Endothelium-dependent vasodilation of peripheral conduit arteries in patients with heart failure

Journal

of Cardiac

Failure

Vol. 1 No. 1 1994

Endothelium-dependent Vasodilation of Peripheral Conduit Arteries in Patients With Heart Failure ALAN J. BANK, MD,* THOMAS S. RECTOR, PhD,” LINDA K. TSCHUMPERLIN, RN,* MARK D. KRAEMER, MD,* JANIS G. LETOURNEAU, MD,? SPENCER H. KUBO, MD, FACC” Minneapolis,

Minnesota

Abstract: Endothelium-dependent vasodilation of peripheral resistance vessels is abnormal in patients with heart failure, but there are little in vivo data on endotheliumdependent vasodilation of peripheral conduit vessels. This study assessed endothehum-dependent vasodilation of forearm conduit and resistance vessels in normal subjects and patients with heart failure. The effects of intraarterial endotheliumdependent and endothelium-independent vasodilators on both forearm conduit (brachial artery) and resistance vessels were assessed in 9 patients with New York Heart Association class II-III heart failure and 11 normal subjects of similar age. Brachial artery diameter was measured by two-dimensional, moderate-frequency (8 MHz) ultrasound, and forearm blood flow was measured by strain gauge plethysmography. The endothelium-dependent vasodilator, methacholine (0.3 and 1.5 kg/min), increased brachial artery diameter by 7.6 * I .3% and 12.2 + 1.5% in normal subjects as compared to 6.9 * 2.1% and 10.4 2 2.4% in patients with heart failure (P = NS, normal vs heart failure). The endothelium-independent vasodilator, nitroglycerin (0.15 kg), also produced similar increases in brachial artery diameter in the two groups (8.2 * 1.3% in normal subjects vs 11.1 * 1.4% in patients with heart failure, P = NS). In contrast, forearm blood flow responses to methacholine were significantly (P < .05) greater in normal subjects (4.1 2 0.5 and 9.2 ? 1.4 mL/min/lOO mL forearm volume) than in patients with heart failure (2.0 ? 0.8 and 5.1 +- 1.3 mL/ min/lOO mL forearm volume). Forearm blood flow responses to the endotheliumindependent vasodilator, sodium nitroprusside, were similar between the two groups. This study suggests that endothelium-dependent and endothelium-independent vasodilation of the brachial artery is not impaired in patients with class II-III heart failure. This finding contrasts with abnormal endothelium-dependent vasodilation of forearm resistance vessels. These data suggest that there are regional differences in endothelial function in patients with heart failure. Key words: endothelium-derived relaxing factor, heart failure, conduit vessel, vasodilation.

From the Cardiovascular Division. Departments of *Medicine iRudiology, University of Minnesota Medical School, Minneapolis. Minnesota.

The endothelium is an important modulator of vascular tone and reactivity.lm4 Previous studies in patients with heart failure have demonstrated abnormal peripheral resistance vessel dilation to the endothelium-dependent agents methacholine and acetylcholine, but not to the direct smooth muscle vasodilator sodium nitroprusside.5-7 However, there are little in vivo data regarding endothelial modulation of peripheral conduit vessel tone and

und

Supported in part by an American Heart Association Grant-inAid, an NIH-NHLBI Research Fellowship Award, and Program Project Grant POl-HL32427. Presented in part at the Scientific Sessions of the American Heart Association, New Orleans, Louisiana, November 1992. Reprint requests: Alan J. Bank, MD. Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware Street SE. Minneapolis, MN 55455.

35

36

Journal of Cardiac Failure Vol. 1 No. 1 October 1994

Although conduit vessels do not regulate organ blood flow under basal conditions, they serve important functions, including buffering of pulsatile left ventricular outflow’ and vasodilation in response to increased flow. 9*1oAbnormal endothelial function could adversely affect the ability of conduit vessels to perform these functions in patients with heart failure. This study was designed to assess endotheliumdependent and endothelium-independent vasodilation of a peripheral conduit vessel in patients with heart failure. Brachial artery diameter was measured by two-dimensional (8.0 MHz) ultrasound, and changes in diameter in response to intraarterial vasodilators were compared in normal subjects and patients with heart failure. reactivity.

Materials and Methods Study Sample The study sample consisted of 9 patients with New York Heart Association class II-III heart failure and 11 normal subjects of similar age. Patients with heart failure were referred to the University of Minnesota for cardiac transplantation evaluation. Patients with diabetes mellitus, hypertension (> 160/ 90 mmHg), significant peripheral vascular disease, or recent myocardial infarction (~3 months) were excluded from the study. All patients had left ventricular systolic dysfunction as measured’ by radionuclide ventriculography and/or echocardiography. The etiology of heart failure was coronary artery disease in five and idiopathic dilated cardiomyopathy in four patients. Medications included diuretics (n = 9), digitalis (n = 7), angiotensin converting enzyme inhibitors (n = S), calcium blockers (n = 3), quinidine (n = 2), isosorbide dinitrate (n = I), and amiodarone (n = 1). None of the patients were taking nonsteroidal antiinflammatory agents, except one patient on aspirin. All medications were withheld for at least 12 hours. Digitalis, angiotensin converting enzyme inhibitors, and other vasodilators were withheld for at least 24-48 hours prior to the study. Normal subjects were recruited from newspaper advertisements. Subjects with hypertension, cardiovascular disease, or systemic medical problems as determined by history, physical examination, routine blood tests, and electrocardiogram were excluded. Normal subjects were not taking any medications. This study was approved by the Human Rights and Research Committee and all participants gave written informed consent. This investigation conforms with the principles outlined in the Declaration of Helsinki.

Study Preparation Studies were performed in a temperature-controlled (22” 2 1’C) room in the morning. Subjects ate a light breakfast without caffeinated beverages on the morning of the study. An 18-gauge, 7.6 cm catheter was placed into the brachial artery of the nondominant arm using sterile technique and 1% lidocaine. The catheter was connected to a pressure transducer and an eight-channel recorder (Gould, TA 3200, Valley View, OH). Intraarterial infusions were administered using a mechanical syringe pump (Harvard Apparatus, South Natick, MA). Forearm blood flow was measured with a double strand mercury-in-Silastic strain gauge connected to an electronically calibrated plethysmograph (Hokanson EC 5, DE Hokanson, Bellevue, WA), as previously described.““2 A pediatric blood pressure cuff was placed around the wrist and inflated to suprasystolic pressure to exclude hand circulation 30-60 seconds prior to measuring forearm blood flow. Five consecutive flow measurements were averaged for each condition. Heart rate and contralateral arm blood pressure (cuff sphygmomanometer) were recorded before and during each infusion to assess the systemic effects of the interventions. Forearm volume (FAV) was measured by water displacement. Forearm vascular resistance was calculated as the ratio of mean arterial pressure to forearm blood flow. Measurement of Brachial Artery Diameter Brachial artery diameter was measured by twodimensional, moderate-frequency (8.0 MHz) ultrasound (Biosound 2000 II sa, Biosound, Indianapolis, IN). This device has been previously used in noninvasive studies of carotid artery atherosclerosis due to the high-quality images obtained.‘3,‘4 The 8 MHz frequency provides good tissue-blood interface resolution, and a built-in water bath allows both offset of the ultrasound transducer from the vessel being imaged and improved focus of the ultrasound beam on superficial structures, such as the brachial artery. The transducer was held lightly on the skin overlying the brachial artery approximately 4 cm proximal to the antecubital area. The transducer was positioned until a circular cross-section of the brachial artery was obtained. Any elliptic or noncircular images were rejected. The brachial artery was distinguished from venous structures based on (1) the presence of pulsations, (2) the lack of collapse with light pressure, and (3) the identification of the previously placed catheter. The brachial artery image was recorded for 30 seconds on a standard videotape recorder. In approximately 15% of the individuals

Conduit

screened for this study, the image was of insufficient quality to accurately determine brachial artery diameter. Subjects with poor quality images on screening assessment were excluded prior to participation in the study. Upon completion of the study, end-systolic frames were printed on paper for subsequent measurement of brachial artery diameter. End-systole was defined as the largest arterial diameter for each cardiac cycle. Diameters were measured in the axial plane, rather than in the lateral plane, because axial resolution is superior to lateral resolution (0.3 vs 0.7 mm, respectively according to manufacturers’ specifications). The lumen-wall border was marked with a fine-point pencil, measured to the nearest 0.25 mm, and converted to actual length using a scale factor based on the ultrasound machine internal calipers. All diameters were measured by a single individual who was blinded to the experimental condition during which the image was obtained. Eight frames were averaged for each condition. Examples of brachial artery ultrasound frames at baseline and during infusion of methacholine (1.5 pg/min) are shown in Figure 1. Reproducibility studies (Fig. 2) were performed in 28 normal subjects and 15 patients with heart failure and included measurements of brachial artery diameter performed 10 minutes apart. Between measurements, the transducer was removed from its original position and repositioned on the forearm prior to the second measurement. The mean difference between two measurements was 0.002 & 0.002 cm (P = NS), which is approximately 0.5% of the brachial artery diameter. The difference between diameter measurements of the arterial image by two different individuals averaged 0.008 + 0.003 cm,

Fig. 1. Cross-sectional ultrasound image of the brachial artery in a patient with heart failure at (A) baseline and (B) after 1.5 p,g/min intraarterial methacholine. Brachial artery diameter increased from 0.394 to 0.460 cm. (B) The black line represents a distance of 0.5 cm.

Artery Vasodilation

in Heart Failure

l

Bank et al.

37

0.30 0.30

0.40

0.50

DIAMETER

0.60

1 (cm)

Fig. 2. Reproducibility

of brachial artery diameter ultrasound measurements in 43 individuals. The mean difference between the two measurements was 0.002 ? 0.002 cm V’ = NS). Data were randomly distributed near the line of identity.

which was approximately 1.6% of the mean diameter. Validation studies (Fig. 3) were performed by comparing angiographic and two-dimensional ultrasound measurements of conduit vessel diameter. Brachial artery diameter (n = 5) was measured from cineangiograms using quanitative angiography and a method of automated edge detection (Reiber-Coronary Angiography Analysis [CAAS], PIE Medical, Maastricht, Belgium), as previously described.15 Using CAAS, a tine frame of the brachial artery was digitized from film to a matrix of approximately 1,000 x 1,500 pixels. The mean diameter of an ap-

38

Journal of Cardiac Failure ‘Vol. 1 No. 1 October 1994

O.O-

0.6 -

0.7-

0.0 -

0.5-

0.4 -

0.3 Y 0.3

1 0.4

1 0.5

0.6

0.7

0.8

0.9

1.0

I 1.1

ANGlDGRAPHlCDIAMETER (an)

Fig. 3. Comparison of brachial artery (n = 5) and femoral

artery (n = 8) diameter measured by ultrasound and angiography. The mean difference between measurements using the two techniques was 0.015 ? 0.012 cm (P = NS). Data were randomly distributed near the line of identity.

proximately 10 mm long segment whose midportion corresponded with the location of ultrasound measurement of diameter was determined using an automated algorithm and computer smoothing. Common femoral artery diameter (n = 8) was measured using calipers from cut-film angiograms, since cineangiograms were not performed on these patients. The common femoral artery was imaged with ultrasound at a point just below the inguinal ligament (which was used as a landmark for determining the place where angiographic diameter measurement was made). For both brachial and femoral measurements, angiographic catheter (7 or 8 F) diameter was also measured and used as a scale factor to correct for magnification. The mean difference between angiographic and ultrasound conduit vessel diameter measurements was 0.015 ? 0.012 cm (P = NS).

thelium-dependent vasodilation. Nitrovasodilators were given to assess endothelium-independent responses, since both methacholine (through release of endothelium-derived relaxing factor) and nitrates produce vasodilation predominantly via stimulation of soluble guanylate cyclase in vascular smooth muscle cells.16 Sodium nitroprusside (Elkins-Sinn, St. Davids, PA) was administered at 5 and 10 pg/ min to assess resistance vessel endothelium-independent vasodilation. Sodium nitroprusside was given after the brachial artery catheter had been repositioned several centimeters distal to the site of diameter measurement, since preliminary studies showed prolonged effects of this drug on brachial artery diameter and this drug was used only to assess resistance vessel endothelium-independent dilation. Nitroglycerin (DuPont Pharmaceutical, Wilington, DE) was given intraarterially as a bolus infusion of 0.15 p,g to assess endothelium-independent vasodilation of the brachial artery. Brachial artery response to nitroglycerin was measured approximately 30 seconds after administration. Nitroglycerin was administered last due to its prolonged vasodilatory effect on conduit arteries. These two nitrovasodilators were used, since preliminary studies demonstrated that nitroglycerin had a greater effect on conduit vessels, whereas nitroprusside had a greater effect on resistance vessels. Continuous infusions were administered for 1.5 minutes at 1 mL/min before measuring the first diameter and then forearm blood flow because preliminary studies showed steady-state responses by this time. The transducer was kept in the same position for each drug infusion and the corresponding baseline. The transducer was removed between drug infusions and repositioned prior to the next baseline measurements at a location previously marked on the arm. All participants received infusions in ascending doses in the following order: 5% dextrose in water, methacholine, sodium nitroprusside, and nitroglycerin.

Experimental Protocol After the catheter was placed, the patients rested for 30 minutes and then blood samples were obtained for assay of plasma norepinephrine. Baseline forearm blood flow and brachial artery diameter were measured on two occasions, separated by 10 minutes. The catheter tip was several centimeters proximal to the site of the brachial artery diameter measurement, as demonstrated by ultrasound. Five percent dextrose in water was administered as a control measure. Methacholine (Provocholine, Roche Laboratories, Hutley, NJ) was administered intraarterially at 0.3 and 1.5 pg/min to assess endo-

Calculations and Statistical Analyses The reproducibility of repeated ultrasound measurements of brachial artery diameter and the comparison to angiographic diameter measurements were assessed by paired t-tests. Baseline characteristics were compared using unpaired t-tests. Methacholine, nitroprusside, and nitroglycerin responses were evaluated by analysis of variance with a repeated measure (dose) and grouping factor (normal versus heart failure). P values 5 .05 were considered significant. Values reported are mean + SEM except where specified.

Conduit Artery Vasodilation

in Heart Failure

Bank et al.

l

39

Table 1. Baseline Characteristics Heart Failure (n = 9)

Normal (n = 11) Age (years) Male/Female Forearm volume (mL) Forearm blood flow (mLlmini100 mL FAV) Mean arterial pressure (mmHg) Forearm vascular resistance (mmHg/mL/min/100 Brachial artery diameter (cm) Ejection fraction (%) Norepinephrine (pg/mL) Cholesterol (mg/dL)

mL FAV)

41.5 k 5.3 (range, 21-66) 1110 1,145 k 31 2.93 k 0.38 86.4 ” 3.3 33.6 ” 4.1 0.442 + 0.021 287 2 26 192 2 13

45.2 + 3.0 (range, 29-56) 712 1.217 -+ 100 2.53 zk 0.33 79.0 t 6.0 38.6 -c 8.1 0.450 + 0.021 14 k 2 548 2 93* 206 t 23

* P < .05. FAV, forearm volume.

Results Baseline Characteristics Baseline characteristics of the two groups are shown in Table I. The mean ejection fraction in the patients with heart failure was 14 + 2%. There were no statistically significant differences between the groups for any of the baseline characteristics measured, except for plasma norepinephrine concentration, which was significantly higher (548 + 93 vs 287 + 26 pg/mL; P < .05) in the patients with heart failure. Responses to Vasodilators There was no significant change ( - 0.001 k 0.004 cm; 0.23%) in brachial artery diameter in response to intraarterial 5% dextrose in water-vehicle infusion. The percent changes in brachial artery diameter for both groups in response to intraarterial methacholine and nitroglycerin infusions are shown in Figure 4. All individuals, except one, exhibited dilation in response to methacholine. In the normal subjects, brachial artery diameter increased by a mean

Fig. 4. Percent change in brachial artery diameter in response to intraarterial methacholine and nitroglycerin in 11 normal subjects and 9 patients with heart failure. There were no significant differences between the groups in brachial artery response to either drug. MTC 1, methacholine 0.3 kg/ min; MTC 2, methacholine I .5 pg/min; NTG, nitroglycerin 0.15 pg.

of 7.6 + 1.3% and 12.2 +- 1.5% for the two doses of methacholine. The corresponding changes in brachial artery diameter in the patients with heart failure were 6.9 +- 2.1% and 10.4 + 2.4%. There was no significant difference between the two groups regarding the conduit vessel response when analyzed as either absolute or percent change in diameter. The brachial artery responses to nitroglycerin were also not significantly different between the groups, with diameter increasing by 8.2 + 1.3% in the normal subjects and 11.1 + 1.4% in the patients with heart failure. Responses of forearm resistance vessels are shown in Figure 5. Methacholine increased forearm blood flow by 4.1 + 0.5 and 9.2 + 1.4 mL/min/lOO mL FAV in the normal subjects and by 2.0 + 0.8 and 5.1 2 1.3 mL/min/lOO mL FAV in the patients with heart failure (P < .05 normal vs heart failure). Methacholine decreased forearm vascular resistance by 20.7 -+ 4.2 and 25.7 + 5.2 mmHg/mL/min/ 100 mL FAV in the normal subjects and by 9.5 + 3.6 and 19.7 t 4.1 mmHg/mL/min/lOO mL FAV in the patients with heart failure. In contrast to the impaired endothelium-dependent resistance vessel

12s

MART FAILURE

A

40

Journal

of Cardiac

n q

Failure

NORMAL

Vol. 1 No. 1 October

1994

A

(n-l 1)

HEART FAILURE (n-9)

0.3 METHACHCLINE

5.0

1.5 DOSE (mcqhbin)

NlTROPRlJWDE

10.0 DOSE (mc@hM)

Fig. 5. Forearm blood flow responses to the endothelium-dependent vasodilator, (A) methacholine, and the endotheliumindependent vasodilator, (B) sodium nitroprusside. Forearm blood flow increase in response to methacholine was significantly (P < .05) impaired in the patients with heart failure. Although responses to the lower dose of sodium nitroprusside tended to be less in the patients with heart failure, there was no overall difference (P = .49) between the responses in the two groups.

dilation, responses to the endothelium-independent vasodilator, sodium nitroprusside, were not significantly impaired, with forearm blood flow increasing by 8.6 + 1.1 and 10.4 & 1.4 mL/min/lOO mL FAV in the normal subjects and by 5.6 t 1.3 and 10.7 -+ 2.9 mL/min/lOO mL FAV in the patients with heart failure. Forearm vascular resistance decreased by 18.9 + 3.5 and 16.9 & 2.7 mmHg/mL/min/lOO mL FAV in the normal subjects and by 18.1 ? 3.5 and 23.7 ? 5.5 mmHg/mL/min 100 mL FAV in the patients with heart failure. There were four patients in each group with serum cholesterol values greater than 200 mg/dL. The correlation between serum cholesterol and response to vasodilators was assessed to determine if some of the variation in vasodilator response was related to this variable. There was no significant correlation between serum cholesterol and conduit or resistance vessel response (r values ranged from 0 to .33).

Discussion This study demonstrates that endothelium-dependent and endothelium-independent vasodilation of the brachial artery is intact in patients with heart failure. In contrast, endothelium-dependent, but not endothelium-independent, vasodilation of peripheral resistance vessels is impaired. These data are in agreement with previous studies in humans with heart failure that showed impaired resistance vessel dilation to endothelium-dependent vasodilators .5-7

This study suggests that abnormal endothelium-dependent vasodilation is not uniformly present in all arteries. In previous studies of animals and humans with heart failure, impaired endothelium-dependent vasodilation has consistently been demonstrated in peripheral and coronary resistance vessels.5-7,17-19 In contrast, studies of conduit vessel endothelium-dependent vasodilation have shown variable findings. Kaiser et al. demonstrated reduced responses to the topically applied endothelium-dependent vasodilator, acetylcholine, in anesthetized dogs with pacinginduced heart failure. *OIn the rat infarct model of heart failure, Ontkean et al. demonstrated an impairment of endothelium-dependent relaxation of the pulmonary artery in vitro.*’ Endothelium-dependent relaxation of the thoracic aorta was also reduced, but to a lesser extent. However, Forster et al. found that endothelium-dependent relaxation was normal in the dorsalis pedis and coronary arteries of dogs with pacing-induced heart failure.** Peripheral vascular endothelium-dependent vasodilation in patients with heart failure was assessed by Drexler et al. using A-mode echo.6 In this study, a significant radial artery vasodilation to intraarterial acetylcholine could not be demonstrated in the six patients with heart failure or the six normal subjects studied. The reasons for the lack of agreement among these studies are not known, but may be related to differences in species, artery site, method of inducing heart failure, and technique (in vitro vs in vivo).

Conduit Artery Vasodilation

This study demonstrates a differential response of conduit and resistance vessels to endotheliumdependent, but not endothelium-independent, vasodilators in patients with heart failure. This finding contrasts with the results of studies in humans with atherosclerosis that demonstrate both impaired conduit and resistance vessel endothelium-dependent other investigators vasodilation. 23-25 However, have shown size-dependent differences in the endothelial function of human blood vessels.26 For example, calcitonin gene-related peptide and vasoactive intestinal peptide produce endothelium-dependent relaxation in the conduit arteries, but endotheliumindependent relaxation in the resistance vessels2’ Furthermore, in humans with hypertension, endothelium-dependent vasodilation of forearm resistance vessels is impaired,28*29 but flow-mediated vasodilation of the brachial artery (an endotheliumdependent response) is intact.30 Therefore, size-dependent differences in endothelium-dependent vasodilation may be present in both hypertension and heart failure. Measurement of brachial artery diameter was accomplished in this study by using two-dimensional (8.0 MHz) ultrasound. Similar techniques have been used to assess carotid artery atherosclerosis during natural history and intervention trials,‘3*14 and to measure brachial artery response to hyperemia and sublingual nitroglycerin. 31 We have demonstrated that this technique is both accurate and reproducible. This technique also offers some advantages over existing methods of determining human conduit vessel diameter. Angiography and intravascular ultrasound may provide higher resolution, but they are invasive. Calculation of the cross-sectional area and diameter using the quotient of forearm blood flow and Row velocity introduces the error of two different measurements to calculate conduit vessel diameter.32 Unlike bidimensional-pulsed Doppler velocimetry,33 our method allows direct visualization of brachial artery diameter for each heart beat. Resolution is comparable in both techniques, since the smallest sample volume that can be obtained by pulsed Doppler velocimetry is approximately 0.38 mm (approximately 9% of the normal brachial artery diameter) as compared to 0.30 maximal axial resolution with the 8 MHz Biosound ultrasound transducer. There are, however, some limitations to this technique . The accuracy and reproducibility depend highly on the image quality of the brachial artery. This technique requires careful attention to the angle created between the transducer and vessel, since a tangential view would overestimate brachial artery diameter. This problem was minimized by re-

in Heart Failure

l

Bank et al.

41

jetting any cross-sectional images that appear noncircular. In this study, no significant difference was found between patients with heart failure and normal subjects regarding brachial artery diameter response to methacholine. The averages of the responses to the two doses of methacholine were 9.9% in the normal subjects and 8.6% in the patients with heart failure. If the one heart failure patient who vasoconstricted in response to methacholine is excluded from analysis, the brachial artery responses to methacholine are equal at 9.9% in both groups. Based on the 95% confidence interval on the difference in response between the two groups, the true heart failure response should be no more than 3.5% less than the normal response. The magnitude of this potential difference in conduit vessel endothelium-dependent vasodilation is less than that seen in other diseases associated with abnormal large artery endothelial function, such as atherosclerosis, where large arteries frequently fail to dilate or constrict in response to endothelium-dependent vasodilators .23-25 It is possible that atherosclerosis or hypercholesterolemia affected the brachial artery responses. However, no patient had overt peripheral vascular disease, and there was no correlation between the conduit or resistance vessel response to methacholine and serum cholesterol. It is possible that the drugs taken by the patients with heart failure could have altered the response to endothelium-dependent vasodilators. For example, cardiac glycosides impair endothelium-dependent vasodilation in some vascular beds,34,35 but not in others.36,37 Nevertheless, studies in animals with heart failure (and on no medication) still show abnormal endothelium-dependent vasodilation of peripheral resistance vessels. ‘8-‘9 Alternatively, converting enzyme inhibitor therapy has been shown to improve endotheliumdependent vasodilation in spontaneously hypertensive rats,38.39 and in the forearm vasculature of normal subjects4’ and patients with hypertension.4’ However, if these drugs altered endothelium-dependent vasodilation, the magnitude or time course of the effect would have to differ between the conduit and resistance vessels to produce the results obtained. In conclusion, endothelium-dependent vasodilation of forearm resistance, but not conduit vessels, is impaired in patients with heart failure. A better understanding of the regional and size-dependent differences in endothelial function may help in the search for the underlying mechanism of arteriolar endothelial dysfunction in heart failure.

42

Journal of Cardiac Failure Vol. 1 No. 1 October 1994

Acknowledgments The authors thank Andrea Dahl for assistance in preparing the manuscript, and Stephen M. Schwabacher, RVT, for assistance with ultrasound imaging of the brachial artery.

References 1. Furchgott RF, Zawadski JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;280:373-82 2. Vanhoutte PM: Endothelium and control of vascular function: state of the art lecture. Hypertension 1988; 12:797-806 3. Moncada S, Palmer RMJ, Higap EA: The discovery of nitric oxide as the endogenous nitrovasodilator. Hypertension 1988;12:365-72 4. Vane JR, Anggard EE, Botting RM: Regulatory functions of the vascular endothelium. N Engl J Med 1990; 323:27-36 5. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM: Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 1991; 84: 1589-96 6. Drexler H. Hayoz D, Mtinzel T, Hornig B, Just H, Brunner H, Zelis R: Endothelial function in chronic heart failure. Am J Cardiol 1992;69:1596-601 7. Katz SD, Biasucci L, Sabba C, Strom JA, Jondeau G, Galvao M, Solmon S, Nikdic SD, Forman R, LeJemtel TH: Impaired endothelium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Co11 Cardiol 1992;19: 918-25 8. O’Rourke MF: Vascular impendence and cardiac function. In O’Rourke MF: Arterial function in health and disease. Churchill Livingstone, New York, 1982, pp. 153-69 9. Pohl U, Holtz J, Busse R, Bassenge E: Crucial role of the endothelium in the vasodilator response to increased flow in vivo. Hypertension 1986;8:37-44 10. Rubanyi GM, Romero JC, Vanhoutte PM: Flow induced release of endothelium-derived relaxing factor. Am J Physiol 1986;250:H1145-9 11. Cody RJ, Muller FB, Kubo SH, Rutman H, Leonard D: Identification of the direct vasodilator effects of milrinone with an isolated limb preparation in patients with chronic congestive heart failure. Circulation 1986;73:124-9 12 Kubo SH, Rector TS, Heifetz SM, Cohn JN: Alpha* receptor mediated vasoconstriction in patients with congestive heart failure. Circulation 1989;80: 1660-7 13. Bond MG, Wilmoth SK, Enevold GL, Strickland HL: Detection and monitoring of asymptomatic atherosclerosis in clinical trials. Am J Med 1989;86(suppl 4A):33-6 14. Malinow MR, Nieto FJ, Szklo M, Chambles SLE, Bond G: Carotid artery intimal-medial wall thickening

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

and plasma homocyst(e)ine in asymptomatic adults. The atherosclerosis risk in communities study. Circulation 1993;87: 1107-13 Reiber JH, Serruys PW, Kooijman CJ, Wijns W, Slager CJ, Gerbrands JJ, Schuubiers JCH, den Boer A, Hugenholtz PG: Assessment of short-, medium-, and long-term variations in arterial dimensions from computer-assisted quantitation of coronary cineangiograms. Circulation 1985;71:280-8 Griffith TM, Lewis MJ, Newby A, Henderson AH: Endothelium-derived relaxing factor. J Am Co11Cardiol 1988;12:797-806 Treasure CB, Vita JA, Cox DA, Fish D, Gordon JB, Mudge GH, Colucci WS, St. John Sutton MG, Selwyn AP, Alexander RW, Ganz P: Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 1990;81:772-9 Drexler H, Lu W: Endothelial dysfunction of hindquarter resistance vessels in experimental heart failure. Am J Physiol 1992;262:H1640-5 Kiuchi K, Sata N, Shannon RP, Vatner DE, Morgan K, Vatner SF: Depressed B-adrenergic receptor- and endothelium-mediated vasodilation in conscious dogs with heart failure. Circ Res 1993;73: 1013-23 Kaiser L, Spickard RC, Olivier NB: Heart failure depresses endothelium-dependent responses in canine femoral artery. Am J Physiol 1989;256:H962-7 Ontkean M, Gay R, Greenberg B: Diminished endothelium-derived relaxing factor activity in an experimental model of chronic heart failure. Circ Res 1991; 69: 1088-96 Forster C, Main JS, Armstrong PW: Endothelium modulation of the effects of nitroglycerin on blood vessels from dogs with pacing-induced heart failure. Br J Pharmacol 1990;101:109-14 Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P: Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986:315: 1046-5 1 Zeiher AM, Drexler H, Wollschlager H, Just H: Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis. Circulation 1991;84:1984-92 Liao JK, Bettmann MA, Sandor T, Tucker JI, Coleman SM, Creager M: Differential impairment of vasodilator responsiveness of peripheral resistance and conduit vessels in humans with atherosclerosis. Circ Res 1991;68: 1027-34 Hughes AD, Thorn SA, Martin GN, Nielsen H, Hair WM, Schachter M, Sever PS: Size and site-dependent heterogeneity of human vascular responses in vitro. J Hypertension 1988;6:5173-5 Thorn S, Hughes A, Goldberg P, Martin G, Schacter M, Sever P: The action of CGRP and VIP as vasodilators in man in vivo and in vitro. Br J Clin Pharmacol 1987;24:139-44 Panza JA, Quiyyumi AA, Brush JE, Epstein SE: Abnormal endothelium-dependent vascular relaxation in

Conduit hypertension. N Engl J Med 1990;323;22-7 Linder L, Kiowski W, Buhler FR, Luscher TF: Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo: blunted response in essential hypertension. Circulation 1990;8 1: 1762-7 Laurent S, Lacolley P, Brunei P, Laloux B, Pannier B, Safar M: Flow-dependent vasodilation of brachial artery in essential hypertension. Am J Physiol 1990: H1004-11 Celermajer D, Sorensen KE, Gooch VM, Spiegelhauter DJ, Miller 01, Sullivan ID, Lloyd JK, Deanfield JE: Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340: 111l-5 Sinoway LI, Hendrickson C, Davidson WR, Prophet S, Zelis R: Characteristics of flow-mediated brachial artery vasodilation in human subjects. Circ Res 1989; 64:32-42 Safar ME, Perronneau PA, Levenson JA, Tot-Moukouo JA, Simon AC: Pulsed Doppler diameter, blood flow velocity and volumic flow of the brachial artery in essential hypertension. Circulation 1981:63: 393-400 Woolfson RG, Poston L: Effect of ouabain on endothelium-dependent relaxation of human resistance arteries. Hypertension 1991;17:619-25

patients with essential 29.

30.

31

32.

33.

34.

Artery Vasodilation

in Heart Failure

l

Bank et al.

43

35. De Mey JG, Vanhoutte PM: Interaction between Na,K exchanges and the direct inhibitory effect of acetylcholine on canine femoral arteries. Circ Res 1980;46:826-35 36. Chen G, Hashitani H, Suzuki H: Endothelium-dependent relaxation and hyperpolarization of canine coronary artery smooth muscles in relaxation to the electrogenic Na-K pump. Br J Pharmacol 1989;98:950-6 37. Suzuki H: The electrogenic Na-K pump does not contribute to endothelium-dependent hyperpolarization in the rabbit ear artery. Eur J Pharmacol 1988;156: 295-7 38. Clozel M, Kuhn H, Hefti F: Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats. Hypertension 1990:16:532-40 39. Clozel M: Mechanism of action of angiotensin converting enzyme inhibitors on endothelial function in hypertension. Hypertension 1991:18(suppl II): 1X37-42 40. Nakamura M, Funakoshi T, Yoshida H, Arakawa N, Suzuki T, Hiramori K: Endothelium-dependent vasodilation is augmented by angiotensin converting enzyme inhibitors in healthy volunteers. J Cardiovasc Pharmacol 1992;20:949-54 41 Hirooka Y, Imaizumi T, Masaki H, Ando S, Harada S, Momohara M, Takeshita A: Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients. Hypertension 1992;20: 175-80