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The European Society of Cardiology

Arterial stiffness in heart failure patients: dependance on diastolic dysfunction and plasma aldosterone levels

Cristina Giannattasioa,d, Felice Achillib, Monica Faillaa, Anna Capraa, Antonella Vincenzib, Gaetano Gentilea, Davide Corsia, Chiara Zazzerona, Lucia Turoloc, Alberto Morgantic and Giuseppe Manciaa,c,d,*

a Clinica Medica, Dipartimento di Medicina, Clinica Prevenzione e Biotecnologie Sanitarie, Università  di Milano-Bicocca, Milano, Italy
b Divisione di Cardiologia, Ospedale S. Gerardo di Monza, Milano, Italy
c Istituto Interuniversitario Fisiologia Clinica e Ipertensione, Policlinico di Milano-Pavia-Monza, Milano, Italy
d IRCCS Istituto Auxologico, Milano, Italy

* Correspondence: Giuseppe Mancia, Medicina Interna I , Ospedale San Gerardo, Via Donizetti 106, 20052, Monza (MI), Italy. Tel.: +39 2333357; fax: +39 322274 (E-mail: giuseppe.mancia{at}unimib.it).

Abstract

BACKGROUND: Heart failure is accompanied by large artery wall stiffening. Aim of the present study was to see whether the stiffening correlates (1) with the severity of the disease, (2) with the concomitant diastolic dysfunction and (3) with plasma aldosterone concentration, i.e. the concentration of a substance stimulating vessel fibrosis.

PATIENTS AND METHODS: We measured diameter (D) and distensibility (Dist) of a common carotid artery (CA) and abdominal aorta (AO) by an echotracking technique in 34 patients with mild to moderate congestive heart failure under diuretic, digitalis and ace-inhibitors treatment.

RESULTS: AO Dist correlated with the E/A or Dec time obtained by an echocolordoppler examination (r 0.62 and – 0.42, respectively, p<0.02) while showing an inverse relationship with the VO2 max obtained by cardiopulmonary stress test (r –0.47, p<0.01) and with the plasma concentration of aldosterone (r 0.39, p<0.04). Similar findings were obtained for CA Dist.

CONCLUSIONS: Thus the arterial stiffening increases with the heart failure severity and shows a parallelism with the reduced ability of the heart to relax in response to transmural pressure. The increased plasma levels of aldosterone (even in patients under ace-inhibitor) may play a role in this alteration of arterial mechanical properties.

Keywords Arterial stiffness; Diastolic dysfunction; Plasma aldosterone; Vessel fibrosis

Introduction

Several studies have shown that congestive heart failure is accompanied by an increase in large artery wall stiffness.1–8 This is clinically relevant because arterial stiffening is per se responsible for a greater cardiac afterload which further increases the work of the failing left ventricular.9–10

The present study was undertaken to obtain further information on the arterial stiffening of heart failure patients. One, whether the stiffening correlates with the heart failure severity. Two, whether in heart failure there is any parallelism between arterial stiffening and left ventricular dysfunction, i.e. the inability of the heart rather than the artery to relax in response to transmural pressure. Three, whether the arterial stiffening of heart failure is related to the plasma concentration of aldosterone, a hormone (1) which has been shown to favour cardiac and vascular fibrosis,11–15 i.e. to stimulate the growth of an inextensible tissue component which has potential stiffening properties and (2) whose secretion is not permanently suppressed with administration of drugs reducing the production of angiotension II (ace-inhibitors) or opposing its influence at the angiotensin receptor level (angiotensin II antagonists) because of its dependence on a number of additional factors.16–17

Methods

Subjects
We investigated a total of 34 subjects (mean age: 61.9±1.3 years, mean±SE, 28 males) selected on a consecutive basis if they had (1) an age <75 years, (2) a chronic heart failure condition belonging to the New York Heart Association Class I (n=18), II (n=10) or III (n=6) with either an ischemic (n=25) or non-ischemic (n=9) origin, (3) no major valvular abnormalities, (4) a left ventricular ejection fraction <40% (see below), (5) standard medical treatment (diuretic, digitalis and enalapril at a dose of 20 mg daily) since at least three months, (6) no hemodynamically significant atherosclerotic lesions in carotid, femoral and aortic arteries at an echocolorDoppler examination, (7) no chronic arrythmias and (8) no major disease besides heart failure and thus no chronic treatment with drugs other than those mentioned above. All subjects agreed to participate in the study after being informed of its nature and purpose. The protocol of the study was approved by the Ethics Committee of our Hospital.

Carotid and aortic distensibility measurement
With the subject supine and the neck in partial extension, the diameter and wall motion of the right common carotid artery were measured 2 cm below the carotid bifurcation by a B-M mode echotracking device based on Doppler shift (Wall Track System, PIE Medical, Maastricht, The Netherlands) and on a transducer operating at a frequency of 7.5 MHz.18 The transducer was manually oriented perpendicularly to the longitudinal axis of the vessel under B-mode guidance. After switching to A-mode the backscattered echoes from the anterior and posterior carotid artery walls were visualized on a screen and the corresponding radiofrequency signal was tracked by electronic tracers to allow the digitalized signal of the internal diameter variations to be derived at 50 Hz. The spatial resolution was 300 μm.18 Blood pressure was measured from the brachial artery at the same time of the ultrasound evaluation via a semiautomatic device (Dinamap 1846 SX/SXP, Critikon, Chatenay Malabry Cedex, France) and carotid artery distensibility was derived according to the following formula:


{04001270si1}

where Dist was distensibility, Dd the diastolic diameter of the vessel, DD the systo-diastolic diameter change and DP the corresponding pulse pressure.

With the subject supine the diameter and wall motion of the subdiaphragmatic portion of the aorta were measured 2–3 cm above the origin of the celiac plexus, by the same B-M mode echotracking device employed for the carotid artery.18 The transducer (which operated at a frequency of 3.5 MHz) was manually oriented perpendicularly to the longitudinal axis of the vessel under B-mode guidance and brachial artery blood pressure was measured at the same time of the ultrasound evaluation via the same semiautomatic device used for the carotid artery. Aortic distensibility was derived from the same formula employed for the carotid artery.

Carotid and aortic measurements were made by a single operator. The within-operator variability of carotid artery and aortic diameter measurements at diastole (i.e. the coefficient of variation of the mean values of two measurements performed at two different times) was on average 3.5% and 4.5%, respectively.

Additional evaluations
Each subject underwent an echocardiocolor-Doppler examination to obtain standard ecographic data (left ventricular wall thickness, ejection fraction and diastolic diameter) and, more importantly early (E) and atrial (A) transmitral flows which were used to quantify diastolic function both by the E/A ratio and by the deceleration time (Dec. Time).19–21 He or she also underwent two cardiopulmonary stress tests with a cycloergometer ramp protocol (10 watt/min) using a breath by breath VO2 and CO2 sampling for continuous gas analysis, averaging expiratory data over 15 s periods and quantifying the heart failure severity by the VO2 max (%) during the test.22

Blood pressure was also measured by a mercury sphygmomanometer taking the first and fifth Korotkoff sounds to identify systolic and diastolic values, respectively. Heart rate was derived from an electrocardiogram.

Plasma concentrations of aldosterone was measured from venous blood by radioimmunoassay. This was complemented by radioimmunoassay measurement of angiotensin II and endothelins I because of the evidence that they also may modulate vessel growth.17,23

Protocol and data analysis
Each subject underwent the first cardiopulmonary stress test a week before and the ecocardiographic examination a day before proper study. He or she was then asked to come to the outpatient clinic of the San Gerardo University Hospital in the morning following a 12 h abstinence from alcohol, caffeine consumption and cigarette smoking. The study (which began three hours after a light breakfast) had the following protocol.24 One, the subject was brought to a quiet room kept at constant temperature (21°). Two, blood pressure was measured three times by mercury sphygmomanometer with the subject in the sitting position. Three, the subject was placed supine fitted with a peripheral venous cannula and subjected to the echotracking and semiautomatic blood pressure measurements to obtain arterial diameter values in concomitance with blood pressure values. In half of the patients the carotid artery evaluation preceded the aortic one whereas the reverse was the case in the remaining half. Four, a venous blood sample was withdrawn for measurement of plasma concentration of aldosterone, angiotensin II and endothelin I. Five, the patient was seen again the following day to perform the second cardiopulmonary stress test.

In each subject the three sphygmomanometric blood pressure values were averaged. Carotid artery or aortic diastolic diameters and distensibilities were obtained by averaging data from five 6 s acquisition periods. Results from individual subjects were averaged and shown as means±SE. Data were also analyzed by univariate regression taking carotid or aortic distensibilitry as the dependent variable and echocardiographic, biohumoral and cardiopulmonary stress test data as the independent ones. Significant correlations were then tested also by multivariate analysis. A p value <0.05 was taken as the level of statistical significance.

Results

Table 1 shows the patients' average values of blood pressure, heart rate, echocardiographic and humoral variables, VO2 max and aortic and carotid distensibilities. As shown in Fig. 1 aortic and carotid distensibility correlated positively to each other. Aortic distensibility also correlated with (1) left ventricular diastolic function either when measured as E/A ratio and when measured by the deceleration time and (2) heart failure severity as measured by the VO2 max and (3) plasma aldosterone concentration although not with the concentration of angiotensin II and endothelin I. Carotid distensibility also showed a correlation with E/A ratio, deceleration time and VO2 max, however, nor with any of the plasma concentration of the humoral substances considered (Fig. 2). Multivariate analysis did not modify the conclusions reached by univariate correlations.


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  		Table 1. Baseline hemodynamic and biohumoral values in congestive heart failure patients
 


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  		Fig. 1 Histograms represent Spearman r value of correlation between aortic distensibility and each of the listed variables. *p< 0.05.

 


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  		Fig. 2 Hystograms represent Spearman r value of correlation between carotid distensibility and each of the listed variables. *p< 0.05.

 
Discussion

In our heart failure patients the distensibility of the carotid artery and the abdominal aorta correlated to each other indicating that the arterial stiffening of this condition involves vessels of different size and thus affects presumably the whole elastic portion of the arterial tree.1,6,9 Furthermore, and more importantly, both carotid and aortic distensibility values were related to left ventricular diastolic function indicating that in heart failure the impairment of the alterations of large artery and the heart proceeds in a rather parallel fashion, possibly because of the involvement of similar mechanisms.25 Finally, both carotid and aortic distensibility were related to VO2 max, indicating that the arterial stiffening increases with the severity of heart failure. This has clinical implications because a greater arterial stiffening means a greater arterial impedance and cardiac afterload in the face of a progressively lower ability of the left ventricule to cope.26

An additional aim of our study was to determine whether in heart failure the arterial stiffening showed a relationship with the plasma concentration of aldosterone because of the evidence that aldosterone stimulates the growth of collagen,11–16 thereby potentially increasing the possibility of a less distensible tissue in the vessel wall.27 The results show that was indeed the case, i.e. that in the aorta and, while not significantly, but in the carotid artery distensibility were related to the concentration of aldosterone in the venous blood. The elevated secretion rate and plasma concentration of this substance that occur in heart failure can thus be one of the factors involved in the alterations of the arterial mechanical properties that are associated with this condition, possibly through a modification of the vessel wall structure that favours more unelastic tissues. Removal of the stiffening influence of aldosterone on large artery may be one of the mechanisms accounting for the benefit of antialdosteronic agents shown in heart failure trials.14,15,28

In our study there was no correlation between carotid or aortic distensibility and plasma concentration of angiotensin II. This may be due to the fact that at variance from aldosterone these substances do not participate in the determination of the arterial structure and distensibility in heart failure. It may also be due, however, to the fact that our patients were under ace-inhibitor treatment which causes a drastic reduction in angiotensin II concentration while being unable, in the long term, to substantially modify aldosterone secretion which importantly depends on factors other than angiotensin II. Similar considerations can be made for the lack of relationship between arterial distensibility and plasma concentration of endothelin I which is closely related, for its secretion, to angiotensin II.

References

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