, multiple regression analysis in the group with NE levels
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
1301
less than 222 ng/liter (n = 21) showed mean BP (F = 8.57; p = 0.009) and body surface area (F = 10.2; p = 0.005) as the sole 2 independent factors related to septal thickness, body surface area as the sole factor related to posterior wall thickness index (F = 17.8; p = 0.005), and mean BP as the sole factor related to LV mass index (F = 8.3; p = 0.009). In the group with NE levels above 222 ng/liter (n = 16), ventricular septal thickness index was related to NE (F = 16.3; p = 0.001) and body surface area (F = 8.27; p = O.Ol), posterior wall thickness index was related to mean BP (F = 33.4; p = 0.0001) and body surface area (F = 15.1; p = O.OOl), and LV mass index was related only to NE (F = 54.7; p = 0.0001). Hypertensive patients without left ventricular hypertrophy: Diastolic BP was the sole independent factor related to ventricular septal thickness index (F = 6.7; p = 0.015) as well as to LV mass index (F = 9.0; p = 0.006). Posterior wall thickness index did not show
.I
.-......
“. “. .
_,
^^,,
._^
FfGURE 3. Positive relationbetween left ventriwlar mass index (LVMI) and plasma norepinephrine concentration (NE) (r = 0.89; p215 g) and circulating NE levels above the mean +2 standard deviations of the normal laboratory range.
NOREPINEPHRINE AND CARDIAC HYPERTROPHY
1302
TABLE I
Results
in the Study Group*
Variable
Age (yr)
Body surface area (m2) Male/female Systolic BP (mm Hg) Diastolic BP (mm Hg) Mean BP (mm Hg) Heart rate (beatslmin) Ventricular septal thickness index (cm/m*) Posterior wall thickness index (cm/m*) Left ventricular mass index (g/m*) NE (ng/liter) E (ng/liter) PRA (ng/ml/hour)
Hypertensive Patients with LV Hypertrophy (n = 37)
Hypertensive Patients without LV Hypertrophy (n = 27)
Healthy Subjects (n = 18)
34 f 7 1.8 f 0.07 3314 172 f 14 108f8 130f 8 78 f 8 0.64 f 0.05
36 f 5 1.8 f 0.1 2413 169 f 12 109f9 129 f 8 76 f 9 0.58 f 0.10
30 f 4 1.8 f 0.06 1513 120% 6 70 f 5 88 f 7 65 f 4 0.48 f 0.08
0.61 f 0.04
0.53 f 0.06
0.53 f 0.07
138 f 21 213 f 68 43 f 20 1.8 f 0.7
97%
15
187 f 46 35f 14 1.9 f 1.0
90f
11
140 f 53 24 f 6 2.3 f 0.7
Values are expressed as mean f standard deviation. BP = blood pressure: E = epinephrine; LV = left ventricular; NE = norepinephrine; PRA = plasma renin activity. l
any relation with any other variable (at least at the 0.05 level). Plasma NE concentration was less than 222 ng/liter in 20 patients, and greater than 222 ng/liter in another 7. In the former group, diastolic BP was the sole independent factor related to ventricular septal thickness index (F = 7.2; p = 0.014) or LV mass index (F = 8.2; p = O.OlO), whereas posterior wall thickness index was not related to any other parameter. No analysis was made in the latter group because of the small number of patients. Healthy subjects: In the healthy subjects, none of the univariate or multivariate analyses showed significant results. Differences between the groups (Table I): Systolic, diastolic and mean BP were similar in the hypertensive patients with LV hypertrophy compared with BP in those without LV hypertrophy, and the heart rate was lower in the normotensive patients than in either group of hypertensive subjects (both p
show a positive relation with some echocardiographic indexes of LV hypertrophy (ventricular septal thickness and LV mass index) only in a subgroup of patients with NE above the normal laboratory range. A positive relation between BP levels and echocardiographic indexes of LV hypertrophy was detectable in the other group, as well as in the patients without LV hypertrophy. This is in line with results of several studies that show a modest positive relation between resting BP and echocardiographic measurements of LV hypertrophy.1g-21 Plasma norepinephrine and left ventricular hypertrophy: The positive relation of NE with the echocardiographic indexes in the subgroup of patients with elevated NE accounted for the significance of the same relation in the overall group of hypertensive patients with LV hypertrophy. However, when comparing the patients without to those with hypertrophy, age-adjusted NE levels did not differ significantly, although there was tendency for it to be higher in the group with LV hypertrophy. In animals, LV hypertrophy induced by NE is well known,22p23and recent studies have provided evidence that cri receptors on the surface of the myocardial cell membrane could mediate such effect.24 There is no unequivocal evidence, however, that a NE-mediated mechanism stimulating LV hypertrophy may be operative in all or at least some patients with essential hypertension. A positive relation of plasma renin activityS or plasma NE7 with ventricular septal thickness in borderline hypertensive patients has been reported, but not confirmed.25 In a group of hypertensive patients, a positive relation between echocardiographic LV mass and 24hour urinary NE excretion has also been found.26 Myocardial sensitivity to catecholamines may not be similar in all of its regions: recent investigations in dogs suggest that the ventricular septum could be more sensitive to the adrenergic stimulation than either the right ventricle or other portions of the left ventricle.27 If this finding were confirmed in human subjects, this
May 1, 1984
and previous observations on a preferential relation between circulating NE levels and degree of septal thickness in hypertensive patients7>28 would receive further support. Plasma renin and left ventricular hypertrophy: It has been suggested that angiotensin II may be involved in the basic mechanisms related to the development of cardiac hypertrophy.2g However, hypertensive patients with normal, low or high renin levels do not differ either in blood pressure levels or in degree of LV hypertrophy,30 and in this study plasma renin activity did not differ at all in patients with hypertrophy compared to those without hypertrophy. References 1. Sen S, Tarazi RC, Khatrallah PA, Bumpus FM. Cardiac hypertrophy in spontaneously hypertensive rats. Circ Res 1974;35:775-781. 2. Sen S, Bumpus FM. Collagen synthesis in development and reversal of cardiac hypertrophy in spontaneously hypertensive rats. Am J Cardiol 1979:44:954-958. 3. TOG&k RJ, Davls JW, Anderson SC. The effects of alpha-methyldopa on cardiac hypertrophy in spontaneously hypertensive rats: ultrastructural, stereological, and morphornetric analysis. Cardiovasc Res 1979;13: 173-182. 4. Ostma?-Smf!h I. Cardiac sympathetic nerves as the final common pathway F7p InductIon of adaphve cardiac hypertrophy. Clin Sci 1981;81:2655. Safar ME, Lehner JP, Vincent MI, Plainfosse MT. Simon Ach. Echocardiographic dimensions in borderline and sustain&d hypertension. Am J Cardiol 1979:44:930-935. 6. Fouad FM, ~akashlma Y, Tarazl RC, Salcedo EE. Reversal of left ventricular hypertrophy in hypertensive patients treated with rnethykfopa. Lack of association with blood pressure control. Am J Cardiol 1982;49:795801. 7. Corea L, Bentlvogllo M, Verdecchla P, Yotolew M. Role of adrenergic overactivity and pressure overload in the pathogenesis of left ventricular hypertro hy in borderline and sustained essential hypertension in man. Clin Sci 198 ! ;63:379s-381s. 8. Gay 0, Gottdlener JS, DlBlanco R, Fletcher RD. Right ventricular wall thickening In systemic hypertension-echocardioaraohic determination of hypertrbphicies nw iri the “non-stressed” ver&cie (abstr). J Am Coil Cardiol 1983:1:59 $ A. 9. Frohllch ED, iarazi RC. Is arterial pressure the sole factor res nsible for hypertensive cardiac hypertrophy? Am J Cardiol 1979;44:95 $ -963. 10. Tarazl RC, Sen S, Saragoca M, Khalrallah P. The multifactorial role of catecholamines in hypertensive cardiac hypertrophy. Eur Heart J 1982; 3:suppl A:l03-110. 11. Devereux RB, Relchek N. Echocardiographic determination of left ven-
THE AMERICAN JOURNAL OF CARDIOLCGY
Vorume 53
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tricular mass In man. Anatomic vahdatior of the method. Circulation 1977;55:613-618, 12. Reichek N, Devereux RB. Left Ventricular Hypertrophy: relationship of anatomic, echocardiiraphic and electrocardiographic findings. Circulation 1981:63:1391-1398. 13. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1979;58:1072-1083. 14. Renzlni V. Brunorl CA. Valori C. A sensitive and soecific fluorimetric method for the d&ermination’of noradrenalin and adrena!in in human plasma. Clin Chim Acta 1970:30:587-594. 15. Maha& k, Zucchelli GC, f&a U, Salvetti A. Measurement of plasma renin activity by angiotensin I radioimmunoassay. I. An assessment of some methodological aspects. J Nucl Biol Med 1972;16:31-34. 16. SAS Institute Inc. SAS User’s Guide: Statistics. 1982 ed. Carv. _ NC: SAS Institute Inc, 1982:101-138. 17. Documenta Geigy. Tables Scientifiques. Geigy S.A., Basle (Switzerland), 1963:642. 18. Snedecor GW, Cochran WG. Statistical Methods. 7th ed. Ames, IA: The Iowa StateUniversity Press, 1980:39. 19. Savage DD, Drayer JIM, Henry WL, Mathews EC, Ware JH, Gardln JM, Cohen ER, Epstein SE, Laragh JH. Echocardiographic assessment of cardiac anatomy and function in hypertensive patients. Circulation 1979; 59:623-632. 20. Devereux RB. Savaae DD. Sachs I. Laraah JH. Relation of hemodvnamic load to left ventricular hypkrtrophyind performance in hypertensibn. Am J Cardiol 1983:51:171-176. 21. Devereux RB, Pickering To, Harshfleld GA, Klelnert HD, Denby L, Clark L, Preglbon D, Jason M, Klelner 8, Borer J, Laragh JH. Left ventricular hypertrophy in patients with hypertension: importance of blood pressure response to regularly recurring stress. Circulation 1983;68:470-476. 22. Gans JH, Cater MR. Norepinephrine induced cardiac hypertrophy in dogs. Life Sci 1970;9:731-734. 23. Laks MM, Morady F, Swant HJ. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in the dog. Chest 1973;64:75-78. 24. Simpson P, McGrath A. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha, adrenergic response. J Clin Invest 1983;
_ _-
77.7x7-738
__.
25. Rowlands DB, Glover DR, Ireland MA, McLeay RAB, Slallard TJ, Watson RDS. Littler WA. Assessment of left-ventricular mass and its resoonse to anticypertensive treatment. Lancet 1982;1:467-470.~ 26. Hartford M, Wlkstrand J, Wallentln I, Ljungman S, Berglund 0. The relation between cardiac hypertrophy and hypertension. Acta Med Stand [suppl] 1983;672:101-104. 27. Raum WJ, Lake MM, Garner D, Swerdloff RS. fl-adrenergic receptor and cyclic AMP alterations in the canine ventricular septum during long-term norepinephrine infusion: implication for hypertrophic cardiomyopathy. Circulation 1983;68:693-699. 28. Corea L, Bentlvogllo M, Verdecchla P. Echocardiographic left ventricular hypertrophy as related to arterial pressure and plasma norepinephrine concentration in arterial hypertension. Reversal by atenolol treatment. Hypertension 1983;5:837-843. 29. Robertson AL, Khalrallah PA. Angiotensin II: rapid localization in nuclei of smooth and cardiac muscle. Science 1971;172:1138-1139. 30. Devereux RB, Savage DD, Drayer JIM, Laragh JH. Left ventricular hypertrophy and function in high, normal and low-renin forms of essential hypertension. Hypertension 1982;4:524-531.
Plasma Norepinephrineand Left Ventricular Hypertrophy in Systemic Hypertension LUIGI COREA, MD, MAURIZIO BENTIVOGLIO, MD, PAOLO VERDECCHIA, MD, and MARIO MOTOLESE, MD
The relations between some pressure and humoral factors, and some echocardiographic indexes of left ventricular (LV) hypertrophy were studied in 64 patients with essential hypertension. Fifty-seven percent of these patients showed echocardiographic evidence of LV hypertrophy (LV mass >215 g). Multivariate stepwise regression analysis showed that only mean blood pressure (BP) and circulating norepinephrine (NE) levels were significantly related to LV mass index in the group of patients with LV hypertrophy. However, mean BP was the only factor related to LV mass index in the subgroup of patients with LV hypertrophy and plasma NE within the normal laboratory range, whereas NE was the sole factor related to LV mass index in the subgroup with LV hypertrophy and abnormally elevated NE levels (greater than mean + 2 standard deviations of the normal laboratory range). Correlation of LV mass index vs NE was -0.35 (not significant) in the for-
mer group of patients and 0.69 (p
Results of several investigations suggest an involvement of humoral factors in the pathogenesis of hypertensive cardiac hypertrophy in animals.14 Even in human hypertension there is some evidence that factors other than pressure overload could be involved.5-8 Catecholamines, thyroid hormones, pituitary growth hormone and the renin-angiotensin system have been considered,gl10 but knowledge about their role is still scanty. In this report we have tested the hypothesis of a positive relation between left ventricular (LV) wall thickness and some pressure and humoral factors in patients with untreated essential hypertension, with or without echocardiographic evidence of LV hypertrophy.
Methods
(Am J Cardiol 1964;53:1299-1303)
Patients: We studied 37 hypertensive patients with echocardiographic LV mass (Penn cube formulall) >215 g, suggesting LV hypertrophy at least of mild degree;12 27 hypertensive patients with echocardiographic LV mass <215 g; and 18 healthy control subjects. The hypertensive subjects were recently diagnosed and previously untreated. They were consecutively studied in our laboratory; 11 additional hypertensive patients who met study criteria were excluded because of poor-quality echocardiograms. In all patients, systolic and diastolic BPS were always found to be greater then 150 and 95 mm Hg, respectively, during a 3-month period of outpatient observation. The study group was hospitalized for at least 1 week before the study, which was performed the morning after an overnight fast. Sodium (100 mmol/day) and potassium (80 mmol/day) were kept constant during hospitalization. Experimental procedures: BP was recorded with a conventional mercury sphygmomanometer after 10 minutes of supine rest. The first and fifth Korotkoff phases were con-
From the II Clinica Medica, University of Perugia, Perugia, Italy. Manuscript received September 29, 1983; revised manuscript received January 12, 1984, accepted January 16, 1984. Address for reprints: Professor Luigi Corea, MD, Associate Professor of Cardtology, Via degli Olivetani, 8 06100-Perugia PG, Italy. 1299
1300
NOREPINEPHRINE AND CARDIAC HYPERTROPHY
sidered for systolic and diastolic BP. The echocardiographic study was performed using an ATL MK 500 ultrasound system (Advanced Technology Laboratories) with M-mode examination under cross-sectional control, and standard recording and measurement t.echniques.i3 Tracings were coded and read by 2 independent observers who were unaware of the subjects’ blood pressure status. Differences in wall thickness I1 mm were averaged; greater differences were resolved in conference. Before beginning the echocardiographic study, venous blood samples for norepinephrine (NE),14 epinephrine14 and plasma renin activity15 determination were collected, after the subject rested for at least 60 minutes supine with an indwelling butterfly needle in an arm vein. The day-to-day variability in plasma NE concentration was assessed in the hypertensive subjects by performing 2 additional determinations 1 and 2 days before that of the echocardiographic study, under similar experimental conditions. NE values measured just before beginning the echocardiographic study were used in the statistical analysis, similar to the BP values. Statistical analysis: Statistical analysis was performed using the Statistical Analysis System package.16 In each of the 3 study groups the independent relation of systolic BP, diastolic BP, mean BP (diastolic BP + l/3 pulse pressure), heart rate, NE, E and plasma renin activity with ventricular septum thickness index (ventricular septum divided by body surface area17), posterior wall thickness index or LV mass index was assessed by the stepwise multiple regression procedure. This
includes 1 X 1 in the model all the independent variables contributing to the model with a significance level of at least 0.05. Analysis of covariance (age as covariate) was used in the comparison between the groups.
Results A representative echocardiographic healthy subject is shown in Figure 1.
--._._
- *-- -\_-.
“_‘li ,’
-
_x -..
‘----J
;’
;’
-,)_
.“. _e--+
from a
Hypertensive patients with left ventricular hypertrophy: The day-to-day variability of plasma NE concentration (Fig. 2) was not statistically significant (F = 0.40). Multiple regression analysis showed that the 3 sole independent factors related to septal thickness index were diastolic BP (F = 13.6; p = 0.0008), NE (F = 16.9; p = 0.0002) and body surface area (F = 19.8; p = 0.0001); no other variable was significant. The 2 independent factors related to posterior wall thickness index were mean BP (F = 21.6; p = 0.0001) and body surface area (F = 10.3; p = 0.002). LV mass index results were related only to mean BP (F = 9.1; p = 0.004) and NE (F = 14.8; p = 0.0005). The hypertensive patients with LV hypertrophy were separated in 2 subgroups according to circulating NE levels. Because our laboratory method for NE reports normal values of 174 f 24 ng/liter (mean f standard deviation),14 NE values >222 ng/liter (i.e., more than
-
-_.--.
tracing
fi
”
“--w-n_.i
1ooL
I FIGURE 1. Echocardiographic tracing from a healthy subject. The Mmode tracing, obtained under cross-sectional control at or just below the tips of the mitral valve leaflets, shows continuous endocardial echoes of both septum and posterior wall. A control phonocardiogram (lop), carotid pulse (mlddle) and electrocardiogram (bottom) are included.
clay 1
I
& day 2
day 3
FIGURE 2. The day-today variability of plasma norepinephrine concentration in hypertensive subjects with an echocardiographic suggestion of left ventricular hypertrophy (left ventricular mass >215 g). There is no significant day-today variability of the norepinephrine levels.
May 1.1984
mean + 2 standard deviations above the mean) should be considered as abnormally elevated; they are typical in only 2.28% of subjects in a normally distributed population.18 Sixteen of 37 hypertensive patients with LV hypertrophy showed plasma NE levels greater than 222 ng/liter. The correlation coefficient of septal thickness index vs NE was -0.17 (NS) in patients with NE levels less than 222 ng/liter, and 0.55 (p = 0.024) in the patients with NE levels above 222 ng/liter. The correlation coefficient of posterior wall thickness index vs NE was -0.29 (NS) in the group with NE <222 ng/liter, and 0.18 (NS) in the group with NE above such limit. LV mass index showed a positive relationship with NE in the group with NE of greater than 222 ng/liter (r = 0.89; p = O.OOOl),(Fig. 3) but not in the other group (r = -0.35; NS). Although limited by the small number of subjects, multiple regression analysis in the group with NE levels
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
1301
less than 222 ng/liter (n = 21) showed mean BP (F = 8.57; p = 0.009) and body surface area (F = 10.2; p = 0.005) as the sole 2 independent factors related to septal thickness, body surface area as the sole factor related to posterior wall thickness index (F = 17.8; p = 0.005), and mean BP as the sole factor related to LV mass index (F = 8.3; p = 0.009). In the group with NE levels above 222 ng/liter (n = 16), ventricular septal thickness index was related to NE (F = 16.3; p = 0.001) and body surface area (F = 8.27; p = O.Ol), posterior wall thickness index was related to mean BP (F = 33.4; p = 0.0001) and body surface area (F = 15.1; p = O.OOl), and LV mass index was related only to NE (F = 54.7; p = 0.0001). Hypertensive patients without left ventricular hypertrophy: Diastolic BP was the sole independent factor related to ventricular septal thickness index (F = 6.7; p = 0.015) as well as to LV mass index (F = 9.0; p = 0.006). Posterior wall thickness index did not show
.I
.-......
“. “. .
_,
^^,,
._^
FfGURE 3. Positive relationbetween left ventriwlar mass index (LVMI) and plasma norepinephrine concentration (NE) (r = 0.89; p
NOREPINEPHRINE AND CARDIAC HYPERTROPHY
1302
TABLE I
Results
in the Study Group*
Variable
Age (yr)
Body surface area (m2) Male/female Systolic BP (mm Hg) Diastolic BP (mm Hg) Mean BP (mm Hg) Heart rate (beatslmin) Ventricular septal thickness index (cm/m*) Posterior wall thickness index (cm/m*) Left ventricular mass index (g/m*) NE (ng/liter) E (ng/liter) PRA (ng/ml/hour)
Hypertensive Patients with LV Hypertrophy (n = 37)
Hypertensive Patients without LV Hypertrophy (n = 27)
Healthy Subjects (n = 18)
34 f 7 1.8 f 0.07 3314 172 f 14 108f8 130f 8 78 f 8 0.64 f 0.05
36 f 5 1.8 f 0.1 2413 169 f 12 109f9 129 f 8 76 f 9 0.58 f 0.10
30 f 4 1.8 f 0.06 1513 120% 6 70 f 5 88 f 7 65 f 4 0.48 f 0.08
0.61 f 0.04
0.53 f 0.06
0.53 f 0.07
138 f 21 213 f 68 43 f 20 1.8 f 0.7
97%
15
187 f 46 35f 14 1.9 f 1.0
90f
11
140 f 53 24 f 6 2.3 f 0.7
Values are expressed as mean f standard deviation. BP = blood pressure: E = epinephrine; LV = left ventricular; NE = norepinephrine; PRA = plasma renin activity. l
any relation with any other variable (at least at the 0.05 level). Plasma NE concentration was less than 222 ng/liter in 20 patients, and greater than 222 ng/liter in another 7. In the former group, diastolic BP was the sole independent factor related to ventricular septal thickness index (F = 7.2; p = 0.014) or LV mass index (F = 8.2; p = O.OlO), whereas posterior wall thickness index was not related to any other parameter. No analysis was made in the latter group because of the small number of patients. Healthy subjects: In the healthy subjects, none of the univariate or multivariate analyses showed significant results. Differences between the groups (Table I): Systolic, diastolic and mean BP were similar in the hypertensive patients with LV hypertrophy compared with BP in those without LV hypertrophy, and the heart rate was lower in the normotensive patients than in either group of hypertensive subjects (both p
show a positive relation with some echocardiographic indexes of LV hypertrophy (ventricular septal thickness and LV mass index) only in a subgroup of patients with NE above the normal laboratory range. A positive relation between BP levels and echocardiographic indexes of LV hypertrophy was detectable in the other group, as well as in the patients without LV hypertrophy. This is in line with results of several studies that show a modest positive relation between resting BP and echocardiographic measurements of LV hypertrophy.1g-21 Plasma norepinephrine and left ventricular hypertrophy: The positive relation of NE with the echocardiographic indexes in the subgroup of patients with elevated NE accounted for the significance of the same relation in the overall group of hypertensive patients with LV hypertrophy. However, when comparing the patients without to those with hypertrophy, age-adjusted NE levels did not differ significantly, although there was tendency for it to be higher in the group with LV hypertrophy. In animals, LV hypertrophy induced by NE is well known,22p23and recent studies have provided evidence that cri receptors on the surface of the myocardial cell membrane could mediate such effect.24 There is no unequivocal evidence, however, that a NE-mediated mechanism stimulating LV hypertrophy may be operative in all or at least some patients with essential hypertension. A positive relation of plasma renin activityS or plasma NE7 with ventricular septal thickness in borderline hypertensive patients has been reported, but not confirmed.25 In a group of hypertensive patients, a positive relation between echocardiographic LV mass and 24hour urinary NE excretion has also been found.26 Myocardial sensitivity to catecholamines may not be similar in all of its regions: recent investigations in dogs suggest that the ventricular septum could be more sensitive to the adrenergic stimulation than either the right ventricle or other portions of the left ventricle.27 If this finding were confirmed in human subjects, this
May 1, 1984
and previous observations on a preferential relation between circulating NE levels and degree of septal thickness in hypertensive patients7>28 would receive further support. Plasma renin and left ventricular hypertrophy: It has been suggested that angiotensin II may be involved in the basic mechanisms related to the development of cardiac hypertrophy.2g However, hypertensive patients with normal, low or high renin levels do not differ either in blood pressure levels or in degree of LV hypertrophy,30 and in this study plasma renin activity did not differ at all in patients with hypertrophy compared to those without hypertrophy. References 1. Sen S, Tarazi RC, Khatrallah PA, Bumpus FM. Cardiac hypertrophy in spontaneously hypertensive rats. Circ Res 1974;35:775-781. 2. Sen S, Bumpus FM. Collagen synthesis in development and reversal of cardiac hypertrophy in spontaneously hypertensive rats. Am J Cardiol 1979:44:954-958. 3. TOG&k RJ, Davls JW, Anderson SC. The effects of alpha-methyldopa on cardiac hypertrophy in spontaneously hypertensive rats: ultrastructural, stereological, and morphornetric analysis. Cardiovasc Res 1979;13: 173-182. 4. Ostma?-Smf!h I. Cardiac sympathetic nerves as the final common pathway F7p InductIon of adaphve cardiac hypertrophy. Clin Sci 1981;81:2655. Safar ME, Lehner JP, Vincent MI, Plainfosse MT. Simon Ach. Echocardiographic dimensions in borderline and sustain&d hypertension. Am J Cardiol 1979:44:930-935. 6. Fouad FM, ~akashlma Y, Tarazl RC, Salcedo EE. Reversal of left ventricular hypertrophy in hypertensive patients treated with rnethykfopa. Lack of association with blood pressure control. Am J Cardiol 1982;49:795801. 7. Corea L, Bentlvogllo M, Verdecchla P, Yotolew M. Role of adrenergic overactivity and pressure overload in the pathogenesis of left ventricular hypertro hy in borderline and sustained essential hypertension in man. Clin Sci 198 ! ;63:379s-381s. 8. Gay 0, Gottdlener JS, DlBlanco R, Fletcher RD. Right ventricular wall thickening In systemic hypertension-echocardioaraohic determination of hypertrbphicies nw iri the “non-stressed” ver&cie (abstr). J Am Coil Cardiol 1983:1:59 $ A. 9. Frohllch ED, iarazi RC. Is arterial pressure the sole factor res nsible for hypertensive cardiac hypertrophy? Am J Cardiol 1979;44:95 $ -963. 10. Tarazl RC, Sen S, Saragoca M, Khalrallah P. The multifactorial role of catecholamines in hypertensive cardiac hypertrophy. Eur Heart J 1982; 3:suppl A:l03-110. 11. Devereux RB, Relchek N. Echocardiographic determination of left ven-
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tricular mass In man. Anatomic vahdatior of the method. Circulation 1977;55:613-618, 12. Reichek N, Devereux RB. Left Ventricular Hypertrophy: relationship of anatomic, echocardiiraphic and electrocardiographic findings. Circulation 1981:63:1391-1398. 13. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1979;58:1072-1083. 14. Renzlni V. Brunorl CA. Valori C. A sensitive and soecific fluorimetric method for the d&ermination’of noradrenalin and adrena!in in human plasma. Clin Chim Acta 1970:30:587-594. 15. Maha& k, Zucchelli GC, f&a U, Salvetti A. Measurement of plasma renin activity by angiotensin I radioimmunoassay. I. An assessment of some methodological aspects. J Nucl Biol Med 1972;16:31-34. 16. SAS Institute Inc. SAS User’s Guide: Statistics. 1982 ed. Carv. _ NC: SAS Institute Inc, 1982:101-138. 17. Documenta Geigy. Tables Scientifiques. Geigy S.A., Basle (Switzerland), 1963:642. 18. Snedecor GW, Cochran WG. Statistical Methods. 7th ed. Ames, IA: The Iowa StateUniversity Press, 1980:39. 19. Savage DD, Drayer JIM, Henry WL, Mathews EC, Ware JH, Gardln JM, Cohen ER, Epstein SE, Laragh JH. Echocardiographic assessment of cardiac anatomy and function in hypertensive patients. Circulation 1979; 59:623-632. 20. Devereux RB. Savaae DD. Sachs I. Laraah JH. Relation of hemodvnamic load to left ventricular hypkrtrophyind performance in hypertensibn. Am J Cardiol 1983:51:171-176. 21. Devereux RB, Pickering To, Harshfleld GA, Klelnert HD, Denby L, Clark L, Preglbon D, Jason M, Klelner 8, Borer J, Laragh JH. Left ventricular hypertrophy in patients with hypertension: importance of blood pressure response to regularly recurring stress. Circulation 1983;68:470-476. 22. Gans JH, Cater MR. Norepinephrine induced cardiac hypertrophy in dogs. Life Sci 1970;9:731-734. 23. Laks MM, Morady F, Swant HJ. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in the dog. Chest 1973;64:75-78. 24. Simpson P, McGrath A. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha, adrenergic response. J Clin Invest 1983;
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25. Rowlands DB, Glover DR, Ireland MA, McLeay RAB, Slallard TJ, Watson RDS. Littler WA. Assessment of left-ventricular mass and its resoonse to anticypertensive treatment. Lancet 1982;1:467-470.~ 26. Hartford M, Wlkstrand J, Wallentln I, Ljungman S, Berglund 0. The relation between cardiac hypertrophy and hypertension. Acta Med Stand [suppl] 1983;672:101-104. 27. Raum WJ, Lake MM, Garner D, Swerdloff RS. fl-adrenergic receptor and cyclic AMP alterations in the canine ventricular septum during long-term norepinephrine infusion: implication for hypertrophic cardiomyopathy. Circulation 1983;68:693-699. 28. Corea L, Bentlvogllo M, Verdecchla P. Echocardiographic left ventricular hypertrophy as related to arterial pressure and plasma norepinephrine concentration in arterial hypertension. Reversal by atenolol treatment. Hypertension 1983;5:837-843. 29. Robertson AL, Khalrallah PA. Angiotensin II: rapid localization in nuclei of smooth and cardiac muscle. Science 1971;172:1138-1139. 30. Devereux RB, Savage DD, Drayer JIM, Laragh JH. Left ventricular hypertrophy and function in high, normal and low-renin forms of essential hypertension. Hypertension 1982;4:524-531.