Effect of Renin-Angiotensin Blockers on Left Ventricular

Remodeling in Severe Aortic Stenosis

Serene Si-Ning Goh, MBBSa, Ching-Hui Sia, MBBS, MRCP(UK), MMed (Int Med)b,
Nicholas Jinghao Ngiam, MBBSb, Benjamin Yong-Qiang Tan, MBBS, MRCP(UK)b,
Poay Sian Lee, PhDa, Edgar Lik-Wui Tay, MBBS, MRCP(UK), MMed (Int Med)a,c,
William Kok-Fai Kong, MBChB, FRACP, FRCP (Edin)a,c, Tiong Cheng Yeo, MBBS, MRCP(UK)a,c,
and Kian-Keong Poh, MBBChir, FRCP (Edin), FACCa,c,*

Studies have shown that medical therapy with renin-angiotensin blockers (RABs) may
benefit patients with aortic stenosis (AS). However, its use and efficacy remains contro-
versial, including in patients with low flow (LF) with preserved left ventricular ejection
fraction (LVEF). We examined the effects of RAB use on LV remodeling in patients with
severe AS with preserved LVEF, analyzing the differential effects in patients with LF
compared with normal flow (NF). This is a retrospective study of 428 consecutive subjects
from 2005 to 2014 with echocardiographic diagnosis of severe AS and preserved LVEF.
Clinical and echocardiographic parameters were systematically collected and analyzed.
Two hundred forty-two (57%) patients had LF. Sixty-four LF patients (26%) were treated
with RAB. Patients on RAB treatment had a higher incidence of hyperlipidemia (69% vs
44%) and diabetes mellitus (53% vs 34%). Severity of AS in terms of valve area, trans-
valvular mean pressure gradient, and aortic valve resistance were similar between both
groups as was the degree of LV diastolic function. The RAB group demonstrated signifi-
cantly lower LV mass index with a correspondingly lower incidence of concentric LV
hypertrophy. Regardless of the duration of RAB therapy, patients had increased odds of
having a preserved LV mass index compared with those without RAB therapy. In
conclusion, RAB therapy may be associated with less LV pathological remodeling and have
a role in delaying patients from developing cardiovascular complications of AS. Ó 2017
Elsevier Inc. All rights reserved. (Am J Cardiol 2017;119:1839e1845)

Aortic stenosis (AS) is a common and progressive
valvular heart disease.1 Pressure overload secondary to AS
results in an initial adaptive remodeling, which subsequently
deteriorates to maladaptive remodeling and eventually,
diastolic dysfunction and contractile failure.2 Some studies
demonstrate that renin-angiotensin blockers (RAB; which
includes both angiotensin-converting enzyme inhibitors
[ACEIs] and angiotensin receptor blockers [ARBs]) may
reduce pathological ventricular remodeling,3e6 slow pro-
gression, and exert protective effects at the level of the
vasculature.7 The few studies on RAB use in AS demon-
strate controversy, although results are promising.8e11 In
studies on patients with severe AS, results on the outcomes
of low flow (LF) versus those with normal flow (NF) have
been mixed.12e15 Our study examines the effect of RAB use
on LV remodeling in patients with severe AS and preserved
a
Department of Medicine, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore, Singapore; bDepartment of Medicine,
University Medicine Cluster, National University Health System,
Singapore, Singapore; and cDepartment of Cardiology, National University
Heart Centre, National University Health System, Singapore, Singapore.
Manuscript received December 26, 2016; revised manuscript received and
accepted February 23, 2017.
Drs. Goh and Sia contributed equally to this article.
See page 1844 for disclosure information.
*Corresponding author: Tel: (65) 6772-2476; fax: (65) 6779-5678.
E-mail address: kian_keong_poh@nuhs.edu.sg (K.-K. Poh).
LVEF, in particular the differential effects in LF compared
with NF.
Methods
We studied 428 consecutive subjects from the National
University Heart Center, Singapore retrospectively, with an
echocardiographic diagnosis of severe AS (aortic valve area

1 cm2) and preserved LVEF (50%), from the year 2005
to 2014. All patients were medically managed. Subjects with
other significant valvular lesions, congenital heart disease,
or prosthetic valves were excluded from the study.
Demographic, clinical, and echocardiographic parame-
ters were collected. All patients underwent comprehensive
transthoracic echocardiography, including tissue Doppler
assessment of mitral annular systolic (S0 ), early (E0 ), and
late (A0 ) diastolic velocities. LV dimensions (at end-systole
and end-diastole), LV mass, and relative wall thickness
(RWT) were derived from M-mode measurements, based
on the recommendations of the American Society of
Echocardiography.16 LV mass was calculated using the
Devereux formula and indexed to the body surface area.
Based on the LV mass index (LVMI) and RWT, patterns of
LV geometry were categorized into: normal geometry,
eccentric hypertrophy, concentric remodeling, or concentric
hypertrophy.17,18 An LVMI cut off of >95 g/m2 in women
and >115 g/m2 in men was used, whereas increased RWT
was >0.42.

0002-9149/17/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. www.ajconline.org
http://dx.doi.org/10.1016/j.amjcard.2017.02.037
1840 The American Journal of Cardiology (www.ajconline.org)
Figure 1. Study population of patients with severe AS with preserved LVEF. AVA ¼ aortic valve area; SVI ¼ stroke volume index.
In addition, subjects were divided into the LF group (LV
stroke volume index of <35 ml/m2) and the NF group.
Furthermore, treatment with RAB and duration of RAB
therapy were recorded (Figure 1). Univariate analyses were
used to compare the effects of RAB treatment on the pat-
terns of LV geometry in both groups. Univariate analyses
were also performed to compare RAB to without RAB
treatment using t tests for continuous variables and chi-
square tests for categorical variables. Variables that
appeared significant on univariate analyses were subse-
quently fit into a multivariable logistic regression model to
identify variables independently associated with RAB
treatment. Further analyses were also conducted to evaluate
if the specific type of RAB treatment (ACEI or ARB) had
impacted the patterns of LV geometry observed.
All statistical analysis was performed with SPSS for
windows, version 20.0, SPSS Inc, Chicago, Illinois. A p
value <0.05 was considered to be statistically significant.
Approval was obtained by the relevant institutional review
board.
Results
Of the 428 patients studied, 242 (57%) were LF. Twenty-
six percent of this group (n ¼ 64) were treated with RAB.
Comparing those treated with RAB to those without RAB
treatment in this group, they did not differ significantly in
terms of age, gender, ethnicity, or incidence of previous
myocardial infarction but had a higher incidence of hyper-
lipidemia and diabetes mellitus (Table 1).
In terms of echocardiographic parameters, both groups,
with and without RAB, had similar degree of diastolic and
systolic LV dysfunction. The severity of the AS in terms of
valve area, transvalvular mean pressure gradient, and aortic
valve resistance was also not significantly different. How-
ever, the RAB group differed significantly in terms of LV
remodeling. LVMI was significantly lower in the RAB
group, and correspondingly, the incidence of concentric LV
hypertrophy (LVH) was also significantly lower in the RAB
group (Table 1). A lower LVMI, lower incidence of
concentric hypertrophy, and presence of hyperlipidemia
remained independently associated with the RAB treatment
group on multivariate analyses.
Subgroup analysis of the LF group comparing different
duration of RAB therapy found that regardless of period of
RAB therapy (i.e., therapy for <6 months, 6 to 12 months,
12 to 18 months, or >18 months), patients on RAB therapy
were associated with a preserved/lower LVMI compared
with those without RAB therapy (Figure 2).
Comparatively, of the 186 patients in the NF group, 26%
(n ¼ 49) were treated with RAB. Unlike the LF group, we
did not demonstrate any significant difference in clinical
parameters, LV diastolic or systolic function, aortic valve
indexes, or LV remodeling patterns when comparing those
on RAB treatment and those without in the NF group. Only
end-systolic wall stress was documented to be higher in the
group with RAB compared with that without (Table 2).
There was higher RWT in the LF versus NF group.
Further comparisons were made between patients treated
with ACEI and ARB in patients with severe AS and pre-
served LVEF. Among those with LF, patients on ARB had a
higher proportion of having diabetes mellitus compared with
those on ACEI (Table 3). Comparing between populations
across all categories of flow, they differed significantly in
terms of end-systolic wall stress, which was higher in those
on ARB than on ACEI. There was no significant difference
in the patterns of LV geometry observed between the group
on ACEI and the group on ARB (Table 4).
Discussion
The effects of the use of RAB on LV remodeling in
patients with NF versus LF severe AS with preserved LVEF
has not been studied previously. We found that RAB was
beneficial in LV remodeling in LF versus NF severe AS.
The prevalence of LF severe AS ranges from 35% to
55%.1,19 We find 57% of our subjects to be LF category,
which is on the higher end of the spectrum.
Regression of LVH in severe AS is a surrogate for fewer
major adverse cardiovascular events.20 We demonstrate that
 Valvular Heart Disease/Renin-Angiotensin Blockers in Aortic Stenosis 1841

Table 1
Univariate analyses identifying clinical and echocardiographic parameters associated with treatment with renin-angiotensin blockers compared to controls in
patients with low-flow (stroke volume index <35 ml/m2) severe aortic stenosis (aortic valve area <1 cm2) with preserved left ventricular ejection fraction
(>50%)
Parameter Univariate analysis

RAB (n¼64) No RAB (n¼178) Mean Difference/Odds Ratio P-value

(95%CI)*

Clinical parameters
Age (years) 72.6 (9.7) 73.5 (13.4) -0.9 (-4.5 e 2.6) 0.611
Men 28 (44%) 80 (45%) 0.999 (0.564 e 1.770) 0.888
Ethnicity
Chinese 35 (55%) 101 (57%) Control
Malay 12 (19%) 26 (15%) 1.444 (0.668 - 3.123) 0.348
Indian 7 (11%) 24 (14%) 0.667 (0.253 - 1.757) 0.410
Others 10 (16%) 27 (15%) 0.926 (0.398 e 2.156) 0.862
Hypertension 40 (63%) 99 (56%) 1.330 (0.740 e 2.390) 0.340
Hyperlipidemia 44 (69%) 78 (44%) 2.821 (1.539 e 5.169) 0.001
Diabetes mellitus 32 (53%) 57 (34%) 2.185 (1.200 e 3.982) 0.010
Previous acute myocardial infarction 3 (5%) 3 (2%) 2.869 (0.564 e 14.593) 0.185
Echocardiographic parameters
LV diastolic function
Deceleration time (ms) 195.7 (100.2) 202.6 (97.1) -6.9 (-35.0 e 21.2) 0.629
E/A ratio 0.63 (0.33) 0.78 (0.65) -0.15 (-0.33 e 0.040) 0.122
Septal E/e’ ratio 14.2 (8.9) 15.6 (9.2) -1.4 (-4.2- 1.4) 0.340
Pulmonary artery systolic pressure/mmHg 26.4 (20.4) 31.3 (18.5) -4.8 (-10.3 e 0.62) 0.082
LV systolic function
Left ventricular ejection fraction (LVEF) (%) 64.6 (16.3) 66.5 (11.7) -2.0 (-5.7 e 1.8) 0.305
Stroke volume index (SVI) (ml/m2) 26.3 (4.4) 25.6 (5.0) 0.8 (-0.6 e 2.2) 0.280
Stroke work loss (%) 23.0 (16.4) 25.8 (16.0) -2.8 (-7.5 e 1.8) 0.225
Septal S’ velocity (cm/s) 5.16 (3.05) 5.48 (3.13) -0.31 (-1.21 e 0.58) 0.488
End-systolic wall stress (x 103 dyn/cm2) 56.7 (17.3) 55.3 (15.6) 1.4 (-3.3 e 6.1) 0.561
Systemic arterial compliance (ACU) 0.95 (0.54) 1.02 (0.49) -0.07 (-0.22 e 0.07) 0.327
Valvuloarterial impedance (mmHg/ml/m2) 5.63 (1.54) 5.52 (1.66) 0.11 (-0.35 e 0.58) 0.635
Aortic valve indices
Aortic valve area (AVA) (cm2) 0.74 (0.27) 0.77 (0.21) 0.02 (-0.09 e 0.04) 0.512
Transaortic mean pressure gradient (mmHg) 30.5 (18.5) 33.9 (20.0) -3.4 (-9.0 e 2.3) 0.239
Aortic valve resistance (dyn s /cm2) 163.7 (134.4) 145.0 (142.4) 18.8 (-9.0 e 2.3) 0.379
LV structure
End-diastolic volume index (ml/m2) 89.0 (30.8) 90.2 (26.9) -1.1 (-9.2 e 6.9) 0.779
Left Ventricular mass index (g/m2) 99.9 (–25.1) 121.6 (–37.8) -21.7 (-31.6 - -11.7) <0.001
Relative Wall Thickness 0.47 (0.15) 0.50 (0.13) -0.03 (-0.07 e 0.007) 0.110
Normal LV geometry 10 (16%) 22 (12%) Control
Eccentric LV hypertrophy 5 (8%) 24 (14%) 0.398 (0.119 e 1.332) 0.129
Concentric LV remodeling 28 (44%) 39 (22%) 1.371 (0.571 e 3.292) 0.480
Concentric LV hypertrophy 21 (33%) 93 (52%) 0.431 (0.181 e 0.999) 0.049

The bold terms and values are those which are statistically significant.
CI ¼ confidence interval; RAB ¼ renin-angiotensin blocker.
* Odds ratios presented for categorical variables, whereas mean difference (SD) presented for continuous variables.

subjects with severe LF AS on RAB treatment have
significantly lower LVMI even after adjustment for con-
founders such as hypertension. There exist several mecha-
nisms that may explain this. RABs have been shown to
reverse LV mass in patients with hypertension.21 In addi-
tion, ACEI may be associated with reduction of aortic valve
calcification.5 This may indirectly result in lowering LV
afterload and thus reduce the LVH. However, we did not
find any difference between aortic valve area and severity
indexes between those with RAB treatment versus those
without.
The safety of RAB in patients with severe AS was
questioned previously as renin-angiotensin blockade may
result in a reduction in systemic vascular resistance, which
may lead to syncope in the presence of fixed LV outflow
obstruction.22 This may explain the low proportion of both
LF and NF severe AS patients in our study who are on RAB.
However, RAB resulted in regression of LVH in animal
models of AS and delayed progression to heart failure.23
Furthermore, clinical data on RAB have demonstrated
reduction of cardiovascular morbidity and mortality in
patients with LVH.24 Indeed, several studies have demon-
strated a significantly lower all-cause mortality and few
cardiovascular events in those on RAB.15
We demonstrate that in LF AS but not in NF AS, RAB
confers its benefits in reversing maladaptive LV remodeling.
1842 The American Journal of Cardiology (www.ajconline.org)

Figure 2. Association between RAB duration and preserved LVMI in low-flow severe aortic stenosis with preserved LVEF. OR ¼ odds ratio. *Siginficant at p <0.05.

Table 2
Univariate analyses identifying clinical and echocardiographic parameters associated with treatment with renin-angiotensin blockers compared with controls in patients
with normal-flow (stroke volume index 35 ml/m2) severe aortic stenosis (aortic valve area <1 cm2) with preserved left ventricular ejection fraction (>50%)
Parameter Univariate analysis

RAB (n¼49) No RAB (n¼137) Mean Difference/Odds Ratio (95%CI)* P-value

Clinical parameters
Age (years) 70.5 (16.7) 71.5 (13.6) -1.0 (-5.8 e 3.8) 0.680
Men 26 (62%) 70 (51%) 1.565 (0.796 e 3.078) 0.192
Ethnicity
Chinese 26 (53%) 86 (63%) Control
Malay 15 (31%) 24 (18%) 1.700 (0.763 e 3.788) 0.192
Indian 5 (10%) 10 (7%) 1.635 (0.513 e 5.214) 0.522
Others 3 (6%) 17 (12%) 0.516 (0.142 e 1.884) 0.406
Hypertension 29 (59%) 80 (59%) 0.938 (0.480 e 1.834) 0.862
Hyperlipidemia 29 (59%) 55 (40%) 1.684 (0.797 e 3.557) 0.169
Diabetes mellitus 28 (34%) 54 (41%) 1.535 (0.788 e 2.993) 0.207
Previous acute myocardial infarction 4 (8%) 16 (11.6%) 0.981 (0.460 e 2.092) 0.999
Echocardiographic parameters
LV diastolic function
Deceleration time (ms) 178.1 (112.7) 157.1 (88.4) 20.9 (-10.3 e 52.3) 0.188
E/A ratio 0.63 (0.40) 0.64 (0.36) 0.07 (-0.15 e 0.13) 0.902
Septal E/e’ ratio 21.1 (17.1) 19.3 (12.3) 1.8 (-3.2 e 6.9) 0.480
Pulmonary artery systolic pressure/mmHg 33.3 (22.9) 32.7 (23.9) 0.7 (-7.1 e 8.4) 0.670
LV systolic function
Left ventricular ejection fraction (LVEF) (%) 63.1 (14.8) 60.6 (18.5) 2.5 (-3.3 e 8.3) 0.395
Stroke volume index (SVI) (ml/m2) 59.7 (22.4) 58.8 (22.0) 1.0 (-6.4 e 8.3) 0.796
Stroke work loss (%) 26.1 (23.6) 24.9 (17.9) 1.2 (-5.3 e 7.6) 0.723
Septal S’ velocity (cm/s) 3.33 (2.4) 3.47 (2.51) -0.14 (-0.96 e 6.7) 0.733
End-systolic wall stress (x 103 dyn/cm2) 106.1 (–38.2) 90.1 (–44.2) 16.1 (1.7 e 30.3) 0.028
Systemic arterial compliance (ACU) 1.23 (0.65) 1.07 (0.66) 0.16 (-0.06 e 0.38) 0.148
Valvuloarterial impedance (mmHg/ml/m2) 2.43 (0.91) 2.43 (1.07) 0.00 (-0.33 e 0.34) 0.988
Aortic valve indices
Aortic valve area (AVA) (cm2) 0.65 (0.28) 0.64 (0.29) 0.01 (-0.09 e 0.11) 0.822
Transaortic mean pressure gradient (mmHg) 31.3 (24.9) 29.9 (19.7) 1.41 (-5.5 e 8.4) 0.690
Aortic valve resistance (dyn s /cm2) 153.7 (23.3) 182.9 (181.0) -29.2 (-88.6 e 30.2) 0.333
LV structure
End-diastolic volume index (ml/m2) 149.0 (51.4) 133.9 (61.8) 15.0 (-4.4 e 34.5) 0.129
Left Ventricular mass index (g/m2) 142.3 (41.3) 147.3 (43.2) -5.0 (-19.3 e 9.2) 0.485
Relative Wall Thickness 0.360.11 0.350.14 0.01 (-0.03 e 0.06) 0.582
Normal LV geometry 5 (10%) 16 (12%) Control
Eccentric LV hypertrophy 32 (65%) 82 (60%) 1.569 (0.544 e 4.523) 0.403
Concentric LV remodeling 1 (2%) 1 (1%) - -
Concentric LV hypertrophy 11 (22%) 38 (28%) 1.216 (0.372 e 3.972) 0.751

The bold terms and values are those which are statistically significant.
CI ¼ confidence interval; RAB ¼ renin-angiotensin blocker.
* Odds ratios presented for categorical variables, whereas mean difference (SD) presented for continuous variable.
 Valvular Heart Disease/Renin-Angiotensin Blockers in Aortic Stenosis 1843

Table 3
Univariate analyses identifying clinical and echocardiographic parameters associated with treatment with angiotensin-converting enzyme inhibitors compared
with angiotensin receptor blockers in patients with low-flow (SVI <35 ml/m2) severe aortic stenosis (aortic valve area <1 cm2) with preserved left ventricular
ejection fraction (>50%)
Parameter Univariate analysis

ACEI (n¼38) ARB (n¼22) Mean Difference/Odds P-value

Ratio (95%CI)*

Clinical parameters
Age (years) 74.18 (9.48) 72.45 (8.97) 1.73 (-3.26 e 6.72) 0.490
Men 19 (50%) 6 (27%) 0.38 (0.12 e 1.17) 0.085
Ethnicity
Chinese 19 (50%) 12 (55%) Control
Malay 8 (21%) 4 (18%) 0.95 (0.22 e 4.07) 0.94
Indian 5 (13%) 2 (9%) 0.75 (0.13 e 4.29) 0.75
Others 6 (16%) 4 (18%) 0.60 (0.08 e 4.76) 0.63
Hypertension 23 (61%) 14 (64%) 1.14 (0.39 e 3.38) 0.81
Hyperlipidemia 24 (63%) 17 (77%) 1.98 (0.60 e 6.55) 0.26
Diabetes mellitus 14 (38%) 17 (77%) 5.49 (1.63 e 18.48) 0.004
Previous acute myocardial infarction 2 (5%) 0 (0%) 0.62 (0.51 e 0.76) 0.27
Echocardiographic parameters
LV diastolic function
Deceleration time (ms) 201.68 (104.61) 202.32 (84.10) -0.63 (-50.18 e 48.91) 0.981
E/A ratio 0.84 (0.37) 0.92 (0.31) -0.08 (-0.28 e 0.12) 0.438
Septal E/e’ ratio 13.00 (9.39) 16.63 (8.14) -3.63 (-8.69 e 1.43) 0.156
Pulmonary artery systolic pressure/mmHg 27.08 (19.93) 27.50 (21.97) -0.42 (-11.08 e 10.67) 0.940
LV systolic function
Left ventricular ejection fraction (%) 65.08 (5.47) 66.45 (5.07) -1.38 (-4.23 e 1.48) 0.339
Stroke volume index (ml/m2) 26.00 (4.59) 26.08 (4.31) -0.08 (-2.49 e 2.33) 0.949
Stroke work loss (%) 24.27 (18.23) 20.17 (11.54) 4.09 (-3.61 e 11.80) 0.292
Septal S’ velocity (cm/s) 5.13 (3.26) 5.66 (2.48) -0.53 (-2.14 e 1.08) 0.516
End-systolic wall stress (x 103 dyn/cm2) 54.78 (17.22) 62.18 (12.84) -7.40 (-15.89 e 1.09) 0.086
Systemic arterial compliance (ACU) 1.02 (0.60) 0.86 (0.33) 0.17 (-0.07 e 0.41) 0.172
Valvuloarterial impedance (mmHg/ml/m2) 5.54 (1.44) 5.98 (1.69) -0.45 (-1.27 e 0.37) 0.282
Aortic valve indices
Aortic valve area (cm2) 0.74 (0.25) 0.74 (0.28) -0.01 (-0.15 e 0.14) 0.940
Transaortic mean pressure gradient (mmHg) 30.78 (19.73) 29.75 (16.18) 1.03 (-8.90 e 10.96) 0.836
Aortic valve resistance (dyn s /cm2) 171.69 (145.72) 149.40 (109.46) 22.29 (-52.68 e 97.27) 0.554
LV structure
End-diastolic volume index (ml/m2) 57.10 (17.09) 55.87 (12.32) 1.23 (-7.09 e 9.57) 0.767
Left Ventricular mass index (g/m2) 110.92 (37.33) 110.95 (22.20) -0.04 (-17.65 e 17.58) 0.997
Relative Wall Thickness 0.46 (0.15) 0.52 (0.09) -0.05 (-0.12 e 0.01) 0.116
Normal LV geometry 6 (16%) 2 (9%) Control
Eccentric LV hypertrophy 3 (8%) 1 (5%) 0.83 (0.13 e 5.35) 0.848
Concentric LV remodeling 14 (37%) 13 (60%) 0.83 (0.07 e 9.69) 0.884
Concentric LV hypertrophy 15 (40%) 6 (27%) 2.32 (0.69 e 7.79) 0.173

The bold terms and values are those which are statistically significant.
ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; CI ¼ confidence interval; RAB ¼ renin-angiotensin blocker.
* Odds ratios presented for categorical variables, whereas mean difference (SD) presented for continuous variables.

This may be related to the concentric remodeling pattern of
hypertrophy (associated with diastolic dysfunction and a
small LV cavity), which is more common observed in LF
than in NF AS.25 Furthermore, LF subjects have higher
valvuloarterial impedance than NF. The renin-angiotensin
system may be more highly activated in the LF group,
and RAB may benefit LF more. Delay in starting ACEI
during the heart’s remodeling process may result in less
beneficial effect on the LV,26 which could partly explain our
results, although we have not ascertained the degree of LV
remodeling in NF versus LF when RABs are initiated.
An inherent limitation is the cross-sectional nature of this
study. Therefore, we are not able to determine causality but
only association between RAB treatment and LV remodel-
ing is determined. In this vein, this study is hypothesis-
generating for a larger prospective study which may
include effects on LVMI and outcome data. The subjects’
compliance to RAB treatment was not individually
confirmed. However, prescription was collected as reflected
from the electronic records. Another limitation of this study
was that the dose of ACEI or ARB was not obtained. We
were hence unable to examine a dose-response relation of
RABs on LV remodeling.
Further studies are warranted to look at the major adverse
event outcomes and survival benefit with RAB therapy.
These prospective studies are nevertheless difficult to
1844 The American Journal of Cardiology (www.ajconline.org)

Table 4
Univariate analyses identifying clinical and echocardiographic parameters associated with treatment with angiotensin converting enzyme inhibitors compared
with angiotensin receptor blockers in all patients with severe aortic stenosis (aortic valve area <1 cm2) with preserved left ventricular ejection fraction (>50%)
Parameter Univariate analysis

ACEI (n¼46) ARB (n¼34) Mean Difference/Odds P-value

Ratio (95%CI)*

Clinical parameters
Age (years) 72.83 (11.19) 70.82 (10.51) 2.00 (-2.91 e 6.92) 0.419
Men 24 (52%) 13 (38%) 0.57 (0.23 e 1.40) 0.216
Ethnicity
Chinese 24 (52%) 20 (59%) Control
Malay 9 (20%) 5 (15%) 1.00 (0.27 e 3.77) 1.00
Indian 7 (15%) 4 (12%) 0.67 (0.13 e 3.35) 0.62
Others 6 (13%) 5 (15%) 0.69 (0.12 e 3.78) 0.67
Hypertension 27 (59%) 23 (68%) 1.47 (0.58 e 3.72) 0.41
Hyperlipidemia 28 (61%) 24 (71%) 1.54 (0.60 e 3.97) 0.37
Diabetes mellitus 17 (38%) 25 (72%) 3.90 (1.49 e 10.24) 0.005
Previous acute myocardial infarction 2 (4%) 1 (3%) 0.67 (0.058 e 7.67) 0.74
Echocardiographic parameters
LV diastolic function
Deceleration time (ms) 203.63 (103.71) 196.18 (101.71) 7.45 (-38.86 e 53.77) 0.750
E/A ratio 0.86 (0.40) 1.02 (0.55) -0.16 (-0.380 e 0.070) 0.173
Septal E/e’ ratio 15.11 (11.81) 16.25 (9.50) -1.14 (-6.31 e 4.02) 0.661
Pulmonary artery systolic pressure/mmHg 27.50 (18.85) 29.91 (22.74) -2.41 (-11.68 e 6.86) 0.606
LV systolic function
Left ventricular ejection fraction (%) 64.50 (5.21) 62.94 (7.47) 1.56 (-1.44 e 4.55) 0.301
Stroke volume index (ml/m2) 28.51 (7.08) 32.41 (9.65) -3.90 (-7.82 e 0.016) 0.051
Stroke work loss (%) 26.10 (23.11) 26.51 (17.68) -0.42 (-9.866 - 9.03) 0.931
Septal S’ velocity (cm/s) 4.94 (3.06) 4.67 (2.73) 0.27 (-1.05 e 1.58) 0.689
End-systolic wall stress (x 103 dyn/cm2) 58.22 (–18.03) 70.15 (–18.84) -11.93 (-20.32 e 3.54) 0.006
Systemic arterial compliance (ACU) 1.13 (0.71) 0.97 (0.46) 0.16 (-0.17 e 0.44) 0.251
Valvuloarterial impedance (mmHg/ml/m2) 5.14 (1.62) 4.93 (2.00) 0.20 (-0.60 e 1.01) 0.620
Aortic valve indices
Aortic valve area (cm2) 0.75 (0.23) 0.72 (0.25) 0.030 (-0.082 e 0.14) 0.599
Transaortic mean pressure gradient (mmHg) 31.96 (21.82) 36.49 (21.97) -4.53 (-14.39 e 5.32) 0.363
Aortic valve resistance (dyn s /cm2) 170.73 (142.57) 188.81 (158.36) -18.09 (-87.24 e 51.07) 0.604
LV structure
End-diastolic volume index (ml/m2) 61.53 (18.98) 60.41 (18.06) 1.12 (-7.26 e 9.49) 0.791
Left Ventricular mass index (g/m2) 115.09 (39.13) 116.36 (22.99) -1.27 (-16.51 e 13.97) 0.868
Relative Wall Thickness 0.45 (0.14) 0.46 (0.13) -0.01 (-0.07 e 0.05) 0.691
Normal LV geometry 8 (17%) 3 (9%) Control
Eccentric LV hypertrophy 7 (15%) 8 (24%) 0.64 (0.14 e 2.97) 0.567
Concentric LV remodeling 14 (30%) 13 (38%) 1.94 (0.54 e 6.99) 0.309
Concentric LV hypertrophy 17 (37%) 10 (29%) 1.58 (0.53 e 4.68) 0.41

The bold terms and values are those which are statistically significant.
ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; RAB ¼ renin-angiotensin blocker; CI ¼ confidence interval.
* Odds ratios presented for categorical variables, whereas mean difference (SD) presented for continuous variables.

perform because definitive therapy of valve replacement,
either by open surgery or percutaneous approach, results
in LVH regression from afterload relief and lowers
adverse events.27,28
Disclosures
The authors have no conflicts of interest to disclose.
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