(Circulation. 2000;101:1729.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Serum Carboxy-Terminal Propeptide of Procollagen Type I Is a Marker of Myocardial Fibrosis in Hypertensive Heart Disease
From the Division of Cardiology, Nuestra Señora de Aránzazu Hospital, San Sebastian (R.Q., M.G.-S., J.I.E.); Divisions of Pathology (E.A.) and Hemodynamics (M.L., J.L.M.U.), Guipuzcoa Policlinics, San Sebastian; Departments of Clinical Chemistry (N.V., M.J.G., I.M.), Pathology (J.P.M.), and Cardiology (J.D.), University Clinic, and Vascular Pathophysiology Unit (B.L., J.C.E., J.D.), School of Medicine, University of Navarra, Pamplona, Spain.
Correspondence to Javier Díez, MD, PhD, Unidad de Fisiopatología Vascular, Facultad de Medicina, C/Irunlarrea s/n, 31080 Pamplona, Spain. E-mail jadimar{at}unav.es
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Abstract |
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Background—This study was designed to investigate whether the serum concentration of the carboxy-terminal propeptide of procollagen type I (PIP), a marker of collagen type I synthesis, is related to myocardial fibrosis in hypertensive patients.
Methods and Results—The study was performed in 26 patients with essential hypertension in which ischemic cardiomyopathy was excluded after a complete medical workup. Right septal endomyocardial biopsies were performed in hypertensive patients to quantify collagen content. Collagen volume fraction (CVF) was determined on picrosirius red–stained sections with an automated image analysis system. The serum concentration of PIP was measured by specific radioimmunoassay. Compared with normotensives, both serum PIP and CVF were increased (P<0.001) in hypertensives. A direct correlation was found between CVF and serum PIP (r=0.471, P<0.02) in all hypertensives. Histological analysis revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 18 with nonsevere fibrosis. Serum PIP was higher (P<0.05) in patients with severe fibrosis than in patients with nonsevere fibrosis. Using receiver operating characteristic curves, we observed that a cutoff of 127 µg/L for PIP provided 78% specificity and 75% sensitivity for predicting severe fibrosis with a relative risk of 4.80 (95% CI, 1.19 to 19.30).
Conclusions—These results show a strong correlation between myocardial collagen content and the serum concentration of PIP in essential hypertension. Although preliminary, these findings suggest that the determination of PIP may be an easy and reliable method for the screening and diagnosis of severe myocardial fibrosis associated with arterial hypertension.
Key Words: collagen • hypertension • myocardium • peptides • remodeling
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Introduction |
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Fibrous tissue accumulation is an integral feature of the adverse structural remodeling of cardiac tissue seen in hypertensive heart disease. In fact, an exaggerated accumulation of fibrillar collagens type I and type III occurs throughout the free wall and interventricular septum of animals1 2 3 and humans4 5 6 7 with primary arterial hypertension. A rise in collagen content has been proposed to raise myocardial stiffness and promote abnormalities of cardiac function and electrical activity.8 9 It has been proposed that the excess of myocardial collagen seen in hypertension is the result of both increased collagen synthesis and unchanged or decreased collagen degradation.10
The question arises as to how fibrous tissue should be monitored in hypertensive heart disease. Invasive endomyocardial biopsy is certainly one approach, albeit not widely applicable and manageable. High-frequency backscatter ultrasound is a noninvasive approach that has received attention.11 12 Monitoring of collagen synthesis in serum and other biological fluids has been applied to address tissue repair and collagen turnover in a number of diseases characterized by organ fibrosis.13 More specifically, determinations of serological collagen-derived peptides have been used as markers of fibrillar collagen turnover in various conditions that lead to cardiac fibrosis.14
In spontaneously hypertensive rats (SHR) and patients with essential hypertension, we measured serum concentrations of the carboxy-terminal propeptide of procollagen type I (PIP) as a marker of extracellular collagen type I synthesis and the carboxy-terminal telopeptide of collagen type I (CITP) as a marker of extracellular collagen type I degradation. Whereas the serum concentration of PIP was higher in SHR15 and hypertensive patients16 than in their normotensive controls, no differences in the serum concentration of CITP were observed between hypertension and normotension either in rats17 or in humans.18 In addition, we found a direct correlation between histologically assessed cardiac collagen content and serum PIP in SHR.15
These findings allowed us to hypothesize that in arterial hypertension, serum concentration of PIP may be a diagnostic marker of collagen type I–dependent myocardial fibrosis. To definitively test this hypothesis in patients with essential hypertension, the present study was designed to compare PIP with histomorphometric assessment of myocardial fibrosis observed in the interventricular septum tissue obtained by transvenous endomyocardial biopsy. The rationale for the use of this procedure is based on the previous finding that fibrosis present in the septum in postmortem tissue from hypertensive human hearts is representative of fibrosis existing in the free wall.7
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Methods |
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Subjects
The study population consisted of 26 patients (19 men and 7 women; mean age 56 years; range 39 to 70 years) with repeatedly documented elevated systolic blood pressure of >139 mm Hg and diastolic pressure of >89 mm Hg who were referred to our clinic for evaluation and treatment of arterial hypertension. Antihypertensive medication was reported by 16 patients (61%) as monotherapy or in combination. No patient was receiving treatment with either ACE inhibitors or angiotensin II AT1 receptor antagonists, which have been shown to modify serum PIP.15 16 17
All patients had appropriate clinical and laboratory evaluations to exclude hypertension secondary to renal disorders, renal artery abnormalities, adrenocortical disorders, pheochromocytoma, and iatrogenic causes.19 All patients had a negative treadmill exercise tolerance test. Selective coronary angiography showed normal epicardial arteries without significant stenoses in all patients. To discard abnormalities in the myocardial microcirculation, a 99mTc tetrofosmin perfusion imaging study was performed in each patient, and no perfusion defects were observed. Conditions associated with alterations in serum levels of PIP (alcoholic liver disease, metabolic bone disease, hyperthyroidism) were excluded after complete medical examination.
Ten hearts (6 men and 4 women; mean age 59 years, range 40 to 68 years) were collected from a total of 100 autopsies performed at the University Clinic of the University of Navarra during 1998 and 1999. These cases were assumed to represent normal hearts according to the following criteria: (1) sudden death associated with traumatic injury, (2) no medical history or physical and laboratory findings of cardiovascular disease process, (3) absence of clinically recognized systemic disorders, (4) absence of atherosclerosis of the major coronary arteries, and (5) normal cardiac weight. Septal specimens were taken to assess normal values of CVF in these hearts. A group of 24 healthy subjects (15 men and 9 women; mean age 57 years, range 31 to 66 years) who did not undergo the biopsy procedure was also studied to calibrate the values of PIP.
All subjects gave written informed consent to participate in the study, and the local committee on human research approved the study protocol. The study conformed to the principles of the Declaration of Helsinki.
Assessment of Left Ventricular Mass and
Function
Two-dimensional, targeted M-mode, and Doppler ultrasound
recordings were obtained in each patient as previously
described.16 18 Left ventricular mass and
interventricular septal thickness were measured, and LVMI
was calculated by dividing left ventricular mass by body
surface area. The following pulsed Doppler measurements were
obtained: maximal early transmitral velocity in diastole
(VE); maximal late transmitral velocity in
diastole (VA); and IVRT. The ejection fraction
was calculated from the measurements performed in a
99mTc ventriculography (multigated acquisition
scan, MUGA).
Determination of Serum PIP
Serum samples to determine PIP and CITP were taken at the time
of clinical studies and stored at -40°C for up to 6 months. Serum
PIP was determined by radioimmunoassay according to a method previously
described.16 The interassay and intra-assay variations for
determining PIP were 7% and 3%, respectively. The sensitivity (lower
detection limit) was 1.20 µg PIP/L.
Histomorphological Study
Transvenous endomyocardial biopsies were
taken from the middle area of the interventricular septum
with a bioptome Cordis 96 cm (7F) under fluoroscopic guidance after
angiographic examination. The biopsy procedure was well tolerated. For
each patient, 1 to 4 (mean 2.07) biopsy specimens were
analyzed. All together, these specimens represented
an average endomyocardial space of 2.49
mm2 for each patient.
Histological evaluation was performed without knowledge
of from which patient the tissue section had been obtained.
Myocardial samples were immediately fixed in 10% buffered
formalin, embedded in paraffin, and serially sectioned in 4-µm-thick
sections. Sections were stained with collagen-specific picrosirius red
(Sirius red F3BA in aqueous picric acid) according to Dolber and
Spach.20 CVF was determined by quantitative morphometry
with an automated image analysis system (Visilog 4.1.5.,
Noesis). Sections were analyzed under the microscope (x20),
and all the fields covering an endomyocardial area
were digitized. Images had a final resolution of 3.37
µm2/pixel (374x276 pixels). Stained collagen
areas (dark) were segmented by interactive gray-level thresholding of
shading-corrected images, and then the subendocardial regions were
interactively discarded. CVF was calculated as the sum of all
connective tissue areas divided by the sum of all connective tissue and
muscle areas in all the fields analyzed in each section. It has
been shown that the total CVF determined by this morphometric approach
is closely related to myocardial hydroxyproline
concentration.21 22 Repeated measurements were performed
to assess intraobserver and interobserver variability of
histomorphological data. To define the variability of repeated studies,
we calculated the coefficient of variation (CV) between the initial and
second measurements by use of the SD of differences from measurement of
the CVF in the studied patients. The coefficient of error, defined by
CV/
n, where n represents the number of measurements, was
used to describe the precision of the estimate.23
The abnormal accumulation of fibrous tissue was seen as a diffuse
increase in red-stained fibers (ie, interstitial fibrosis)
and as a localized deposition (ie, perivascular fibrosis and/or
microscopic scarring). Three histological grades of
interstitial fibrosis were characterized in biopsy tissue:
minimal (Figure 1A
), minimal to moderate
(Figure 1B), and severe (Figure 1C).
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Statistical Analysis
Kruskal-Wallis 1-way ANOVA followed by a Mann-Whitney
U test (adjusting the 
-level by Bonferroni inequality)
was used to assess the statistical significance in PIP between
normotensives and the 2 subgroups of hypertensives: those with
nonsevere fibrosis and those with severe fibrosis. Differences between
normotensives and hypertensives and between the 2 subgroups of
hypertensives were tested by a Student’s t test for
unpaired data once normality was demonstrated (Shapiro-Wilks test);
otherwise, a nonparametric test (Mann-Whitney U
test) was used. Categorical variables were analyzed by the
2 test or Fisher’s exact test when necessary.
The correlation between continuously distributed variables was
tested by univariate and multivariate
regression analysis. ROC curves allowed determination of the
overall performance of several biochemical (PIP) and
echocardiographic (LVMI,
VE/VA) criteria for
predicting severe fibrosis in hypertensive
patients.24 Values are expressed as mean±SEM. A
value of P<0.05 was considered statistically
significant.
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Results |
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Biopsy Data
Collagen volume fraction (CVF) ranged from 1.39% to 2.15% in normal hearts (mean 1.95±0.07%). CVF was out of range in all hypertensive patients but 1, ranging from 2.08% to 9.83% (mean 5.23±0.38%). Thus, CVF was higher (P<0.001) in the myocardium from hypertensive patients than in normal hearts.
Three patients exhibited minimal interstitial fibrosis, 15 patients exhibited mild to moderate interstitial fibrosis, and the remaining 8 patients exhibited severe interstitial fibrosis. Therefore, whereas patients from the first 2 categories were considered to be hypertensives with the nonsevere forms of interstitial fibrosis, patients from the third category were considered to be hypertensives with the severe form of interstitial fibrosis. Perivascular fibrosis was seen in 67% and 31% of patients with severe and nonsevere interstitial fibrosis, respectively. The frequency of microscopic scars was identical (40%) in the 2 subgroups of patients.
As expected, Figure 2 shows
that CVF was increased (P<0.05) in hypertensives with
severe fibrosis (7.60±0.44%) compared with hypertensives with
nonsevere fibrosis (4.08±0.21%) and normal hearts. In addition, CVF
was increased (P<0.05) in hypertensives with nonsevere
fibrosis compared with normotensives (Figure 2).
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Serum PIP
Serum concentration of PIP was higher (P<0.001)
in hypertensive patients than in normotensive subjects (118±6 versus
70±5 µg/L). As shown in Figure 3, serum concentration of PIP was higher (P<0.05) in
hypertensives with severe fibrosis (140±13 µg/L) than in
hypertensives with nonsevere fibrosis (108±6 µg/L) and
normotensives. Serum PIP was also increased (P<0.05) in
hypertensives with nonsevere fibrosis compared with normotensives
(Figure 3).
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A direct correlation was found between serum PIP and CVF
(r=0.471, P<0.02) in all hypertensives (Figure 4). Multivariate
analysis showed that mean arterial pressure and
left ventricular mass index (LVMI) enhanced the correlation
between PIP and CVF (r=0.649, P<0.01). No
significant correlations were found between PIP and other
parameters measured in this study.
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The receiver operating characteristic (ROC) curves show the
overall performance of PIP, LVMI, and the
VE/VA ratio for predicting severe
myocardial fibrosis (Figure 5). The area
under the ROC curve was larger for PIP (0.76±0.10) than for LVMI
(0.56±0.13) and for the VE/VA ratio
(0.51±0.14). Only the area under the ROC curve for PIP was
significantly higher (P<0.05) than 0.50.
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According to the ROC curves, the cutoff values of reference for
the 3 parameters tested were calculated (Table 1). The sensitivity and
specificity of each of these 3 values for predicting severe myocardial
fibrosis are presented in Table 1. Overall, the cutoff
value of PIP showed the best sensitivity and specificity. Thus, the
relative risk of presenting severe myocardial fibrosis was much
higher for hypertensive patients with PIP values >127 µg/L than for
hypertensive patients with LVMI values >122 g/m2
or hypertensive patients with VE/VA ratio
values <1.02 (Table 1).
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Clinical and Echocardiographic Aspects
The clinical parameters of the 2 subgroups of
hypertensive patients are presented in Table 2. Male patients were predominant in the
subgroup with nonsevere fibrosis, but the differences in sex
distribution between the 2 subgroups of patients were not statistically
significant. Although the duration of hypertension was almost twice as
great in hypertensives with severe fibrosis as in hypertensives with
nonsevere fibrosis, the differences did not reach statistical
significance. No significant differences were observed in the values of
blood pressure measured in the 2 subgroups of patients. However, the
distribution of the patients in the different stages of
arterial hypertension25 was
significantly different (P<0.001), with most hypertensives
with nonsevere fibrosis in stage 2 and most hypertensives with severe
fibrosis in stage 3. Whereas 44% of hypertensives in the subgroup with
nonsevere fibrosis had never been treated, only 25% of hypertensives
in the subgroup with severe fibrosis had never been treated.
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The calculated LVMI and the interventricular septal
thickness were similar in the 2 subgroups of patients (Table 3). The frequency of left
ventricular hypertrophy (defined as a LVMI
>125 g/m2)26 was 50% in
hypertensives with nonsevere fibrosis and 75% in hypertensives with
severe fibrosis; this difference was not statistically significant. The
values of VE/VA ratio and isovolumic relaxation
time (IVRT) were similar in the 2 subgroups of hypertensives (Table 3).
The presence of diastolic dysfunction (defined
as an altered VE/VA ratio and/or altered IVRT
according to age)27 was 61% in hypertensives with
nonsevere fibrosis and 62% in hypertensives with severe fibrosis; the
difference did not reach statistical significance. Similar values of
ejection fraction were measured in the 2 subgroups of hypertensives
(Table 3). None of the patients studied exhibited
systolic dysfunction.
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Discussion |
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The main findings of this study are as follows: (1) a strong association exists between histologically assessed collagen accumulation in biopsied myocardial tissue and serum PIP in patients with essential hypertension, and (2) serum PIP is more accurate than some echocardiographic parameters in the discrimination of severe myocardial fibrosis from nonsevere myocardial fibrosis in hypertensives.
Pathophysiological Meaning
The rate of extracellular synthesis of collagen type I can
be assessed by measuring the serum concentration of PIP, which is freed
during the extracellular processing of procollagen type I before
collagen molecules form fibers.28 This peptide is
eliminated from the blood by the liver.29 Taking into
account that hepatobiliary function was normal in hypertensive patients
studied here, it can be proposed that the abnormally high serum
concentration of PIP represents an increased production
of the peptide.
A number of observations have led to the proposal that increased production of PIP is a useful marker of stimulated fibrogenesis.13 Accordingly, the finding of elevated serum concentration of PIP in hypertensives with myocardial fibrosis is in agreement with our previous experimental15 17 and clinical16 findings and reinforces the idea that essential hypertension represents a condition characterized by fibrogenic hyperactivity.
As previously found by others,6 12 30 31 we did observe that all patients studied showed an excessive collagen accumulation into the myocardium. Furthermore, we found that serum PIP correlates directly with myocardial CVF in hypertensives. Therefore, it is tempting to speculate that increased serum PIP present in patients with essential hypertension may reflect an increased myocardial synthesis of fibrillar collagen type I. This can be of particular relevance in the subgroup of hypertensives characterized by very high concentrations of serum PIP and severe myocardial fibrosis.
Clinical Application
Because myocardial fibrosis is increased in several common
types of cardiac disease, including hypertensive heart disease,
performing noninvasive characterization of myocardial structure to
delineate the extent of collagen accumulation in tissue may play a
relevant role in the clinical outcome of these patients.
In this conceptual framework, some findings reported here may be of interest. First, as shown by the ROC curve analysis, serum PIP is a highly sensitive and specific parameter in the identification of severe myocardial fibrosis in hypertension. Second, hypertensives with serum concentrations of PIP >127 µg/L have an almost 5-fold higher probability of presenting with severe myocardial fibrosis than do hypertensives with serum PIP below this value. Third, serum PIP has the highest performance for estimating severe myocardial fibrosis when tested against the standard echocardiographic parameters of left ventricular anatomy (LVMI) and diastolic function (VE/VA ratio). Therefore, because the determination of serum PIP is simple, reproducible, and low-cost,32 it may be useful for screening for severe myocardial fibrosis in hypertensive patients, namely in those with stage 3 arterial hypertension.
Our results demonstrate that no association exists between the prevalence of left ventricular hypertrophy and diastolic dysfunction and the extent of myocardial fibrosis in hypertensives. In addition, we found that both LVMI and VE/VA ratio have a low performance for estimating severe myocardial fibrosis in hypertensives. These findings would suggest that the utility of conventional echocardiographic procedures in the identification of hypertensives with severe forms of myocardial fibrosis is questionable and that the development of alternative methodologies is desirable. In this regard, a correlation between echoreflectivity and histologically assessed collagen was recently shown in hypertensive patients,12 suggesting the possibility of noninvasive ultrasonic characterization of myocardial texture in hypertensive heart disease.
Limitations of the Study
Some limitations of the study should be acknowledged. The
majority of our patients were under antihypertensive treatment; even
though the treatment was inadequate in terms of blood pressure control
for all patients, it may have influenced the amount of fibrosis. It is
notable that although calcium channel blockers have been shown to
prevent myocardial fibrosis in SHR,33 34 we did observe
that these drugs were more frequently used in the subgroup of
hypertensives with severe myocardial fibrosis.
Second, because picrosirius red binds to collagen molecules other than type I, such as type III,35 and an excess of collagen type III deposition occurs in the left ventricle of patients with essential hypertension,4 we cannot exclude the possibility that myocardial fibrosis found in the hypertensives studied here is also due to increased deposition of fibril-forming collagen type III molecules.
Finally, it is clear that PIP detectable in serum is not exclusively heart-specific. Nevertheless, we have demonstrated that other extracardiac sources able to elevate serum PIP can be excluded in SHR with increased serum concentration of the peptide.15 In addition, we have shown that changes in the cardiac compartment of collagen type I alter concentrations of PIP in the circulation of SHR.15 Whether this is also the case in hypertensive patients deserves further studies.
Conclusions
For the first time, we show that serum levels of PIP
correlate with the extent of left ventricular fibrosis in
patients with essential hypertension. Thus, the measurement of serum
PIP could be practical and useful in the noninvasive assessment of
myocardial remodeling in arterial hypertension. In
particular, it might have clinical importance in documenting the extent
of collagen accumulation and in assessing pharmacological measures
designed to prevent its appearance or even to cause its regression.
Nevertheless, because of the limitations of this investigation, we are
aware that further large studies are necessary to definitively validate
this approach.
Received July 27, 1999; revision received October 18, 1999; accepted November 10, 1999.
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 B. Lopez, A. Gonzalez, J. Beaumont, R. Querejeta, M. Larman, and J. Diez Identification of a Potential Cardiac Antifibrotic Mechanism of Torasemide in Patients With Chronic Heart Failure J. Am. Coll. Cardiol., August 28, 2007; 50(9): 859 - 867. [Abstract] [Full Text] [PDF]
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 M M. Lindsay and F. G Dunn Biochemical evidence of myocardial fibrosis in veteran endurance athletes Br. J. Sports Med., July 1, 2007; 41(7): 447 - 452. [Abstract] [Full Text] [PDF]
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 R. Martos, J. Baugh, M. Ledwidge, C. O'Loughlin, C. Conlon, A. Patle, S. C. Donnelly, and K. McDonald Diastolic Heart Failure: Evidence of Increased Myocardial Collagen Turnover Linked to Diastolic Dysfunction Circulation, February 20, 2007; 115(7): 888 - 895. [Abstract] [Full Text] [PDF]
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B. Lopez, A. Gonzalez, R. Querejeta, M. Larman, and J. Diez Alterations in the Pattern of Collagen Deposition May Contribute to the Deterioration of Systolic Function in Hypertensive Patients With Heart Failure J. Am. Coll. Cardiol., July 4, 2006; 48(1): 89 - 96. [Abstract] [Full Text] [PDF]
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 M. C. C. Borges, R. C.R. Colombo, J. G. F. Goncalves, J. d. O. Ferreira, and K. G. Franchini Longitudinal Mitral Annulus Velocities Are Reduced in Hypertensive Subjects With or Without Left Ventricle Hypertrophy Hypertension, May 1, 2006; 47(5): 854 - 860. [Abstract] [Full Text] [PDF]
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 M. J. Goikoetxea, J. Beaumont, A. Gonzalez, B. Lopez, R. Querejeta, M. Larman, and J. Diez Altered cardiac expression of peroxisome proliferator-activated receptor-isoforms in patients with hypertensive heart disease Cardiovasc Res, March 1, 2006; 69(4): 899 - 907. [Abstract] [Full Text] [PDF]
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 C. Cuspidi, M. Ciulla, and A. Zanchetti Hypertensive myocardial fibrosis Nephrol. Dial. Transplant., January 1, 2006; 21(1): 20 - 23. [Full Text] [PDF]
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H. Izawa, T. Murohara, K. Nagata, S. Isobe, H. Asano, T. Amano, S. Ichihara, T. Kato, S. Ohshima, Y. Murase, et al. Mineralocorticoid Receptor Antagonism Ameliorates Left Ventricular Diastolic Dysfunction and Myocardial Fibrosis in Mildly Symptomatic Patients With Idiopathic Dilated Cardiomyopathy: A Pilot Study Circulation, November 8, 2005; 112(19): 2940 - 2945. [Abstract] [Full Text] [PDF]
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 S H Poulsen, N H Andersen, L Heickendorff, and C E Mogensen Relation between plasma amino-terminal propeptide of procollagen type III and left ventricular longitudinal strain in essential hypertension Heart, May 1, 2005; 91(5): 624 - 629. [Abstract] [Full Text] [PDF]
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D. Rizzoni, E. Porteri, C. De Ciuceis, I. Sleiman, L. Rodella, R. Rezzani, S. Paiardi, R. Bianchi, G. Ruggeri, G. E.M. Boari, et al. Effect of Treatment With Candesartan or Enalapril on Subcutaneous Small Artery Structure in Hypertensive Patients With Noninsulin-Dependent Diabetes Mellitus Hypertension, April 1, 2005; 45(4): 659 - 665. [Abstract] [Full Text] [PDF]
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R. Querejeta, B. Lopez, A. Gonzalez, E. Sanchez, M. Larman, J. L. Martinez Ubago, and J. Diez Increased Collagen Type I Synthesis in Patients With Heart Failure of Hypertensive Origin: Relation to Myocardial Fibrosis Circulation, September 7, 2004; 110(10): 1263 - 1268. [Abstract] [Full Text] [PDF]
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M. M. Ciulla, R. Paliotti, A. Esposito, J. Diez, B. Lopez, B. Dahlof, M. G. Nicholls, R. D. Smith, L. Gilles, F. Magrini, et al. Different Effects of Antihypertensive Therapies Based on Losartan or Atenolol on Ultrasound and Biochemical Markers of Myocardial Fibrosis: Results of a Randomized Trial Circulation, August 3, 2004; 110(5): 552 - 557. [Abstract] [Full Text] [PDF]
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G. B. J. Mancini, B. Dahlof, and J. Diez Surrogate Markers for Cardiovascular Disease: Structural Markers Circulation, June 29, 2004; 109(25_suppl_1): IV-22 - IV-30. [Full Text] [PDF]
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B. Lopez, R. Querejeta, A. Gonzalez, E. Sanchez, M. Larman, and J. Diez Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure J. Am. Coll. Cardiol., June 2, 2004; 43(11): 2028 - 2035. [Abstract] [Full Text] [PDF]
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A Rossi, M Cicoira, G Golia, L Zanolla, L Franceschini, P Marino, M Graziani, and P Zardini Amino-terminal propeptide of type III procollagen is associated with restrictive mitral filling pattern in patients with dilated cardiomyopathy: a possible link between diastolic dysfunction and prognosis Heart, June 1, 2004; 90(6): 650 - 654. [Abstract] [Full Text] [PDF]
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N. H. Andersen, S. H. Poulsen, K. Helleberg, P. Ivarsen, S. T. Knudsen, and C. E. Mogensen Impact of Essential Hypertension and Diabetes Mellitus on Left Ventricular Systolic and Diastolic Performance Eur J Echocardiogr, December 1, 2003; 4(4): 306 - 312. [Abstract] [Full Text] [PDF]
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R. Lombardi, S. Betocchi, M. A. Losi, C. G. Tocchetti, M. Aversa, M. Miranda, G. D'Alessandro, A. Cacace;, Q. Ciampi, and M. Chiariello Myocardial Collagen Turnover in Hypertrophic Cardiomyopathy Circulation, September 23, 2003; 108(12): 1455 - 1460. [Abstract] [Full Text] [PDF]
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 B. Dahlof End-organ damage: does it really matter how we prevent it? Eur. Heart J. Suppl., August 1, 2003; 5(suppl_F): F33 - F39. [Abstract] [PDF]
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 F. Marin, V. Roldan, V. Climent, A. Garcia, P. Marco, and G. Y.H. Lip Is Thrombogenesis in Atrial Fibrillation Related to Matrix Metalloproteinase-1 and Its Inhibitor, TIMP-1? Stroke, May 1, 2003; 34(5): 1181 - 1186. [Abstract] [Full Text] [PDF]
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