International Journal of Cardiology 167 (2013) 67–72

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International Journal of Cardiology

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A comprehensive assessment of cardiac structure and function in patients with

treated malignant phase hypertension: The West Birmingham Malignant
Hypertension project
Alena Shantsila, Girish Dwivedi, Eduard Shantsila, Mehmood Butt, D. Gareth Beevers, Gregory Y.H. Lip ⁎
University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Background: Previous studies have confirmed that cardiac structural and functional abnormalities exist in pa-
Received 14 September 2011 tients with malignant hypertension (MHT). The effect of long-term blood pressure control in MHT patients
Received in revised form 28 October 2011 on cardiac structure and function is still unknown.
Accepted 27 November 2011 Methods: We performed detailed left ventricle (LV) assessment using two-dimensional (2DE) and three-
Available online 20 December 2011
dimensional (3DE) echocardiography, and tissue Doppler imaging (TDI) in patients with previous MHT
(but now in stable phase) who were compared with patients with treated ‘high risk’ hypertension (HHT,
Keywords:
Malignant hypertension
but non-MHT) and healthy controls (HC). Vasodilator stress myocardial contrast echocardiography (in addi-
Tissue Doppler imaging tion to wall motion analysis) was used to exclude significant coronary artery disease, as part of our compre-
Left ventricular function hensive echocardiographic assessment. Septal and posterior wall thickness, LV mass index, LV volumes and
Three-dimensional echocardiography ejection fraction, mitral valve inflow indices (E, A) mitral annular velocity (S, E′) and left atrial volume
index (LAVI), were calculated using 2DE, 3DE, and TDI. MHT patients had good blood pressure control for
an average of 144 months.
Results: A total of 95 subjects (MHT = 15; HHT and HC = 40 each) were studied. Both posterior and septal
wall thickness were significantly higher in the MHT and hypertensive groups compared to normal controls
with no difference between MHT and HHT. No significant difference in LV ejection fraction was found be-
tween the 3 groups. Increased LAVI (p b 0.05 MHT vs. HC and HHT vs. HC), reduced ‘S’ velocity on TDI
(p = 0.05 MHT vs. HC and vs.HHT, p b 0.001 HHT vs. HC) and higher E/E′ (p = 0.029 HHT vs. HC) and lower
E/A ratio (p = 0.001 MHT vs. HC, p b 0.001 HHT vs. HC) values were detected in the two hypertensive groups.
Conclusion: Despite long-term good blood pressure control, MHT patients have persistent structural and func-
tional changes in LV function on echocardiography, comparable to that seen in HHT.
© 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Malignant hypertension (MHT) is the most extreme form of hyper-
tension and is clinically defined by the presence of high blood pressure
(BP) in association with bilateral retinal haemorrhages and/or exudates,
with or without papilloedema [1–3]. In the past, MHT was strongly as-
sociated with severe multi-organ damage with grim prognosis with
an 80% two-year mortality, if it was left untreated [3–5]. Despite good
BP control achieved with modern antihypertensive therapy, MHT con-
tinues to remain an important clinical entity and significantly contrib-
utes to the development of stroke, myocardial infarction, heart failure
and renal failure [6]. In a large prospective analysis, we have previously,
shown that the demography and number of new cases of MHT has not
changed substantially over the past 40 years, although the prognosis
has greatly improved [5,6].
⁎ Corresponding author. Tel.: + 44 121 507 5080; fax: + 44 121 507 5907.
E-mail address: g.y.h.lip@bham.ac.uk (G.Y.H. Lip).
We have recently shown that despite good long-term blood pres-
sure control, patients with MHT have persistent macro- and micro-
vascular dysfunction which may be responsible for MHT recurrence
in some patients [7]. Given the persistence of endothelial abnormali-
ties it is possible that adverse cardiac remodelling observed early
after the diagnosis of MHT may not regress even after effective
blood pressure control. However, there are very few studies which
have assessed long term cardiac consequences of treated MHT [8,9].
Indeed, previous studies have had major limitations, such as a short
follow up duration and absence of use of three-dimensional echocar-
diography (3DE), the latter being considered the current gold stan-
dard echocardiographic technique for evaluating left ventricular
systolic function [8,9]. Moreover, in one study, the ‘control group’
was composed of healthy normotensive individuals rather than pa-
tients with non-malignant essential hypertension, which precludes
speculations on MHT-specific cardiac changes [8].
In the present study, we hypothesised that cardiac functional and
structural changes would still be present in patients with previously
diagnosed MHT and good long-term BP control, compared to controls.

0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2011.11.077

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68 A. Shantsila et al. / International Journal of Cardiology 167 (2013) 67–72
To test this hypothesis, we performed a comprehensive assessment
using two-dimensional echocardiography (2DE) with tissue Doppler
imaging (TDI) and 3DE in patients with previous MHT and compared
the results with patients having high-risk hypertension (HHT, but
non-MHT, as “disease controls”) and normotensive healthy controls.
Of note, vasodilator stress myocardial contrast echocardiography (in
addition to wall motion analysis) was also used in all study groups,
to non-invasively exclude significant coronary artery disease, as part
of our comprehensive echocardiographic assessment.
2. Methods
We recruited consecutive eligible patients with a prior history of confirmed MHT. The
diagnosis of MHT was clinically defined by severe hypertension with the characteristic oc-
ular fundal changes detected by fundoscopy and retinal photography: bilateral retinal
haemorrhages, cotton wool spots or exudates, with or without papilloedema [1,2,5]. All
MHT patients were clinically stable and treated for at least 12 months before recruitment
(average time since diagnosis 144 ± 108 months, range 12–353 months) and under
regular outpatient follow up. As expected, the highest registered systolic (mean 238 ±
20.8 mm Hg) and diastolic (mean 157 ± 19.2 mm Hg) BP recordings were at time of initial
MHT presentation and with the initiation of effective antihypertensive treatment, both
mean systolic and diastolic BP readings demonstrated good BP control, with values of
138.1 ± 10.1 mm Hg and 88.0± 6.2 mm Hg, respectively. Secondary hypertension was ex-
cluded in all MHT patients after careful clinical and laboratory workup, as appropriate.
Initially we identified a group of 101 with MHT from our MHT database who met
the study inclusion criteria [7]. Of these, 40 patients undergoing regular outpatient fol-
low up did not have exclusion criteria specified below and were invited to take part in
the study — only 15 patients consented to take part, which fulfilled our a priori power
calculation (see below, n = 15 needed in the MHT group). The relatively small proportion
of the patients consented for the study was mainly due to envisage of stress myocardial
contrast echocardiography to exclude coronary artery disease (a strong confounding
factor for adverse cardiac remodelling) as part of the study protocol [7]. The study was
approved by the local research ethics committee and written informed consent has
been obtained from all participants.
Patients with MHT were compared with 40 age and consecutively recruited sex
matched patients with treated HHT as ‘disease controls’, and 40 age and sex matched
healthy normotensive subjects (‘healthy controls’). HHT was defined by the presence
of established hypertension (but non-MHT) with one or more of the following cardio-
vascular risk factors: left ventricle (LV) hypertrophy [using Sokolow-Lyon or Cornell
voltage criteria on 12-lead electrocardiogram (ECG)], age > 55 years, peripheral vascu-
lar disease, or with a known family history of coronary artery disease [10,11]. Broadly
similar criteria for defining HHT have been used in a contemporary clinical trial [11].
All healthy control participants were recruited from accompanying relatives/carer of
patients attending our outpatient clinics and colleagues working in hospital. They
were defined as ‘healthy’ by careful history, clinical examination, baseline blood
tests, ECG and transthoracic echocardiography.
We excluded subjects with known underlying renal, renovascular or adrenal
causes for their hypertension. Other exclusion criteria were coronary artery disease,
valvular heart disease, left ventricular dysfunction (ejection fraction b 50%), diabetes
mellitus, liver disease, serum creatinine > 200 μmol/L, malignancy, recent (b 3 months)
arterial or venous thromboembolic disease, active infections and/or a history of inflam-
matory or connective tissue disorders.
All study subjects abstained from smoking, alcohol, tea and coffee for 24 h prior to the
study. Hypertensive subjects were advised to omit their medications on the study day, as
prolonged treatment omission was deemed unethical. All scans were performed in a
quiet, darkened, temperature controlled room after patient rested for 15–20 min.
2.1. Echocardiography
All subjects underwent M-mode, 2DE, TDI and 3DE using Phillips iE33 ultrasound
machine (Bothel, WA, USA). Modern off-line QLAB software [Xcelera, Phillip (iE33) Ul-
trasound Quantification Module, USA] was used for quantification of LV function. The
inter- and intra-observer variability for echocardiography parameters was assessed
(n = 10) and calculated as 11% and 6.8%, respectively.
2.1.1. M-mode, TDI and 2D echocardiography
Resting images of parasternal long axis, short axis (at aortic valve level, mitral leaf-
let level, papillary muscle level and apex), apical 4-chamber, apical 5-chamber, apical
2-chamber and apical 3-chamber views were acquired during transthoracic echocardi-
ography. The relevant American Society of Echocardiography (ASE) guideline recom-
mendations were used during M-mode, TDI and 2DE image acquisition and
calculation of various parameters [12–14]. Area–length method was used to calculate
left atrial (LA) volume on 2DE. LA volume was indexed to body surface area to obtain
LA volume index (LAVI).
2.1.2. 3D echocardiography
3DE was performed in apical views. Three-dimensional LV and LA images were
taken by wide-angled acquisition (full-volume method) during end expiration. Off-
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line QLAB software was used for displaying and quantifying 3DE images. The LV and
LA volumes were measured using a semiautomatic tracing of endocardial border at
systole and diastole at each frame during one cardiac cycle; however, automatic trac-
ings were manually modified if necessary [15]. LA appendage and pulmonary vein ap-
erture were excluded from LA volume calculations.
2.1.3. Left ventricular parameters
Septal wall thickness, posterior wall thickness and LV mass index (all obtained on
M-mode) were used to assess LV structural parameters. LV ejection fraction (LVEF), LV
end-diastolic volume (EDV) and LV end-systolic volume (ESV) were assessed using the
modified Simpson's biplane method, M-mode and 3DE. LV volumes, LVEF and mitral
annular septal systolic velocity (S) were used to assess LV systolic function. Acute dia-
stolic functional assessment was performed by evaluating E/A (mitral inflow indices),
E/E′ (early mitral inflow velocity/TDI derived early septal mitral annular diastolic ve-
locity) and isovolumic relaxation time (IVRT). LAVI provided a measure of chronic di-
astolic function.
2.2. Statistical analysis
Data are expressed as mean ± standard deviations (SD) for normally distributed
data; or median and inter-quartile range (IQR) for descriptive and/or non-normally
distributed data. Data among three groups (MHT, HHT and healthy controls) were ana-
lysed by one way analysis of variance (ANOVA). Log transformation of non-normally
distributed variables was performed prior to ANOVA. A post-hoc Tukey test was per-
formed to assess inter-group differences, where appropriate. Correlation analysis was
performed by Pearson method for normally-distributed parameters and Spearman
method for non-normally distributed variables. A p-value of b 0.05 was considered sta-
tistically significant. SPSS 17 (SPSS, Inc, Chicago, Illinois, USA) statistical software was
used to perform the statistical analyses.
2.3. Power calculation
The power calculation was based on our previous published results on LV end di-
astolic diameter (EDD), which were 4.8 ± 0.8 cm in both MHT and controlled hyper-
tension groups [9]. Accordingly, in order to detect a 0.5 SD difference in the
parameter (i.e. a difference in 0.4 cm or above) a minimum of 15 participants per
group are needed provided that the observed SD values are within the previously
reported SD values (i.e., 0.8 cm or less).
3. Results
Study subjects were comparable in age, sex and body mass index
between the three groups (Table 1). BP was similar in the two-
hypertensive groups (MHT and HHT), both of which had significantly
higher systolic BP levels when compared with healthy subjects
(p b 0.05). The two hypertensive groups had a similar profile of car-
diovascular risk factors. As expected, there were significant differ-
ences in antihypertensive treatment. Although the usage of beta-
blockers and inhibitors of the renin–angiotensin system was similar
in the two hypertensive groups, significantly higher proportions of
MHT patients were receiving calcium channel blockers (p = 0.008)
and diuretics (b0.001) compared to HHT subjects.
3.1. Left ventricular structure
The patients with MHT and HHT had significantly higher interven-
tricular septal (p = 0.001 and p b 0.001, respectively) and posterior
wall thickness (p = 0.04 and p = 0.001, respectively) and also higher
LV mass index (both p = 0.01) compared to healthy controls
(Table 2). There were no significant differences in these three param-
eters between the MHT and HHT groups.
3.2. Left ventricular systolic function
Although, 2DE assessed ESV and EDV were significantly increased
in MHT compared with HHT (p = 0.04 and p = 0.04, respectively); no
significant differences were detected in these parameters using either
M-mode or 3D-E (Table 2). No significant difference in LVEF was
found between the study groups with 2DE, M-mode or 3DE tech-
niques. Septal systolic velocity (S′) was significantly reduced in the
MHT and HHT groups compared with healthy controls (p = 0.05 and
 A. Shantsila et al. / International Journal of Cardiology 167 (2013) 67–72 69

Table 1
Demographic and clinical characteristics of the study groups.

Malignant hypertension ‘High risk’ hypertension Healthy controls p

n 15 40 40
Age 53.1 ± 12.9 48.6 ± 11.2 47.1 ± 8.26 0.17
Male, % 73 65 68 0.85
Body mass index, kg/m2 29.8 ± 5.56 31.5 ± 6.43 29.9 ± 6.76 0.50
Systolic BP, mm Hg 149 ± 20.3† 151 ± 20.5‡ 135 ± 15.3 0.001
Diastolic BP, mm Hg 87.7 ± 10.5 85.2 ± 9.32 81.6 ± 9.60 0.08
Smoking, % 40 42 35 0.83
Glucose, mmol/l 5.05 (4.90–5.78) 5.00 (4.80–5.70) 5.10 (4.70–5.40) 0.78
Haemoglobin, dg/l 14.9 ± 1.09⁎ 13.9 ± 1.39 14.4 ± 1.22 0.027
Leukocytes, × 106/ml 7.76 ± 2.20 7.10 ± 1.89 6.85 ± 1.54 0.26
Platelets, × 109/ml 264 ± 101 245 ± 74.7 225 ± 56.4 0.18
Creatinine, μmol/l 118 ± 39.9⁎,† 86.6 ± 19.9 78.1 ± 16.6 0.001
Urea, mmol/l 8.52 ± 3.55⁎,† 5.64 ± 1.73 5.19 ± 1.03 0.001
Total cholesterol, mmol/l 4.84 ± 0.79 5.06 ± 1.04 5.49 ± 1.07 0.06
Medications
ACE inhibitors/ARB 14 (93%) 35 (88%) – 0.54
Calcium channel blockers 12 (80%) 16 (40%) – 0.008
Beta blockers 4 (27%) 8 (20%) – 0.59
Aspirin 2 (13%) 17 (42%) – 0.03
Diuretics 9 (60%) 5 (12%) b0.001
Statins 8 (53%) 30 (75%) 0.12

Values expressed as mean ± standard deviation or median (Inter quartile range).

†
p b 0.05 MHT vs. healthy controls groups.
‡
p b 0.05 HHT vs. controls groups (none of the recruited patients had hyperlipidaemia).
⁎ p b 0.05 MHT vs HHT groups.

p b 0.001, respectively) (Fig. 1); the S values were higher in MHT than The mean LAVI obtained with 2DE, a surrogate for chronic diastol-
in HHT (p = 0.05). ic dysfunction was significantly increased to similar extent in MHT
and HHT compared with normal controls (p = 0.049, and p b 0.001,
respectively). LAVI obtained with 3DE was increased only in the
3.3. Left ventricular diastolic function HHT group (p b 0.001 compared with healthy controls) (Table 2).

Of the parameters of acute diastolic function, the E/A ratio was
suggestive of significant diastolic impairment in both hypertensive
groups compared to healthy subjects (p ≤ 0.001 for both) (Table 2)
(Fig. 2). No difference was seen in E/A between the MHT and HHT
groups. As compared to healthy controls, E/E′ and IVRT were only sig-
nificantly increased in the HHT (p = 0.03, and p = 0.005, respective-
ly), but not in the MHT group (Table 2).
3.4. Correlations
In the MHT group, age negatively correlated with LVEF (2DE, r =
−0.58, p = 0.03), and body mass index positively correlated with
3DE EDV (r = 0.77, p = 0.002) and ESV (r = 0.81, p = 0.001). The du-
ration of treatment negatively correlated with 2DE EF (r = − 0.60,
p = 0.038) and LV posterior wall thickness (r = −0.60, p = 0.037).

Table 2
Echocardiographic parameters of cardiac geometry and functions.

Malignant hypertension ‘High risk’ hypertension Healthy controls p

Parameters of LV structure and systolic function

Interventricular septum, cm 1.22 ± 0.13† 1.17 ± 0.29‡ 0.95 ± 0.15 b0.001
LV posterior wall, cm 1.19 ± 0.18† 1.17 ± 0.22‡ 0.99 ± 0.17 0.001
LV mass index, g/m2 118 ± 20.2† 121 ± 36.1‡ 99.0 ± 31.5 0.014
M mode EDD, cm 4.49 ± 0.40 4.71 ± 0.64 4.78 ± 0.68 0.34
ESD, cm 2.89 ± 0.49 2.92 ± 0.57 2.95 ± 0.53 0.93
EF, % 66.4 ± 9.96 67.6 ± 8.11 68.1 ± 8.48 0.83
2D-Echo EDV, ml 101.0 ± 32.0⁎ 81.6 ± 19.6 92.0 ± 27.2 0.04
ESV, ml 39.6 ± 14.5⁎ 28.6 ± 12.5 33.9 ± 14.6 0.037
EF, % 60.9 ± 6.64 66.4 ± 8.54 64.1 ± 8.05 0.097
3D-Echo EDV, ml 96.9 ± 21.4 86.8 ± 23.5 83.6 ± 24.8 0.23
ESV, ml 35.8 ± 11.5 28.3 ± 9.80 28.8 ± 11.5 0.091
EF, % 63.5 ± 6.41 67.4 ± 6.60 65.9 ± 6.84 0.20
S septal, cm/s 6.86 ± 1.37⁎† 5.90 ± 1.10‡ 7.23 ± 1.37 b0.001

Parameters of LV diastolic function

E/A 0.87 (0.67–1.28)† 0.90 (0.76–1.06)‡ 1.48 (1.20–1.83) b0.001
E/E′ 8.83 (7.11–10.9) 9.01(8.09–11.3)‡ 8.05 (6.69–9.53) 0.043
IVRT, ms 0.08 ± 0.03 0.10 ± 0.03‡ 0.08 ± 0.02 0.006
LAVI (2D-Echo), ml/m2 22.6 ± 4.60† 24.2 ± 5.79‡ 18.5 ± 5.01 b0.001
LAVI (3D-Echo), ml/m2 21.2 ± 3.83 23.6 ± 5.36‡ 18.0 ± 4.43 b0.001

IVRT, isovolumic relaxation time, LAVI, left ventricular volume index, LV, left ventricular, EDD, end diastolic diameter, EDV, end diastolic volume, EF, ejection fraction, ESD, end
systolic diameter, ESV, end systolic volume.
†
p b 0.05 MHT vs. healthy controls (0.05 for S septal).
‡
p b 0.05 HHT vs. healthy controls.
⁎ p b 0.05 MHT vs. HHT (p = 0.05 for S septal).

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70 A. Shantsila et al. / International Journal of Cardiology 167 (2013) 67–72
P=0.05
P=0.05 P<0.001
Fig. 1. Septal systolic velocity in the study groups. MHT, malignant hypertension, HHT,
high risk hypertension, HC, healthy controls.
There were no significant correlations between BP, creatinine values
and any echocardiographic parameters (p = NS).
In the HHT group, body mass index positively correlated with 3DE
EDV (r = 0.38, p = 0.024), 2DE EDV (r = 0.43, p = 0.008), EDD
(r = 0.37, p = 0.027), ESD (r = 0.46, p = 0.005), IVS (r = 0.36,
p = 0.036), LVMI (r = 0.37, p = 0.03) and negatively correlated with
M-mode LVEF (r = −0.38, p = 0.026).
4. Discussion
The present study demonstrates for the first time that in patients
with long-term treated and adequately controlled MHT, many param-
eters of cardiac geometry and function are adversely affected and are
comparable to those seen in patients with HHT with similar BP values.
Of note, the study participants were free of other associated con-
founders such as coronary artery disease. Indeed, this is the first
study which has used a robust and well validated state of the art tech-
nique, vasodilator stress myocardial contrast echocardiography (in
addition to wall motion analysis) to exclude coronary artery disease,
as part of the comprehensive echocardiographic assessment.
Despite the trend of the declining incidence of MHT after the
widespread introduction of modern antihypertensive agents, MHT
P=0.001
NS
P<0.001
Fig. 2. E/A ratio (mitral inflow index) in the study groups. MHT, malignant hyperten-
sion, HHT, high risk hypertension, HC, healthy controls.
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represents the most severe form of hypertension and still represents
an important clinical entity [5,16]. Although features of cerebral and
renal impairment are leading manifestations of MHT, heart failure
may be a presenting feature of new onset MHT. In a large cohort of
patients with MHT diagnosed between 1970 and 1993, the incidence
of heart failure has been reported to be around 8% [5,17]. In the pre-
sent study, all patients had preserved LVEF despite a median 12-
year history of MHT, and this was not different from the values seen
in both control groups. These findings appear similar to observations
of Gosse et al. who used global longitudinal strain to demonstrate re-
covery of LV function with treatment in MHT patients albeit with
short follow-up [8]. As previously mentioned, their control group
composed of healthy normotensive individuals rather than patients
with non-malignant hypertension, and thus MHT-specific cardiac
changes are difficult to speculate. Previously, Nadar et al. showed a
deterioration in LVEF in MHT based on 2DE, perhaps due to worse
BP control in patients recruited in that study [9]. Also, the only
study showing the evolution of cardiomyopathy in MHT was pub-
lished about three decades ago, at time when prognosis in these pa-
tients was extremely poor [18].
Some discrepancy in LV size in the groups has been observed be-
tween different echocardiographic methods (i.e., 2DE and 3DE). An
increased LV volume was present on 2DE, but not on 3DE. This is like-
ly to reflect the specific pattern of LV remodelling, which can be more
comprehensively measured by 3DE approach,. Accordingly, whilst a
different pattern of LV remodelling between MHT and HHT may
lead to increased LV measurements in certain dimensions (assessed
by 2DE), the total LV volumes (accurately assessed by 3DE) may be
similar in MHT and HHT. Indeed, 3DE in which no geometrical as-
sumptions are made is considered the current gold standard tech-
nique of LV volume assessment [19].
Features of cardiac damage/compensatory remodelling are typical
of new onset MHT [8]. We have recently shown that despite good
long-term blood pressure control, patients with MHT have persistent
macro- and micro-vascular dysfunction which may be responsible for
MHT recurrence in some patients [7]. LV hypertrophy in new onset
MHT may at least partly reflect an adaptive response to persistently
raised BP, but its presence is associated with unfavourable prognosis
[5]. Indeed, the quality of BP control at follow-up has a direct and
strong impact on prognosis in MHT patients [5]. In this study, we
have shown that patients with controlled MHT have similar degree
of LV hypertrophy to those with HHT, in contrast to previous observa-
tions made in a cohort of MHT patients with less rigorous BP control
[9]. Similar to the previous report, there was no correlation between
BP values and the cardiac echocardiographic measures [8]. Although
we have not seen any relationship between creatinine levels and car-
diac changes, patients with severe impairment of renal function were
excluded from this study.
Our findings in patients with long-term history of MHT are com-
plimentary to those recently reported by Gosse et al. who reported
that cardiac changes seen at MHT presentation tend to resolve during
short-term and medium-term follow-up [8]. Nonetheless, we have
added to the existing knowledge on the pattern of cardiac changes
in the patients with good BP control compared to previous report
from MHT patients with only suboptimal BP control achieved [9].
4.1. Left ventricular diastolic function
Our study has shown deranged indices of acute diastolic function
in hypertension patients compared to healthy subjects. The decreased
E/A ratio reflects impaired early LV filling during diastole, suggesting
that in addition to impaired systolic function, there may be impaired
diastolic function as well. These findings are consistent with other
studies [9].
LAVI has been considered as the ‘morphophysiologic expression’
of chronic diastolic dysfunction, reflecting the duration and the
 A. Shantsila et al. / International Journal of Cardiology 167 (2013) 67–72
P=0.049
NS P<0.001
Fig. 3. LAVIs in the study groups. LAVI, left ventricular volume index (2DE), MHT, ma-
lignant hypertension, HHT, high risk hypertension, HC, healthy controls.
severity of increased LA pressure. Indeed, we found a greater LAVI, on
both 2DE (Fig. 3) and 3DE in the hypertensive groups. An enlarged LA
is an independent risk factor for atrial fibrillation and other cardiovas-
cular events such as heart failure and mortality [20–22]. Thus, ours is
the first study which has estimated the LAVI in MHT patients by 3DE,
a technique considered more accurate (as it takes into account eccen-
tric LA enlargement) and faster than 2DE based methods [23].
The correlation analysis indicates that an efficient prolong antihy-
pertensive therapy in MHT was associated with regression of LV hy-
pertrophy but could not stop a decline in LV contractility. The latter
finding might reflect ageing of the population or other less known
mechanisms presumably triggered during acute phase MHT which
are persistent despite the treatment (and possibly similar to persis-
tent endothelial dysfunction, as reported previously) [7].
4.2. Limitations
This study is limited by its cross-sectional design and the limited
number of patients due to relative rarity of MHT, and our very careful
exclusion of many patients with concomitant coronary artery disease,
diabetes and significant renal impairment (which is so typical amongst
the MHT population). However the size of the study groups was suffi-
cient to detect the persistent differences in endothelial function in the
same population [7]. Such careful selection of the study patients was
necessary to reduce any bias that could have been introduced by
major clinical confounders know to adversely affect endothelial func-
tion. As discussed above, many patients declined participation due to
the need for stress myocardial contrast echocardiography. However,
sufficient numbers of patients were still successfully recruited in the
MHT group to fulfilment of our a priori power calculation.
The average duration of MHT prior the recruitment was 144 months
(as they were followed up carefully in our clinic) but the duration of hy-
pertension in the HHT group is less well defined, as many patients could
not specify the exact number of years with diagnosed hypertension and
in contrast to MHT patients, many were not routinely followed up in our
specialist hypertensive clinic but by their family physicians. However,
the subjects in the HHT group had at least 3 years history of prior hyper-
tension. Also, given that an exclusion criterion was a serum creatinine of
≥200 μmol/l (as kidney dysfunction could have been a confounding
factor for cardiac remodelling and also use of ultrasound contrast
agent is contraindicated in patients with significant renal dysfunction),
some patients with MHT still had mildly increased creatinine levels (but
b200 μmol/l) leading to statistically higher creatinine values in MHT pa-
tients than in the two control groups. Thus, the effect of (mild) adverse
renal (dys)function on cardiac structure and function in the MHT
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71
patients has not been completely excluded altogether in our study,
but the introduction of even stricter exclusion criteria would have re-
duced the study population even further.
5. Conclusions
In conclusion, patients with stable MHT with good long-term
blood pressure control have significant cardiac hypertrophy, impaired
relaxation and dilated left atria compared to normotensive subjects.
These findings would indicate ongoing cardiac remodelling despite
antihypertensive therapy and warrant prompt recognition and early
treatment of this condition.
Acknowledgements
‘The authors of this manuscript have certified that they comply
with the Principles of Ethical Publishing in the International Journal
of Cardiology’. Dr. Alena Shantsila was supported by a 2008 Interna-
tional Fellowship from the Lancet.
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