Radial, Carotid and Aortic Distensibility in Congestive Heart Failure

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Journal of the American College of Cardiology Vol. 39, No. 8, 2002 © 2002 by the American College of Cardiology Foundation ISSN 0735-1097/02/$22.00 Published by Elsevier Science Inc. PII S0735-1097(02)01755-2 Radial, Carotid and Aortic Distensibility in Congestive Heart Failure: Effects of High-Dose Angiotensin-Converting Enzyme Inhibitor or Low-Dose Association With Angiotensin Type 1 Receptor Blockade Cristina Giannattasio, MD, PHD,*‡ Felice Achilli, MD,† Monica Failla, MD,* Anna Capra, MD,* Antonella Vincenzi, MD,† Franco Valagussa, MD,† Giuseppe Mancia, MD*‡ Milano and Monza, Italy

OBJECTIVES The aim of this study was to determine whether in patients with congestive heart failure (CHF) a distensibility (Dist) reduction: 1) similarly occurs in different arteries; 2) is related to CHF severity; and 3) is reversible with treatment. BACKGROUND Several studies suggest that CHF is accompanied by a reduced arterial Dist. METHODS We measured diameter in radial artery, carotid artery (CA) and abdominal aorta (AO) by echotracking. Distensibility was obtained by relating it to blood pressure. Data were collected in 30 patients with CHF (New York Heart Association functional class I to III) under standard treatment with diuretic, digitalis and angiotensin-converting enzyme (ACE) inhibitor in whom CHF severity was assessed by maximum oxygen consumption (VO2max) percentage and in 30 age- and gender-matched controls. Patients with CHF were then randomized to maintain standard treatment (n ϭ 10), double the ACE inhibitor dose (n ϭ 10) or add an angiotensin II antagonist (n ϭ 10) and restudied after two months. RESULTS Distensibility was markedly reduced in the CHF group in all three vessels (p Ͻ 0.01), CA and AO Dist being related to CHF severity (p Ͻ 0.05). After two months, Dist did not change in the group maintained under standard treatment, but it increased signiﬁcantly (p Ͻ 0.05) and similarly when the ACE inhibitor dose was doubled or an angiotensin II antagonist was added. CONCLUSIONS Congestive heart failure is characterized by a reduction of Dist of large-elastic and middle-sized muscular arteries. The reduction of large-elastic artery Dist is related to the CHF severity. These alterations can be reversed by drugs, effectively interfering with the renin-angiotensin system either at the ACE or at the angiotensin receptor level. (J Am Coll Cardiol 2002;39:1275–82) © 2002 by the American College of Cardiology Foundation

Several cardiovascular diseases are characterized by a re- characterizes heart failure is reversible with different drug duced distensibility (Dist) of large arteries (1–11). This has approaches that interfere with the renin-angiotensin system. undesirable consequences because a reduction of arterial In the present study we have addressed these issues by Dist leads to: 1) an increase in arterial impedance and, thus, measuring middle-sized and large-elastic artery Dist in in cardiac afterload; 2) a reduction in diastolic pressure and, controls and in patients with CHF of different severity thus, in perfusion of organs such as the heart; and 3) an before and after two months of a standard therapy acceleration of atherosclerosis due to an increase in systolic (angiotensin-converting enzyme [ACE] inhibitor, diuretic and pulse pressure and to a greater traumatic effect on the and digitalis) and therapy based on doubling the dose of the vessel walls (1–11). It has been suggested that congestive ACE inhibitor or associating an angiotensin type 1 receptor heart failure (CHF) is associated with a reduction of arterial antagonist to the low-dose ACE inhibitor. Dist (12–16). However, information on this phenomenon is largely incomplete. For example, no data have been obtained on whether a reduction of arterial Dist occurs METHODS similarly or differently in large-elastic and smaller muscle- Subjects. We investigated 60 subjects. Thirty subjects type arteries. Furthermore, whether the reduction of arterial (CHF: 27 men; age: 60.4 Ϯ 1.4 years) were selected on a Dist relates to the heart failure severity is unknown. Finally, consecutive basis if they had: 1) age Ͻ75 years; 2) chronic it is also not known whether the arterial stiffening that heart failure belonging to New York Heart Association functional class I (n ϭ 10), II (n ϭ 13) or III (n ϭ 7) with From the *Clinica Medica, Department of Medicina Clinica, Prevenzione e ϭ ϭ Biotecnologie Sanitarie, Milano-Bicocca University, Milano, Italy; †Divisione di either an ischemic (n 20) or nonischemic (n 10) origin; Cardiologia, S. Gerardo Hospital, Monza, Italy; and ‡IRCCS Istituto Auxologico, 3) no major valvular abnormalities; 4) a left ventricular Milano, Italy. Supported by a grant from the Minister of Health of the Italian ejection fraction Յ40% (as described in the following text); Government. Manuscript received May 31, 2001; revised manuscript received January 14, 2002, 5) a standard medical treatment (diuretic, digitalis and accepted January 28, 2002. enalapril at a dose Ͻ20 mg daily) stable for at least three 1276 Giannattasio et al. JACC Vol. 39, No. 8, 2002 Arterial Distensibility in Heart Failure: Effects of Treatment April 17, 2002:1275–82

diameter/BP curve was analyzed according to its fitting with Abbreviations and Acronyms the arctangent model of Langewouters and then cross- ACE ϭ angiotensin-converting enzyme sectional Dist derived (cross-sectional compliance Ϭ vessel ANOVA ϭ analysis of variance area) (20). ϭ AO abdominal aorta Carotid artery (CA) Dist, WT and AO Dist. With the BP ϭ blood pressure CA ϭ carotid artery subject supine and the neck in partial extension, the diam- CHF ϭ congestive heart failure eter motion of the right common CA was measured 2 cm Dd ϭ diastolic diameter below the CA bifurcation by a B-M mode echo-tracking Dist ϭ distensibility device based on Doppler shift (Wall Track System, PIE ϭ Ds systolic diameter Medical, Maastricht, the Netherlands) and on a transducer E/A ϭ ratio between early and atrial transmitral peak flow operating at a frequency of 7.5 MHz (21). The transducer RA ϭ radial artery was manually oriented perpendicularly to the longitudinal ϭ VO2 volume of oxygen consumption axis of the vessel under B-mode and Doppler guidance. ϭ VO2max maximum oxygen consumption After switching to A-mode, the back-scattered echoes from ϭ WT wall thickness the anterior and posterior CA walls were visualized and the corresponding radiofrequency signal tracked to allow the digitalized signal of the internal diameter variations to be months; 6) no hemodynamically significant atherosclerotic derived at 50 Hz. The spatial resolution was 300 ␮m (21). carotid, femoral or aortic lesions (echocolor-Doppler exam- Blood pressure was measured from the brachial artery at the ination), no chronic arrhythmias, no major disease besides same time of the ultrasound evaluation via a semiautomatic heart failure and no chronic treatment with drugs other than device (Dinamap 1846 SX/SXP, Critikon, Chatenay Ma- those mentioned in the preceding text; and 7) an adequate labry Cedex, France), and CA Dist was derived according to ultrasonographic window for visualization of the abdominal the following formula (21): aorta (AO) (as described in the following text). The Dist ϭ 2 ϫ ͑Ds Ϫ Dd͒ / ͑Dd͒ / ͑PP͒ remaining 30 subjects (controls: 28 men; age: 56.9 Ϯ 1.5 years) were age-matched normotensive healthy individ- where Ds is the systolic diameter, Dd is the diastolic uals. Two patients with CHF and three control subjects diameter and PP is the corresponding pulse pressure (sys- were smokers. All subjects agreed to participate in the study tolic BP Ϫ diastolic BP, average of three measurements). after being informed of its nature and purpose. The protocol The same procedure with a 3.5 MHz transducer was of the study was approved by the Ethics Committee of our employed to measure the diameter motion of the subdia- hospital. phragmatic portion of the aorta, 2 to 3 cm above the origin Radial artery (RA) Dist and wall thickness (WT). Radial of the celiac plexus and to calculate AO Dist (21,22). For artery diameter and WT were measured by an A-mode technical reasons, however, no measurement of AO WT ultrasonic device (NIUS 02, Omega, Bienne, Switzerland) could be reliably made. Carotid artery intima-media WT (17). Briefly, a highly focalized transducer operating at a was measured at a posterior wall site located 3 cm below frequency of 10 MHz was stereotaxically positioned over the bifurcation through an ultrasonographic device (Hewlett RA using a gel as a medium. With the subject supine and Packard Sonos 5500, Palo Alto, California). Measurements the arm immobile at the heart level, the transducer was were obtained by first scanning the artery in B-mode, then oriented perpendicularly to the longitudinal axis of the freezing the digitized image in M-mode and finally tracking vessel based on the acoustic Doppler signal. After switching the inner ipoechogenic and the middle anechogenic layers to A-mode, the echocardiography beams corresponding to (23). the posterior lumen-intima and media-adventitia interfaces All RA, CA and AO measurements were made by a were visualized on a computer screen, and RA WT was single operator. The within-operator variability of RA, CA measured as the distance between the inner and outer wall and AO diameter measurements at diastole (i.e., the coef- echoes (18). The back-scattered echoes from the inner ficient of variation of the mean values of two measurements posterior and anterior wall of the artery were also visualized performed at two different times) was on average 2.3%, 2.8% and electronically digitized (analogic/digital fast transducer) and 3.9%, respectively. The within-operator variability for to allow internal diameter variations to be derived at 50 Hz RA and CA WT were 2.0% and 3.0%, respectively. with a spatial dynamic resolution of 0.0025 mm (17,18). Additional evaluations. One week before the study, each A photopletysmographic system (Finapres 2003, Ohm- subject underwent a standard echocardiocolor-Doppler to eda, Englewood, Colorado) allowed blood pressure (BP) to obtain clinical information on left ventricular end-diastolic be concomitantly recorded at 50 Hz from a finger ipsilateral diameter, left ventricular WT (septal plus posterior wall), to the RA examined, with an accuracy similar to intra- early and atrial transmitral flow and left ventricular ejection arterial BP recording (19). The concomitant acquisition of fraction (Simpson formula). In addition, each patient with continuous diameter and BP signals allowed the calculation CHF underwent two cardiopulmonary stress tests (at a one of diameter across the diastolic-systolic BP range. The week interval) with a cycloergometer ramp protocol (10 JACC Vol. 39, No. 8, 2002 Giannattasio et al. 1277 April 17, 2002:1275–82 Arterial Distensibility in Heart Failure: Effects of Treatment

W/min) using a breath-by-breath volume of oxygen con- Table 1. Hemodynamic Characteristics of Patients with CHF and Controls sumption (VO2) and CO2 sampling for continuous gas analysis, averaging expiratory data over 15-s periods and Control Heart Failure (30 ؍ n) (30 ؍ n) calculating the maximum oxygen consumption (VO2max) (%) during the test (24). The maximal exercise time was also SBP (mm Hg) 136.0 Ϯ 3.6 * 120.5 Ϯ 3.8 Ϯ Ϯ calculated. The VO2max and maximal exercise time were DBP (mm Hg) 80.9 5.6 75.8 1.9 obtained also after two months of therapy. PP (mm Hg) 55.0 Ϯ 3.2 45.2 Ϯ 2.5 Ϯ Ϯ In each subject, BP was measured also by a mercury SBP Din (mm Hg) 128.5 3.6 118.6 3.2 DBP Din (mm Hg) 75.0 Ϯ 1.7 69.5 Ϯ 1.6 sphygmomanometer, taking the first and fifth Korotkoff PP Din (mm Hg) 53.5 Ϯ 2.0 49.1 Ϯ 1.5 sounds to identify systolic and diastolic values, respectively. HR (beats/min) 66.8 Ϯ 2.4 69.6 Ϯ 2.8 Heart rate was derived continuously from the finger pressure LVEDD (mm) 50.8 Ϯ 1.3 † 66.8 Ϯ 1.2 signal as the reciprocal of the pulse interval between LVWT (mm) 18.2 Ϯ 0.3 * 20.8 Ϯ 0.5 LVEF (%) 67.4 Ϯ 2.8 † 31.2 Ϯ 0.8 consecutive beats. A venous blood sample was obtained after Ϯ Ϯ Ϫ E/A 1.1 0.1 * 1.4 0.2 a 30-min supine position and used (after storage at 80°)to PRA (pg/ml) 1.0 Ϯ 0.6 * 7.2 Ϯ 1.5 Ϯ measure plasma-renin activity (radioimmunoassay). VO2 max (%) — 66.6 3.0 Protocol and data analysis. Each subject was asked to Max Ex Time (min) — 8.7 Ϯ 0.6 come to the outpatient clinic of the San Gerardo Hospital in RA diameter (mm) 2.5 Ϯ 0.07 2.7 Ϯ 0.09 Ϯ Ϯ the morning after a 12-h abstinence from alcohol, caffeine CA diameter (mm) 7.3 0.14 † 8.1 0.5 AO diameter (mm) 16.2 Ϯ 0.3 † 18.1 Ϯ 0.5 Ϫ consumption and cigarette smoking. The study (which RA Dist Isob (1/mm Hg 10 3) 0.7 Ϯ 0.06 * 0.4 Ϯ 0.05 began 3 h after a light meal) had the following protocol: 1) *p Ͻ 0.05; †p Ͻ 0.01. Data are shown as means Ϯ SE. BP was measured three times by mercury sphygmomanom- AO ϭ abdominal aorta; CA ϭ carotid artery; CHF ϭ congestive heart failure; eter with the subject in the sitting position; 2) the subject DBP ϭ diastolic blood pressure; Din ϭ Dinamap; Dist. ϭ distensibility; E/A ϭ ratio between early and atrial transmitral peak flow; Ex ϭ exercise; HR ϭ heart rate; was placed supine in a quiet room at a constant temperature Isob ϭ isobaric; LVEDD ϭ left ventricular end-diastolic diameter; LVEF ϭ left (21°C) and fitted with the finger BP and the RA echo- ventricular ejection fraction; LVWT ϭ left ventricular wall thickness; PP ϭ pulse pressure; PRA ϭ plasma renin activity; RA ϭ radial artery; SBP ϭ systolic blood tracking devices; 3) after a 15-min resting interval, finger pressure. BP, heart rate and RA diameter were continuously measured for 15 min; 4) RA echo-tracking device was discon- having the same BP range, that is, the isobaric RA Dist nected, the semiautomatic BP measuring device was placed index (25). Carotid artery and AO diameter and Dist were on the brachial artery, and the probe for CA evaluation was obtained by averaging data from the five 6-s acquisition positioned on the neck; 5) five 6-s acquisitions of CA periods. Radial artery WT was measured over a 30-s period, diameter throughout the cardiac cycle were obtained during based on the ultrasound image. a 10-min period together with semiautomatic BP measure- Results from individual subjects were averaged and shown ments; 6) the probe for evaluation of the AO was posi- as means Ϯ SE, separately for the control group, the CHF tioned; 7) five 6-s acquisitions of the AO diameter through- group as a whole and the CHF groups under different out the cardiac cycle were obtained during a 10-min period treatments. The statistical significance of the differences in together with semiautomatic BP measurements. mean values was assessed by two-way analysis of variance The above-mentioned measurements were obtained in (ANOVA) and ANOVA for repeated measurements (pe- the same fashion after two months during which the riod and group, interactions, Stat View software, Abacus patients with CHF had been randomly assigned to: 1) Concepts Inc.). The two-tailed t test for paired and un- continuation of the previous standard therapy (10 patients); paired observations was used (with the Bonferroni correc- 2) modification of the previous therapy by increasing the tion for multiple comparisons) to locate the statistical dose of enalapril up to 40 mg daily (10 patients); and 3) significance of between-group differences. Data were also modification of the previous therapy by adding losartan analyzed by univariate regression taking Dist or WT as the 50 mg daily (10 patients). Treatment was continued for two dependent variables and echocardiographic, laboratory or months. Compliance to treatment was checked by pill ergospirometric variables as the independent ones. Signifi- counting. Vascular measurements were made by operators cant correlations were then tested by multivariate analysis. A unaware of therapy assignation. p value Ͻ0.05 was taken as the minimum level of statistical In each subject and for each study session, the sphygmo- significance. manometric and Dinamap BP values were averaged. In the baseline condition, RA diameter and Dist/BP curves were RESULTS obtained by averaging data from five periods of 30 s each, taken at 2-min intervals. The area under the RA Dist/BP Table 1 shows that, compared with controls, patients with curve was corrected for pulse pressure and used as a single CHF had a lower systolic BP and left ventricular ejection integrated Dist value, which was called “operative” RA Dist fraction but a greater left ventricular end-diastolic diameter, index. Comparisons between different groups and condi- left ventricular WT, ratio between early and atrial transmi- tions were also made by using the portion of the curve tral peak flow (E/A),CA and AO diameter. Heart rate was 1278 Giannattasio et al. JACC Vol. 39, No. 8, 2002 Arterial Distensibility in Heart Failure: Effects of Treatment April 17, 2002:1275–82 similar in the two groups, whereas the CHF group showed elastic-type arteries are characterized by a clear-cut stiffen- a much greater plasma renin activity than controls. ing, which implies that in this condition arterial mechanical As shown in Figure 1 and Table 1, in all three vessels the properties are impaired throughout the arterial tree. Sec- operative and isobaric RA Dist values were markedly ondly, in the large elastic arteries (which account for the smaller in the former than in the latter group, the difference larger portion of overall arterial Dist), this impairment is being more marked for CA and AO and always statistically related to the severity of heart failure, which implies that the significant. In the RA, the reduced Dist of CHF was visible arterial stiffening of heart failure is not an all or none but through the systolic-diastolic pressure range (Fig. 2). The rather a gradual phenomenon. And thirdly, because of the reduced Dist of CHF was accompanied by a significantly concomitant increase in arterial WT, the stiffening can be greater WT both in the thinner RA and in the thicker CA. ascribed to an alteration of the composition of the vessel Radial artery and CA WT showed an inverse relationship wall, that is, it can be accounted for, at least in part, by a with the respective Dist values (Ϫ0.38 and Ϫ0.32, p Ͻ structural factor (26). 0.01). Radial artery Dist was not related to CA and AO Effects of treatment on arterial stiffness. In a previous Dist, which were, on the other hand, positively related to study we have shown that adding an ACE inhibitor to a each other (r ϭ 0.51, p Ͻ 0.01). There was also a positive treatment regimen based on diuretics and digitalis increased ϭ relationship between CA and AO Dist and VO2max (r RA Dist (27). In the present study patients were already 0.45 and 0.41, p Ͻ 0.01) or E/A values (r ϭ 0.51 and 0.62, under treatment with diuretics, digitalis and an ACE p Ͻ 0.01) but not with left ventricular ejection fraction. inhibitor. The novel finding, however, is that when treat- Table 2 shows the data obtained in the three groups that ment was modified by either doubling the ACE inhibitor underwent different treatments for two months. Compared dose or by adding to the treatment regimen an angiotensin with the initial values, in no group did BP, heart rate, left II antagonist, RA Dist was further improved, the change ventricular ejection fraction, left ventricular end-diastolic being significant also when tested by ANOVA for repeated diameter, left ventricular WT or E/A show any significant measures (main effects and interactions). Furthermore, an change. In each group VO2max percentage was also not improvement was seen also in the Dist of larger more elastic significantly different from baseline. Maximal exercise time vessels such as AO and CA. Thus, a more effective blockade significantly increased both after the two months of the of the renin-angiotensin system has favorable consequences greater dose ACE inhibitor administration and after the on impaired arterial mechanical properties of CHF. This is two months of administration of the ACE inhibitor plus the case regardless of whether the more effective blockade is angiotensin II antagonist. Plasma-renin activity was un- obtained by enhancing the ACE inhibitory effect on forma- changed in the group with unchanged treatment and not tion of angiotensin II or by preventing the action of this significantly increased in the group given an ACE inhibitor substance at the receptor level. at a greater dose or the lower dose of ACE inhibitor plus the Methodologic aspects of Dist measurement. Several angiotensin II receptor antagonist. No treatment modified other findings deserve to be mentioned. One, in our study diameter and WT. In contrast, while in the group kept on AO and CA Dist were measured by the changes in vessel previous treatment, Dist also did not show any modification diameter induced by pulse pressure changes, which were in the groups given either the ACE inhibitor at the greater quantified in the brachial artery. Although being a com- dose or the low-dose ACE inhibitor plus the angiotensin II monly used approach, this represents a limitation because, receptor antagonist; Dist showed an increase that was ideally, vessel diameter and BP changes should be measured significant also when tested by ANOVA two-way analysis at the same vascular site (2,4,6,7,11,15). However, this for repeated measurements (main, period effect 0.01, inter- cannot be obtained for the AO unless invasive (and hardly action NS) in all three arteries (Fig. 3). In the RA this was feasible) BP measurements are employed. It is also difficult the case, also when isobaric Dist was considered. to be obtained for the CA because: 1) patients with CHF cannot easily sustain the relatively prolonged vessel com- DISCUSSION pression and breath-holding procedures that are necessary for direct assessment of CA pulse pressure through tonom- Arterial stiffening in CHF. In our patients with CHF, etry; and 2) this assessment is not devoid of inconveniences, arterial Dist was markedly less than in age-matched controls among which is limited reproducibility (28). More impor- both at the level of the RA and at the level of the CA and tantly, although the pulse pressure modification along the the AO. Furthermore, the reduction of CA and AO Dist arterial tree has not been thoroughly investigated in patients was directly related to an objective measure of the severity of with CHF, it is unlikely this condition could be character- heart failure such as the VO2max estimated by cardiopul- ized by a greater difference between values measured pe- monary stress test. Finally, the reduction of RA and CA ripherally and more centrally and, thus, by a greater than Dist of CHF was accompanied by, and correlated with, an normal attenuation in CA and AO pulse pressure that could increase in WT. This provides an answer to several ques- have been responsible for a reduced excursion of vessel tions that were addressed by our study. Namely, in heart diameter. First, differences between central and peripheral failure either muscle-type middle-size arteries and larger pulse pressure are more evident during vasodilation, that is, ACVl 9 o ,2002 2002:1275– 8, 17, No. April 39, Vol. JACC 82 reilDsesblt nHatFiue fet fTreatment of Effects Failure: Heart in Distensibility Arterial Giannattasio

Figure 1. Radial artery (RA) and carotid artery (CA) wall thickness and RA, CA and abdominal aorta distensibility in control subjects (n ϭ 30) and in patients with congestive heart failure (n ϭ 30). Data al. et are shown as mean Ϯ SE. Open bar ϭ controls (n ϭ 30); hatched bar ϭ heart failure (n ϭ 30). 1279 1280 Giannattasio et al. JACC Vol. 39, No. 8, 2002 Arterial Distensibility in Heart Failure: Effects of Treatment April 17, 2002:1275–82

arterial tree and that this progression reflects a similar progression of the stiffening in the heart (30). Our results, however, do not clarify the nature of the structural alteration that leads to the arterial stiffening of patients with CHF. We can speculate that in the vessel wall of these patients the less extensible tissue (e.g., collagen) grows more than the more extensible one (elastin and smooth muscle), presumably because of the influence of the variety of growth factors (e.g., increase in norepinephrine, increase in endothelins and reduction in nitric oxide secre- tion, etc.) whose circulating and tissue concentration is increased when the cardiac pump fails (31–33). We can also speculate, however, that the arterial stiffening of CHF is just vascular “waterlogging,” that is, an increase within the vessel wall of “incompressible” water due to sodium retention Figure 2. Radial artery (RA) distensibility-pressure curves in the control (34,35). We cannot, however, exclude that functional fac- and congestive heart failure groups of Figure 1. Open circle ϭ controls, n ϭ 30; open square ϭ heart failure, n ϭ 30. tors are additionally involved because “growth” substances that can alter tissue composition of the vessel wall can in conditions opposite of that typical of CHF, which is many instances also powerfully contract the smooth muscle characterized by an increase in vascular resistance (29). cells that can be found both in muscle-type arteries and Second, in our patients with CHF, a reduced Dist was (although to a lesser extent) in elastic-type ones, with an documented also in the RA whose diameter changes were increase in vessel elastic modulus with respect to the quantified for nearby measured changes in BP. We can, condition in which smooth muscle is relaxed. Indeed, the therefore, substantially conclude that there is a generalized exclusive participation of structural factors to the reduction arterial stiffening in CHF, which can be improved by the of Dist seen in CHF is made unlikely both by the observa- treatments we employed. tions made in a previous study and data obtained in the Arterial stiffness in CHF: possible mechanisms. In pa- present study. In a previous study on CHF we have shown tients with CHF, CA and AO Dist correlated in a relatively RA Dist to be increased after four to eight weeks of close fashion both to each other and to the E/A value while administration of an ACE inhibitor (27). This may be too showing no relation with RA Dist. This suggests that after short a time for major structural changes to take place. In cardiac pump failure there might be a nonuniform progres- the present study we have seen the increase in CA and RA sion of arterial stiffening in smaller and larger arteries. It also Dist after two months of treatment to be associated with no suggests, however, that the stiffening progresses in a rather change in arterial WT. This makes it possible that a pulse uniform fashion throughout the large elastic portion of the pressure independent functional factor such as reduction of

Table 2. Effects of Treatment Modifications in Patients with CHF T Modified T Modified (T Unchanged (ACEI Doubled) (ACEI Unchanged ؉ ATA (10 ؍ n) (10 ؍ n) (10 ؍ n) BTB TB T SBP (mm Hg) 117.3 Ϯ 4.3 114.0 Ϯ 7.9 128.8 Ϯ 6.9 122.4 Ϯ 3.5 123.9 Ϯ 3.6 118.3 Ϯ 4.6 DBP (mm Hg) 75.8 Ϯ 2.7 72.7 Ϯ 3.9 74.9 Ϯ 2.8 72.3 Ϯ 3.9 77.8 Ϯ 3.4 74.3 Ϯ 2.9 HR (beats/min) 70.3 Ϯ 2.7 72.5 Ϯ 3.2 67.5 Ϯ 5.2 64.3 Ϯ 4.1 69.3 Ϯ 4.2 71.3 Ϯ 4.8 LVEDD (mm) 67.4 Ϯ 2.3 66.1 Ϯ 1.8 65.9 Ϯ 3.7 63.4 Ϯ 4.7 68.4 Ϯ 2.7 66.3 Ϯ 3.1 LVWT (mm) 20.5 Ϯ 0.8 21.0 Ϯ 1.1 20.7 Ϯ 0.9 21.4 Ϯ 0.9 20.3 Ϯ 0.9 21.1 Ϯ 0.9 LVEF (%) 31.2 Ϯ 0.4 31.9 Ϯ 2.3 31.7 Ϯ 0.9 34.2 Ϯ 2.1 30.8 Ϯ 1.9 34.8 Ϯ 1.9 E/A 1.8 Ϯ 0.5 1.6 Ϯ 0.5 1.3 Ϯ 0.6 1.4 Ϯ 0.4 1.5 Ϯ 0.4 1.1 Ϯ 0.2 PRA (pg/ml) 6.5 Ϯ 2.2 6.7 Ϯ 1.8 7.2 Ϯ 2.2 12.1 Ϯ 6.8 5.1 Ϯ 1.8 21.7 Ϯ 8.0 Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Max VO2max (%) 65.8 6.5 69.8 6.4 67.9 5.6 71.2 5.2 63.9 4.8 71.2 3.8 Max Ex Time (min) 8.5 Ϯ 1.2 8.6 Ϯ 1.1 8.5 Ϯ 0.8 * 9.4 Ϯ 0.6 9.2 Ϯ 1.3 * 10.4 Ϯ 0.8 AO diameter (mm) 17.0 Ϯ 0.9 17.3 Ϯ 1.6 18.0 Ϯ 1.0 16.3 Ϯ 1.2 19.2 Ϯ 1.0 * 15.7 Ϯ 1.0 CA diameter (mm) 7.7 Ϯ 0.4 7.9 Ϯ 1.0 8.5 Ϯ 0.4 8.4 Ϯ 0.5 8.1 Ϯ 0.4 8.0 Ϯ 0.4 RA diameter (mm) 2.47 Ϯ 0.08 2.52 Ϯ 0.09 2.56 Ϯ 0.18 2.52 Ϯ 0.16 2.62 Ϯ 0.14 2.73 Ϯ 0.15 RA WT (mm) 0.30 Ϯ 0.02 0.29 Ϯ 0.02 0.30 Ϯ 0.02 0.32 Ϯ 0.02 0.35 Ϯ 0.02 0.33 Ϯ 0.02 CA WT (mm) 0.78 Ϯ 0.05 0.82 Ϯ 0.06 0.99 Ϯ 0.11 1.02 Ϯ 0.13 0.99 Ϯ 0.12 0.96 Ϯ 0.11 RA Dist Isob (1/mm Hg 10-3) 0.39 Ϯ 0.06 0.41 Ϯ 0.07 0.38 Ϯ 0.04 * 0.69 Ϯ 0.09 0.45 Ϯ 0.07 * 0.78 Ϯ 0.08

*p Ͻ 0.05. Data are shown as means Ϯ SE. ACEI ϭ ACE-inhibitor; ATA ϭ angiotensin antagonist; B ϭ baseline; T ϭ treatment; WT ϭ wall thickness; all other abbreviations as in Table 1. JACC Vol. 39, No. 8, 2002 Giannattasio et al. 1281 April 17, 2002:1275–82 Arterial Distensibility in Heart Failure: Effects of Treatment

smooth muscle contraction within the arterial wall by blockade of the renin-angiotensin system is also involved.

treatment. Clinical implications. Our results have clinical implica-

ϭ tions. First, the progressive reduction of Dist as CHF becomes more severe implies a progressive increase in arterial impedance and cardiac afterload when the ability of the heart to face the need of a greater performance is compromised. Second, the arterial stiffening of patients with CHF also means a greater traumatic effect of intravas- cular pressure on the vessel wall, with a greater chance of damaging its endothelial and intimal-medial structure (1,2).

angiotensin II antagonist; T Third, the reduced Dist of the CA and the AO in patients ϭ with CHF means a reduced ability of baroreceptors to sense BP changes and, consequently, reﬂexively restrain sympathetic tone, renin release and vasopressin release (36). The arterial stiffening may, therefore, represent an important mechanism involved in the neurohumoral activation of heart failure. All these consequences can be favorably counter- acted by treatments that block the renin-angiotensin system and more so if the blockade is made highly effective by high ACE inhibitor doses or by opposing the system at different sites. Fourth, the similar increase in Dist seen in patients taking the ACE inhibitor/angiotensin II antagonist combination and the ACE inhibitor alone at a greater dose speaks against

angiotensin-converting enzyme inhibitor; ATA a specific advantage of blocking the renin-angiotensin sys- ϭ tem at two different sites as compared with making the blockade more effective at the ACE site only. With the caution required by the limited number of patients studied, this negative finding emphasizes that for a specific advantage of an ACE inhibitor/angiotensin II antagonist combination the protocol of the study should include comparison with subjects in which an ACE inhibitor is given at a greater dose. This has rarely been done in studies claiming the

treatment, two months. ACEI superiority of combining an ACE inhibitor with an angio-

ϭ tensin II antagonist over ACE inhibition alone.

Reprint requests and correspondence: Dr. Giuseppe Mancia, Clinica Medica, Ospedale San Gerardo, Via Donizetti 106, 20052, hatched bar Monza, Italy. E-mail: [email protected].

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