From the Division of Cardiology, Department of Internal Medicine,
University of Missouri Health Sciences Center, Columbia.
Correspondence to Karl T. Weber, MD, Division of Cardiology, Room MA432, University of Missouri Health Sciences Center, Columbia, MO 65212.
The
pressure with which circulating blood is contained in the
arterial circulation is related to a number of factors.
Prominent among these is the structure of resistance vessels, or
arterioles,1 and conduit vessels, or
arteries.2 3 For a normal intravascular volume
and cardiac output, pathological distortions in arteriolar structure
are accompanied by intravascular pressures greater than the expected
norm. Such abnormalities include endothelial cell
hyperplasia; intimal hyalinization; vascular smooth muscle cell
hypertrophy and/or hyperplasia; and increased vessel wall
collagen,4 5 including its adventitia, here
referred to as a perivascular fibrosis. Subsequent to such arteriolar
remodeling and rise in arterial pressure are iterations in
conduit vessel structure. This includes medial thickening and increased
concentrations of collagen and elastin in arteries and the aorta.
Arteriolosclerosis and arteriosclerosis, a
thickening and hardening of arterioles and arteries, respectively, of
systemic organs, such as kidney, heart, brain, and eyes, account for
and sustain arterial hypertension. Such arteriolar and
arterial remodeling is associated with increased risk of
adverse cardiovascular events, including myocardial
infarction, heart failure, and stroke. Effective monitoring of
arteriolosclerosis and arteriosclerosis would have
important clinical applications. An example addresses vascular
remodeling in response to pharmacological intervention that offers
potential as either a cardioprotective or cardioreparative
strategy.6
How Can Vascular Remodeling Be Monitored?
Microscopic examination of biopsied tissue provides an opportunity
to address the presence and extent of arteriolar remodeling in
hypertensive patients. It has been effectively used by a number of
investigators.4 5 7 The invasive nature of this
approach, however, detracts from its broad-based application to the
many millions of individuals with hypertension.
Funduscopic examination offers a "window to the vasculature,"
albeit primarily the external features of the retinal circulation. It
is an essential feature in the examination of hypertensive patients. In
an important and widely recognized study published in 1939, Keith et al
reported on vascular remodeling observed in the optic fundi of their
patients with hypertension of various levels of severity. Findings used
to classify the severity of vascular remodeling included arteriolar
diameter and fibrosis (or sclerosis); arteriolar sclerosis in
association with compression of neighboring retinal veins; and the
presence or absence of complications, such as hemorrhages,
exudates, and optic disk edema. Retinopathy was related
to the severity and duration of hypertension. The extent of optic
fundus remodeling offered prognostic information and served to predict
patient survival in this and other studies, as recently
reviewed.9 The severity of these changes
correlated with the incidence of cardiac and renal complications in
essential hypertension and predicted the presence and extent of
angiographically demonstrable coronary artery disease. The
utility of direct ophthalmoscopy in the assessment of mild or moderate
hypertension has been questioned.
Are There Alternative Strategies to Monitoring Vascular
Sclerosis?
The adverse accumulation of fibrillar collagen in the heart has a
number of functional consequences. It accounts for a rise in
ventricular diastolic stiffness; a continued
accumulation further impairs diastolic function and
compromises systolic function.6 The
presence of symptomatic heart failure is related to the
increment in left ventricular collagen concentration.
Microscopic examination of endomyocardial biopsy
tissue obtained from patients with hypertension identifies
coronary arteriolosclerosis and is associated with impaired
response of vasodilator reserve to pharmacological
provocation.7 Fibrosis enhances the
arrhythmogenic potential of atria and
ventricles.12 13 14
Echocardiographic characterization of tissue
composition is under development and offers promise in the detection of
ventricular fibrosis.15 16 17
Fibrosis is a histological term that characterizes the
morphological features of tissue remodeling by fibrillar collagen.
Fibrosis has long been assumed to imply a static condition of diseased
tissue. To the contrary, however, fibrous tissue often connotes a
dynamic state of tissue repair—an ongoing process of progressive
collagen deposition based on a persistence of fibroblast-like cells and
their continued turnover of collagen. A dynamic state of fibrogenesis
exists when collagen degradation fails to keep pace with increased
collagen synthesis. A monitoring of collagen turnover would address
formation and degradation of extracellular matrix in disease states
when organ fibrosis is present.
How Can Vascular Collagen Turnover Be Monitored?
Fibrillar types I and III collagens are triple helices. In the
case of type I collagen, there are 2
In recent years and as recently reviewed, this approach has been
extended to address tissue repair in the injured heart, such as after
myocardial infarction.19 Díez and
coworkers in Pamplona, Spain, have used this biochemical approach to
address cardiac fibrosis in hypertensive animals and patients. Their
studies have provided a number of provocative and important
advances.
In rats with genetic hypertension, Díez et
al20 used the carboxy-terminal propeptide of
procollagen type I (PIP) as a marker of type I collagen synthesis and
pyridinoline cross-linked telopeptide domain of collagen type I (CITP)
as a marker of type I collagen degradation. Microscopy and
immunohistochemistry confirmed the expected cardiac fibrosis that
consisted of type I collagen and that others21
have shown is morphologically expressed as a perivascular fibrosis of
intramyocardial coronary arterioles and arteries with
contiguous interstitial fibrosis. Compared with age- and
sex-matched normotensive genetic controls, serum PIP was significantly
increased in 36-week-old hypertensive rats, whereas CITP was no
different between groups. A direct correlation between
ventricular collagen volume fraction and PIP was found. PIP
and collagen volume fraction were equivalent to 36-week-old controls
when a 20-week course of an antihypertensive dose of quinapril was
introduced at age 16 weeks. CITP tended to be higher in hypertensive
rats treated with quinapril but was not statistically different from
controls. It was proposed that serum PIP could be used as a marker of
type I collagen–related cardiac fibrosis in this hypertensive rat
model.
These investigators also demonstrated that serum PIIIP and PIP were
higher in patients with never-before-treated essential hypertension
than in normotensive control subjects.22 23
Direct correlations in the hypertensive group were found between serum
PIIIP and plasma renin activity and between serum PIP and LV mass and
graded severity of ventricular arrhythmias
recorded during ambulatory ECG monitoring. Inverse correlations
were evident between these markers and maximal early and late
transmitral flow velocities, Doppler
echocardiographic markers of left
ventricular diastolic dysfunction. After 6
months of lisinopril treatment, which normalized
arterial pressure, diastolic filling improved,
together with a regression in LV mass and reduced number of
ventricular extrasystoles. It was therefore suggested that
these markers serve to demonstrate increased collagen synthesis in the
cardiovasculature, an adverse association between such collagen
turnover and the mechanical and electrical dysfunction of the heart,
which could be ameliorated by lisinopril.
In the present issue of Circulation, Laviades et
al24 apply serological markers of collagen
turnover in never-before-treated patients with essential hypertension.
They address whether type I collagen degradation is reduced in this
hypertensive population. Serum CITP was monitored as a marker of type I
collagen degradation together with serum concentrations of total MMP-1
and TIMP-1 and the MMP-1/TIMP-1 complex. Measurements were
repeated after 12 months of lisinopril treatment and
compared with untreated normotensive control subjects. At the time of
study enrollment, baseline free MMP-1 was decreased, free TIMP-1
increased, and CITP no different from control levels.
Hypertensive patients with LVH were found to have even lower baseline
values of free MMP-1 and higher values of TIMP-1 than their
counterparts without LVH. After treatment with lisinopril,
free MMP-1 and CITP each increased, whereas free TIMP-1 was reduced.
The importance of bradykinin and associated substances (nitric oxide
and prostaglandins) in promoting degradation of established
fibrosis by an ACE inhibitor remains to be
investigated.
Taken collectively, these studies by Díez and coworkers suggest
that extracellular matrix collagen synthesis in the cardiovasculature
is enhanced and its degradation reduced in patients with essential
hypertension. These biochemical features favor a progressive
arteriolosclerosis and arteriosclerosis of the
heart and other organs that would lead to organ fibrosis and ultimately
organ failure.
Additional work is needed before the usefulness of this
provocative approach is fully realized. This
notwithstanding, Díez and coworkers have provided a stimulus: a
new window of opportunity with which to noninvasively monitor vascular
sclerosis in hypertension.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
© 1998 American Heart Association, Inc.
Editorial
Monitoring Vascular Sclerosis in Hypertension
A New Window of Opportunity
Key Words: Editorials • arteriosclerosis • hypertension
Arteriolosclerosis includes the adverse accumulation of types I
and III fibrillar collagens in the adventitia. This perivascular
fibrosis involves intramyocardial coronary arterioles found in
the normotensive, nonhypertrophied right ventricle and the
hypertensive, hypertrophied left ventricle.10
From the perivascular space of these intramural vessels, collagen
fibers extend into the contiguous interstitium, creating an
interstitial fibrosis. Such vascular sclerosis can be found
in systemic organs as well. The association between cardiac fibrosis
and chronic elevations in circulating angiotensin II and/or
aldosterone has been reviewed
previously.11 
1- and 1
2-polypeptide chains; 3
1-chains make up type III collagen. These
collagens are synthesized and secreted as larger procollagen or
precursor molecules that contain additional peptide sequences, called
propeptides, located at the amino-terminal and carboxy-terminal ends of
these polypeptide chains. These propeptides are cleaved from collagen
molecules before their assembly into a triple helix. Free propeptides
of type I and type III collagens that appear in the circulation reflect
collagen deposition. This is based on certain stoichiometric
considerations reviewed elsewhere.18 Collagen
degradation is provided by an extracellular pool of matrix
metalloproteinases (MMPs), including MMP-1 (or
collagenase), that normally exist in latent form bound by
tissue inhibitors of metalloproteinases (TIMPs).
Serological markers of collagen synthesis and degradation have been
used to monitor wound healing and fibrous tissue accumulation in
injured lung and liver, myeloproliferative disorders associated with
myelofibrosis, and type I collagen formation and degradation in
metabolic bone disease. The use of such noninvasive
biochemical markers to detect organ fibrosis has been reviewed
elsewhere.18
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