American Heart Journal
Volume 152, Issue 1 , Pages 93.e1-93.e6, July 2006

Aortic stiffness correlates with an increased extracellular matrix turnover in patients with dilated cardiomyopathy

Divisione Clinicizzata di Cardiologia, Dipartimento di Scienza Biomediche e Chirurgiche, Università di Verona, Verona, Italy

Received 9 November 2005; accepted 13 April 2006.

Article Outline

Background

An increased extracellular matrix (ECM) turnover has been associated with poor survival in patients with chronic heart failure (CHF) due to dilated cardiomyopathy (DCM). However, the influence of the accelerated collagen turnover on the progressive large artery stiffening process characterizing CHF has not been clarified. This is relevant because aortic stiffening imposes an additional systolic load and impairs exercise tolerance in CHF patients. Therefore, we investigated whether the serum aminoterminal propeptide of type III collagen (PIIINP), an established marker of ECM turnover and tissue fibrosis in DCM, was associated with aortic stiffness in DCM patients.

Methods and Results

A total of 89 patients with clinical diagnosis of DCM (age 62 ± 9 years, 80% men, mean ejection fraction 34% ± 8%) were selected. Aortic pulse-wave velocity (PWV), a well-established marker of aortic stiffness, was measured by Doppler ultrasonography. Serum concentration of PIIINP was determined by radioimmunoassay. Mean aortic PWV was 5.7 ± 2.3 m/s, and PIIINP was 5.0 ± 1.3 μg/L. The variables correlated with aortic PWV were age (r = 0.33, P = .002), PIIINP (r = 0.30, P = .005), heart rate (r = 0.27, P = .02), stroke volume (r = −0.24, P = .03) and New York Heart Association class (r = 0.25, P = .02). In a multivariate analysis, age (P = .02) and PIIINP (P = .01) were independently related with aortic PWV, accounting for 27% of its variance.

Conclusions

Higher serum PIIINP levels are independently associated with a stiffer aorta in DCM patients. This suggests that abnormalities in the ECM turnover might involve the proximal elastic vasculature and could partially explain the progressive large artery stiffening process characterizing CHF.

 

Chronic heart failure (CHF) is characterized by a progressive rise in large artery stiffness.1, 2, 3, 4, 5 This is important because the elastic properties of the aorta are crucial for optimal ventricular-vascular coupling. Reduced distensibility of the aorta alters its cushioning properties and increases pulse-wave velocity (PWV), which causes an earlier return of the reflected wave that arises from the peripheral vascular arterial sites.6 The premature reflected wave moving from diastole to systole increases left ventricular systolic stress and impairs coronary perfusion.6 The ability of the aorta to buffer the pulsatile component of the left ventricular afterload relies on a complex network of elastin, collagen, and smooth muscle cells.6, 7 Changes in the relative proportion of these constituents alter its elastic behavior: elastin is easily stretched, whereas collagen, which is much stiffer, renders the arterial wall less elastic.7 Type III collagen is the most abundant form of collagen found in the media layers of the human aorta.8 It is also found in dense deposits alongside the elastic laminae and in the intima layer of this large elastic conduit.8 The aminoterminal propeptide of type III procollagen (PIIINP) is an extension peptide of type III procollagen, which is cleaved off stoichiometrically during conversion from type III procollagen to type III collagen and liberated to serum.9 Elevated serum concentrations of PIIINP are considered a marker of higher collagen turnover and tissue fibrosis in diverse pathologic conditions.9 Various clinical studies have reported that serum concentrations of PIIINP are increased in CHF,10, 11 hypertension,12 and myocardial infarction.13 Raised serum levels of PIIINP have also been reported to be an independent predictor of worse outcome in patients with CHF.10, 11, 14 Furthermore, the RALES investigators observed that the benefit of spironolactone treatment on mortality in patients with CHF paralleled a reduction in plasma concentrations of PIIINP.11 In addition, patients with heart failure in optimal treatment including angiotensin-converting enzyme (ACE) inhibitors showed decreased aortic compliance, which was inversely correlated with the aldosterone escape phenomenon.15 Experimental data suggest that collagen accumulation due to sustained neurohormonal activation might involve not only the heart16 but also the large elastic arteries.17, 18, 19, 20, 21 Because the reduced distensibility of the elastic arteries has been related with increased severity of CHF2, 4, 5 and impaired exercise tolerance,4, 5, 22 greater understanding of the determinants of the stiffening process in dilated cardiomyopathy (DCM) patients is needed. Therefore, this study was undertaken to assess the possible relationship between serum concentrations of PIIINP and aortic stiffness, measured noninvasively as aortic pulse wave velocity (PWV) in patients with CHF due to DCM.

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Methods 

Study population 

We enrolled 89 patients in a stable clinical status who were followed up at our Outpatient Heart Failure Clinic. All subjects gave informed consent for participation in the study, which was approved by the Ethics Committee of the Ospedale Civile Maggiore of Verona. All patients had a left ventricular ejection fraction (LVEF) <45% and a duration of heart failure of at least 6 months; all were on standard therapy for heart failure and on optimal diuretic dose. Exclusion criteria were (1) renal failure (s-creatinine >150 μmol/L), chronic liver disease, malignancies, or chronic inflammatory disorders because these pathologic conditions might influence PIIINP levels; (2) presence of atrial fibrillation; and (3) more than mild aortic regurgitation as assessed by color Doppler.

Echocardiography 

A complete Doppler echocardiography examination was performed. Left ventricular end-diastolic and end-systolic volumes (area-length method; monoplane 4-chamber view) and LVEF were measured. Mitral E- (Emax) and A- (Amax) wave velocities, E/A ratio, and E-wave deceleration time were measured at the mitral flow Doppler examination, placing the pulsed Doppler sample volume at the tip of the mitral leaflets. Stroke volume (SV) was measured as the product of the left ventricular outflow tract annulus area and time velocity integral measured at the same level by pulsed-wave Doppler.

Pulse wave velocity 

Pulse wave velocity is considered a good surrogate for arterial distensibility because it correlates with direct measurement of arterial stiffness.6 As stated by the Moens Koerteweg equation, PWV, which is proportional to the square root of Young's elastic modulus, travels faster in stiffer arteries.6 Pulsed Doppler was used to measure the time taken by the pulse wave to travel along the thoracic aorta.4, 23 To measure the flow at the aortic arch, the transducer was placed at the suprasternal notch, and the sample volume was placed distally to the origin of the left subclavian artery. The distance (d1) between the transducer and the sample volume was then measured in a 2D frame. The flow in the abdominal aorta was determined from the subcostal approach. The distance (d2) from the suprasternal notch to the position of the probe in the abdomen was then measured with a tape measure. The distance (d) between the 2 sample volumes was calculated as d2 − d1. The R wave of the QRS complex of a simultaneously recorded electrocardiogram was used as a fixed reference time point. The time (t) between the R wave on the electrocardiogram and the foot of each flow wave was subtracted to calculate the transit time, and PWV was then calculated as the distance traveled by the pulse wave divided by the time required [PWV (m/s) = d/t].

Angiographic analyses 

All patients underwent coronary angiography in routine standardized projections. A scoring system was used to assess the extension of atherosclerotic disease in the coronary artery tree.24 Coronary angiograms were visually assessed and scored using a vessel score and a stenosis score. The vessel score reflected the number of coronary arteries with ≥75% reduction in lumen diameter. The stenosis score was based on the most severe stenosis found in each of the main coronary segments evaluated (left main stem, left anterior descending, main diagonal branch, first septal perforator, left circumflex, obtuse marginal and posterolateral branches, proximal and middle right coronary artery, and main posterior descending artery). Stenosis score grading was as follows: lesions with 1% to 49% reduction in lumen diameter were classified as grade 1; stenosis ranging from 50% to 74% as grade 2; stenosis from 75% to 99% of lumen diameter as grade 3; and total coronary occlusions as grade 4.

Biochemical and hormonal measurements 

Venous blood samples were drawn on the day of the study after a 30-minute supine rest in a fasting state between 8 am and 9 am. The general biochemical evaluation included measurement of serum electrolytes, creatinine, uric acid, and blood glucose. Biochemical parameters were measured by routine laboratory methods. Renin and aldosterone were determined by a sandwich radioimmunoassay (Biochem Immuno System, Italy). Intraassay and interassay coefficients of variation (CVs) for renin were 5% and 6%, respectively, and for aldosterone 7% and 8%. Plasma epinephrine and norepinephrine levels were measured by high-performance liquid chromatography with electrochemical detection. Intraday and interday CVs for epinephrine were 7% and 8.5%, respectively, and for norepinephrine, 4.5% and 5%. Plasma concentrations of PIIINP were measured by radioimmunoassay (Orion Diagnostica, Finland) with intraassay and interassay CVs of 5% and 8%, respectively. The sensitivity (lower detection limit) was 0.2 μg/L.

Statistical analysis 

All data are given as mean ± SD. Univariate correlation between aortic PWV and other clinical and hemodynamic variables were calculated. A multivariate model was constructed using those clinical and hemodynamic variables significantly related with PWV at the univariate analysis. Comparison between those subjects with ischemic and nonischemic etiology was made using a 2-tailed unpaired Student t test. Statistical significance was set at a level of P < .05. A commercially available statistical software package was used (Statview 4.5, Abacus Concept Inc, Cary, NC).

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Results 

The clinical and echocardiographic characteristics of the population are shown in Table I. Most of the patients (92%) were treated with ACE inhibitors (captopril, enalapril, or ramipril), 68% with β-blockers (metoprolol or carvedilol), and 90% with diuretics.

Table I. Clinical, hemodynamic, and neurohormonal characteristics of the study population
VariableValue
Age (y)62 ± 9
Male sex71 (80)
NYHA class I-II49 (56)
Ischemic pathogenesis51 (63)
Vessel score (no.)1.5 ± 1.1
Stenosis score (U)7.6 ± 4.8
HR (beat/min)67 ± 12
Systolic BP (mm Hg)133 ± 18
Diastolic BP (mm Hg)81 ± 11
Mean BP (mm Hg)99 ± 12
Pulse pressure (mm Hg)52 ± 14
SV (mL)76 ± 16
End-diastolic LV volume (mL)269 ± 100
End-systolic LV volume (mL)185 ± 90
LV mass (g)342 ± 99
LVEF (%)34 ± 8
Emax (m/s)0.62 ± 0.25
E/A ratio1.15 ± 1.07
Dte (ms)210 ± 79
PWV (m/s)5.7 ± 2.3
Renin (mIU/L)118.8 ± 177.7
Aldosterone (nmol/L)0.26 ± 0.2
Epinephrine (ng/L)48.6 ± 33.3
Norepinephrine (ng/L)416.3 ± 235.6
PIIINP (μg/L)5.0 ± 1.3

Values are presented as mean ± SD or n (%). HR, Heart rate; LV, left ventricular; BP, blood pressure; Dte, E-wave deceleration time.

The mean PWV was 5.7 m/s, and a wide range of measurement was observed (2.7-12.9 m/s). The clinical and hemodynamic variables associated with PWV are reported in Table II. PWV was significantly related with severity of CHF, expressed by New York Heart Association (NYHA) class and with increasing age of patients. A higher PWV was also associated with lower SV. Lower diastolic blood pressure was associated with a higher PWV, whereas pulse pressure and mean blood pressure were positively related to aortic PWV, although these relationships did not reach statistical significance. The diameter of the aorta taken from the subcostal view over the region at which PWV was measured did not relate to PWV. There were no significant relations between PWV and plasma venous levels of norepinephrine, epinephrine, renin, and aldosterone (Table III). A significant correlation was found between serum PIIINP concentration and PWV (Figure 1). Propeptide of type III collagen serum concentrations did not show a significant relation with the severity of the coronary atherosclerosis score. No significant differences were observed between aortic PWV and in PIIINP serum concentrations in subjects with ischemic as against nonischemic etiology (5.8 ± 2.3 vs 5.5 ± 2.0 m/s, P = .6, and 5.05 ± 1.4 vs 4.99 ± 1.3 μg/L, P = .8). A multivariate model, including those variables significantly related with aortic PWV at the univariate analysis, was able to predict 27% of the variability of aortic PWV (age P = .02, aortic SV P = .1, PIIINP P = .01, heart rate P = .4, NYHA class P = .7, overall r = 0.52, P = .0006) (Table IV).

Table II. Linear regression analysis of clinical and hemodynamic predictors of PWV (Univariate analysis)
VariablesrP
Age (y)0.33.002
NYHA class0.25.02
Smoking0.07.5
Creatinine (μmol/L)0.10.4
Sodium (mmol/L)0.02.8
Uric acid (mmol/L)0.03.8
Systolic BP (mm Hg)0.04.7
Diastolic BP (mm Hg)−0.19.1
Mean BP (mm Hg)0.15.2
Pulse pressure (mm Hg)0.16.2
HR (beat/min)0.27.02
SV (mL)−0.24.03
LV mass (g)0.08.7
LVEF (%)0.06.6
Abdominal aorta diameter (cm)0.13.8
Vessel score0.16.2
Stenosis score0.15.2
Table III. Linear regression analysis of neurohormonal predictors of PWV (univariate analysis)
VariablesrP
Renin (mIU/L)0.05.7
Aldosterone (nmol/L)0.09.5
Epinephrine (ng/L)0.05.7
Norepinphrine (ng/L)0.14.2
PIIINP (μg/L)0.30.005
Table IV. Clinical, hemodynamic and neurohormonal predictors of PWV (multivariate analysis)
VariablesP
Age (y).02
SV (mL).1
HR (beat/min).4
NYHA class.7
PIIINP (μg/L).01

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Discussion 

The present study showed that in patients with DCM, higher serum levels of PIIINP, an established marker of collagen synthesis and tissue fibrosis, were independently related to aortic stiffness as assessed by PWV.

Different functional and structural mechanisms might be responsible for the substantial elastic artery stiffening process in patients with CHF due to DCM. Alterations in the production and availability of endothelial-derived relaxing factors25 or the increased generation of vasoconstrictor substances26 might increase the vascular tone, leading to greater aortic stiffness. However, beyond these functional alterations, it is reasonable to speculate that disease-induced structural changes of the aortic wall might also occur. Recently, reduced distensibility of the aorta22 and other large arteries5 was found to correlate with wall thickening in both nonsystolic and systolic heart failure, suggesting possible modifications in the wall composition of these elastic conduits. Interestingly, in the present study population mean blood pressure, which is the distending pressure that causes a functional decrease in arterial distensibility, did not significantly relate to aortic PWV, suggesting that this parameter is not only a surrogate for blood pressure but may also reflect the presence of disease-linked alterations of this large artery segment. Analogous observations have been reported in patients with end-stage renal disease27 and in coronary artery disease.28 In addition, the diameter of the aorta, taken at the level at which PWV was measured, did not relate to aortic PWV, suggesting that intrinsic aortic wall properties rather than the diameter were the major determinants of elasticity.

The observation that PIIINP correlated with aortic stiffness independently of blood pressure is particularly important because the role of hormonal substances stimulated by nonhemodynamic mechanisms promoting collagen synthesis in the vascular wall of patients with DCM must be taken into consideration. Experimental studies reported that angiotensin II and aldosterone infusion, simulating the chronic elevations of these hormones in heart failure, caused collagen accumulation not only in the heart but also in the aortic wall, independently of the loading condition.17, 18 Interestingly, nonantihypertensive doses of ACE inhibitors were shown to prevent aortic collagen deposition.19 Similarly, aldosterone was shown to promote aortic collagen accumulation through nonhemodynamic mechanisms, probably via mineralcorticoid receptors, which are very numerous in the large elastic artery wall,29 whereas spironolactone was able to prevent myocardial and aortic fibrosis despite no hypotensive effect.20, 21 On the other hand, both spironolactone11 and ACE inhibitors12 were able to reduce plasma concentrations of PIIINP in CHF11 and in hypertensive subjects,12 further confirming the role of the renin angiotensin aldosterone system in modulating collagen turnover.

It is also widely recognized that CHF is a sodium- and water-retentive condition through the sustained activation of the renin angiotensin aldosterone system and that this may influence arterial distensibility through various mechanisms. First, although sodium and water accumulation within the arterial wall was shown to cause wall edema, increasing vascular stiffness,30 this is unlikely to be the case in the present study population because all subjects were on optimal diuretic treatment, and there was no edema at the time of the study. Second, in experimental settings, higher sodium intake determined a decrease in large artery distensibility promoting extracellular matrix (ECM) synthesis with minimal changes in blood pressure.31 Interestingly, this pressure-independent effect of sodium on the ECM was associated with changes in the arterial smooth muscle cell phenotype and was prevented by lowering sodium intake and using diuretics.31

It is also reasonable to speculate not only that vascular fibrosis might be promoted by the neurohormonal cascade but also that the inflammatory mediators, which are important in the progression of heart failure, might be involved in the accelerated ECM turnover, which contributes to both myocardial32 and vascular fibrosis.

Aging is another recognized determinant of large artery stiffening, and in our population, age was an independent predictor of aortic PWV. Interestingly, the age-related stiffening process is characterized not only by a progressive fraying of the elastic lamellae and calcium deposition but also by aldosterone-mediated collagen accumulation in the arterial wall.21 However, the age-independent relation between PIIINP concentration and aortic distensibility observed in the present study suggests that the fibrotic vascular changes that occur with aging are probably dissociated from the accelerated ECM turnover, which characterizes CHF.

Furthermore, the lack of a significant difference in either PIIINP serum concentrations or aortic PWV between ischemic and nonischemic forms of DCM, as well as the absence of a significant relation between PIIINP concentrations and the degree of coronary atherosclerosis, suggests that in patients with DCM, the stiffening process of the aorta may be at least partly independent of the underlying atherosclerosis.

This is consistent with earlier observations2, 4 and supports the idea that the changes in ECM components of the aortic wall due to sustained neurohormonal activation or stimulated by inflammatory cytokines might, at least in part, have a more detrimental effect than atherosclerosis in stiffening this conduit.

Study limitations 

Some limitations of the present study should be recognized. First, we did not perform structural analyses of the aortic wall. Therefore, we cannot demonstrate a causative link between PIIINP and aortic PWV. Moreover, we cannot exclude that changes in other proteins found in the aortic wall (ie, fibrillin and fibronectin), which modulate ECM protein interactions,28, 33 might play a key role in the process of large arterial stiffening in DCM patients. In fact, eplerenone, an antialdosteronic drug able to improve survival in patients with left ventricular systolic dysfunction,34 was reported to ameliorate large artery distensibility by preventing fibronectin accumulation.33 In addition, it should be borne in mind that the activity of metalloproteinases that regulate ECM turnover35 might also influence the elastic properties of the aortic wall. Furthermore, our subjects were already taking drugs influencing both plasma levels of neurohormones and large artery distensibility, and this might at least partly explain the lack of a significant relation between neurohormones and aortic distensibility. It should also be acknowledged that the relative composition of the tensile apparatus of the conduit vessels varies from proximal to distal sites, so that the relation found between PIIINP and the segment of the descending aorta we considered might not be valid for other large artery districts.

Conclusion 

In conclusion, this study suggests a possible link between higher serum levels of PIIINP, a marker of increased collagen turnover and tissue fibrosis, and increased aortic stiffness in patients with CHF due to DCM. Furthermore, these data support the hypothesis that in patients with DCM, the stiffening process of the aorta could be at least partly independent of the underlying etiology of the cardiomyopathy. This finding has potential clinical implications because changes in aortic wall elastic properties might become an additional therapeutic target in patients with DCM.

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PII: S0002-8703(06)00396-6

doi:10.1016/j.ahj.2006.04.026

American Heart Journal
Volume 152, Issue 1 , Pages 93.e1-93.e6, July 2006

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