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European Journal of Heart Failure 2005 7(1):43-48; doi:10.1016/j.ejheart.2004.04.008
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© 2004 European Society of Cardiology

Chronic heart failure is associated with vascular remodeling of the brachial artery

Gerhard Poelzla,*, Matthias Fricka, Heike Huegela, Benedikt Lacknera, Hannes F. Albera, Johannes Maira, Manfred Heroldb, Severin Schwarzachera, Otmar Pachingera and Franz Weidingera

a Division of Cardiology, Department of Medicine University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
b Division of General Medicine, Department of Medicine University of Innsbruck, Austria

* Corresponding author. Tel.: +43-512-504; fax: +43-512-504-3264. E-mail address: gerhard.poelzl{at}uklibk.ac.at


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Aims: Endothelial dysfunction has been shown to correlate with severity of congestive heart failure (CHF) and recent data suggest morphological changes of peripheral vasculature to be associated with the syndrome. We therefore investigated the hypothesis that vascular remodeling is associated with functional changes in peripheral conduit arteries and with systemic overexpression of ET-1 in patients suffering from CHF.

Methods and results: 57 consecutive patients referred to the Innsbruck Heart Failure and Transplantation Program (EF=23±7%) and 16 matched controls (EF=60±5%) were studied. Flow-mediated vasodilation (FMD), nitroglycerin-mediated vasodilation (NMD), wall thickness (WT), and incremental elastic modulus (Einc) were assessed by high-resolution ultrasound of the brachial artery. FMD (P=0.004) and NMD (P=0.02) were significantly higher in controls as compared to moderate and severe CHF patients. In contrast, brachial artery-wall thickness (BA-WT) was increased in severe CHF patients (P=0.038). BA-WT was significantly correlated with both FMD (r=–0.28; P=0.049) and NMD (r=–0.38; P=0.003), and with the Einc (r=0.45, P=0.001). Lumen diameter was not different among groups. In patients with BA-WT>0.31 mm, bigET-1 was higher compared to BA-WT<0.31 mm (P<0.05).

Conclusion: CHF is associated with remodeling of the brachial artery, which is characterized by morphological, mechanical and functional changes of the vessel wall. Endothelin-1 may play a role in the vascular remodeling process.

Key Words: Endothelium • Heart failure • Growth substances • Remodeling • Vasculature

Received September 16, 2003; Revised February 18, 2004; Accepted April 7, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Chronic heart failure (CHF) is a common and disabling condition with substantial morbidity and mortality [1]. LV remodeling, which is inherent to CHF is characterized by progressive changes in LV function and geometry and is centrally involved in disease progression. There is accumulating evidence that remodeling of the peripheral vasculature also contributes to the heart failure syndrome together with endothelial dysfunction, which has been shown to be related to severity of CHF [2–6]. Growth factors such as endothelin-1 (ET-1) appear to be involved in the process of vascular remodeling [7].

Therefore, in this study we investigated the hypothesis that vascular remodeling is associated with functional changes in peripheral conduit arteries and with systemic overexpression of ET-1 in patients suffering from CHF.

For evaluation of morphological and functional changes in conduit arteries we performed high-resolution ultrasound of the brachial artery (BA), which is an established method for the assessment of nitric oxide (NO)-mediated and NO-independent vasodilation [8]. In addition, this method has been used for the assessment of brachial artery-wall thickness (BA-WT) in patients with coronary artery disease [9,10].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients
Fifty-seven (57) consecutive patients referred to the Innsbruck Heart Failure and Transplantation program were studied. All patients gave informed consent to participate in the study. Investigations were done in accordance with the Declaration of Helsinki. All patients underwent screening by clinical history and physical examination, routine hematology and biochemical analysis, ECG, and transthoracic echocardiography. Coronary angiography was performed when deemed clinically necessary.

Sixteen (16) patients matched for age, gender, and cardiovascular risk factors, and with preserved LV-function served as controls. Coronary artery disease in these patients was excluded by coronary angiography.

Coronary risk factors were assessed as follows: Smokers were defined as subjects who had smoked regularly during the previous 12 months [11]. Hypertension was defined as a systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg [=hypertension stage I in JNC-V definition [12]] based on the average of two or more readings taken at each of two or more different days or as current use of antihypertensive drugs. Subjects with plasma LDL cholesterol level>130 mg/dl or on cholesterol lowering therapy were classified as hypercholesterolemic patients [11]. Patients were considered as diabetic if they were under treatment with insulin or oral hypoglycemic agents or if fasting blood glucose exceeded 140 mg/dl [11]. A family history of CAD and a history regarding diabetes were obtained.

2.2. Ultrasound studies of the BA
High-resolution ultrasound (13 MHz, Acuson Sequoia C 256, USA) of the brachial artery (BA) was performed for the assessment of morphological, functional, and mechanical properties as described previously in detail [8–10]. Ultrasound examination was done by an observer blinded to the patient's diagnoses. Medication was not stopped before examination. After a resting period of at least 10 min in supine position images were stored to the peak of the T-wave on the hard disk for off-line measurements.

Morphologic parameters: Brachial artery-wall thickness (BA-WT) at the far wall was measured directly as the distance between lumen-intima and media-adventitia border by using RES (regional expansion system) in addition to 13 MHz ultrasound. Measurements were made at two sites per image in four different images per patient. The mean of eight measurements was defined as BA-WT. In addition, wall cross sectional area (WCSA) was calculated to assess possible influences of lumen diameter on BA-WT measurements (as to the formula see the following text).

Mechanical parameters: For calculation of incremental elastic modulus (Einc), end-diastolic (Ddia) and peak systolic luminal diameters (Dsys) were measured in M-mode-image with longitudinal B-mode guiding. BA mechanical properties were calculated according to the following formula:


Formula



Formula

Cross sectional distensibility (CD)=(2{Delta}DxDdia+{Delta}D2)/({Delta}PxDdia2) where {Delta}D is the difference between Ddia and Dsys, {Delta}P is the difference between systolic pressure (Ps) and diastolic pressure (Pd), and {gamma} is BA-WT/(Ddia/2) ratio [13].

Blood pressure was taken non-invasively by manual sphygmomanometer immediately after the assessment of the mechanical parameters.

Brachial artery function: Changes in vessel diameter (intima to intima) after reactive hyperemia (FMD) and sublingual nitroglycerin (NMD) were examined according to previously described methods [9,10]. In brief, after recording of resting diameters a cuff was placed on the upper arm and inflated to suprasystolic levels for 5 min. The cuff was deflated and serial post-hyperemia scans were stored on the hard disk. When BA diameter had returned to baseline, 0.8 mg of nitroglycerin (NTG) was given sublingually and diameters within the following 10 min were recorded. Vasodilation (FMD, NMD) was calculated as percent change in diameter compared to baseline. Inter- and intraobserver variability of these parameters in our laboratory have been reported previously [14].

2.3. Laboratory analyses
Venepuncture for blood sampling was carried out after 30 min of supine rest. Big Endothelin-1 (bigET-1) plasma levels were measured by ELISA (BIOMEDICA, Vienna, Austria). We evaluated circulating bigET-1, the precursor of ET-1, on the basis of the assumption that it may reflect ET overproduction more accurately than circulating ET-1. Because ET-1, like other peptides with biological activity, is rapidly cleared and acts mainly paracrine, the majority of it may never reach the circulation [15,16]. However, precursor elements without biological activity often circulate in higher concentrations, integrate the secretory activity of endocrine cells, and open an analytic window. In addition, there is no evidence for an increase in ET-converting enzyme activity in patients with heart failure compared with normal patients [17]. Serum levels of NT-proBNP were obtained by a commercially available enzyme immunometric assay on an automated analyzer (Elecsys® 1010, Roche Diagnostics, Vienna, Austria).

2.4. Statistical analysis
Results are presented as mean±S.D. for continuous, and as percentages for categorical data. Normal distribution was tested using the Kolmogorov–Smirnov test. Pearson's or Spearman's correlation coefficients were determined to assess the association of vascular parameters. Patient characteristics between groups were compared using ANOVA with post-hoc LSD-test for continuous variables and {chi}2-test or Fisher's exact test for categorical variables, as appropriate. The SPSS 7.5.2G statistical software package (SPSS Inc.) was used for all calculations.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Baseline characteristics
Baseline characteristics of controls and patients with moderate and severe heart failure are presented in Table 1. Groups were comparable regarding clinical characteristics and coronary risk factors except for hypercholesterolemia. Left ventricular ejection fraction (LV-EF), left ventricular enddiastolic diameter (LVEDD), and heart rate were different between controls and heart failure patients whereas no differences were found among heart failure groups. Also, ischemic heart disease was distributed equally among heart failure patients. NT-proBNP levels were significantly different between groups and increased according to severity of the heart failure syndrome (Fig. 1). Baseline medication is shown in Table 2.


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  		Table 1 Characteristics of patients

 


Figure 1
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  		Fig. 1 Differences in NT-proBNP serum levels and bigET-1 plasma levels in controls and in patients with moderate (NYHA I/II) and severe (NYHA III/IV) heart failure symptoms. *P<0.05.

 


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  		Table 2 Baseline medication

 
3.2. Arterial structure
Systolic lumen diameter at rest (B mode) was identical among groups (4.2±0.6 mm). Interobserver variability for resting diameters in our study was 0.06±0.04 mm (r=0.98; P<0.001). Accurate assessment of BA-WT was feasible in 91% of CHF patients and in all controls. Interobserver and intraobserver variability for the measurements of BA-WT were 0.02±0.02 mm (r=0.89; P<0.001), and 0.03±0.02 mm (r=0.92; P<0.001; Fig. 2), respectively. BA-WT and WCSA were highly correlated (r=0.91, P<0.001) indicating no relevant influence of lumen diameter on the accuracy of BA-WT measurements. Patients with severe heart failure demonstrated significantly higher BA-WT (344±96 µm) than patients with moderate symptoms (297±67 µm) and controls (289±54 µm) (P=0.03 and P=0.02, respectively; Fig. 2). There was no relevant difference between controls and patients with moderate heart failure. No association was found between BA-WT and the etiology of CHF.


Figure 2
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  		Fig. 2 Differences in brachial artery functional (FMD, NMD), morphologic parameters (BA-WT), and mechanical properties in controls and in patients with moderate (NYHA I/II) and severe (NYHA III/IV) heart failure symptoms. FMD, flow-mediated vasodilation; NMD, nitroglycerin-mediated vasodilation; BA-WT, brachial artery wall thickness; *P<0.05; **P≤0.001.

 
3.3. Wall mechanics
Incremental elastic modulus (Einc) was higher in severe and moderate CHF patients as compared to controls (1185±1349, 1158±990, 571±196 mmHg; P=NS; Fig. 2). Although the differences among groups did not reach statistical significance there was a strong trend towards higher values in heart failure patients as compared to controls. Notably, pulse pressure was not different among groups (controls 45±6, NYHA I/II 48±15, and NYHA III/IV 44±16; P=0.43) indicating no relevant influence of this parameter on Einc. BA-WT was significantly correlated with the Einc (r=0.452, P=0.001).

3.4. Arterial function
Results of FMD and NMD are shown in Fig. 2. FMD was significantly impaired in patients with severe and moderate heart failure patients when compared to controls (7.0±4.1 vs. 11.7±4.6; P=0.001 and 8.8±4.8 vs. 11.7±4.6; P=0.04, respectively). The difference in FMD between moderate and severe heart failure patients was of borderline significance (P=0.09). Likewise, NMD was reduced in both severe and moderate heart failure patients as compared to controls (16.6±8.1 vs. 23.4±7.2; P=0.01 and 17.8±6.8 vs. 23.4±7.2; P=0.03, respectively). FMD (r=–0.28, P=0.049) and NMD (r=–0.38; P=0.003) were inversely correlated with BA-WT.

Plasma levels of bigET-1 were significantly different among groups (P=0.004; Fig. 1). When heart failure patients were subdivided into two groups according to the median of BA-WT (=0.31 mm), plasma bigET-1 levels were elevated in patients with higher BA-WT (2.27±1.11 vs. 1.75±0.63; P=0.04; Fig. 3). No linear correlation was found, though, between bigET-1 and BA-WT.


Figure 3
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  		Fig. 3 Circulating plasma levels of bigET-1 in heart failure patients with low and high BA-WT, brachial artery wall thickness; *P<0.05.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The main findings of this study are that CHF is associated with changes in morphological, mechanical and functional properties of peripheral conduit arteries. Furthermore, increased plasma levels in endothelin-1 may play a role in the vascular remodeling process.

Our results reveal progressive wall thickness of the brachial artery that parallels increasing severity of CHF. Changes in BA-WT are associated with an increase in Einc, a measure of intrinsic arterial stiffness.

These findings are supported by data from previous studies that have promoted the concept of vascular remodeling in heart failure. In a dog model of CHF Wang and co-workers demonstrated inward remodeling of the femoral artery indicated by increasing medial thickness and reduced vessel size [7]. In humans, CHF has been associated with changes in arterial structure of the brachial and carotid arteries as shown by increases in wall-to-lumen ratio and in wall thickness, respectively, [2–4]. However, results in the latter studies are not consistent regarding internal vessel diameter as well as wall stiffness. We found progressive increases in wall thickness of the brachial artery at constant lumen diameters, which were paralleled by increases, although statistically not significant, in wall stiffness.

Increases in BA-WT and in wall stiffness could be related to phenotypic changes in the vessel wall such as augmented hyalinosis and basement membrane thickening that have been shown in the microvasculature of human subjects with CHF or an increase in collagen fraction as has been demonstrated in the study by Wang et al. [7,18,19].

In addition, experimental data indicate an association between vascular remodeling and ET-1 [7]. We found elevated levels of bigET-1, the precursor of ET-1, showing a correlation with the severity of CHF, which is in line with findings of previous studies [20]. Notably, CHF patients with increased BA-WT demonstrated higher plasma concentrations of bigET-1. This may indicate a possibly causal relationship that might be explained by the known vasoconstrictive and promitogenic qualities of ET-1, which are associated with growth of the vascular smooth muscle cells and stimulation of matrix production. This hypothesis is supported by animal data that demonstrate a significant correlation of vascular remodeling of the femoral artery with the number of ET-1 positive cells in the vessel wall [7]. Furthermore, in this study vascular remodeling could be significantly suppressed by the endothelin-converting enzyme inhibitor FR901533. It cannot be excluded, though, that the increase in bigET-1 in our patients is just a concomitant marker of neurohumoral activation in heart failure and does not play a direct role in vascular remodeling since we did not see a linear correlation with BA-WT. However, this is mostly due to outliers in the upper tertile of BA-WT and thus it is conceivable that including more patients into the study might have demonstrated this association.

In our study morphological assessment was followed by the evaluation of endothelial function of the brachial artery. In addition to morphological changes, we also found a correlation of endothelium dependent vasodilation (FMD) with the severity of CHF, and even more intriguing, a correlation of FMD with remodeling of the BA. Also, the endothelium independent NTG-mediated vasodilation (NMD) was associated with BA-WT suggesting an attenuated response to nitrovasodilators, which may result from impaired diffusion or augmented destruction of nitric oxide in the vessel wall or a dysfunctional cGMP-relaxation mechanism in vascular smooth muscle cells [21]. The fact that both, endothelium dependent and endothelium independent vasodilation were reduced in our patients may-based on the assumption that endothelial dysfunction precedes phenotypic changes in the vessel wall of heart failure patients-support the notion that structural alterations in the vasculature could further complicate endothelial dysfunction [22].

In summary, our findings highlight an intriguing relationship between phenotypic changes and functional impairment in peripheral conduit arteries of patients with CHF. This process is very similar to what is known for ventricular remodeling in heart failure.

However, it has to be confined that ventricular remodeling as judged by LV dimensions and LV ejection fraction does not parallel the changes in BA-WT. This may indicate that the two processes are independently regulated.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
We have demonstrated an association between CHF and remodeling of the brachial artery, which is characterized by morphological, mechanical and functional changes of the vessel wall. Whether phenotypic changes in peripheral vasculature are involved in the progression of the heart failure syndrome, and hence represent a therapeutic target remains subject of further investigation.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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