- Email: [email protected]
Reduced vascular compliance is associated with impaired endothelium-dependent dilatation in the brachial artery of patients with congestive heart failure
Journal of Cardiac Failure Vol. 10 No. 1 2004
Reduced Vascular Compliance is Associated With Impaired Endothelium-dependent Dilatation in the Brachial Artery of Patients With Congestive Heart Failure MOTOYUKI NAKAMURA, MD, SHOUMA SUGAWARA, MD, NAOSHI ARAKAWA, MD, MASAHIDE NAGANO, MD, TAKEHITO SHIZUKA, MD, YUHDAI SHIMODA, MD, TOSHIAKI SAKAI, MD, AND KATSUHIKO HIRAMORI, MD Morioka, Japan
ABSTRACT Background: Alterations in elastic properties and vascular structure of conduit vessels are important detrimental factors contributing to increased cardiac load and reduced tissue perfusion in patients with congestive heart failure (CHF). It has been demonstrated that endothelial function in the peripheral vasculature is impaired in this disorder, which may induce abnormal vascular elastic properties and remodeling. However, it remains unknown whether changes in vascular structure or mechanical properties are related to endothelial dysfunction in conduit arteries of patients with CHF. Methods and Results: Twenty-five CHF patients with nonischemic heart disease and 20 sex/age–matched controls were enrolled. Brachial artery diameter, intima-media thickness (IMT), and vascular stiffness as represented by distensibility and compliance were determined using a high-frequency linear transducer attached to a high-quality ultrasound system. In addition, flow-mediated dilatation (FMD) after 5-minute forearm occlusion and sublingual nitroglycerin-induced dilatation (NTG) were measured in the brachial artery. Brachial arterial diameter was similar between CHF and controls; however, IMT and wall/lumen ratio were significantly greater in CHF patients than in controls (IMT, 0.37 ⫾ 0.01 versus 0.31 ⫾ 0.01 mm; wall/lumen, 18.7 ⫾ 0.8 versus 15.1 ⫾ 0.8%: both P ⬍ .01). In addition, vascular stiffness parameters were lower in CHF than in controls (distensibility; 1.09 ⫾ 0.14 versus 1.60 ⫾ 0.15%/kPa, P ⬍ .01: compliance; 0.17 ⫾ 0.02 versus 0.26 ⫾ 0.02 mm2 kPa, P ⬍ .05). FMD and TNG were significantly reduced in CHF (both P ⬍ .001). Although stiffness parameters in CHF were not significantly correlated with vascular structure (ie, IMT, wall/lumen) or clinical parameters (ie, age, lipids, glucose, blood pressure), elastic parameters were significantly correlated with FMD (distensibility; r ⫽ 0.579, P ⬍ .005: compliance; r ⫽ 0.433, P ⬍ .05), but not with NTG. Conclusion: The present study found that, in limb muscle conduit artery in patients with CHF, there are hypertrophic remodeling and endothelial dysfunction-associated alterations in vascular wall elastic properties. Key Words: Stiffness, nitric oxide, remodeling, flow.
heart failure (CHF). This suggests that conduit arterial walls have greater stiffness in this disorder, with resulting impairment of left ventricular load, peripheral and coronary circulation, and baroreflex sensitivity. Similar elastic abnormalities in conductance vessels of patients with CHF have been suggested using different methodologies,2,3 whereas other investigations have not confirmed wall mechanical abnormalities.4,5 Otherwise, peripheral vascular function in patients with symptomatic CHF is characterized by increased vascular tone at rest and impaired dilatory response to vasodilator stimuli. Previous studies have shown that the mechanisms behind heightened vascular tone are caused by activation of neurohumoral factors, such as the renin-angiotensin system, the sympathetic nervous system, and endothelin. In recent years,
Conduit arteries behave as cushions that buffer pulsatile pressure. This property of vascular elasticity results in steady perfusion blood flow at the tissue level. Arnold et al1 have reported that pulse wave velocity was increased and brachial artery compliance was reduced in patients with congestive
From the Second Department of Internal Medicine, Iwate Medical University, Morioka, Japan. Manuscript received March 3, 2003; revised manuscript received June 10, 2003; revised manuscript accepted June 12, 2003. Reprint requests: Motoyuki Nakamura, MD, Second Department of Internal Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan. 1071-9164/$ - see front matter 쑕 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1071-9164(03)00585-2
36
Vascular Compliance and Endothelium in CHF
several vasoactive substances derived from the endothelium (specifically nitric oxide) have been reported to be important in the regulation of basal vascular tone and structure.6–8 In fact, endothelial-dependent dilatory function as assessed by flow-mediated or cholinergic stimuli in the limb vasculature is impaired in this disorder.9–12 However, no reports have examined directly the relationship between endotheliumdependent vascular function and vascular mechanical properties or structure in conduit arteries of patients with CHF. The present study has therefore used an innovative highresolution, high-frequency transducer-equipped ultrasound system to investigate the relationship between endotheliumdependent vascular function and vascular wall mechanical properties and structure in upper-limb conduit artery of patients with CHF. Methods Subjects The participants in this study included 25 patients with CHF (20 men, 5 women; mean age 57.1 ⫾ 3.0). The cause of CHF was idiopathic dilated cardiomyopathy in 18 patients and valvular heart disease in 7 patients. No significant coronary arterial lesions (ⱖ75% stenosis) were found by routine coronary angiography before enrollment into the study. Control subjects were 20 healthy sexage–matched volunteers (15 men, 5 women; mean ages 55.4 ⫾ 4.3). None of these subjects had hypertension (systolic blood pressure ⱖ150 mm Hg or diastolic blood pressure ⱖ90 mm Hg), hypercholesterolemia (ⱖ220 mg/dL), diabetes mellitus (fasting blood glucose ⱖ120 mg/dL or a history of insulin use), or chronic renal failure (serum creatinine ⱖ1.5 mg/dL). In addition, subjects having a history of any of these conditions or receiving ongoing medication were also excluded. Twelve of the CHF patients were in New York Heart Association functional Class I or II, and 13 were in Class III. None had gross peripheral edema or clinical evidence of peripheral vascular disorders and all were clinically stable at the time of the study. Alcohol, caffeine, and smoking were prohibited for at least 6 hours before the study. Echocardiography was performed to determine left ventricular function within 1 month before the study (ejection fraction, 33 ⫾ 3% in cardiomyopathy; 45 ⫾ 8% in valvular heart disease). Medication use was discontinued at least 24 hours before the study (digoxin, 17 patients; diuretics including furosemide and spironolactone, 25 patients; angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 21 patients). Measurement Experiments were carried out in a temperature-controlled room (22 to 24⬚C) by a single operator (S.S.). Each subject reclined on the examination table for 10 minutes before initial ultrasound scanning. The right brachial artery was scanned over a longitudinal section 3 to 5 cm above the right elbow using a broad-band linear array transducer (8 to 15 MHz; Acuson 15L8w) attached to a highquality mainframe ultrasound system (Acuson Sequoia). Automated blood pressure recording in the left arm was carried out every 2 minutes throughout the study. An electrocardiogram monitor integrated with the ultrasound machine was also applied. Depth and gain were optimized to identify the lumen-arterial wall interface. The images were recorded on an S-VHF videotape.
•
Nakamura et al
37
Ultrasonographic vascular parameters such as intima-media thickness (IMT) and systolic and diastolic brachial artery diameter were determined initially. The operator recognized and traced the posterior wall boundary (far wall), corresponding to the interface between the lumen and intima, and the anterior wall boundary (near wall). Using an internal caliber in the system, brachial artery diameter, and IMT thickness were measured as the shortest distance between different points. IMT measured at the time point of R wave of electrocardiogram (end-diastolic phase) was determined at the posterior wall of the brachial artery. The mean values of 3 measurements of IMT and brachial arterial diameter in each patient were used for calculation of the following parameters. Wall/Lumen ratio⫽(2 × IMT)/Dd Distensibility⫽100 × [(Ds2 ⫺ Dd2)/Dd2]/Pulse pressure Compliance⫽(Ds2 ⫺ Dd2)/Pulse pressure where Ds is the brachial artery diameter in systole and Dd is the brachial artery diameter in diastole After the measurement of vascular structural and mechanical properties, a blood pressure cuff was placed around the forearm distal to the target artery, inflated to a pressure of 200 mm Hg for 5 minutes, and then released. To determine flow-mediated endothelium-dependent dilatation, brachial artery images were recorded continuously during postocclusive reactive hyperemia for 5 minutes. Ten minutes later, another resting scan was recorded to confirm vessel recovery. Thereafter, to determine endotheliumindependent dilatory function, nitroglycerin (300 µg) tablets were administered sublingually and brachial images were again recorded for 5 minutes. Flow-mediated dilatation (FMD) and nitroglycerin (NTG)-induced dilatation of the brachial artery were calculated according to the following equations. FMD ⫽ [(maximum Dd after reactive hyperemia⫺Dd)/Dd] × 100 NTG⫽[maximum Dd after nitroglycerin⫺Dd)/Dd] × 100 Statistical Analysis All data in this study are expressed as mean ⫾ SEM. Differences between the 2 groups were analyzed by Student’s unpaired t test. Repeatability of IMT and diameter was examined in a separate set of 10 subjects by Bland and Altman plot analysis. Pearson’s correlation coefficients were used to examine the relationship between elastic parameters and vascular structural data or dilatory function. A value of P ⬍ .05 was considered statistically significant.
Results The repeatability coefficient (RC) was determined as (RC)2 ⫽ 1.96 × ΣDi2/(n⫺1), where n is sample size (n ⫽ 10) and Di is the difference between 2 measurements in a pair. The RC values for intraobserver repeatability (comparison of 2 determinations separated by a 1-week interval by the same observer) concerning Dd and IMT were 0.25 and 0.10, respectively. Figure 1 shows the Bland-Altman plots of the mean differences plotted against the average values. The mean differences for Dd and IMT were ⫺0.004 mm and ⫺0.013 mm, respectively, which were not statistically different from 0 (see Fig. 1).
38
Journal of Cardiac Failure Vol. 10 No. 1 February 2004
Fig. 1. Reproducibility of intima-media thickness (IMT) and brachial arterial diameter at diastole (Dd). Bland-Altman plots showing differences between measurements by a single observer on 2 occasions.
There were no significant differences in systemic blood pressure, pulse pressure, and heart rate between the CHF and control groups. Metabolic biochemical parameters such as total cholesterol, high-density lipoprotein cholesterol, and fasting blood sugar levels did not differ between the 2 groups (Table 1). Table 1. Comparison of Clinical Characteristics Between Control Subjects and Patients With Congestive Heart Failure
Age (y) Male/female BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) PP (mm Hg) HR (beats/min) LVEF (%) DCM/VHD TC (mg/dL) TG (mg/dL) HDL-C (mg/dL) Glucose (mg/dL)
Control (n ⫽ 20)
CHF (n ⫽ 25)
55.4 ⫾ 4.3 15/5 23.3 ⫾ 0.7 120.9 ⫾ 3.0 71.2 ⫾ 3.2 50.2 ⫾ 1.5 62.4 ⫾ 2.1 — — 194 ⫾ 7 133 ⫾ 30 51 ⫾ 4 99 ⫾ 5
57.1 ⫾ 3.0 20/5 21.3 ⫾ 0.8 112.1 ⫾ 3.2 65.8 ⫾ 2.3 46.4 ⫾ 2.3 69.0 ⫾ 2.1 35.8 ⫾ 2.9 18/7 165 ⫾ 7 90 ⫾ 11 60 ⫾ 5 104 ⫾ 7
P value NS NS NS NS NS NS NS — — NS NS NS NS
BMI, body mass index; DBP, diastolic blood pressure; DCM, dilated cardiomyopathy; HR, heart rate; HDL-C, HDL-cholesterol; LVEF, left ventricular ejection fraction; PP, pulse pressure; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; VHD, valvular heart disease. Mean ⫾ SEM
Brachial artery diameter did not differ between the CHF and control groups (4.11 ⫾ 0.14 versus 3.94 ⫾ 0.10 mm, not significant [NS]). However, IMT was significantly greater in CHF patients than controls (0.31 ⫾ 0.01 versus 0.37 ⫾ 0.01 mm, P ⬍ .01). Wall/lumen ratio was also higher in CHF patients (15.1 ⫾ 0.8 versus 18.7 ⫾ 0.8%, P ⬍ .005) (Fig. 2). Brachial artery distensibility was significantly lower in CHF patients than in controls (1.09 ⫾ 0.14 versus 1.60 ⫾ 0.15/kPa%, P ⬍ .05). Similarly, brachial arterial compliance was significantly decreased in the CHF group (0.17 ⫾ 0.02 versus 0.26 ⫾ 0.02 mm2 kPa, P ⬍ .01) (Fig. 3). No relationship was observed between elastic parameters and IMT (distensibility, r ⫽ .01, NS; compliance, r ⫽ .07, NS). Also, no significant correlations were found between elastic parameters and clinical parameters (ie, age, lipids, glucose, blood pressure). Brachial artery FMD was significantly lower in CHF patients than in controls (6.60 ⫾ 0.50 versus 9.51 ⫾ 0.67%, P ⬍ .001). NTG was also lower in the CHF group (11.63 ⫾ 0.80 versus 16.19 ⫾ 1.02%, P ⬍ .001) (Fig. 4). There was no significant difference in peak blood flow velocity after forearm occlusion between the 2 groups (0.38 ⫾ 0.02 versus 0.37 ⫾ 0.02 m/sec; NS). In the CHF group, brachial arterial distensibility was significantly correlated with FMD (r ⫽ .579, P ⬍ .005; Fig. 5), but not with NTG (r ⫽ .379, NS; Fig. 6). Brachial
Vascular Compliance and Endothelium in CHF
•
Nakamura et al
39
Fig. 2. Scatter plots of brachial arterial diameter at diastole (Dd), intima-media thickness (IMT), and wall-to-lumen ratio in control subjects and patients with congestive heart failure (CHF). Horizontal bar shows mean value.
arterial compliance was also significantly correlated with FMD (r ⫽ .433, P ⬍ .05), but not with NTG (r ⫽ .146, NS). In the control group, no relationships were observed between arterial wall mechanical properties and vasodilatory response.
Fig. 3. Scatter plots of brachial arterial distensibility (DC) and compliance (CC) in control subjects and patients with congestive heart failure (CHF). Horizontal bar shows mean value.
Discussion The main findings of this study are: (1) brachial arterial IMT and wall-to-lumen ratio were significantly greater in
Fig. 4. Scatter plots of flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NTG) of the brachial artery in control subjects and patients with congestive heart failure (CHF). Horizontal bar shows mean value.
40
Journal of Cardiac Failure Vol. 10 No. 1 February 2004
Fig. 5. Relationships between flow-mediated dilatation (FMD) and distensibility (DC; left) and compliance (CC: right) of the brachial artery in patients with congestive heart failure.
patients with CHF than in controls; (2) conduit vessel walls showed greater stiffness in the CHF group than in the control group; and (3) there were significant relationships between several elastic parameters and degree of impairment of flowmediated dilatation in the brachial artery of patients with CHF. The ultrasound system employed in this study was based on a recently developed image-acquisition algorithm using coherent image formation and minimization of band aberration effects using a Gaussian pulse equipped high-frequency linear transducer. These innovative imaging capabilities enabled us to gain images with greater precision and crispness than ordinary apparatus would have allowed. As demonstrated by our results, the repeatability of echo measurements was sufficient for clinical research use. Using this methodology, we found that brachial IMT was abnormally increased in patients with CHF resulting from nonischemic heart disease. In general, increased IMT may be viewed as a consequence of atherosclerotic arterial changes. However, the etiology of CHF in the present cohort was nonischemic heart disease without a hypertensive background, and levels of cardiovascular risk in CHF patients are comparable with those in control subjects. In accord with this observation,
Fig. 6. Relationships between nitroglycerin-induced dilatation (NTG) and distensibility (DC; left) and compliance (CC: right) of the brachial artery in patients with congestive heart failure.
Lage et al have reported that carotid arterial IMT in patients with idiopathic dilated cardiomyopathy was about 20% more than in healthy sex- and age-matched controls.13 This increased level was very similar to the present result (⫹19%). Wrobleski et al have shown abnormal histopathologic arteriole changes such as basement membrane hypertrophy and hyalinosis in biopsy-obtained tissue samples from CHF patients.14 In an experimental model of heart failure, myocardial infraction produced by coronary artery ligation resulted in large arterial remodeling as defined by alterations in elastic properties and arterial wall structure.15 In addition, aortic wall thickness and wall-to-lumen ratio were significantly increased within several weeks after pacing-induced heart failure in a canine model.16 Recently, Giannattaso et al have shown in human CHF that arterial wall thickness was consistently elevated in 3 different sizes of vessels such as the radial artery, carotid artery, and abdominal aorta.17 Thus it is likely that CHF itself rather atherosclerosis may be responsible for increased IMT in conduit vessels. The present study has also found abnormal elastic properties of the brachial artery in patients with CHF. Several previous reports have also demonstrated that conduit vessel in upper limb and carotid artery are stiffer in patients with CHF than in control subjects.13,18–20 Arterial compliance is determined by structural factors—such as collagen, elastin, and vascular smooth muscle—and metabolic factors—such as vasoactive neurohormones, including endothelium-derived nitric oxide. Although the possibility that the observed increase in wall-to-lumen ratio would itself result in reduced arterial compliance cannot be completely excluded, we have not found any relationship between elastic parameters and vascular structural changes (ie, wall-to-lumen ratio or IMT). In this regard, the abnormal elastic properties in the brachial artery observed in this study may be related to alterations in metabolic factors rather than structural factors. Indeed, functional metabolic factors significantly control distensibility of conduit arteries by constricting or dilating vascular smooth muscle. The constricting factors are represented by increased activity of the sympathetic nervous system, the renin-angiotensin systems, and endothelin, all of which are activated in severe CHF. Moreover, endotheliumderived nitric oxide has potent dilatory and antiproliferative properties on vascular smooth muscle,21 so this substance may be particularly important in the regulation of vascular elasticity and vascular structure.22 Several previous reports have shown that bioavailability of nitric oxide as assessed by cholinergic stimuli or flow-dependent shear stress is significantly reduced in limb vasculature in patients with CHF even with mild to moderate symptoms.9–12 Ramsey et al have shown that brachial arterial distensibility increased with levels of flow-mediated dilatation during hyperemia in healthy subjects, but this relationship was not found in CHF patients.18 These observations suggest that arterial distensibility is mainly regulated by endothelium-dependent mechanisms. This hypothesis is supported by a recent observation reported by Kinlay et al, who have shown that inhibition of
Vascular Compliance and Endothelium in CHF
nitric oxide synthase clearly reduced brachial arterial compliance and increased pulse wave velocity in the brachial artery of healthy volunteers.23 Thus the present study has examined the relationship between flow-dependent endothelial function and vascular mechanical properties, and found a significant correlation between the two. This observation suggests that endothelium-derived nitric oxide is important in the regulation of vascular elastic properties in patients with CHF. Alternatively, arterial conduit stiffening in patients with CHF means less cushion effect and greater pulsatile flow-induced damage to the endothelium in this disorder. In view of this, conduit arterial stiffening and arterial endothelial dysfunction may create a positive feedback loop or vicious cycle, thus reducing tissue perfusion and increasing cardiac afterload in patients with CHF. Study Limitations
The present study has shown that both endothelium-dependent (FMD) and endothelium-independent (NTG) responses were reduced in CHF patients. In contrast, several previous reports have observed preservation of nitrate-induced vasodilatory response in the limb vasculature in patients with CHF.9,10 However, several reports have found impairment of endothelium-“independent” dilatation in the peripheral artery of patients with CHF. Creager et al showed a marked blunting of vascular response to sodium nitroprusside in patients with end-stage CHF.24 A classical study by Zelis et al25 demonstrated a clear reduction in lower limb blood flow after intraarterial administration of a nitrovasodilator in patients with nonischemic CHF. Moreover, several recent reports have suggested that nitrovasodilator-induced relaxation response in forearm resistance and conduit vessels was blunted in CHF patients.26–28 Although accurate reasons for this discrepancy remain unknown, we have speculated that the variation may be due to differences in duration of CHF. The longstanding nature of valvular heart disease and primary cardiomyopathy (nonischemic CHF) may alter not only endothelial function but also vascular smooth muscle function and structure in peripheral vessels.11,29 FMD, NTG, and vascular stiffness parameters might therefore be expected to be somewhat related to each other, yet the present study has found that stiffness parameters were correlated with FMD but not with NTG in patients with CHF. These observations lend force to the hypothesis that although observed endothelial function is partly dependent on vascular smooth muscle function, endothelial function is independently related to vascular stiffness parameters in the brachial artery of patients with CHF. Although all vasoactive drugs were withdrawn at least 24 hour before the study, some carryover effects may have influenced the present results. It was not possible, for ethical reasons, to incorporate a complete washout period in the study design. However, a number of recent reports have shown that several kinds of vasoactive drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers significantly improve arterial wall elastic
•
Nakamura et al
41
properties and endothelial function in patients with CHF.17,30–32 Because some patients with CHF in this study were taking these types of drugs, our results may underestimate the abnormal vascular functional properties characteristic of this disorder. In conclusion, the present study found that in patients with CHF muscular conduit artery remodeling occurs with alterations in arterial wall elastic properties, and that this vascular wall functional change may be related to endothelial dysfunction. Further studies will be necessary to determine whether recovery of endothelial function by some form of intervention would restore conduit mechanical properties and thus improve the outcome of CHF.
References 1. Arnold JM, Marchiori GE, Imrie JR, Burton GL, Pflugfelder PW, Kostuk WJ. Large artery function in patients with chronic heart failure. Studies of brachial artery diameter and hemodynamics. Circulation 1991;84:2418–25. 2. Finkelstein SM, Cohn JN, Collins VR, Carlyle PF, Shelley WJ. Vascular hemodynamic impedance in congestive heart failure. Am J Cardiol 1985;55:423–7. 3. Mitchell GF, Tardif JC, Arnold JM, Marchiori G, O’Brien TX, Dunlap ME, et al. Pulsatile hemodynamics in congestive heart failure. Hypertension 2001;38:1433–9. 4. Eliakim M, Sapoznikov D, Weinman J. Pulse wave velocity in healthy subjects and in patients with various disease states. Am Heart J 1971;82:448–57. 5. Kromer EP, Elsner D, Holmer SR, Muntze A, Riegger GA. Aortic input impedence and neurohormonal activation in patients with mild to moderate chronic congestive heart failure. Cardiovasc Res 1992;26: 265–72. 6. Katz SD, Krum H, Khan T, Knecht M. Exercise-induced vasodilatation in forearm circulation of normal subjects and patients with congestive heart failure: role of endothelium-derived nitric oxide. J Am Coll Cardiol 1996;28:585–90. 7. Yoshida H, Nakamura M, Akatsu T, Arakawa N, Hiramori K. Effects of nitric oxide inhibition on basal forearm blood flow in patients with nonischemic chronic heart failure. Heart Vessels 1998;13:142–6. 8. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 1998;101:731–6. 9. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endotheliumdependent vasodilatation is attenuated in patients with heart failure. Circulation 1991;84:1589–96. 10. Drexler H, Hayoz D, Munzel T, Hornig B, Just H, Brunner HR, Zelis R. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992;69:1596–601. 11. Bank AJ, Lee PC, Kubo SH. Endothelial dysfunction in patients with heart failure: relationship to disease severity. J Card Fail 2000;6:9–36. 12. Nakamura M, Ishikawa M, Funakoshi T, Hashimoto K, Chiba M, Hiramori K. Attenuated endothelium-dependent peripheral vasodilatation and clinical characteristics in patients with chronic heart failure. Am Heart J 1994;128:1164–9. 13. Lage SG, Kopel L, Monachini MC, Medeiros CJ, Pileggi F, Polak JF, et al. Carotid arterial compliance in patients with congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 1994;74:691–5. 14. Wroblewski H, Kastrup J, Norgaard T, Mortensen SA, Haunso S. Evidence of increased microvascular resistance and arteriolar hyalinosis in skin in congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 1992;69:769–74.
42
Journal of Cardiac Failure Vol. 10 No. 1 February 2004
15. Gaballa MA, Jacob CT, Raya TE, Liu J, Simon B, Goldman S. Large artery remodeling during aging: biaxial passive and active stiffness. Hypertension 1998;32:437–43. 16. Khan Z, Millard RW, Gabel M, Walsh RA, Hoit BD. Effect of congestive heart failure on in vivo canine aortic elastic properties. J Am Coll Cardiol 1999;33:267–72. 17. Giannattasio C, Achilli F, Failla M, Capra A, Vincenzi A, Valagussa F, et al. Radial, carotid and aortic distensibility in congestive heart failure: effects of high-dose angiotensin-converting enzyme inhibitor or lowdose association with angiotensin type 1 receptor blockade. J Am Coll Cardiol 2002;39:1275–82. 18. Ramsey MW, Goodfellow J, Jones CJ, Luddington LA, Lewis MJ, Henderson AH. Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation 1995;92:3212–9. 19. Giannattasio C, Failla M, Stella ML, Mangoni AA, Carugo S, Pozzi M, et al. Alterations of radial artery compliance in patients with congestive heart failure. Am J Cardiol 1995;76:381–5. 20. Kaiser DR, Mullen K, Bank AJ. Brachial artery elastic mechanics in patients with heart failure. Hypertension 2001;38:1440–5. 21. Numaguchi K, Egashira K, Takemoto M, Kadokami T, Shimokawa H, Sueishi K, et al. Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension 1995;26: 957–62. 22. Nakamura M. Peripheral vascular remodeling in chronic heart failure: clinical relevance and new conceptualization of its mechanisms. J Card Fail 1999;5:127–38. 23. Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, et al. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension 2001;38:1049–53. 24. Creager MA, Quigg RJ, Ren CJ, Roddy MA, Colucci WS. Limb vascular responsiveness to beta-adrenergic receptor stimulation in patients with congestive heart failure. Circulation 1991;83:1873–9.
25. Zelis R, Mason DT, Braunwald E. A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 1968; 47:960–70. 26. Maguire SM, Nugent AG, McGurk C, Johnston GD, Nicholls DP. Abnormal vascular responses in human chronic cardiac failure are both endothelium dependent and endothelium independent. Heart 1998; 80:141–5. 27. Carville C, Adnot S, Sediame S, Benacerraf S, Castaigne A, Calvo F, et al. Relation between impairment in nitric oxide pathway and clinical status in patients with congestive heart failure. J Cardiovasc Pharm 1998;32:562–70. 28. Khder Y, El Ghawi R, Boscs LB, Aliot E, Zannad F. Investigations of the peripheral vascular mechanisms implicated in congestive heart failure by the non-invasive evaluation of radial artery compliance and reactivity. Int J Cardiol 1996;56:149–58. 29. Nakamura M, Yoshida H, Arakawa N, Mizunuma Y, Makita S, Hiramori K. Endothelium-dependent vasodilatation is not selectively impaired in patients with chronic heart failure secondary to valvular heart disease and congenital heart disease. Eur Heart J 1996;17:1875–81. 30. Joannides R, Bizet-Nafeh C, Costentin A, Iacob M, Derumeaux G, Cribier A, et al. Chronic ACE inhibition enhances the endothelial control of arterial mechanics and flow-dependent vasodilatation in heart failure. Hypertension 2001;38:1446–50. 31. Nakamura M, Funakoshi T, Arakawa N, Yoshida H, Makita S, Hiramori K. Effect of angiotensin-converting enzyme inhibitors on endotheliumdependent peripheral vasodilatation in patients with chronic heart failure. J Am Coll Cardiol 1994;24:1321–7. 32. Nakamura M, Saito S, Yoshida H, Arakawa N, Sugawara S, Hiramori K. Effects of chronic subdepressor dose of angiotensin II type 1 receptor antagonist on endothelium-dependent vasodilatation in patients with congestive heart failure. J Cardiovasc Pharmacol 2002;40:411–9.
Reduced Vascular Compliance is Associated With Impaired Endothelium-dependent Dilatation in the Brachial Artery of Patients With Congestive Heart Failure MOTOYUKI NAKAMURA, MD, SHOUMA SUGAWARA, MD, NAOSHI ARAKAWA, MD, MASAHIDE NAGANO, MD, TAKEHITO SHIZUKA, MD, YUHDAI SHIMODA, MD, TOSHIAKI SAKAI, MD, AND KATSUHIKO HIRAMORI, MD Morioka, Japan
ABSTRACT Background: Alterations in elastic properties and vascular structure of conduit vessels are important detrimental factors contributing to increased cardiac load and reduced tissue perfusion in patients with congestive heart failure (CHF). It has been demonstrated that endothelial function in the peripheral vasculature is impaired in this disorder, which may induce abnormal vascular elastic properties and remodeling. However, it remains unknown whether changes in vascular structure or mechanical properties are related to endothelial dysfunction in conduit arteries of patients with CHF. Methods and Results: Twenty-five CHF patients with nonischemic heart disease and 20 sex/age–matched controls were enrolled. Brachial artery diameter, intima-media thickness (IMT), and vascular stiffness as represented by distensibility and compliance were determined using a high-frequency linear transducer attached to a high-quality ultrasound system. In addition, flow-mediated dilatation (FMD) after 5-minute forearm occlusion and sublingual nitroglycerin-induced dilatation (NTG) were measured in the brachial artery. Brachial arterial diameter was similar between CHF and controls; however, IMT and wall/lumen ratio were significantly greater in CHF patients than in controls (IMT, 0.37 ⫾ 0.01 versus 0.31 ⫾ 0.01 mm; wall/lumen, 18.7 ⫾ 0.8 versus 15.1 ⫾ 0.8%: both P ⬍ .01). In addition, vascular stiffness parameters were lower in CHF than in controls (distensibility; 1.09 ⫾ 0.14 versus 1.60 ⫾ 0.15%/kPa, P ⬍ .01: compliance; 0.17 ⫾ 0.02 versus 0.26 ⫾ 0.02 mm2 kPa, P ⬍ .05). FMD and TNG were significantly reduced in CHF (both P ⬍ .001). Although stiffness parameters in CHF were not significantly correlated with vascular structure (ie, IMT, wall/lumen) or clinical parameters (ie, age, lipids, glucose, blood pressure), elastic parameters were significantly correlated with FMD (distensibility; r ⫽ 0.579, P ⬍ .005: compliance; r ⫽ 0.433, P ⬍ .05), but not with NTG. Conclusion: The present study found that, in limb muscle conduit artery in patients with CHF, there are hypertrophic remodeling and endothelial dysfunction-associated alterations in vascular wall elastic properties. Key Words: Stiffness, nitric oxide, remodeling, flow.
heart failure (CHF). This suggests that conduit arterial walls have greater stiffness in this disorder, with resulting impairment of left ventricular load, peripheral and coronary circulation, and baroreflex sensitivity. Similar elastic abnormalities in conductance vessels of patients with CHF have been suggested using different methodologies,2,3 whereas other investigations have not confirmed wall mechanical abnormalities.4,5 Otherwise, peripheral vascular function in patients with symptomatic CHF is characterized by increased vascular tone at rest and impaired dilatory response to vasodilator stimuli. Previous studies have shown that the mechanisms behind heightened vascular tone are caused by activation of neurohumoral factors, such as the renin-angiotensin system, the sympathetic nervous system, and endothelin. In recent years,
Conduit arteries behave as cushions that buffer pulsatile pressure. This property of vascular elasticity results in steady perfusion blood flow at the tissue level. Arnold et al1 have reported that pulse wave velocity was increased and brachial artery compliance was reduced in patients with congestive
From the Second Department of Internal Medicine, Iwate Medical University, Morioka, Japan. Manuscript received March 3, 2003; revised manuscript received June 10, 2003; revised manuscript accepted June 12, 2003. Reprint requests: Motoyuki Nakamura, MD, Second Department of Internal Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan. 1071-9164/$ - see front matter 쑕 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1071-9164(03)00585-2
36
Vascular Compliance and Endothelium in CHF
several vasoactive substances derived from the endothelium (specifically nitric oxide) have been reported to be important in the regulation of basal vascular tone and structure.6–8 In fact, endothelial-dependent dilatory function as assessed by flow-mediated or cholinergic stimuli in the limb vasculature is impaired in this disorder.9–12 However, no reports have examined directly the relationship between endotheliumdependent vascular function and vascular mechanical properties or structure in conduit arteries of patients with CHF. The present study has therefore used an innovative highresolution, high-frequency transducer-equipped ultrasound system to investigate the relationship between endotheliumdependent vascular function and vascular wall mechanical properties and structure in upper-limb conduit artery of patients with CHF. Methods Subjects The participants in this study included 25 patients with CHF (20 men, 5 women; mean age 57.1 ⫾ 3.0). The cause of CHF was idiopathic dilated cardiomyopathy in 18 patients and valvular heart disease in 7 patients. No significant coronary arterial lesions (ⱖ75% stenosis) were found by routine coronary angiography before enrollment into the study. Control subjects were 20 healthy sexage–matched volunteers (15 men, 5 women; mean ages 55.4 ⫾ 4.3). None of these subjects had hypertension (systolic blood pressure ⱖ150 mm Hg or diastolic blood pressure ⱖ90 mm Hg), hypercholesterolemia (ⱖ220 mg/dL), diabetes mellitus (fasting blood glucose ⱖ120 mg/dL or a history of insulin use), or chronic renal failure (serum creatinine ⱖ1.5 mg/dL). In addition, subjects having a history of any of these conditions or receiving ongoing medication were also excluded. Twelve of the CHF patients were in New York Heart Association functional Class I or II, and 13 were in Class III. None had gross peripheral edema or clinical evidence of peripheral vascular disorders and all were clinically stable at the time of the study. Alcohol, caffeine, and smoking were prohibited for at least 6 hours before the study. Echocardiography was performed to determine left ventricular function within 1 month before the study (ejection fraction, 33 ⫾ 3% in cardiomyopathy; 45 ⫾ 8% in valvular heart disease). Medication use was discontinued at least 24 hours before the study (digoxin, 17 patients; diuretics including furosemide and spironolactone, 25 patients; angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 21 patients). Measurement Experiments were carried out in a temperature-controlled room (22 to 24⬚C) by a single operator (S.S.). Each subject reclined on the examination table for 10 minutes before initial ultrasound scanning. The right brachial artery was scanned over a longitudinal section 3 to 5 cm above the right elbow using a broad-band linear array transducer (8 to 15 MHz; Acuson 15L8w) attached to a highquality mainframe ultrasound system (Acuson Sequoia). Automated blood pressure recording in the left arm was carried out every 2 minutes throughout the study. An electrocardiogram monitor integrated with the ultrasound machine was also applied. Depth and gain were optimized to identify the lumen-arterial wall interface. The images were recorded on an S-VHF videotape.
•
Nakamura et al
37
Ultrasonographic vascular parameters such as intima-media thickness (IMT) and systolic and diastolic brachial artery diameter were determined initially. The operator recognized and traced the posterior wall boundary (far wall), corresponding to the interface between the lumen and intima, and the anterior wall boundary (near wall). Using an internal caliber in the system, brachial artery diameter, and IMT thickness were measured as the shortest distance between different points. IMT measured at the time point of R wave of electrocardiogram (end-diastolic phase) was determined at the posterior wall of the brachial artery. The mean values of 3 measurements of IMT and brachial arterial diameter in each patient were used for calculation of the following parameters. Wall/Lumen ratio⫽(2 × IMT)/Dd Distensibility⫽100 × [(Ds2 ⫺ Dd2)/Dd2]/Pulse pressure Compliance⫽(Ds2 ⫺ Dd2)/Pulse pressure where Ds is the brachial artery diameter in systole and Dd is the brachial artery diameter in diastole After the measurement of vascular structural and mechanical properties, a blood pressure cuff was placed around the forearm distal to the target artery, inflated to a pressure of 200 mm Hg for 5 minutes, and then released. To determine flow-mediated endothelium-dependent dilatation, brachial artery images were recorded continuously during postocclusive reactive hyperemia for 5 minutes. Ten minutes later, another resting scan was recorded to confirm vessel recovery. Thereafter, to determine endotheliumindependent dilatory function, nitroglycerin (300 µg) tablets were administered sublingually and brachial images were again recorded for 5 minutes. Flow-mediated dilatation (FMD) and nitroglycerin (NTG)-induced dilatation of the brachial artery were calculated according to the following equations. FMD ⫽ [(maximum Dd after reactive hyperemia⫺Dd)/Dd] × 100 NTG⫽[maximum Dd after nitroglycerin⫺Dd)/Dd] × 100 Statistical Analysis All data in this study are expressed as mean ⫾ SEM. Differences between the 2 groups were analyzed by Student’s unpaired t test. Repeatability of IMT and diameter was examined in a separate set of 10 subjects by Bland and Altman plot analysis. Pearson’s correlation coefficients were used to examine the relationship between elastic parameters and vascular structural data or dilatory function. A value of P ⬍ .05 was considered statistically significant.
Results The repeatability coefficient (RC) was determined as (RC)2 ⫽ 1.96 × ΣDi2/(n⫺1), where n is sample size (n ⫽ 10) and Di is the difference between 2 measurements in a pair. The RC values for intraobserver repeatability (comparison of 2 determinations separated by a 1-week interval by the same observer) concerning Dd and IMT were 0.25 and 0.10, respectively. Figure 1 shows the Bland-Altman plots of the mean differences plotted against the average values. The mean differences for Dd and IMT were ⫺0.004 mm and ⫺0.013 mm, respectively, which were not statistically different from 0 (see Fig. 1).
38
Journal of Cardiac Failure Vol. 10 No. 1 February 2004
Fig. 1. Reproducibility of intima-media thickness (IMT) and brachial arterial diameter at diastole (Dd). Bland-Altman plots showing differences between measurements by a single observer on 2 occasions.
There were no significant differences in systemic blood pressure, pulse pressure, and heart rate between the CHF and control groups. Metabolic biochemical parameters such as total cholesterol, high-density lipoprotein cholesterol, and fasting blood sugar levels did not differ between the 2 groups (Table 1). Table 1. Comparison of Clinical Characteristics Between Control Subjects and Patients With Congestive Heart Failure
Age (y) Male/female BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) PP (mm Hg) HR (beats/min) LVEF (%) DCM/VHD TC (mg/dL) TG (mg/dL) HDL-C (mg/dL) Glucose (mg/dL)
Control (n ⫽ 20)
CHF (n ⫽ 25)
55.4 ⫾ 4.3 15/5 23.3 ⫾ 0.7 120.9 ⫾ 3.0 71.2 ⫾ 3.2 50.2 ⫾ 1.5 62.4 ⫾ 2.1 — — 194 ⫾ 7 133 ⫾ 30 51 ⫾ 4 99 ⫾ 5
57.1 ⫾ 3.0 20/5 21.3 ⫾ 0.8 112.1 ⫾ 3.2 65.8 ⫾ 2.3 46.4 ⫾ 2.3 69.0 ⫾ 2.1 35.8 ⫾ 2.9 18/7 165 ⫾ 7 90 ⫾ 11 60 ⫾ 5 104 ⫾ 7
P value NS NS NS NS NS NS NS — — NS NS NS NS
BMI, body mass index; DBP, diastolic blood pressure; DCM, dilated cardiomyopathy; HR, heart rate; HDL-C, HDL-cholesterol; LVEF, left ventricular ejection fraction; PP, pulse pressure; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; VHD, valvular heart disease. Mean ⫾ SEM
Brachial artery diameter did not differ between the CHF and control groups (4.11 ⫾ 0.14 versus 3.94 ⫾ 0.10 mm, not significant [NS]). However, IMT was significantly greater in CHF patients than controls (0.31 ⫾ 0.01 versus 0.37 ⫾ 0.01 mm, P ⬍ .01). Wall/lumen ratio was also higher in CHF patients (15.1 ⫾ 0.8 versus 18.7 ⫾ 0.8%, P ⬍ .005) (Fig. 2). Brachial artery distensibility was significantly lower in CHF patients than in controls (1.09 ⫾ 0.14 versus 1.60 ⫾ 0.15/kPa%, P ⬍ .05). Similarly, brachial arterial compliance was significantly decreased in the CHF group (0.17 ⫾ 0.02 versus 0.26 ⫾ 0.02 mm2 kPa, P ⬍ .01) (Fig. 3). No relationship was observed between elastic parameters and IMT (distensibility, r ⫽ .01, NS; compliance, r ⫽ .07, NS). Also, no significant correlations were found between elastic parameters and clinical parameters (ie, age, lipids, glucose, blood pressure). Brachial artery FMD was significantly lower in CHF patients than in controls (6.60 ⫾ 0.50 versus 9.51 ⫾ 0.67%, P ⬍ .001). NTG was also lower in the CHF group (11.63 ⫾ 0.80 versus 16.19 ⫾ 1.02%, P ⬍ .001) (Fig. 4). There was no significant difference in peak blood flow velocity after forearm occlusion between the 2 groups (0.38 ⫾ 0.02 versus 0.37 ⫾ 0.02 m/sec; NS). In the CHF group, brachial arterial distensibility was significantly correlated with FMD (r ⫽ .579, P ⬍ .005; Fig. 5), but not with NTG (r ⫽ .379, NS; Fig. 6). Brachial
Vascular Compliance and Endothelium in CHF
•
Nakamura et al
39
Fig. 2. Scatter plots of brachial arterial diameter at diastole (Dd), intima-media thickness (IMT), and wall-to-lumen ratio in control subjects and patients with congestive heart failure (CHF). Horizontal bar shows mean value.
arterial compliance was also significantly correlated with FMD (r ⫽ .433, P ⬍ .05), but not with NTG (r ⫽ .146, NS). In the control group, no relationships were observed between arterial wall mechanical properties and vasodilatory response.
Fig. 3. Scatter plots of brachial arterial distensibility (DC) and compliance (CC) in control subjects and patients with congestive heart failure (CHF). Horizontal bar shows mean value.
Discussion The main findings of this study are: (1) brachial arterial IMT and wall-to-lumen ratio were significantly greater in
Fig. 4. Scatter plots of flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NTG) of the brachial artery in control subjects and patients with congestive heart failure (CHF). Horizontal bar shows mean value.
40
Journal of Cardiac Failure Vol. 10 No. 1 February 2004
Fig. 5. Relationships between flow-mediated dilatation (FMD) and distensibility (DC; left) and compliance (CC: right) of the brachial artery in patients with congestive heart failure.
patients with CHF than in controls; (2) conduit vessel walls showed greater stiffness in the CHF group than in the control group; and (3) there were significant relationships between several elastic parameters and degree of impairment of flowmediated dilatation in the brachial artery of patients with CHF. The ultrasound system employed in this study was based on a recently developed image-acquisition algorithm using coherent image formation and minimization of band aberration effects using a Gaussian pulse equipped high-frequency linear transducer. These innovative imaging capabilities enabled us to gain images with greater precision and crispness than ordinary apparatus would have allowed. As demonstrated by our results, the repeatability of echo measurements was sufficient for clinical research use. Using this methodology, we found that brachial IMT was abnormally increased in patients with CHF resulting from nonischemic heart disease. In general, increased IMT may be viewed as a consequence of atherosclerotic arterial changes. However, the etiology of CHF in the present cohort was nonischemic heart disease without a hypertensive background, and levels of cardiovascular risk in CHF patients are comparable with those in control subjects. In accord with this observation,
Fig. 6. Relationships between nitroglycerin-induced dilatation (NTG) and distensibility (DC; left) and compliance (CC: right) of the brachial artery in patients with congestive heart failure.
Lage et al have reported that carotid arterial IMT in patients with idiopathic dilated cardiomyopathy was about 20% more than in healthy sex- and age-matched controls.13 This increased level was very similar to the present result (⫹19%). Wrobleski et al have shown abnormal histopathologic arteriole changes such as basement membrane hypertrophy and hyalinosis in biopsy-obtained tissue samples from CHF patients.14 In an experimental model of heart failure, myocardial infraction produced by coronary artery ligation resulted in large arterial remodeling as defined by alterations in elastic properties and arterial wall structure.15 In addition, aortic wall thickness and wall-to-lumen ratio were significantly increased within several weeks after pacing-induced heart failure in a canine model.16 Recently, Giannattaso et al have shown in human CHF that arterial wall thickness was consistently elevated in 3 different sizes of vessels such as the radial artery, carotid artery, and abdominal aorta.17 Thus it is likely that CHF itself rather atherosclerosis may be responsible for increased IMT in conduit vessels. The present study has also found abnormal elastic properties of the brachial artery in patients with CHF. Several previous reports have also demonstrated that conduit vessel in upper limb and carotid artery are stiffer in patients with CHF than in control subjects.13,18–20 Arterial compliance is determined by structural factors—such as collagen, elastin, and vascular smooth muscle—and metabolic factors—such as vasoactive neurohormones, including endothelium-derived nitric oxide. Although the possibility that the observed increase in wall-to-lumen ratio would itself result in reduced arterial compliance cannot be completely excluded, we have not found any relationship between elastic parameters and vascular structural changes (ie, wall-to-lumen ratio or IMT). In this regard, the abnormal elastic properties in the brachial artery observed in this study may be related to alterations in metabolic factors rather than structural factors. Indeed, functional metabolic factors significantly control distensibility of conduit arteries by constricting or dilating vascular smooth muscle. The constricting factors are represented by increased activity of the sympathetic nervous system, the renin-angiotensin systems, and endothelin, all of which are activated in severe CHF. Moreover, endotheliumderived nitric oxide has potent dilatory and antiproliferative properties on vascular smooth muscle,21 so this substance may be particularly important in the regulation of vascular elasticity and vascular structure.22 Several previous reports have shown that bioavailability of nitric oxide as assessed by cholinergic stimuli or flow-dependent shear stress is significantly reduced in limb vasculature in patients with CHF even with mild to moderate symptoms.9–12 Ramsey et al have shown that brachial arterial distensibility increased with levels of flow-mediated dilatation during hyperemia in healthy subjects, but this relationship was not found in CHF patients.18 These observations suggest that arterial distensibility is mainly regulated by endothelium-dependent mechanisms. This hypothesis is supported by a recent observation reported by Kinlay et al, who have shown that inhibition of
Vascular Compliance and Endothelium in CHF
nitric oxide synthase clearly reduced brachial arterial compliance and increased pulse wave velocity in the brachial artery of healthy volunteers.23 Thus the present study has examined the relationship between flow-dependent endothelial function and vascular mechanical properties, and found a significant correlation between the two. This observation suggests that endothelium-derived nitric oxide is important in the regulation of vascular elastic properties in patients with CHF. Alternatively, arterial conduit stiffening in patients with CHF means less cushion effect and greater pulsatile flow-induced damage to the endothelium in this disorder. In view of this, conduit arterial stiffening and arterial endothelial dysfunction may create a positive feedback loop or vicious cycle, thus reducing tissue perfusion and increasing cardiac afterload in patients with CHF. Study Limitations
The present study has shown that both endothelium-dependent (FMD) and endothelium-independent (NTG) responses were reduced in CHF patients. In contrast, several previous reports have observed preservation of nitrate-induced vasodilatory response in the limb vasculature in patients with CHF.9,10 However, several reports have found impairment of endothelium-“independent” dilatation in the peripheral artery of patients with CHF. Creager et al showed a marked blunting of vascular response to sodium nitroprusside in patients with end-stage CHF.24 A classical study by Zelis et al25 demonstrated a clear reduction in lower limb blood flow after intraarterial administration of a nitrovasodilator in patients with nonischemic CHF. Moreover, several recent reports have suggested that nitrovasodilator-induced relaxation response in forearm resistance and conduit vessels was blunted in CHF patients.26–28 Although accurate reasons for this discrepancy remain unknown, we have speculated that the variation may be due to differences in duration of CHF. The longstanding nature of valvular heart disease and primary cardiomyopathy (nonischemic CHF) may alter not only endothelial function but also vascular smooth muscle function and structure in peripheral vessels.11,29 FMD, NTG, and vascular stiffness parameters might therefore be expected to be somewhat related to each other, yet the present study has found that stiffness parameters were correlated with FMD but not with NTG in patients with CHF. These observations lend force to the hypothesis that although observed endothelial function is partly dependent on vascular smooth muscle function, endothelial function is independently related to vascular stiffness parameters in the brachial artery of patients with CHF. Although all vasoactive drugs were withdrawn at least 24 hour before the study, some carryover effects may have influenced the present results. It was not possible, for ethical reasons, to incorporate a complete washout period in the study design. However, a number of recent reports have shown that several kinds of vasoactive drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers significantly improve arterial wall elastic
•
Nakamura et al
41
properties and endothelial function in patients with CHF.17,30–32 Because some patients with CHF in this study were taking these types of drugs, our results may underestimate the abnormal vascular functional properties characteristic of this disorder. In conclusion, the present study found that in patients with CHF muscular conduit artery remodeling occurs with alterations in arterial wall elastic properties, and that this vascular wall functional change may be related to endothelial dysfunction. Further studies will be necessary to determine whether recovery of endothelial function by some form of intervention would restore conduit mechanical properties and thus improve the outcome of CHF.
References 1. Arnold JM, Marchiori GE, Imrie JR, Burton GL, Pflugfelder PW, Kostuk WJ. Large artery function in patients with chronic heart failure. Studies of brachial artery diameter and hemodynamics. Circulation 1991;84:2418–25. 2. Finkelstein SM, Cohn JN, Collins VR, Carlyle PF, Shelley WJ. Vascular hemodynamic impedance in congestive heart failure. Am J Cardiol 1985;55:423–7. 3. Mitchell GF, Tardif JC, Arnold JM, Marchiori G, O’Brien TX, Dunlap ME, et al. Pulsatile hemodynamics in congestive heart failure. Hypertension 2001;38:1433–9. 4. Eliakim M, Sapoznikov D, Weinman J. Pulse wave velocity in healthy subjects and in patients with various disease states. Am Heart J 1971;82:448–57. 5. Kromer EP, Elsner D, Holmer SR, Muntze A, Riegger GA. Aortic input impedence and neurohormonal activation in patients with mild to moderate chronic congestive heart failure. Cardiovasc Res 1992;26: 265–72. 6. Katz SD, Krum H, Khan T, Knecht M. Exercise-induced vasodilatation in forearm circulation of normal subjects and patients with congestive heart failure: role of endothelium-derived nitric oxide. J Am Coll Cardiol 1996;28:585–90. 7. Yoshida H, Nakamura M, Akatsu T, Arakawa N, Hiramori K. Effects of nitric oxide inhibition on basal forearm blood flow in patients with nonischemic chronic heart failure. Heart Vessels 1998;13:142–6. 8. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 1998;101:731–6. 9. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endotheliumdependent vasodilatation is attenuated in patients with heart failure. Circulation 1991;84:1589–96. 10. Drexler H, Hayoz D, Munzel T, Hornig B, Just H, Brunner HR, Zelis R. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992;69:1596–601. 11. Bank AJ, Lee PC, Kubo SH. Endothelial dysfunction in patients with heart failure: relationship to disease severity. J Card Fail 2000;6:9–36. 12. Nakamura M, Ishikawa M, Funakoshi T, Hashimoto K, Chiba M, Hiramori K. Attenuated endothelium-dependent peripheral vasodilatation and clinical characteristics in patients with chronic heart failure. Am Heart J 1994;128:1164–9. 13. Lage SG, Kopel L, Monachini MC, Medeiros CJ, Pileggi F, Polak JF, et al. Carotid arterial compliance in patients with congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 1994;74:691–5. 14. Wroblewski H, Kastrup J, Norgaard T, Mortensen SA, Haunso S. Evidence of increased microvascular resistance and arteriolar hyalinosis in skin in congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol 1992;69:769–74.
42
Journal of Cardiac Failure Vol. 10 No. 1 February 2004
15. Gaballa MA, Jacob CT, Raya TE, Liu J, Simon B, Goldman S. Large artery remodeling during aging: biaxial passive and active stiffness. Hypertension 1998;32:437–43. 16. Khan Z, Millard RW, Gabel M, Walsh RA, Hoit BD. Effect of congestive heart failure on in vivo canine aortic elastic properties. J Am Coll Cardiol 1999;33:267–72. 17. Giannattasio C, Achilli F, Failla M, Capra A, Vincenzi A, Valagussa F, et al. Radial, carotid and aortic distensibility in congestive heart failure: effects of high-dose angiotensin-converting enzyme inhibitor or lowdose association with angiotensin type 1 receptor blockade. J Am Coll Cardiol 2002;39:1275–82. 18. Ramsey MW, Goodfellow J, Jones CJ, Luddington LA, Lewis MJ, Henderson AH. Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation 1995;92:3212–9. 19. Giannattasio C, Failla M, Stella ML, Mangoni AA, Carugo S, Pozzi M, et al. Alterations of radial artery compliance in patients with congestive heart failure. Am J Cardiol 1995;76:381–5. 20. Kaiser DR, Mullen K, Bank AJ. Brachial artery elastic mechanics in patients with heart failure. Hypertension 2001;38:1440–5. 21. Numaguchi K, Egashira K, Takemoto M, Kadokami T, Shimokawa H, Sueishi K, et al. Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension 1995;26: 957–62. 22. Nakamura M. Peripheral vascular remodeling in chronic heart failure: clinical relevance and new conceptualization of its mechanisms. J Card Fail 1999;5:127–38. 23. Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, et al. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension 2001;38:1049–53. 24. Creager MA, Quigg RJ, Ren CJ, Roddy MA, Colucci WS. Limb vascular responsiveness to beta-adrenergic receptor stimulation in patients with congestive heart failure. Circulation 1991;83:1873–9.
25. Zelis R, Mason DT, Braunwald E. A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 1968; 47:960–70. 26. Maguire SM, Nugent AG, McGurk C, Johnston GD, Nicholls DP. Abnormal vascular responses in human chronic cardiac failure are both endothelium dependent and endothelium independent. Heart 1998; 80:141–5. 27. Carville C, Adnot S, Sediame S, Benacerraf S, Castaigne A, Calvo F, et al. Relation between impairment in nitric oxide pathway and clinical status in patients with congestive heart failure. J Cardiovasc Pharm 1998;32:562–70. 28. Khder Y, El Ghawi R, Boscs LB, Aliot E, Zannad F. Investigations of the peripheral vascular mechanisms implicated in congestive heart failure by the non-invasive evaluation of radial artery compliance and reactivity. Int J Cardiol 1996;56:149–58. 29. Nakamura M, Yoshida H, Arakawa N, Mizunuma Y, Makita S, Hiramori K. Endothelium-dependent vasodilatation is not selectively impaired in patients with chronic heart failure secondary to valvular heart disease and congenital heart disease. Eur Heart J 1996;17:1875–81. 30. Joannides R, Bizet-Nafeh C, Costentin A, Iacob M, Derumeaux G, Cribier A, et al. Chronic ACE inhibition enhances the endothelial control of arterial mechanics and flow-dependent vasodilatation in heart failure. Hypertension 2001;38:1446–50. 31. Nakamura M, Funakoshi T, Arakawa N, Yoshida H, Makita S, Hiramori K. Effect of angiotensin-converting enzyme inhibitors on endotheliumdependent peripheral vasodilatation in patients with chronic heart failure. J Am Coll Cardiol 1994;24:1321–7. 32. Nakamura M, Saito S, Yoshida H, Arakawa N, Sugawara S, Hiramori K. Effects of chronic subdepressor dose of angiotensin II type 1 receptor antagonist on endothelium-dependent vasodilatation in patients with congestive heart failure. J Cardiovasc Pharmacol 2002;40:411–9.