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reduction in blood pressure and heart rate. The degree of pressure reduction induced by treatment
did not correlate the change in IVS or PW thickness. In contrast, the change in diastolic and mean
arterial pressure positively correlated the change in LVMI (r = 0.72 and r = 0.75, respectively; both
p < 0.05).
These findings suggest that both arterial pressure levels and NE could influence the degree of LVH
in stable arterial hypertension with LVH, and that IVS and PW thickness seem more sensitive
indicators of LVH, than LVMI, in the research of subtle relationships with hypothetical pathogenetic
factors. In contrast, LVMI seems more suitable than the thickness of either wall in the overall
assessment of LVH regression during antihypertensive drug treatment when a possible relationship
with pressure reduction is being investigated. (Hypertension 5: 837-843, 1983)
Materials and Methods the mean value from three consecutive readings taken
at 1-minute interval was recorded. The MAP was de-
Trial Population rived by the formula: diastolic pressure + Vi (systolic
Twenty hypertensive patients and 11 healthy nor- pressure — diastolic pressure).
motensive subjects (table 1) gave written informed
consent to be included in the study. In all hypertensive Echocardiography
patients, sphygmomanometric blood pressure levels Echocardiography was performed using a Kontron
were constantly found above 150/95 mm Hg during a Irex II System Echograph, with a 2.25 MHz transducer
3-month period of ambulatory observation, with bi- and photorecording at paper speed of 100 mm/sec. All
weekly examinations always at the same time of the procedures were performed in the same room with the
day. At the end of the 3rd month of observation, pa- same equipment, on patients who had fasted overnight
tients were hospitalized for at least 1 week for diagnos- and were resting supine for at least 1 hour. Smokers
tic evaluation of the hypertensive state. The normoten- were asked to avoid cigarettes for 24 hours before the
sive group was composed of subjects hospitalized for study. All echocardiograms were carried out and read
clinical evaluation who were eventually found to be by the same investigator, with the patient in supine or
healthy. partial left lateral position, and after placing the trans-
Essential arterial hypertension was diagnosed ac- ducer on the fourth or fifth intercostal space near the
cording to the criteria established by the World Health left sternal edge. Echograms were taken at or just be-
Organization (WHO).19 All patients were in WHO low the tips of the mitral valve leaflets, in a position
Stage II, with no target organ damage apart from LVH showing continuous echoes of both septum and poste-
as evidenced by echocardiography. In particular, car- rior wall.
diothoracic ratio was normal and cardiac transverse End-diastolic left ventricular internal dimensions,
diameter did not exceed 10% above the predicted val- IVS thickness, and PW thickness were identified at the
ue.20 In two patients, electrocardiography revealed peak of the R wave on the simultaneous ECG. Echo-
signs of "probable LVH," according to the point- cardiographic left ventricular mass was calculated ac-
score system of Rohmilt and Estes.21 All patients were cording to the Penn Cube formula,6-7 which includes
at their first diagnosis of hypertension and none of the thickness of the endocardial echoes from both IVS
them had received therapy. and PW in the measurement of ventricular internal
Blood pressure was measured by a conventional dimension, and thus excludes them from measurement
sphygmomanometer. The appearance of brachial ar- of IVS and PW thickness.6 Left ventricular mass was
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tery sounds and the complete disappearance of the divided by body surface area to obtain LVMI. Values
sounds (5th Korotkoff phase) was used for systolic and reported herein are the means of six consecutive echo-
diastolic pressure recordings, respectively. Measure- cardiographic readings, three in mild inspiration and
ments were always performed by the same observer; three in expiration at lung functional residual capacity
TABLE 1. Demographic Characteristics, Blood Pressure, Heart Rale, Echocardiographic and Humoral Findings in
Normotensive Subjects at Initial Examination (B) and after 12 to 18 Months (A), and in Hypertensive Patients Basally (B)
and after Treatment (Atenolol)
Hypertensive group (n = 20)
Normotensive group (n = 11) Patients undergoing follow up (n = 9)
B A B (n = 20) B (n = 9) Atenolol (n = 9)
Age (yrs) 29.2±5.4 30.5 + 5.2 36.1 ±7.6 36.7±7.8 38.2±7.7
Sex (M/F) 8/3 8/3 16/4 9/0 9/0
BSA (m2) 1.74 ±0.05 1.76 + 0.08 1.82 + 0.06 1.84 ±0.05 1.85 ±0.06
SAP (mm Hg) I21.6±I1.2 123.5 ±11.3 169.0±11.6 165.3±6.5 133.7 + 6.8
DAP (mm Hg) 72.0±8.6 74.0 + 9.6 107.9±5.6 109.9 + 3.8 82.7±3.6
MAP (mm Hg) 88.7±9.0 91.7 + 8.5 128.2±4.6 128.4 + 3.8 99.7±4.0
HR (bpm) 72.6±8.7 73.9 + 8.4 82.4±6.6 78.7±6.9 58.7 + 5.5
IVS thickness (cm) 0.89±0.09 0.90 + 0.09 1.15±0.06 1 I5±O.IO 1.02 ±0.06
PW thickness (cm) O.98±0.O6 0.98 + 0.08 I.1O±O.O6 1.08 + 0.06 0.99 ±0.05
LVMI (g/m2) 77.0±7.8 77.8 + 8.6 128.8± 10.7 136.3+10.6 113.8+10.3
NE (ng/liter) 141.0±50.3 137.6 + 41.9 216.0±63.6 227.9 + 65.1 192 4±65.9
E (ng/liter) 22.1 ±5.0 20.9 + 6.6 53.6± 19.9 59.2± 17.6 53.3± 12.4
PRA (ng/ml/hr/angio1) 2.1 ±0.9 2.2 + 0.8 1.68 + 0.80 1.80±0.8 1.03 ±0.6
Results expressed as means + SD. BSA = body surface area , SAP o... — systolic arterial pressure; DAP = diastolic
arterial pressure; MAP = mean arterial pressure; HR = heart rate;IVS = interventricular septum; PW = posterior wall;
LVMI = left ventricular mass index; NE = norepinephnne; E = epinephrine; PRA = plasma rcnin activity.
ARTERIAL PRESSURE, NOREPINEPHRINE, AND CARDIAC HYPERTROPHY/Corea et al. 839
(recognized by means of a nasal probe). Values of each the calculated regression. Calculation of the standard-
reading are the means of three consecutive cycles. ized partial regression coefficients (the product of the
Four otherwise eligible hypertensive patients were partial regression coefficient of either independent
not included in the study because of unsatisfactory variable and the square root of the ratio between the
echocardiographic tracings. None of the study patients observed mean sum square of the corresponding inde-
showed segmental impairments of cardial wall motion. pendent variable and the sum square of the dependent
variable24), allowed a separate assessment of the influ-
Diagnosis of Left Ventricular Hypertrophy ence of either independent variable on the dependent
LVH was defined as a left ventricular mass (Penn one.
Cube formula) greater than 215 g. This limit was cho- Student's / test for paired samples was used to com-
sen since, in the validation study by Reichek and Dev- pare pre- with post-follow-up values. A p value less
ereux, 7 13 of 14 patients with an echocardiographic left than 0.05 was assumed to be significant.
ventricular mass (Penn Cube formula) greater than 215
g also had a postmortem left ventricular weight greater
than 215 g, the upper limit of normal left ventricular Results
weight in the same study.7
Baseline Evaluation
Plasma Renln Activity and Catecholamines Compared to the overall group of hypertensive pa-
Venous blood for plasma renin activity (PRA), nor- tients, as well as to the group of patients undergoing
epinephrine (NE), and epinephrine (E) determinations follow-up, normotensive subjects showed lower val-
was withdrawn during hospitalization when equil- ues of systolic arterial pressure (SAP), diastolic arteri-
ibrium state was attained by urinary sodium excre- al pressure (DAP), MAP, heart rate (HR), IVS thick-
tion equaling sodium intake. After subjects rested for ness, PW thickness, LVMI, NE, and E (all/7 < 0.01);
60 minutes supine with an indwelling butterfly needle the PRA was similar in both groups (tables 1 and 2).
inserted in an arm vein, samples for PRA22 and Age was slightly younger in the normotensives com-
catecholamine23 plasma levels determinations were pared with the overall group of hypertensives (p <
collected. 0.05, analysis of variance), as well as with the patients
undergoing follow-up (p < 0.05). Body surface area
Follow-Up Period (BSA) was slightly smaller in the normotensives in
Normotensive subjects were studied again at 12 to respect to the overall hypertensive population (p <
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18 months after the initial study. During this time 0.05), as well as to the patients undergoing follow-up
interval, all subjects had followed a free diet and had (p < 0.05).
not received any drug treatment apart from occasional In the overall hypertensive population, PW thick-
antipyretics or analgesics. Nine consecutive hyperten- ness positively correlated with SAP (r = 0.55; p <
sive patients (of the original 20) were dismissed from 0.01) and MAP (r = 0.50; p < 0.05), but not with
the hospital on atenolol (Tenormin) monotherapy and
scheduled for two monthly examinations in the outpa-
tient clinic. After 18 months of continuous treatment,
the echocardiographic study of the left ventricle and TABLE 2. Coefficients of Linear Correlation between Echocar-
the measurement of humoral parameters were repeat- diographic and Pressure as well as Humoral Data before Treatment
in the Hypertensive Group (n = 20)
ed. The experimental conditions were kept constant
before and during the follow-up. On both hospitaliza- Coefficients of correlation with
tions, sodium and potassium intakes were kept con- Interven-
stant (100 mmol/day and 80 mmol/day, respectively). tricular Posterior Left
All echocardiograms were carried out and read by the septal wall ventricular
thickness thickness mass index
same investigator as in the first study.
SAP 0.21 0.55 0.36
P. NS <0.01 NS
Statistical Analysis
A Hewlett-Packard 41 CV calculator, programmed DAP 0.17 0.21 0.16
by the H.P. 00041-15009 application pack as soft- P NS NS NS
ware, was used for statistical analysis. Differences be-
MAP 0.31 0.50 0.36
tween normotensives and hypertensives on baseline NS <0.05 NS
P
values were tested by one-way analysis of covariance
(age as covariate). Comparisons between two quantita- NE 0.53 0.37 0.24
tive variables were carried out by means of the stan- P <0.05 NS NS
dard least-square linear regression analysis.
E 0.17 0.24 0.25
The multiple linear regression of one dependent NS NS NS
P
variable (IVS thickness, PW thickness, LVMI) on two
independent variables (basal values of MAP and NE) PRA 0.42 0.11 0.31
was analyzed by multiple regression analysis, fol- P NS NS NS
lowed by analysis of variance to test the significance of See table 11 for abbreviations.
840 HYPERTENSION VOL 5, No 6, NOVEMBER-DECEMBER 1983
and 3). Reduction in IVS thickness induced by treat- 0.01), but not with SAP (r = 0.53),NE(r = 0.47), E
ment did not show any relationship with the concomi- ( r = 0.54), and PRA (r = 0.11). Reduction in PW
tant reduction in SAP (r = 0.33), DAP (r = 0.49), or thickness induced by treatment did not show any rela-
MAP (r = 0.27). Pretreatment IVS thickness correlat- tionship with the concomitant reduction in SAP (r =
ed with the degree of reduction following treatment (r 0.54), DAP(r = 0.54), or MAP (r = 0.47). Pretreat-
= 0.79; p < 0.01) (fig. 1). ment PW thickness correlated the degree of its reduc-
tion following treatment (r = 0.72; p < 0.05).
Changes in Posterior Wall Thickness
In the normotensive subjects, PW thickness did not
change during the follow-up. In the hypertensive pa- 1.2
tients (n = 9), the mean PW thickness was 1.08 before
treatment and 0.99 after treatment (p < 0.01) (fig. 2).
This reduction correlated with pretreatment values of
E
iN
o
1.1
Changes in Left Ventricular Mass Index levels (mainly, SAP and MAP), and between IVS
LVMI did not show any significant change during thickness and plasma NE concentration. Neither PW
the follow-up in the normotensive subjects. In the hy- thickness showed any relationship with NE, E, or
pertensive patients (n = 9), LVMI was 136.3 g/m2 PRA, nor IVS thickness with arterial pressure levels.
before treatment, and fell to 113.8 g/m2 during treat- Results of multivariate regression analysis would indi-
ment {p < 0.01). This reduction correlated with pre- cate a concomitant relationship of MAP and NE to the
treatment MAP (r = 0.69; p < 0.05), but not with degree of thickness of both IVS and PW, but this
SAP (r = 0.42), DAP (r = 0.62), NE (r = 0.20), and possibility must be considered with caution because of
PRA (r = 0.29). Reduction in LVMI following treat- the small sample size, probably less than that needed
ment correlated with the concomitant change in DAP for two-variable multivariate analysis.23 Moreover,
(r = 0.72;p< 0.05), and MAP (r = 0.75;p < 0.05), none of the correlations of LVMI with other pressure
but not with the change in SAP (r = 0.17). No correla- or humoral parameters was strong enough to attain
tion was found between pretreatment LVMI and its statistical significance.
change following treatment (r = 0.46). Several echocardiographic studies from inde-
pendent laboratories are in agreement in indicating a
Changes in Blood Pressure, Heart Rate, and Humoral weak but significant positive correlation between arte-
Parameters rial pressure levels and the degree of LVH. '•2-28 The
All data are reported in table 1. Normotensive sub- rise in peripheral vascular resistance could play an
jects did not show any significant change during fol- even more important role than the rise in arterial pres-
low-up. In contrast, atenolol treatment induced a re- sure levels in determining the degree of LVH.29 More-
duction in SAP (p < 0.01), DAP (p < 0.01), and HR over, the average pressure value resulting from several
(p < 0.01) in the treated patients (n = 9). NE and E measurements over the 24 hours seems to show a clos-
did not change significantly during the follow-up in er positive relationship with the degree of LVH in
both normotensive and hypertensive subjects. PRA de- respect to a casual pressure reading.30
creased significantly in the hypertensives following As opposed to the well-established role of blood
atenolol treatment (p < 0.01), while it did not change pressure, the role of some humoral factors, such as of
in the normotensives. the renin-angiotensin system or the catecholamines, in
the pathogenesis of LVH is still controversial.17-18-28 3I
Unwanted Effects The possibility that humoral factors may participate in
Two of nine patients complained of mild asthenia the mechanisms determining LVH in spontaneous hy-
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during the whole treatment period with atenolol. It was pertensive rats appears supported by strong evi-
not strong enough to interfere with the normal daily dence.9- "• l2 32 As far as the sympathetic nervous sys-
activities, and thus treatment was not discontinued. tem is concerned, a number of experimental studies
None of the other patients reported unwanted effects. indicate that catecholamines can induce cardiac hyper-
None of the subjects undergoing follow-up was with- trophy.33"35 Such an effect seems to be mediated by a
drawn from the study. catecholamine stimulation of myocardial /3-adrenergic
receptors.13-36 It is uncertain whether cardiac hyper-
trophy may develop even in the absence of hemody-
namic stimuli such as periods of increased cardiac out-
Discussion put related to /3-adrenergic stimulation.13-l3-37
In this study we sought to evaluate the possible In the last few years, several studies have indicated
relationships among arterial pressure levels, catechola- that hypertensive subjects falling into the borderline
mines, and plasma renin activity, and the degree of category of the WHO classification19 tend to have an
LVH in patients with stable arterial hypertension and increased IVS thickness compared to normotensive
LVH. As we used echocardiography to quantify LVH, subjects.l7 l8- 3I-38 39 Such an increase would not be re-
results of this study are to be considered in the light of lated to the levels of arterial pressure, 17-l8-3I-39 but rath-
all limits of the echocardiographic techniques for LVH er to those of PRA, l7 or plasma NE, l8 the latter taken as
assessment. In particular, calculation of left ventricu- a crude marker of sympathetic activity. On the con-
lar mass from one-dimensional M-mode echocardio- trary, PW thickness would still be normal in borderline
graphic data, although supported by strict correlations hypertensive patients, and increased in patients with
with corresponding anatomic values, 6 - 7 provides re- stable hypertension, l7 - l8 in these latter revealing a good
sults that are difficult to evaluate as accurate actual positive correlation with the pressure levels. l7 - 18 In one
values. 626 Extrapolating from one-dimensional to study carried out in borderline hypertensive patients
three-dimensional data may expose a bias.4-26 27 How- apparently older in respect to the patients considered in
ever, none of the subjects examined in this study was the previous studies, no differences were found be-
affected by valvular disease, myocardial infarction, tween hypertensives and normotensives in terms of
impairments of left ventricular wall motion, heart en- IVS thickness.40 According to results of other studies,
largement, or other conditions likely to impair the ac- neither the renin-angiotensin system31 nor the sympa-
curacy of the echocardiographic measurements. thetic nervous system28 would play a major direct role
We obtained a positive relationship between left in determining the degree of LVH in unselected pa-
ventricular PW thickness and resting arterial pressure tients with arterial hypertension.
842 HYPERTENSION VOL 5, No 6, NOVEMBER-DECEMBER 1983
of factors determining interventricular septal hyper- reversal of cardiac hypertrophy in spontaneously hypertensive
rats. Am J Cardiol 44: 954, 1979
trophy is not the same as that which influences the 12. Tomanek RJ. Davis JW, Anderson SC: The effects of alpha-
hypertrophy of the posterior wall, a discrepancy may methyldopa on cardiac hypertrophy in spontaneously hyper-
be expected when the same factors (i.e., MAP and NE tensive rats: ultrastructural, stereological, and morphometric
in the present study) are related to the thickness of analysis. Cardiovasc Res 13: 173, 1979
either wall or to LVMI, which is derived including 13. Garner D, Laks M: Is the physiological hypertrophy produced
by a 3 month subhypertensive norepinephrine infusion blocked
both of the walls. by propranolol? Circulation 62 (suppl III): 111-68. 1980
Thus, LVMI seems less sensitive than IVS thickness 14. Ostman-Smith I: Cardiac sympathetic nerves as the final com-
or PW thickness in the study of subtle relationships mon pathway in the induction of adaptive cardiac hypertrophy.
with possible causal factors. On the contrary, if an ClinSci 61: 265. 1981
15. Larson DF. Womble JR, Copeland JC, Haddock D: Hyper-
overall assessment of LVH is needed and a relationship trophy in the denervatcd. non-working heterotopic heart trans-
between changes in LVH and degree of pressure reduc- plant. Circulation 66 (suppl II): 11-14. 1982
tion is looked for, LVMI appears to be the most reli- 16. Fouad FM. Nakashima Y, Tarazi RC. Salcedo EE: Reversal of
able parameter. With larger populations than in our left ventricular hypertrophy in hypertensive patients treated
with methyldopa. Lack of association with blood pressure con-
present study, it may be possible to obtain true correla- trol. Am J Cardiol 49: 795, 1982
tions between LVMI and factors possibly important in 17. SafarME. LehnerJP, Vincent MI. Plainfosse MT, Simon AC:
the pathogenesis of LVH. Echocardiographic dimensions in borderline and sustained hy-
In conclusion, our findings support a possible role of pertension. Am J Cardiol 44: 930, 1979
catecholamines as additional stimulus to left ventricu- 18. Corea L, Bentivoglio M, Verdecchia P, Motolese M: Left
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ble arterial hypertension. Further studies on larger 1982
populations are needed to confirm these data and to 19 World Health Organization: Arterial Hypertension: Report of a
clarify whether factors stimulating LVH may differ- WHO Expert Committee. Tech Rep Ser No. 628. Geneva:
World Health Organization, 1978, p 7
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Acknowledgments 1968
The authors thank Fausto Ercolanelli. for skilled technical assis- 22. Malvano R. Zucchelli GC, Rosa U. Salvetti A: Measurement
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