(Hypertension. 1995;26:497-502.)
© 1995 American Heart Association, Inc.
Articles |
Postischemic Blood Flow Response in Hypercholesterolemic Patients
From the Division d'Hypertension, CHUV, and Policlinique Médicale Universitaire, Lausanne, Switzerland.
Correspondence to Daniel Hayoz, Division d'Hypertension, CHUV, 1011 Lausanne, Switzerland.
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Abstract |
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Abstract We undertook this cross-sectional study to compare the mechanical behavior and postischemic response of the radial artery of 15 newly diagnosed hypercholesterolemic patients with those of 15 age- and sex-matched normocholesterolemic control subjects and 21 hypercholesterolemic patients treated for 2 years with an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (simvastatin, 10 to 20 mg/d). At the time of the study total cholesterol levels were at 7.9±0.2, 4.9±0.2, and 6.0±0.3 mmol/L in the three groups, respectively (mean±SEM, P<.001). High-resolution, noninvasive echotracking for assessment of internal arterial diameter was combined with measurements of blood flow velocity by Doppler and blood pressure by photoplethysmography. Radial cross-sectional compliance and distensibility were similar in all groups. Forearm blood flow and flow-mediated dilation were measured after a 5-minute upper arm occlusion. Flow was calculated from the vessel diameter and blood flow velocity recorded simultaneously at the same site. Flow-mediated dilation after ischemia was not significantly different among the three groups. However, forearm blood flow increase was markedly blunted (P<.01) in untreated hypercholesterolemic patients (211%) compared with the normocholesterolemic control subjects (411%) and treated patients (365%). These findings suggest that the distensibility of the radial artery, a muscular conduit vessel usually devoid of atherosclerotic lesions, and its flow-mediated dilation are preserved in hypercholesterolemic patients. In contrast, forearm resistance vessels exhibit a markedly reduced postischemic blood flow response that may be restored by prolonged lipid-lowering intervention.
Key Words: hypercholesterolemia • radial artery
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Introduction |
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Hypercholesterolemia, a well-established risk factor for atherosclerosis,1 induces early impairment of vascular function as manifested by a depressed endothelium-dependent vasodilation before onset of atherosclerotic lesions.2 3 4 5 Possible contributors to the attenuated vascular responses with elevated low-density lipoprotein levels include a diminished synthesis,6 7 a reduced release,8 or an accelerated inactivation of the endothelium-derived relaxing factor nitric oxide.9 An alternative explanation would be an enhanced diffusion barrier to vasodilators.2
Invasive animal and clinical studies have revealed a reduced vascular relaxation to a variety of pharmacological stimuli. Acetylcholine, a muscarinic receptor antagonist, is the most widely tested substance. The noninvasive assessment of the vascular response to an ischemic stimulus represents an alternative to intra-arterial drug infusion for testing of the functional capacity of blood vessels in asymptomatic hypercholesterolemic patients at a stage when any lesion may still be reversible. Reduction of vascular resistance after interruption of blood flow results from metabolic factors such as ATP-sensitive potassium channels,10 11 adenosine,12 13 and cyclooxygenase products14 15 16 and from a myogenic response.17 It has been shown that in the face of several cardiovascular risk factors the peak hyperemic response is abnormal in certain vascular beds, whereas it remains unaffected in others.18 19 20 The diversity of methodologies used for assessment of the blood flow response may account for the inconsistency of the reported results.
In this study we assessed the effects of hypercholesterolemia on the function of a conduit artery. The methods we used allowed us to differentiate the contribution of resistance vessels from that of conduit arteries on vascular reactivity. We used a high-resolution echotracking system coupled to a continuous-wave Doppler to measure simultaneously and continuously arterial diameter and blood flow. The addition of a blood pressure signal obtained by photoplethysmography to the above parameters enabled us to assess in a totally noninvasive manner the elastic behavior of the artery and flow changes and their effects on arterial diameter as well as to examine the results of pharmacological and physiological interventions.
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Methods |
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Initially, 21 hypercholesterolemic patients (10 women, 11 men; aged 27 to 70 years; mean, 56 years) were enrolled in a study of arterial compliance of the radial artery. All of them had primary type II hyperlipoproteinemia and a normal office blood pressure (122/77±3/2 mm Hg, mean±SD). Patients with secondary hyperlipidemia, diabetes mellitus, advanced hepatic disease, history of gallstones, angina pectoris, or recent (<3 months) cardiovascular events (stroke, myocardial infarction, coronary artery bypass graft, or arrhythmia) were excluded. No patients received calcium channel blockers, ß-blockers, angiotensin-converting enzyme inhibitors, or nitrates. Two patients were taking low-dose aspirin. All patients were informed of the nature of the study and gave their oral consent. The protocol of the study had been previously approved by the Hospital Ethics Committee.
Before entering the study patients were submitted to a 4-week standard lipid-lowering diet without any hypolipemic agents. If total cholesterol remained higher than 6.5 mmol/L at the end of the period, patients were treated with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor simvastatin (Merck Sharp & Dohme), 10 to 20 mg once a day depending on their lipid profile response.
After more than 2 years of therapy the arterial compliance of these treated patients was reassessed and found to be identical. Meanwhile, the echotracking device had been further developed and combined with continuous blood flow measurement; therefore, we initiated the present cross-sectional study to compare the postischemic blood flow response and flow-mediated vasodilation of these patients now treated for more than 2 years with that of 15 matched subjects with untreated primary type II hyperlipidemia and 15 normocholesterolemic subjects. All three groups were matched with respect to age, sex, and smoking habits. Their clinical characteristics are summarized in Table 1. The untreated hypercholesterolemic patients were matched also for clinical characteristics and lipid levels measured in the treated group before they started cholesterol-lowering medication (see Table 2). Since these untreated patients were not a priori included in a subsequent prospective study, they were then followed by their private physician.
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All subjects were examined in the supine position after 30 minutes of rest in a room with a constant temperature of 22°C. Arterial diameter measurements were carried out on the right radial artery, 5 cm proximal to the wrist. The right supinated arm was placed in a splint to limit involuntary movements. Description of the measuring device (NIUS 02, Asulab SA), which is an upgraded version of an apparatus that used hardware tracking,21 22 as well as reproducibility data have been reported previously.23 Briefly, the ultrasonic echoes reflected by the interfaces between blood and both anterior and posterior walls (radio frequency [RF] echo line) are sampled at 100 MHz and stored at 500-Hz repetition frequency (PRF). The vascular interfaces are subsequently selected by the operator on the RF echo line and automatically tracked to obtain the diameter and its variation over time. The exact position of each selected interface is obtained by calculating the real-time position of the maximum of the corresponding peak in the RF line. The initial resolution given by the 100-MHz sampling frequency (corresponding to a spatial depth of 7.5 µm) is enhanced to approximately 1 µm. The diameter signal is finally stored at 50 Hz. The reduction from PRF to this final sampling frequency is performed by averaging 10 samples, which allows the reduction of both noise and memory requirement.
Blood pressure was measured at the right middle finger by a
photoplethysmographic instrument (Finapres, Ohmeda) linked to the
ultrasonic echotracking device. This apparatus provides
noninvasive continuous recordings of finger blood pressure with
a resolution of 0.25 kPa (2 mm Hg). This technique has been studied
extensively and described in detail elsewhere.24
Cross-sectional compliance (C) in the case of a cylindrical vessel is
given by C=(
S/P), where S represents the change in
cross section, and P represents the change in blood
pressure. Arterial cross-sectional distensibility (D) is
the compliance value normalized for the cross section and defined by
D=1/S · (S/P).
Forearm blood flow velocity was measured by continuous-wave Doppler (8-MHz transducer at a 60° angle, Doptek 2002) distal to the 10-MHz probe used for diameter measurements. Resting blood flow (milliliters per minute) was the product of time-averaged mean velocity and arterial cross-sectional area obtained simultaneously from the arterial diameter at 30-second intervals.
Ischemia was induced for 5 minutes by occluding the upper arm with a cuff inflated at 30 mm Hg above systolic pressure. After cuff deflation (reactive hyperemia) arterial diameter and blood flow velocity were determined at 20-second intervals during 3 minutes and every 30 seconds thereafter until the diameter returned to baseline. This technique yields accurate relative changes in blood flow after the ischemia maneuver.25
Eleven of the 15 subjects who had been nontreated hypercholesterolemic patients at the time of the cross-sectional study were again available for reevaluation 2 years later. Among them, 5 subjects were taking an HMG CoA reductase inhibitor and 3 were on a low-cholesterol diet. With the exception of the lipid-lowering drug, no other long-term cardiovascular medication had been prescribed to the patients during the time interval between the two measurements. The same conditions were used for the measurements.
An ordinary one-way ANOVA with a Student-Newman-Keuls multiple comparisons test was used to compare general and clinical characteristics of the experimental groups. Differences were considered significant for values of P<.05. Statistical analysis of compliance-pressure and distensibility-pressure curves was done with a multivariate analysis based on Hotelling's T2, considering compliance or distensibility values at three arbitrary defined blood pressures within measured values (80, 100, and 120 mm Hg). Correlation coefficients were calculated according to standard methods.
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Results |
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The general characteristics of the three groups are given in Table 1. Besides cholesterol levels there was no statistically significant difference in baseline risk factors among the three groups. In the treated group total cholesterol had been significantly reduced after 6 months of treatment from 7.49±0.87 to 5.36±0.72 mmol/L (mean±SEM, P<.001), and it remained low after 2 years at the time of the cross-sectional study. The lipid profiles of the three study groups are shown in Table 2. Total cholesterol and low-density lipoprotein cholesterol were significantly higher in the untreated hypercholesterolemic population than in the two other groups.
Good-quality A-mode echographic diameter recordings were obtained in all patients. No difference in mean arterial diameter was noticed among the three groups (2880±100 µm for normocholesterolemic control subjects, 2830±130 µm for hypercholesterolemic patients, and 2700±130 µm for treated hypercholesterolemic patients [mean±SEM]). Cross-sectional compliance- and distensibility-pressure curves of the treated and untreated hypercholesterolemic patients and normocholesterolemic control subjects were found to be similar (Fig 1). The fact that arterial compliance and distensibility of the hypercholesterolemic patients treated for 2 years with simvastatin had not changed (data not shown) corroborated this observation. Resting mean blood flow obtained by averaging 10 measurements (one every 30 seconds) during the 5-minute control period preceding upper arm artery occlusion showed no significant difference between the three groups, even though resting blood flow was slightly higher in the untreated hypercholesterolemic patients (41.5±7.8 mL/min) compared with control subjects and treated patients (24.4±4.7 and 25.4±3.7 mL/min, respectively).
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),
untreated hypercholesterolemic patients (
),
and treated (2 years of simvastatin) patients (
).
Values are mean±SEM.The changes in diameter observed after the release of the occlusion are shown in Fig 2. as percent increases from either baseline values or from the minimal diameter measured during occlusion. The reactive hyperemia is expressed as percent increase from the baseline blood flow value. The peak forearm blood flow 20 seconds after release of the upper arm occlusion was significantly lower (P<.01) in untreated hypercholesterolemic patients (211±23%) compared with normocholesterolemic control subjects (411±41%) (Fig 3, top). Interestingly, the treated hypercholesterolemic patients exhibited a postischemic blood flow response (365±42%) similar to that of the normocholesterolemic control subjects. The flow debt repayment, defined as the area under the curve of flow above baseline flow during the 120 seconds after occlusion release, was significantly depressed in untreated hypercholesterolemic patients compared with the other two groups (P<.05). The flow-mediated dilation of the radial artery expressed either from the baseline diameter (A) or from the minimal value during occlusion (B) was not statistically different among the three groups (Fig 3, bottom, panels A and B) (untreated hypercholesterolemic patients: A, 6.7±1.0%; B, 15.6±1.9%; treated patients: A, 7.6±1.0%; B, 15.7±1.6%; normocholesterolemic control subjects: A, 7.6±1.2%; B, 14.7±1.7%).
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Arterial dilation normalized for the magnitude of the postischemic reactive peak blood flow, which reflects more closely true flow-dependent dilation, was not statistically different among the three groups. The ratio was calculated as the percent change in diameter divided by the percent change in peak reactive blood flow multiplied by 100. Values were 1.82±0.3 for normocholesterolemic subjects, 3.4±0.6 for hypercholesterolemic patients, and 2.5±0.4 for treated hypercholesterolemic patients.
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Discussion |
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This study provides an answer to the question of whether the mechanical behavior of a muscular artery exposed to hypercholesterolemia is altered. No identifiable modification of the viscoelastic properties of the vessel wall was found in the radial artery. Although it has been shown in different arterial segments that hyperlipidemia induces alterations of the mechanical properties,26 27 28 29 the present data obtained with a new technique allowing the acquisition of simultaneous diameter and pressure signals demonstrate that compliance- and distensibility-pressure curves are preserved in a conduit vessel free of macroscopic atheromatous lesions exposed to high cholesterol. Giannattasio et al,30 using our measuring device, have reported lowered compliance-pressure curves in familial hypercholesterolemia but not in nonfamilial forms of dyslipidemia. Endothelial dysfunction in peripheral arteries manifested by attenuated release or accelerated degradation of endothelium-derived relaxing factors (nitric oxide, prostacyclin) early in the hypercholesterolemic state might be expected to play a role in tone regulation, thus altering the viscoelastic properties of the vessel wall. However, the present findings suggest that regional vasomediators are either normally effective or that they do not play a critical role in modulating the elasticity of medium-sized vessels. Furthermore, if hypercholesterolemia is associated with vascular wall thickening, it seems to be accompanied by an adaptive transformation of wall components that maintain arterial elasticity constant.
Flow-mediated dilation of the radial artery is not impaired in untreated hypercholesterolemic patients when compared with simvastatin-treated patients and control subjects. Indeed, the arterial dilation normalized for the magnitude of the peak reactive hyperemic blood flow showed the greatest ratio of diameter changes over increase in flow for untreated hypercholesterolemic patients although no significant differences were found between the groups. Previous data obtained in the brachial arteries of symptomatic adults suffering from coronary artery disease with elevated cholesterol levels demonstrated an impaired flow-mediated dilation.20 However, Zeiher and collaborators31 have shown that patients with hypercholesterolemia and angiographically normal coronary arteries exhibited a preserved flow-dependent dilation of the proximal left anterior descending coronary artery segments. The microvascular endothelial dysfunction observed in hypercholesterolemic patients may be very selective. Indeed, normal nitric oxide bioavailability to bradykinin was found in hypercholesterolemic patients presenting a markedly impaired vasodilator response to acetylcholine.32 The apparent discrepancy between the above-mentioned studies may be partially explained by age differences of the study populations, the degree of atherosclerosis, the vascular bed under study, and the techniques used.
Endothelium-independent factors related to smooth muscle cell alteration may also contribute under some circumstances to impaired vasoreactivity.19 20 This is suggested by the reduced vasodilator response to sodium nitroprusside observed in hypercholesterolemic patients, although the effect was manifest only at the highest test dose (10 µg/min).20 But again, contradictory results exist. Münzel and coworkers33 recently reported that the radial artery of hypercholesterolemic patients did not show a reduced dilation after glyceryl trinitrate infusion compared with healthy control subjects. Other researchers34 observed an impaired flow-mediated dilation of the superficial femoral artery in young asymptomatic children with familial hypercholesterolemia. Unlike the radial artery, the femoral artery is one of the privileged sites for atheromatous transformation, together with the coronary and carotid arteries. This vascular bed may show different responses to pharmacological and physiological stimuli compared with the upper extremities. Like many other investigators we found a reduced or absent blood flow increase in the forearm of hypercholesterolemic patients after intra-arterial infusion of a muscarinic receptor agonist.33 No significant difference in the response of the radial artery to acetylcholine infusion (vasodilation) could be demonstrated when hypercholesterolemic patients were compared with control subjects.33
The basal blood flow obtained in the untreated hypercholesterolemic patients was slightly higher than in the other two groups even though the difference was not statistically significant. In contrast to forearm plethysmography, our technique yields absolute blood flow values but does not allow normalization of blood flow for tissue volume.25 This must account for the difference in baseline blood flow measurements because adequate resting blood flow is determined by the metabolic requirements of the tissue mass. Since no difference in blood pressure between the three groups was documented 20 seconds after release of the occlusion, the reduced blood flow response observed in hypercholesterolemic patients most likely results from a higher peripheral vascular resistance. Divergent results have been reported about peak reactive hyperemic blood flow in hypercholesterolemic patients. In agreement with our findings, Zelis and coworkers18 found a reduced response in the legs of hypercholesterolemic patients, whereas other authors19 20 observed no difference in their hypercholesterolemic patients. Again, differences in methodology may explain some of these discrepancies. In addition, our population was older than the patients studied in the above-mentioned investigations. Interestingly, patients with angina-like chest pain and normal coronary arteries who have limited coronary flow responses to either rapid atrial pacing or to dipyridamole infusion were found to have an impairment of forearm flow reserve.35 Unfortunately, no data concerning their lipid status were provided in that study.
Both an endothelial dysfunction with a relative deficiency in endothelium-derived relaxing factors and/or an abnormal vascular smooth muscle cell reactivity to endothelium-derived relaxing factors or other vasodilators could be responsible for the decreased reactive hyperemic blood flow. However, recent data assessing the role of nitric oxide in reactive hyperemia suggest that nitric oxide plays a minimal role at the peak of and a moderate role during the flow debt repayment.36 ATP-sensitive potassium channels, cyclooxygenase products, and adenosine have been shown to be the most significant vasodilators of the microvessels during the ischemic phase.10 11 12 13 14 15 16 Endothelial dysfunction in resistance vessels induced by exposure to hypercholesterolemia alters the protective mechanisms to ischemia, as evidenced by acetylcholine infusion. In several vascular beds exposed to hypercholesterolemia the administration of the precursor of nitric oxide, L-arginine, has been shown to restore vascular responses to vasoactive drugs.37 38 39 Moreover, dietary treatment40 and lipid-lowering therapies41 have been successful in restoring endothelium-dependent relaxation in animals, and more recently, cholesterol-lowering therapy with either cholestyramine42 or pravastatin43 has been shown to improve endothelium-dependent dilation evoked with acetylcholine in the large coronary arteries in humans. In the present study we demonstrate that patients having lowered their cholesterol with long-term simvastatin treatment exhibit a forearm blood flow reserve similar to that of control subjects. The suggestion that reduction of plasma cholesterol restores a normal postischemic flow response is corroborated by the findings obtained in 11 of the 15 originally untreated patients who could be reevaluated 2 years after the cross-sectional study. Indeed, at that time because of variable lipid-lowering therapy, an inverse correlation was observed between the change in low-density lipoprotein cholesterol over a 2-year period and the change in postischemic blood flow response (Fig 4).
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In conclusion, hypercholesterolemia induces an impaired response of the resistance vessels to an ischemic stimulus in the upper extremities commonly free of detectable atheromatous transformation, whereas the conduit arteries do not show any evidence of dysfunction. The noninvasive assessment of the functional properties of a peripheral and easily accessible blood vessel represents a valuable alternative to intra-arterial infusion studies. Reduction of hypercholesterolemia at an early preclinical stage may have the highest chance of restoring normal vasomotion.
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Acknowledgments |
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This work was supported by grants from UNIL/EPFL, Lausanne, Switzerland.
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References |
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H. A. Silber, J. A.C. Lima, D. A. Bluemke, B. C. Astor, S. N. Gupta, T. K. Foo, and P. Ouyang Arterial Reactivity in Lower Extremities Is Progressively Reduced as Cardiovascular Risk Factors Increase: Comparison With Upper Extremities Using Magnetic Resonance Imaging J. Am. Coll. Cardiol., March 6, 2007; 49(9): 939 - 945. [Abstract] [Full Text] [PDF]
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P. Nazzaro, M. Manzari, M. Merlo, R. Triggiani, A. Scarano, L. Ciancio, and A. Pirrelli Distinct and Combined Vascular Effects of ACE Blockade and HMG-CoA Reductase Inhibition in Hypertensive Subjects Hypertension, February 1, 1999; 33(2): 719 - 725. [Abstract] [Full Text] [PDF]
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C. Giannattasio, M. Failla, A. Grappiolo, M. Bigoni, S. Carugo, M. Denti, and G. Mancia Effects of Prolonged Immobilization of the Limb on Radial Artery Mechanical Properties Hypertension, September 1, 1998; 32(3): 584 - 587. [Abstract] [Full Text] [PDF]
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 R. S. Rosenson and C. C. Tangney Antiatherothrombotic Properties of Statins: Implications for Cardiovascular Event Reduction JAMA, May 27, 1998; 279(20): 1643 - 1650. [Abstract] [Full Text] [PDF]
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C. Giannattasio, A. A. Mangoni, M. Failla, M. L. Stella, S. Carugo, M. Bombelli, R. Sega, and G. Mancia Combined Effects of Hypertension and Hypercholesterolemia on Radial Artery Function Hypertension, February 1, 1997; 29(2): 583 - 586. [Abstract] [Full Text]
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R. Weber, N. Stergiopulos, H. R. Brunner, and D. Hayoz Contributions of Vascular Tone and Structure to Elastic Properties of a Medium-Sized Artery Hypertension, March 1, 1996; 27(3): 816 - 822. [Abstract] [Full Text]
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