Download Echocardiographic Left Ventricular Hypertrophy as

Echocardiographic Left Ventricular Hypertrophy as
Related to Arterial Pressure and Plasma Norepinephrine
Concentration in Arterial Hypertension
Reversal by Atenolol Treatment
LUIOI COREA, M.D.,
MAURIZIO BENTIVOGLIO, M.D.,
AND PAOLO VERDECCHIA,
M.D.
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SUMMARY We tried to assess relationships between echocardiographic left ventricular hypertrophy (LVH), arterial pressure levels, and plasma norepinephrine concentration (NE) in 20 previously untreated stable hypertensive patients with LVH, and in 11 healthy normotensive control subjects.
Interventricular septal (IVS) thickness, posterior wall (PW) thickness, and left ventricular mass index
(LVMI) were related to arterial pressure levels and to NE by univariate and multivariate regression
analyses. In addition, after 18 months of monotherapy with atenolol (carried out in nine of 20
patients), the relationship between echocardiographic changes and degree of pressure reduction was
tested. Before treatment, PW thickness weakly correlated with systolic (r = 0.55; p < 0.01) and mean
(r = 0.50; p < 0.05) arterial pressure. IVS thickness weakly correlated with NE (r = 0.53; p < 0.05).
On this relatively small sample, multivariate regression analysis showed an association of both IVS
thickness (R = 0.57; p < 0.05) and PW thickness (R = 0.58; p < 0.05) with mean arterial pressure
(MAP) and NE. After atenolol, there was a reduction in IVS thickness (1.15 to 1.02 cm; p < 0.01), PW
thickness (1.08 to 0.99 cm; p < 0.01), and LVMI (136.3 to 113.8 g/m2; p < 0.01), besides a significant
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)
KEY WORDS • hypertension
catecholamines • atenolol
• cardiac hypertrophy
I
• echocardiography
•
nique in the study of possible mechanisms involved in
the pathogenesis of LVH as well as in its reversal
following antihypertensive treatments.
Studies in animals8"15 as well as in hypertensive patients15"18 suggest that other factors besides pressure
overload could be involved in the mechanisms responsible for LVH development. In this concern, we sought
to evaluate the possible relationships between some
echocardiographic signs of LVH interventricular septal (IVS) thickness, posterior wall (PW) thickness, left
ventricular mass index (LVMI), and some hypothetical pathogenetic factors (arterial pressure levels, catecholamines, plasma renin activity), in newly diagnosed stable hypertensive patients with echocardiographic evidence of LVH. We also studied some of the
patients again after 18 months of monotherapy with
atenolol, to test the relationships between change in
arterial pressure levels and change in LVH.
N patients with arterial hypertension, left ventricular hypertrophy (LVH) can be diagnosed by
echocardiography at an early stage of development, even in the absence of electrocardiographic or
radiological evidence.1
As a result, echocardiography can detect LVH in a
larger percentage of hypertensive patients than electrocardiographic or radiological techniques.2 Despite
some limitations,3"5 echocardiography also offers the
opportunity of repeatedly' and accurately*-7 quantifying the thickness of the ventricular walls as well as the
left ventricular mass. Thus, it appears a valuable tech-
From the Institute of Semeiotica Medica, University of Perugia,
Perugia, Italy.
Address for reprints: Luigi Corea, Associate Professor of Cardiology, Via degli Olivetani 8, 06100 Perugia PG, Italy.
Received November 29. 1982; revision accepted June 3, 1983.
837
HYPERTENSION
838
Materials and Methods
Trial Population
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Twenty hypertensive patients and 11 healthy normotensive subjects (table 1) gave written informed
consent to be included in the study. In all hypertensive
patients, sphygmomanometric blood pressure levels
were constantly found above 150/95 mm Hg during a
3-month period of ambulatory observation, with biweekly examinations always at the same time of the
day. At the end of the 3rd month of observation, patients were hospitalized for at least 1 week for diagnostic evaluation of the hypertensive state. The normotensive group was composed of subjects hospitalized for
clinical evaluation who were eventually found to be
healthy.
Essential arterial hypertension was diagnosed according to the criteria established by the World Health
Organization (WHO).19 All patients were in WHO
Stage II, with no target organ damage apart from LVH
as evidenced by echocardiography. In particular, cardiothoracic ratio was normal and cardiac transverse
diameter did not exceed 10% above the predicted value.20 In two patients, electrocardiography revealed
signs of "probable LVH," according to the pointscore system of Rohmilt and Estes.21 All patients were
at their first diagnosis of hypertension and none of
them had received therapy.
Blood pressure was measured by a conventional
sphygmomanometer. The appearance of brachial artery sounds and the complete disappearance of the
sounds (5th Korotkoff phase) was used for systolic and
diastolic pressure recordings, respectively. Measurements were always performed by the same observer;
VOL 5, No 6, NOVEMBER-DECEMBER
1983
the mean value from three consecutive readings taken
at 1-minute interval was recorded. The MAP was derived by the formula: diastolic pressure + Vi (systolic
pressure — diastolic pressure).
Echocardiography
Echocardiography was performed using a Kontron
Irex II System Echograph, with a 2.25 MHz transducer
and photorecording at paper speed of 100 mm/sec. All
procedures were performed in the same room with the
same equipment, on patients who had fasted overnight
and were resting supine for at least 1 hour. Smokers
were asked to avoid cigarettes for 24 hours before the
study. All echocardiograms were carried out and read
by the same investigator, with the patient in supine or
partial left lateral position, and after placing the transducer on the fourth or fifth intercostal space near the
left sternal edge. Echograms were taken at or just below the tips of the mitral valve leaflets, in a position
showing continuous echoes of both septum and posterior wall.
End-diastolic left ventricular internal dimensions,
IVS thickness, and PW thickness were identified at the
peak of the R wave on the simultaneous ECG. Echocardiographic left ventricular mass was calculated according to the Penn Cube formula,6-7 which includes
the thickness of the endocardial echoes from both IVS
and PW in the measurement of ventricular internal
dimension, and thus excludes them from measurement
of IVS and PW thickness.6 Left ventricular mass was
divided by body surface area to obtain LVMI. Values
reported herein are the means of six consecutive echocardiographic readings, three in mild inspiration and
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 (n = 20)
B
A
B (n = 9) Atenolol (n = 9)
Age (yrs)
Sex (M/F)
BSA (m2)
SAP (mm Hg)
DAP (mm Hg)
MAP (mm Hg)
29.2±5.4
8/3
1.74 ±0.05
I21.6±I1.2
72.0±8.6
88.7±9.0
72.6±8.7
0.89±0.09
O.98±0.O6
77.0±7.8
30.5 + 5.2
8/3
1.76 + 0.08
123.5 ±11.3
74.0 + 9.6
91.7 + 8.5
73.9 + 8.4
0.90 + 0.09
0.98 + 0.08
36.1 ±7.6
16/4
1.82 + 0.06
169.0±11.6
107.9±5.6
128.2±4.6
82.4±6.6
1.15±0.06
I.1O±O.O6
128.8± 10.7
216.0±63.6
53.6± 19.9
1.68 + 0.80
36.7±7.8
9/0
1.84 ±0.05
165.3±6.5
109.9 + 3.8
128.4 + 3.8
78.7±6.9
1 I5±O.IO
1.08 + 0.06
136.3+10.6
227.9 + 65.1
59.2± 17.6
1.80±0.8
38.2±7.7
9/0
1.85 ±0.06
133.7 + 6.8
82.7±3.6
99.7±4.0
58.7 + 5.5
HR (bpm)
IVS thickness (cm)
1.02 ±0.06
PW thickness (cm)
0.99 ±0.05
77.8 + 8.6
LVMI (g/m2)
113.8+10.3
137.6
+
41.9
141.0±50.3
NE (ng/liter)
192 4±65.9
22.1 ±5.0
20.9 + 6.6
E (ng/liter)
53.3± 12.4
2.1 ±0.9
2.2 + 0.8
PRA (ng/ml/hr/angio1)
1.03 ±0.6
o... — systolic arterial pressure; DAP = diastolic
Results expressed as means + SD. BSA = body surface area , SAP
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.
(recognized by means of a nasal probe). Values of each
reading are the means of three consecutive cycles.
Four otherwise eligible hypertensive patients were
not included in the study because of unsatisfactory
echocardiographic tracings. None of the study patients
showed segmental impairments of cardial wall motion.
Diagnosis of Left Ventricular Hypertrophy
LVH was defined as a left ventricular mass (Penn
Cube formula) greater than 215 g. This limit was chosen since, in the validation study by Reichek and Devereux, 7 13 of 14 patients with an echocardiographic left
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
weight in the same study.7
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Plasma Renln Activity and Catecholamines
Venous blood for plasma renin activity (PRA), norepinephrine (NE), and epinephrine (E) determinations
was withdrawn during hospitalization when equilibrium state was attained by urinary sodium excretion equaling sodium intake. After subjects rested for
60 minutes supine with an indwelling butterfly needle
inserted in an arm vein, samples for PRA22 and
catecholamine23 plasma levels determinations were
collected.
Follow-Up Period
Normotensive subjects were studied again at 12 to
18 months after the initial study. During this time
interval, all subjects had followed a free diet and had
not received any drug treatment apart from occasional
antipyretics or analgesics. Nine consecutive hypertensive patients (of the original 20) were dismissed from
the hospital on atenolol (Tenormin) monotherapy and
scheduled for two monthly examinations in the outpatient clinic. After 18 months of continuous treatment,
the echocardiographic study of the left ventricle and
the measurement of humoral parameters were repeated. The experimental conditions were kept constant
before and during the follow-up. On both hospitalizations, sodium and potassium intakes were kept constant (100 mmol/day and 80 mmol/day, respectively).
All echocardiograms were carried out and read by the
same investigator as in the first study.
Statistical Analysis
A Hewlett-Packard 41 CV calculator, programmed
by the H.P. 00041-15009 application pack as software, was used for statistical analysis. Differences between normotensives and hypertensives on baseline
values were tested by one-way analysis of covariance
(age as covariate). Comparisons between two quantitative variables were carried out by means of the standard least-square linear regression analysis.
The multiple linear regression of one dependent
variable (IVS thickness, PW thickness, LVMI) on two
independent variables (basal values of MAP and NE)
was analyzed by multiple regression analysis, followed by analysis of variance to test the significance of
839
the calculated regression. Calculation of the standardized partial regression coefficients (the product of the
partial regression coefficient of either independent
variable and the square root of the ratio between the
observed mean sum square of the corresponding independent variable and the sum square of the dependent
variable24), allowed a separate assessment of the influence of either independent variable on the dependent
one.
Student's / test for paired samples was used to compare pre- with post-follow-up values. A p value less
than 0.05 was assumed to be significant.
Results
Baseline Evaluation
Compared to the overall group of hypertensive patients, as well as to the group of patients undergoing
follow-up, normotensive subjects showed lower values of systolic arterial pressure (SAP), diastolic arterial pressure (DAP), MAP, heart rate (HR), IVS thickness, PW thickness, LVMI, NE, and E (all/7 < 0.01);
the PRA was similar in both groups (tables 1 and 2).
Age was slightly younger in the normotensives compared with the overall group of hypertensives (p <
0.05, analysis of variance), as well as with the patients
undergoing follow-up (p < 0.05). Body surface area
(BSA) was slightly smaller in the normotensives in
respect to the overall hypertensive population (p <
0.05), as well as to the patients undergoing follow-up
(p < 0.05).
In the overall hypertensive population, PW thickness positively correlated with SAP (r = 0.55; p <
0.01) and MAP (r = 0.50; p < 0.05), but not with
TABLE 2. Coefficients of Linear Correlation between Echocardiographic and Pressure as well as Humoral Data before Treatment
in the Hypertensive Group (n = 20)
Coefficients of correlation with
Interventricular
septal
thickness
Posterior
wall
thickness
Left
ventricular
mass index
SAP
P.
0.21
NS
0.55
<0.01
0.36
NS
DAP
P
0.17
NS
0.21
NS
0.16
NS
MAP
P
0.31
NS
0.50
<0.05
0.36
NS
0.53
<0.05
0.37
NS
0.24
NS
0.17
NS
0.24
NS
0.25
NS
0.11
NS
0.31
NS
NE
P
E
P
0.42
PRA
NS
P
See table 11 for abbreviations.
HYPERTENSION
840
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other parameters. In contrast, IVS thickness positively
correlated with NE (r = 0.53; p < 0.05), and its
correlation with PRA bordered on statistical significance (r = 0.42; r 005 = 0.43). In this relatively small
group of patients (n = 20), the multiple linear regression of IVS thickness or PW thickness on MAP and NE
was significant for both IVS and PW thickness (F
values of 4.19 (p < 0.05) for IVS, and 4.22 (p < 0.05)
for PW thickness). Multiple correlation coefficients23
for IVS and PW thickness were 0.57 and 0.58, respectively. IVS thickness appeared as mainly related to NE
(standardized partial regression coefficients of 0.50 for
NE and 0.38 for MAP), whereas PW thickness was
mainly related to MAP (standardized partial regression
coefficients of 0.45 for MAP and 0.32 for NE).
There was no significant correlation between LVMI
and each of the other parameters. Also, the multiple
linear regression of LVMI on MAP and NE was not
significant.
Changes During Follow-Up
Changes in Interventricular Septal Thickness
In the normotensive subjects, IVS thickness did not
change during the follow-up period. In the hypertensive patients (n = 9), the mean IVS thickness was 1.15
cm before treatment and fell to 1.02 cm after treatment
(p < 0.01). This reduction correlated with pretreatment values of DAP (r = 0.66; p < 0.05), and MAP (r
= 0.68; p < 0.05), but not with SAP (r = 0.34), NE
(r = 0.58), E(r = 0.51), or PRA (r = 0.08) (tables 1
and 3). Reduction in IVS thickness induced by treatment did not show any relationship with the concomitant reduction in SAP (r = 0.33), DAP (r = 0.49), or
MAP (r = 0.27). Pretreatment IVS thickness correlated with the degree of reduction following treatment (r
= 0.79; p < 0.01) (fig. 1).
Changes in Posterior Wall Thickness
In the normotensive subjects, PW thickness did not
change during the follow-up. In the hypertensive patients (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
1.3
u
1.1
• •
1.O
•*p<O.O1
0.9
I
B
FIGURE I.
Change in
IVS thickness
P
0.33
NS
0.49
NS
0.27
NS
PW thickness
P
0.54
NS
0.54
NS
0.47
NS
LVMI
P
0.17
NS
0.72
•C0.05
0.75
<0.05
See table 1 for abbreviations.
A
Interventricular septal (IVS) thickness before (B)
and after (A) 18 months of atenolol treatment in hypertensive
patients undergoing follow-up (n = 9). Values expressed as
means ± SEM.
DAP (r = 0.73; p < 0.05), and MAP (r = 0.82; p <
0.01), but not with SAP (r = 0.53),NE(r = 0.47), E
( r = 0.54), and PRA (r = 0.11). Reduction in PW
thickness induced by treatment did not show any relationship with the concomitant reduction in SAP (r =
0.54), DAP(r = 0.54), or MAP (r = 0.47). Pretreatment PW thickness correlated the degree of its reduction following treatment (r = 0.72; p < 0.05).
1.2
E
1.1
iN
1.O
Coefficient of correlation with change in
Mean
arterial
pressure
-
E
TABLE 3. Coefficients of Linear Correlation between Echocardiographic Changes and Blood Pressure Changes Induced by
Treatment in the Hypertensive Group
Diastolic
arterial
pressure
1983
1.2
o
Systolic
arterial
pressure
VOL 5, No 6, NOVEMBER-DECEMBER
>>•
•*p<O.O1
O.9
B
FIGURE 2.
A
Posterior wall (PW) thickness before (B) and after
(A) 18 months of atenolol treatment in hypertensive patients
undergoing follow-up (n = 9). Values expressed as means ±
SEM.
ARTERIAL PRESSURE, NOREPINEPHRINE, AND CARDIAC HYPERTROPHY/Corea et al.
Changes in Left Ventricular Mass Index
LVMI did not show any significant change during
the follow-up in the normotensive subjects. In the hypertensive patients (n = 9), LVMI was 136.3 g/m2
before treatment, and fell to 113.8 g/m2 during treatment {p < 0.01). This reduction correlated with pretreatment MAP (r = 0.69; p < 0.05), but not with
SAP (r = 0.42), DAP (r = 0.62), NE (r = 0.20), and
PRA (r = 0.29). Reduction in LVMI following treatment correlated with the concomitant change in DAP
(r = 0.72;p< 0.05), and MAP (r = 0.75;p < 0.05),
but not with the change in SAP (r = 0.17). No correlation was found between pretreatment LVMI and its
change following treatment (r = 0.46).
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Changes in Blood Pressure, Heart Rate, and Humoral
Parameters
All data are reported in table 1. Normotensive subjects did not show any significant change during follow-up. In contrast, atenolol treatment induced a reduction in SAP (p < 0.01), DAP (p < 0.01), and HR
(p < 0.01) in the treated patients (n = 9). NE and E
did not change significantly during the follow-up in
both normotensive and hypertensive subjects. PRA decreased significantly in the hypertensives following
atenolol treatment (p < 0.01), while it did not change
in the normotensives.
Unwanted Effects
Two of nine patients complained of mild asthenia
during the whole treatment period with atenolol. It was
not strong enough to interfere with the normal daily
activities, and thus treatment was not discontinued.
None of the other patients reported unwanted effects.
None of the subjects undergoing follow-up was withdrawn from the study.
Discussion
In this study we sought to evaluate the possible
relationships among arterial pressure levels, catecholamines, and plasma renin activity, and the degree of
LVH in patients with stable arterial hypertension and
LVH. As we used echocardiography to quantify LVH,
results of this study are to be considered in the light of
all limits of the echocardiographic techniques for LVH
assessment. In particular, calculation of left ventricular mass from one-dimensional M-mode echocardiographic data, although supported by strict correlations
with corresponding anatomic values, 6 - 7 provides results that are difficult to evaluate as accurate actual
values. 626 Extrapolating from one-dimensional to
three-dimensional data may expose a bias.4-26 27 However, none of the subjects examined in this study was
affected by valvular disease, myocardial infarction,
impairments of left ventricular wall motion, heart enlargement, or other conditions likely to impair the accuracy of the echocardiographic measurements.
We obtained a positive relationship between left
ventricular PW thickness and resting arterial pressure
841
levels (mainly, SAP and MAP), and between IVS
thickness and plasma NE concentration. Neither PW
thickness showed any relationship with NE, E, or
PRA, nor IVS thickness with arterial pressure levels.
Results of multivariate regression analysis would indicate a concomitant relationship of MAP and NE to the
degree of thickness of both IVS and PW, but this
possibility must be considered with caution because of
the small sample size, probably less than that needed
for two-variable multivariate analysis.23 Moreover,
none of the correlations of LVMI with other pressure
or humoral parameters was strong enough to attain
statistical significance.
Several echocardiographic studies from independent laboratories are in agreement in indicating a
weak but significant positive correlation between arterial pressure levels and the degree of LVH. '•2-28 The
rise in peripheral vascular resistance could play an
even more important role than the rise in arterial pressure levels in determining the degree of LVH.29 Moreover, the average pressure value resulting from several
measurements over the 24 hours seems to show a closer positive relationship with the degree of LVH in
respect to a casual pressure reading.30
As opposed to the well-established role of blood
pressure, the role of some humoral factors, such as of
the renin-angiotensin system or the catecholamines, in
the pathogenesis of LVH is still controversial.17-18-28 3I
The possibility that humoral factors may participate in
the mechanisms determining LVH in spontaneous hypertensive rats appears supported by strong evidence.9- "• l2 32 As far as the sympathetic nervous system is concerned, a number of experimental studies
indicate that catecholamines can induce cardiac hypertrophy.33"35 Such an effect seems to be mediated by a
catecholamine stimulation of myocardial /3-adrenergic
receptors.13-36 It is uncertain whether cardiac hypertrophy may develop even in the absence of hemodynamic stimuli such as periods of increased cardiac output related to /3-adrenergic stimulation.13-l3-37
In the last few years, several studies have indicated
that hypertensive subjects falling into the borderline
category of the WHO classification19 tend to have an
increased IVS thickness compared to normotensive
subjects.l7 l8- 3I-38 39 Such an increase would not be related to the levels of arterial pressure, 17-l8-3I-39 but rather to those of PRA, l7 or plasma NE, l8 the latter taken as
a crude marker of sympathetic activity. On the contrary, PW thickness would still be normal in borderline
hypertensive patients, and increased in patients with
stable hypertension, l7 - l8 in these latter revealing a good
positive correlation with the pressure levels. l7 - 18 In one
study carried out in borderline hypertensive patients
apparently older in respect to the patients considered in
the previous studies, no differences were found between hypertensives and normotensives in terms of
IVS thickness.40 According to results of other studies,
neither the renin-angiotensin system31 nor the sympathetic nervous system28 would play a major direct role
in determining the degree of LVH in unselected patients with arterial hypertension.
842
HYPERTENSION
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These results, although conflicting, would suggest
that borderline hypertensive patients should be separated from the stable hypertensives in the study of
factors related to the degree of LVH. Moreover, the
interventricular septum and the left ventricular posterior wall should be separately considered, since the possibility that IVS hypertrophy begins when PW thickness is still normal would imply that different
pathogenetic mechanisms could be involved in their
development.
Atenolol treatment induced a significant reduction
in left ventricular wall thickness and mass index, thus
supporting results of previous reports on LVH regression during treatment with this ^-blocking agent.41-42
There was no significant correlation between the reduction in thickness of either LV wall and the magnitude of arterial pressure reduction induced by treatment. By contrast, the reduction in LVMI significantly
correlated with the magnitude of pressure reduction.
These findings are in line with those obtained in a
recent study,28 in which a significant correlation was
observed between SAP, DAP, and MAP reduction
following various antihypertensive treatments, and
concomitant reduction in LVMI derived by the same
formula as in this study. However, discordance between LVMI and LV wall thickness in their relationship with MAP and NE before treatment, as well as the
discordance between their change and the pressure
change during treatment, was unexpected and raises an
interesting point. If it is assumed that the combination
of factors determining interventricular septal hypertrophy is not the same as that which influences the
hypertrophy of the posterior wall, a discrepancy may
be expected when the same factors (i.e., MAP and NE
in the present study) are related to the thickness of
either wall or to LVMI, which is derived including
both of the walls.
Thus, LVMI seems less sensitive than IVS thickness
or PW thickness in the study of subtle relationships
with possible causal factors. On the contrary, if an
overall assessment of LVH is needed and a relationship
between changes in LVH and degree of pressure reduction is looked for, LVMI appears to be the most reliable parameter. With larger populations than in our
present study, it may be possible to obtain true correlations between LVMI and factors possibly important in
the pathogenesis of LVH.
In conclusion, our findings support a possible role of
catecholamines as additional stimulus to left ventricular hypertrophy in patients with newly diagnosed stable arterial hypertension. Further studies on larger
populations are needed to confirm these data and to
clarify whether factors stimulating LVH may differently affect the interventricular septum and the left
ventricular posterior wall.
Acknowledgments
The authors thank Fausto Ercolanelli. for skilled technical assistance in the determination of PRA and plasma catecholamine concentration, and Luisa Vercellesi and Gabriella Mancina for bibliographic assistance.
VOL 5, No 6, NOVEMBER-DECEMBER
1983
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Hypertension. 1983;5:837-843
doi: 10.1161/01.HYP.5.6.837
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