J Cardiol 2002 Apr; 39（4）: 195 – 204

Long-Term Effects of Benidipine
Hydrochloride on Severe Left
Ventricular Hypertrophy andCollagen Metabolism in Patients
With Essential Hypertension
Osamu

HIRONO, MD

Kaniz FATEMA, MD
Joji NITOBE, MD
Yasuchika TAKEISHI, MD
Kazuyoshi KANEKO, MD
Ryoko

SHIGA, MD＊

Isao

KUBOTA, MD,

Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Objectives. The long-term effects of benidipine on left ventricular hypertrophy（LVH）and collagenmetabolism were examined in patients with essential hypertension.
Methods. Forty patients with untreated essential hypertension were given benidipine at a dose of 6 mg aday. Routine echocardiographic parameters, serum concentrations of matrix metalloproteinase-1（MMP-1）and tissue inhibitor of metalloproteinase-1（TIMP-1）were analyzed before and 12 months after treatment
with benidipine. Patients were classified according to left ventricular mass index（LVMI）into three（159 ＞ LVMI ＞
and no LVH（LVMI ＜ 125）.
groups : severe LVH（LVMI ＞− 159）, mild LVH− 125）
Results. Serum levels of free TIMP-1 to MMP-1 ratio were significantly higher in patients with severe
LVH than in the other two groups before treatment. There was a significant positive correlation between
the free TIMP-1 to MMP-1 ratio and LVMI in all study subjects（r ＝ 0.51, p ＜ 0.01）. Twelve months after
treatment, percentage changes of the LVMI and free TIMP-1 to MMP-1 ratio were significantly larger inthe patients with severe LVH（−27% and −54%）than with mild LVH（−12% and −23%）or no LVH（−4% and −11%）, respectively. Changes in the systolic blood pressure but not changes in the free TIMP1 to MMP-1 ratio correlated with changes in the LVMI in patients with mild LVH（r ＝ 0.78, p ＜ 0.01）.
Changes in the free TIMP-1 to MMP-1 ratio but not changes in the systolic blood pressure correlated withchanges in the LVMI in patients with severe LVH（r ＝ 0.69, p ＜ 0.01）.
Conclusions. Long-term administration of benidipine reduced left ventricular mass and normalized systemic collagen type Ⅰ degradation abnormalities in essential hypertensive patients with severe but not mild
LVH.
─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2002 Apr ; 39
（4）
: 195−204

Key Words
Calcium channel blocking drugs
Hypertension
Collagen
Echocardiography, transthoracic

INTRODUCTION
Left ventricular concentric hypertrophy inHypertrophy

patients with essential hypertension had the worst
cardiovascular morbidity and mortality in the
Framingham study, compared with patients with──────────────────────────────────────────────
山形大学医学部 第一内科 : 〒 990−9585 山形県山形市飯田西 2−2−2 ; ＊みゆき会病院 内科，山形
The First Department of Internal Medicine, Yamagata University School of Medicine ; ＊ Department of Internal Medicine, Miyuki-Kai
Hospital, Yamagata
Address for correspondence : HIRONO O, MD, The First Department of Internal Medicine, Yamagata University School of Medicine,Iida-Nishi 2−2−2, Yamagata, Yamagata 990−9585
Manuscript received December 18, 2001 ; revised February 12, 2002 ; accepted February 12, 2002

195

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Hirono, Fatema, Nitobe et al

eccentric hypertrophy, concentric remodeling andnormal geometry evaluated by echocardiographic
parameters 1）. Such left ventricular concentric
hypertrophy is characterized by an increase in fibrillar collagen type Ⅰ and Ⅲ2−5）.
The left ventricular myocardial collagen matrix
may participate in the maintenance of left ventricular geometry6−10）. Thus, alterations in the composition of the left ventricular myocardial collagenmatrix may influence left ventricular function andhypertrophy11−13）. The matrix metalloproteinases（MMPs）
are a family of enzymes that contribute to
extracellular remodeling in several diseases. MMPs
are significant in the pathological process of
myocardial remodeling in hypertensive patients
2,14−16）.
with left ventricular hypertrophy（ LVH）
Systemic extracellular degradation of collagen type
Ⅰ is depressed in patients with essential hypertension and can be normalized by treatment with theangiotensin converting enzyme（ ACE）inhibitor
lisinopril2,14）. Moreover, the calcium channel blocker benidipine hydrochloride clearly inhibits expression of transforming growth factor-β（TGF-β）in
the left ventricle of Dahl salt-sensitive hypertensive
rats17）.
Previous clinical studies have indicated that
long-term administration of benidipine at a dose of
6 mg a day is effective and safe as monotherapy for
essential hypertension compared with a dose of
4 mg a day18,19）. However, the long-term effects ofbenidipine at a dose of 6 mg a day on LVH and collagen metabolism remain unknown.
This study examined whether disturbances incollagen metabolism were involved in LVH andevaluated the long-term effects of benidipine at adose of 6 mg a day on reduction of LVH and reversal of abnormalities in collagen metabolism inpatients with essential hypertension.
METHODS
Source of study subjects
Fifty consecutive patients with untreated essential hypertension attending the out-patient clinic
from November 1999 to October 2001 wereenrolled in this clinical trial. Eligibility criteria foressential hypertension were right brachial systolicblood pressure ＞− 140 and/or diastolic blood pres90
mmHg（mean of three recordings on at
sure ＞−
least two visits over the 2 weeks observational period）
using a pneumatic tourniquet after each subject
had been sitting for at least 15 min20）. Study sub-jects were given benidipine hydrochloride at a doseof 6 mg a day as monotherapy to achieve a therapeutic goal of blood pressure reduction of
20 mmHg at systole and 10 mmHg at diastole.
Treatment with benidipine was started as soon as
possible after informed consent was obtained, andthe study protocol was discontinued if the patientdeveloped major side effects such as sustained
hypotension and/or bradycardia, or complications
with organ fibrosis. Ten patients were excluded
from the analysis because of drop out（n ＝ 3）orcomplications before treatment with congestive
heart failure（n ＝ 2）, pulmonary fibrosis（n ＝ 1）,
liver cirrhosis（n ＝ 1）, collagen disease（n ＝ 1）andseveral disease states characterized by active
inflammation（n ＝ 2）. All 40 patients had stage Ⅰ
or Ⅱ organ damage due to severity of hypertension
as classified by the World Health Organization21）.
Ten patients had mild proteinuria with normal renal
function and 13 had hyperlipidemia. No patient had
a history of vascular disease, diabetes mellitus or
hyperuricemia or had received antihypertensive
treatment including ACE inhibitors or angiotensin
Ⅱ receptor antagonists. Routine echocardiographic
parameters and serum markers of collagen type Ⅰ
metabolism were measured before and 12 months
after treatment of benidipine. This study wasapproved by the local ethical committee of
Yamagata University School of Medicine, and written informed consent was obtained from all
patients.
Laboratory examinations
The general biochemical parameters were measured by routine laboratory methods. Serum samples were taken to determine total matrix metalloproteinase-1（MMP-1）and total tissue inhibitor of
metalloproteinase-1（TIMP-1）at the time of clinicalstudies and stored at −80°
C until used. Total
MMP-1 and TIMP-1 were determined by a 2-site
ELISA method 22−24）. The inter- and intra-assay
variations for determining MMP-1 were 13% and
8%, respectively, and the lower detection limit was
1.70 ng/ml. The inter- and intra-assay variations fordetermining TIMP-1 were 15% and 11%, respectively, and the lower detection limit was 1.25 ng/ml.
MMP-1/TIMP-1 complex was also determined by a
2-site ELISA method. The inter- and intra-assay
variations for determining MMP-1/TIMP-1 complex were 15% and 10%, respectively, and thelower detection limit was 1.50 ng/ml22）. The serum
J Cardiol 2002 Apr; 39（4）: 195 – 204

Collagen Metabolism in Hypertensive Patients

197

Table 1 Baseline characteristics and hemodynamic parameters before and after treatment withbenidipine in the study subjects

FemaleAge（yr）

No LVH（n＝8）

Severe LVH（n＝16）

Mild LVH（n＝16）

7（44%）

6（38%）

3（38%）

58±7

59±12

57±10

SBP
（mmHg）
Baseline

167±24171±22161±16After treatment

136±23＊135±18＊124±9＊

93±17

94±10

92±14

＊

＊

DBP
（mmHg）
Baseline

74±17After treatment

72±20

73±17＊

Heart rate（beats/min）
68±12

Baseline

67±11

70±10

After treatment

70±6

72±6

70±11

0.9±0.2

0.8±0.3

0.8±0.2

Creatinine（mg/dl）＊

Continuous values are mean±SD. p＜0.05 vs baseline.
LVH＝left ventricular hypertrophy ; Baseline＝before treatment with benidipine ; After treatment＝12 months
after treatment with benidipine ; SBP＝systolic blood pressure ; DBP＝diastolic blood pressure ; Creatinine＝serum creatinine at the baseline.

levels of free MMP-1 and TIMP-1 were calculated
after subtracting the values of MMP-1/TIMP-1
complex from the values of total MMP-1 and
TIMP-1, respectively 22）. Normal ranges of free
MMP-1 and TIMP-1 are 8.5 ± 5.2 and 175 ±39 ng/ml（mean ± SD）, respectively23, 24）.
Echocardiographic studies
Echocardiograms were recorded using a Hewlett
Packard SONOS 5500 instrument equipped with asector transducer（ carrier frequency, 2.5 or
3.75 MHz）. Conventional two-dimensional, Mmode and Doppler studies were obtained using
standard views and techniques. Left ventricularmass was calculated from the formula of Devereux
as follows : 1.04 ×（end-diastolic interventricularseptal wall thickness ＋ left ventricular end-diastolic dimension ＋ left ventricular end-diastolic posterior wall thickness）3 −（left ventricular end-diastolic dimension）3 − 13.6. Left ventricular mass
index
（LVMI）was obtained by dividing left ventricular mass by body surface area. Relative wall thickness was calculated as follows :（end-diastolic
interventricular septal wall thickness ＋ left ventricular end-diastolic posterior wall thickness）/left
ventricular end-diastolic dimension. Patients wereclassified according to LVMI into threegroups : severe LVH（LVMI ＞− 159）, mild LVH＞（ 159 ＞ LVMI − 125）and no LVH（ LVMI ＜J Cardiol 2002 Apr; 39（4）: 195 – 204

25−27）
125）.

Statistical analysis
Data are expressed as mean ± SD. Analysis ofvariance followed by Scheffe s test was used toassess the statistical difference between severe,
mild and no LVH groups of patients with essential
hypertension. A paired t-test was used to compare
the difference before and 12 months after treatmentof benidipine. p values of less than 0.05 were considered significant.
RESULTS
Observational period
Evaluation of the clinical characteristics foundno significant differences in age, sex ratio, bloodpressure, heart rate, left ventricular fractional shortening and relative wall thickness between the threegroups（Tables 1, 2）. There was no significant difference in the percentage of left ventricular concentric hypertrophy（relative wall thickness ＞ 0.45 and
LVMI ＞ 125）between the severe and mild LVH
group（81% vs 75% ; Table 2）. Serum levels of
free TIMP-1 to MMP-1 ratio were significantly
higher in patients with severe LVH than in the othertwo groups（ severe LVH : 36.4 ± 11.0 vs mild
LVH : 28.7 ± 8.9 and no LVH : 27.3 ± 8.2, p ＜0.05 ; Table 3）. There was a significant positive
correlation between the free TIMP-1 to MMP-1

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Hirono, Fatema, Nitobe et al

Table 2 Echocardiographic parameters before and after treatment with benidipine
Severe LVH（n＝16）

Mild LVH（n＝16）No LVH（n＝8）

Baseline

40±5

37±6

37±6

After treatment

38±6

37±8

37±8

Baseline

32±3

34±3

33±4

After treatment

32±4

34±8

32±3

Baseline

0.54±0.28

0.60±0.28

0.64±0.31

After treatment

0.58±0.22

0.62±0.18

0.66±0.30

Baseline

0.71±0.22

0.75±0.32

0.76±0.32

After treatment

0.74±0.18

0.79±0.12

0.85±0.27

Baseline

0.76±0.26

0.80±0.30

0.84±0.31

After treatment

0.78±0.20

0.78±0.14

0.78±0.29

Baseline

202±26††139±9†

107±14After treatment

147±29＊121±18111±15Baseline

0.56±0.15

0.52±0.08

0.52±0.08

After treatment

0.52±0.12

0.49±0.10

0.52±0.14

13
（81%）

12
（75%）

0

LAD
（mm）

%FS
（%）

E wave velocity（m/sec）

A wave velocity（m/sec）

E/A

LVMI（g/m2）

RWT

Concentric LVH

Continuous values are mean±SD. ＊p＜0.05 vs baseline, †p＜0.05 vs no LVH, ††p＜0.05 vs mild and no LVH.
LAD＝left atrial dimension ; %FS＝left ventricular percentage fractional shortening ; E wave velocity＝peak early
diastolic transmitral filling velocity of the left ventricle ; A wave velocity＝peak late diastolic transmitral filling
velocity of the left ventricle ; LVMI＝left ventricular mass index ; RWT＝relative wall thickness ; Concentric LVH＝percentage of concentric left ventricular hypertrophy（RWT＞0.45 and LVMI＞125）at the baseline. Other
abbreviations as in Table 1.

Table 3 Serum markers of extracellular collagen type degradation before and after treatment
with benidipine
Severe LVH（n＝16）

Mild LVH（n＝16）No LVH（n＝8）

Baseline

306±98299±68289±56After treatment

202±78252±70254±74Baseline

8.4±3.4

10.4±4.8

10.6±5.8

After treatment

11.7±6.4

12.4±6.8

11.4±8.1

28.7±8.927.3±8.2

Free TIMP-1（ng/ml）

Free MMP-1（ng/ml）

Free TIMP-1/MMP-1
36.4±11.0††

Baseline＊

17.2±10.5

After treatment＊＊

20.4±6.8

22.3±7.6††

Values are mean±SD. p＜0.05 vs baseline, p＜0.05 vs mild and no LVH.
Free TIMP-1＝serum levels of free tissue inhibitor of matrix metalloproteinase-1 ; Free MMP-1＝serum levels of
free matrix metalloproteinase-1. Other abbreviations as in Table 1.

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Collagen Metabolism in Hypertensive Patients

199

Fig. 1 Scatterplots of free TIMP-1 and MMP-1 ratio（Free TIMP-1/MMP-1）
and LVMI during theobservational period in all study subjects
There was a significant positive correlation between
free TIMP-1/MMP-1 and LVMI（r ＝ 0.51, p ＜ 0.01）.
Abbreviations as in Tables 2, 3.

ratio and LVMI in all patients（ r ＝ 0.51, p ＜0.01 ; Fig. 1）.
Twelve months after treatment
Twelve months after treatment of benidipine
with a dose of 6 mg a day, systolic blood pressure
was reduced by 17% in patients with severe LVH,
20% in patients with mild LVH and 22% in patientswith no LVH, with no associated changes in heartrate（Table 1）. Percentage changes of the LVMI
and free TIMP-1 to MMP-1 ratio were significantly
larger in patients with severe LVH（−27% and−54%）than in patients with mild LVH（−12%
and −25%）and no LVH（−4% and −11%）,
respectively（p ＜ 0.05 ; Tables 2, 3）. Changes ofthe systolic blood pressure, but not changes of thefree TIMP-1 to MMP-1 ratio, correlated withchanges of the LVMI in patients with mild LVH（r ＝ 0.78, p ＜ 0.01 ; Fig. 2）. On the other hand,changes of the free TIMP-1 to MMP-1 ratio, but
not changes of the systolic blood pressure, correlated well with changes of the LVMI in patients withsevere LVH（r ＝ 0.69, p ＜ 0.01 ; Fig. 3）.
DISCUSSION
Previous investigations of the pathophysiology
of LVH in patients with essential hypertension
using necropsy or left ventricular biopsy28−33）havesuggested that LVH is the most common complication in patients with essential hypertension, andpatients with LVH have a worse prognosis than
J Cardiol 2002 Apr; 39（4）: 195 – 204

Fig. 2 Scatterplots of changes in the systolic bloodpressure（ Change of SBP）
and changes in the
LVMI（Change of LVMI）（upper）, and changes
in the free TIMP-1 to MMP-1 ratio（Change offree TIMP-1/MMP-1）and Change of LVMI
（lower）
in essential hypertensive patients withmild LVH
Change of SBP, but not change of free TIMP-1/MMP1, correlated well with change of LVMI after treatment
with benidipine for 12 months（r ＝ 0.78, p ＜ 0.01）.
Abbreviations as in Tables 1−3.

those without LVH at the comparable left ventricular function1,34−36）. Abnormal echocardiographic
parameters may be useful markers in patients starting antihypertensive therapy to predict the development of cardiac failure26,27,32,37,38）. The present study
found larger LVMI and higher ratio of serum free
TIMP-1 to MMP-1 levels in essential hypertensive
patients with severe LVH than in those with mild or
no LVH. Furthermore, there was a significant positive correlation between the free TIMP-1 to MMP1 ratio and LVMI in all study subjects during theobservational period. These findings showed that

200

Hirono, Fatema, Nitobe et al

Fig. 3 Scatterplots of changes in the systolic bloodpressure（ Change of SBP）
and changes in the
LVMI（Change of LVMI）（upper）, and changes
in the free TIMP-1 to MMP-1 ratio（Change offree TIMP-1/MMP-1）and Change of LVMI
（lower）
in essential hypertensive patients withsevere LVH
Change of free TIMP-1/MMP-1, but not change of
SBP, correlated well with change of LVMI after treatment with benidipine for 12 months（ r ＝ 0.69, p ＜0.01）.
Abbreviations as in Tables 1−3.

severe LVH in essential hypertensive patients was
related to disturbances in systemic collagen metabolism.
LVH in hypertensive patients can be classified
into four categories by ventricular geometricalchanges27）. The concentric hypertrophy pattern ischaracterized by increasing LVMI, systolic ventricular wall stress and relative wall thickness associated with pressure overload. In the Framingham
cohort, patients with concentric hypertrophy had
the worst prognosis, followed by those with eccentric hypertrophy, concentric remodeling and normal

geometry classified as echocardiographic parameters1）. Furthermore, 50% of patients with essential
hypertension may have pressure overload and are
partly characterized by cardiovascular structuralchanges such as interstitial fibrosis4,8,9,27）. In ourstudy, 78% of the consecutive patients with LVH
and essential hypertension also showed the concentric LVH pattern.
Systemic extracellular degradation of collagentype Ⅰ may be depressed in essential hypertensive
patients with LVH, and degradative changes of cardiac collagen metabolisms are regulated by MMP-1
and TIMP-12,14）. MMP-1 is a Zn2＋ and Ca2＋ dependent proteinase that degrades structural type Ⅰ to Ⅲ
collagen. TIMP-1 is a member of a family of naturally occurring specific inhibitors that block activation of MMP-1. Recently, it has been suggested thatthe decreased MMP-1 and increased TIMP-1 activity mediates several organ fibrosis such as idiopathic pulmonary fibrosis, liver cirrhosis and cardiovascular remodeling14）. Furthermore, increased levels
of TIMP-1 activity depress the MMP-1 activity inthe myocardium of the adult spontaneously hypertensive rat16）. Such an alteration, in combination
with the increased synthesis of collagen type Ⅰ
molecules, facilitates the exaggerated deposition ofcollagen type Ⅰ fibers seen in the left ventricle ofthese rats. A number of cytokines and growth factors regulate the expression of TIMP-1. The available evidence suggests that there is a molecularmechanism for regulation of the expression of
TIMP-1 at the transcriptional level in most tissues,
including the myocardium. In this regard, TGF-β
has been shown to stimulate the transcription of
TIMP-1. Increased TGF-β gene expression andactivity have recently been found in the left ventricle of the adult spontaneously hypertensive
rat16,39−42）.
MMPs have differing involvements in the cardiac remodeling associated with hypertension or
aging43）. MMP activity may decrease by 40% during aging43,44）. Furthermore, the progression to endstage renal disease is accompanied by degradation
and accumulation of extracellular matrix proteins,which occurs due to increases in MMP
activity45−47）. Our study showed that there was no
significant difference in age between the threegroups. All 40 patients had stage Ⅰ or Ⅱ organ
damage due to severity of hypertension with normal renal function. However, the ratio of free
TIMP-1 to MMP-1 was significantly higher in
J Cardiol 2002 Apr; 39（4）: 195 – 204

Collagen Metabolism in Hypertensive Patientspatients with severe LVH than in mild or no LVH
in the observational period. Further, 12 months
after treatment of benidipine with a dose of 6 mg aday, a positive linear relationship was observed
between changes in the LVMI and the free TIMP-1
to MMP-1 ratio. These results strongly suggest asignificant relationship between LVH and collagentype Ⅰ degradation abnormalities in essential
hypertensive patients with severe LVH.
There are several triggering factors responsible
for such enzymatic changes in extracellular collagen degradation by treatment with benidipinehydrochloride. First, benidipine inhibits expressionof TGF-β17）. Angiotensin Ⅱ has a pathologicaleffect on the production of TGF-β in cardiac
myocytes48−50）. Furthermore, clinical trials havesuggested that abnormalities in the systemic extracellular degradation of collagen type Ⅰ can be normalized by the ACE inhibitor lisinopril2,14）. Second,
the serum concentrations of procollagen derived
peptides, procollagen type Ⅰ carboxy terminal peptide（PIP）, have been proposed as useful markers of
the tissue synthesis of collagen type Ⅰ2）. We did
not examine angiotensin Ⅱ and PIP in the regulation of cardiac collagen metabolisms in essential
hypertension in our study. However, the present
clinical trial suggested that the long-term administration of benidipine at a dose of 6 mg a day
reduced left ventricular mass and normalized systemic collagen type Ⅰ degradation abnormalities inessential hypertensives with severe LVH.
In the past, ACE inhibitors were consideredmore effective than the first- and second-generation
calcium channel blockers （mainlydihydropyridines）, β-blockers and diuretics inreversing left ventricular mass, independent oflength of time of treatment or decrease in bloodpressure51）. However, experiments indicate that thelong-acting third-generation calcium channel
blocker, amlodipine, prevents not only cardiac
hypertrophy but also cardiac remodeling by inhibiting increases in mRNA levels of left ventricular β-

J Cardiol 2002 Apr; 39（4）: 195 – 204

201

myosin heavy chain and type Ⅰ collagen 52）.
Furthermore, a long-term and large scale trial has
proved that amlodipine and the ACE inhibitor
lisinopril reduce left ventricular mass and improve
diastolic function to a similar extent in elderly
newly diagnosed hypertensive patients 53）. Our
study suggests that other long-acting calcium channel blockers may also prevent LVH by improving
collagen type Ⅰ degradation abnormalities in essential hypertensive patients.
In the present study, there was no significant
relationship between reduction of blood pressure
and regression of LVMI in patients with severe
LVH. This indicates that improvement in systemiccollagen type Ⅰ degradation as well as blood pressure control is important for regression of LVMI inessential hypertensive patients with severe LVH.
Our study had the following limitations. First,
the number of subjects in this study were small.
Accordingly, there were no statistically significant
differences in serum levels of free MMP-1, TIMP-1
and the ratio of peak early diastolic transmitral filling to late filling velocity（E/A）as an index of left
ventricular diastolic function between the threegroups. Second, this study was not a randomized,
double-blind prospective trial. Third, we could not
specify the mechanisms by which the improvement
in collagen type Ⅰ degradation abnormalities wasmore prominent in hypertensive patients withsevere LVH than in mild LVH.
CONCLUSIONSThe present results demonstrate that the longterm administration of benidipine hydrochloride at
a dose of 6 mg a day reduced the left ventricularmass and normalized systemic collagen type Ⅰ
degradation abnormalities in essential hypertensive
patients with severe LVH. These findings suggest
the importance of a large scale clinical trial toestablish the long-term use of long-acting calcium
channel blockers for the treatment of LVH with collagen metabolic abnormalities.

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Hirono, Fatema, Nitobe et al

要約

本態性高血圧症に合併する高度左室肥大とコラーゲン代謝異常に対する
塩酸ベニジピン長期投与の有用性
廣 野

目

摂

Kaniz FATEMA

金子

一善

志賀

二藤部丈司
亮子

久保田

竹石

恭知

功

的 : 本態性高血圧症に合併する左室肥大とコラーゲン代謝異常に対する塩酸ベニジピン長期投与の有用性について検討した．
方

法 : 未治療の本態性高血圧症 40 例に対し，塩酸ベニジピン 6 mg を 1 日 1 回朝食後に経口投与した．観察期と投与 12 ヵ月に血圧，心拍数，心エコー図指標と血清中のコラーゲンⅠ型代謝酵素
活性指標［matrix metalloproteinase-1（MMP-1）, tissue inhibitor of metalloproteinase-1（TIMP-1）］を測定した．観察期の心エコー図指標より対象例を高度左室肥大群（高度肥大群 : 16 例），軽度左室肥大群（軽度肥大群 : 16 例），左室肥大非合併群（非肥大群 : 8 例）の 3 群に分類した．
結

果 : 観察期の活性型 TIMP-1/MMP-1 比は高度肥大群が他の 2 群に比べて有意に高値であった（高度肥大群 36.4 ± 11.0，軽度肥大群 28.7 ± 8.9，非肥大群 27.3 ± 8.2）．全対象例の観察期の活性型
TIMP-1/MMP-1 比は，心重量係数と正の相関関係を示した（r ＝ 0.51，p ＜ 0.01）．塩酸ベニジピンの12 ヵ月間継続投与は，各群の収縮期血圧をそれぞれ有意に低下させ（高度肥大群 17%，軽度肥大群
20%，非肥大群 22%），心拍数に影響を与えなかった．ベニジピン投与後の心重量係数と活性型
TIMP-1/ MMP-1 比の減少率は，高度肥大群（心重量係数減少率 27%，活性型 TIMP-1/ MMP-1 比低下
率 54%）が軽度肥大群（12%，23%），非肥大群（4%，11%）に比べてそれぞれ有意に高値であった．
軽度肥大群における心重量係数減少率と収縮期血圧の降圧率は正の相関関係（r ＝ 0.78，p ＜ 0.01）を示した．一方，高度肥大群における心重量係数減少率は，収縮期血圧の降圧率との間に有意な関連はなく，活性型 TIMP-1/MMP-1 比の低下率と正の相関関係を示した（r ＝ 0.69，p ＜ 0.01）．
結論 : 塩酸ベニジピン 6 mg の 12 ヵ月間継続投与は，本態性高血圧症に合併する高度左室肥大を退縮させ，血清中のコラーゲンⅠ型代謝異常を正常化する作用を持つ可能性が示唆された．本研
究の結果は，コラーゲン代謝異常を合併する高血圧性左室肥大に対する長時間作用型 Ca 拮抗薬長期投与の有用性を検討するための大規模研究の必要性を示唆する重要なものと考えられた．

J Cardiol 2002 Apr; 39（4）: 195−204

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