Circulation Journal

Ofcial Journal of the Japanese Circulation Society

http://www. j-circ.or.jp
sessed by ECG for cardiac events in the general Japanese popu-
lation,
2
and echocardiographically assessed LVH strongly
predicts cardiovascular events in hypertensive patients.
3
Fur-
thermore, reduction of LVH is related to favorable outcomes,
4

so LVH may become an important therapeutic target in hyper-
tensive patients.
Article p ????
It is not easy to defne the mechanism of hypertrophy in
he average blood pressure (BP) level has certainly
decreased in Japan since 1960,
1
but the prevalence of
hypertension (HT) may be on the rise in the next 23
decades. When considering national healthcare costs, the treat-
ment of HT and prevention of related diseases is crucial. The
target of treatment is to lower BP in patients with HT, primar-
ily in order to avoid cardiovascular events. Left ventricular
hypertrophy (LVH) is a compensatory reaction to HT that causes
myocardial ischemia and diastolic dysfunction, consequent heart
failure. There is a report of the predictive power of LVH as-
T
The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society.
Received September 23, 2014; accepted September 23, 2014; released online October 6, 2014
Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
Mailing address: Tohru Masuyama, MD, PhD, FACC, Cardiovascular Division, Department of Internal Medicine, Hyogo College of
Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan. E-mail: masuyama@hyo-med.ac.jp
ISSN-1346-9843 doi: 10.1253/circj.CJ-14-1049
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
Left Ventricular Hypertrophy as a Target of
Treatment in Patients With Hypertension
Akiko Goda, MD, PhD; Tohru Masuyama, MD, PhD
Figure. Signaling pathways involved in the development of left ventricular hypertrophy. AnII, angiotensin II; DAG, diacylglycerol;
ERK, extracellular regulated kinase; ET1, endothelin 1; FAK, tyrosine-kinase and focal adhesion kinase; IP3, inositol triphosphate;
IRS, insulin-receptor substrate; MAPK, mitogenic-activating protein kinase; mTOR, mammalian target of rapamycin; NE, norepi-
nephrine; NFAT, nuclear factor of activated T cell; PI3K, phosphatidylinositol 3 kinase; PLC, phospholipase C; Shc, SRC homol-
ogy and collagen protein; Src, steroid receptor coactivator; TLCC, type L calcium channel.
EDITORIAL
Advance Publication by-J-STAGE
GODA A et al.
cardiography.
14,15
Cardiac hypertrophy is induced by not only HT but also
valvular disease, diabetes, ischemic heart disease, and so on,
and it is an important predictor by itself irrespective of the
cause. HT is the most frequent cardiac disease in clinical prac-
tise, and LVH is an important target in the treatment of HT.
The most important thing is to lower BP strictly for the pre-
vention of cardiovascular events and the reduction of LVH.
However, the different effects of the medications on reducing
LVH should be taken into consideration when treating hyper-
tensive patients with LVH.
References
1. Miura K, Nagai M, Ohkubo T. Epidemiology of hypertension in
Japan: Where are we now? Circ J 2013; 77: 2226 2231.
2. Ishikawa J, Ishikawa S, Kario K. Levels of cornell voltage and cor-
nell product for predicting cardiovascular and stroke mortality and
morbidity in the general Japanese population. Circ J 2014; 78:
465 475.
3. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Rela-
tion of left ventricular mass and geometry to morbidity and mortal-
ity in uncomplicated essential hypertension. Ann Intern Med 1991;
114: 345 352.
4. Pierdomenico SD, Cuccurullo F. Risk reduction after regression of
echocardiographic left ventricular hypertrophy in hypertension: A
meta-analysis. Am J Hypertens 2010; 23: 876 881.
5. Devereux RB, Palmieri V, Sharpe N, De Quattro V, Bella JN, de
Simone G, et al. Effects of once-daily angiotensin-converting en-
zyme inhibition and calcium channel blockade-based antihyperten-
sive treatment regimens on left ventricular hypertrophy and diastolic
flling in hypertension: The Prospective Randomized Enalapril Study
Evaluating Regression of Ventricular Enlargement (PRESERVE)
trial. Circulation 2001; 104: 1248 1254.
6. Terpstra WF, May JF, Smit AJ, de Graeff PA, Havinga TK, van den
Veur E, et al. Long-term effects of amlodipine and lisinopril on left
ventricular mass and diastolic function in elderly, previously un-
treated hypertensive patients: The ELVERA trial. J Hypertens 2001;
19: 303 309.
7. Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE.
A meta-analysis of the effects of treatment on left ventricular mass
in essential hypertension. Am J Med 2003; 115: 41 46.
8. Devereux RB, Dahlof B, Gerdts E, Boman K, Nieminen MS,
Papademetriou V, et al. Regression of hypertensive left ventricular
hypertrophy by losartan compared with atenolol: The Losartan Inter-
vention For Endpoint reduction in hypertension (LIFE) trial. Circu-
lation 2004; 110: 1456 1462.
9. Meredith PA. Angiotensin II receptor antagonists alone and com-
bined with hydrochlorothiazide: Potential benefts beyond the anti-
hypertensive effect. Am J Cardiovasc Drugs 2005; 5: 171 183.
10. Okin PM, Hille DA, Kjeldsen SE, Lindholm LH, Edelman JM,
Dahlof B, et al. Greater regression of electrocardiographic left ven-
tricular hypertrophy during hydrochlorothiazide therapy in hyperten-
sive patients. Am J Hypertens 2010; 23: 786 793.
11. Sawa T, Sato Y, Matsuda M, Tanaka M, Miyazaki S, Furukawa Y,
et al. Regression of electrocardiographic signs of left ventricular
hypertrophy by combined treatment with thiazide diuretic and angio-
tensin-II receptor blocker: Randomized multicenter trial. Circ J 2014
September 30, doi:10.1253/circj.CJ-14-0713 [Epub ahead of print].
12. Hypertension Detection and Follow-up Program Cooperative Group.
Five-year fndings of the hypertension detection and follow-up pro-
gram: Prevention and reversal of left ventricular hypertrophy with
antihypertensive drug therapy. Hypertension 1985; 7: 105 112.
13. MacMahon S, Collins G, Rautaharju P, Cutler J, Neaton J, Prineas
R, et al. Electrocardiographic left ventricular hypertrophy and effects
of antihypertensive drug therapy in hypertensive participants in the
multiple risk factor intervention trial. Am J Cardiol 1989; 63: 202
210.
14. Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Gattobigio R,
Zampi I, et al. Prognostic signifcance of serial changes in left ven-
tricular mass in essential hypertension. Circulation 1998; 97: 48 54.
15. Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS,
Papademetriou V, et al. Prognostic signifcance of left ventricular
mass change during treatment of hypertension. JAMA 2004; 292:
2350 2356.
patients with HT. There are many factors related to ventricular
hypertrophy. Although mechanical stimulus is a cause, neuro-
humoral factors such as catecholamines and angiotensin II
(angII) induce LVH either individually or in combination
(Figure). Hypertrophy indicates increased size of cardiomyo-
cytes, and is usually associated with alteration of the collagen
matrix components. This molecular process includes membrane
receptors, second messengers, and transcriptions, resulting in
gene expressions that induce increases in protein synthesis and
changes in sarcomeric structure.
Therefore, the 2 main systems involved in hypertrophy are
mechanical stress and release of neurohumoral factors. The
mechanical signaling has not been completely elucidated, but
it activates multiple messengers and intracellular cascades, and
also induces the local release of cytokines. For the many nu-
erohumoral factors related to hypertrophy (ie, catecholamines,
angII, aldosterone, insulin, oxidative stress, cytokines and
growth factors induced by the infammatory process), the main
stimulus comes from heptahelical G protein coupled receptor,
including 1-adrenergic receptors for epinephrine and norepi-
nephrine, the AT1 receptor for angII and the ET receptor for
endothelin-1. The process of pathological myocardial hyper-
trophy is highly complex, but elucidation of the pathways en-
ables application to medical treatment.
Most antihypertensive medication is associated with reduc-
tion of LVH, but the degree of the reduction is not uniform.
The PRESERVE
5
and ELVELA
6
trials showed similar reduc-
tion of LVH between long-term calcium channel blockade and
angiotensin-converting enzyme inhibitor (ACEI) therapy. How-
ever, a meta-analysis of treatment for the regression of LVH
reported that ACEI and angiotensin receptor blocker (ARB)
showed greater reduction of left ventricular (LV) mass.
7
Now,
there is no doubt that the angiotensin system is the greatest
target for regression of LVH. Furthermore, the LIFE study
showed the effectiveness of ARBs on reducing LVH when
compared with -blocker.
8
In clinical cases, most hypertensive patients need to take
multi-class antihypertensive medication to obtain their target
level of BP. The combination therapy of an ARB and hydro-
chlothiazide (HCTZ) is more effective for reducing BP than
monotherapy of either.
9
In the substudy of the LIFE trial, the
effcacy of adding diuretics for treating LVH has been re-
ported.
10
These several trials have demonstrated that ARBs are
more effective in reducing LVH when used with HCTZ than
without HCTZ.
In this issue of the Journal, Sawa et al
11
report the different
therapeutic effects between adding diuretics and increasing the
dosage of the ARB. The regression of the ECG signs of LVH
was better with the combined therapy of diuretic and ARB than
by increasing the dosage of ARB, and the difference was in-
dependent of the degree of BP reduction. Diuretics are rarely
used in Japanese hypertensive patients as a frst-line medica-
tion, because doctors are apprehensive about adverse effects.
However, Sawa et al also report that no signifcant adverse
effects were seen when low-dose diuresis was combined with
ARB therapy.
For the assessment of LVH, ECG is the initial method used
to recruit patients in many clinical studies. However, some ECG
studies do not support the result that lowering BP induces a
reduction in LVH during treatment of HT.
12,13
Echocardiogra-
phy is the standard method of measuring LV mass, and the
results of Sawa et als study are consistent with the results of
previous studies in which LV mass was assessed with echo-
Advance Publication by-J-STAGE