CORONARY ARTERY DISEASE
Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia
Piero O. Bonetti, MD*,
Geralyn M. Pumper, RN*,
Stuart T. Higano, MD, FACC*,
David R. Holmes, Jr, MD, FACC*,
Jeffrey T. Kuvin, MD, FACC and
Amir Lerman, MD, FACC*,*
* Center for Coronary Physiology and Imaging, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
Division of Cardiology, New England Medical Center Hospitals, Tufts University School of Medicine, Boston, Massachusetts
Manuscript received April 22, 2004;
revised manuscript received August 16, 2004,
accepted August 23, 2004.
* Reprint requests and correspondence: Dr. Amir Lerman, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905 (Email: lerman.amir{at}mayo.edu).
 |
Abstract
|
|---|
OBJECTIVES: We investigated the value of reactive hyperemia peripheral arterial tonometry (RH-PAT) as a noninvasive tool to identify individuals with coronary microvascular endothelial dysfunction.
BACKGROUND: Coronary endothelial dysfunction, a systemic disorder, represents an early stage of atherosclerosis; RH-PAT is a technique to assess peripheral microvascular endothelial function.
METHODS: Using RH-PAT, digital pulse volume changes during reactive hyperemia were assessed in 94 patients without obstructive coronary artery disease and either normal (n = 39) or abnormal (n = 55) coronary microvascular endothelial function; RH-PAT index, a measure of reactive hyperemia, was calculated as the ratio of the digital pulse volume during reactive hyperemia divided by that at baseline.
RESULTS: Average RH-PAT index was lower in patients with coronary endothelial dysfunction compared with those with normal coronary endothelial function (1.27 ± 0.05 vs. 1.78 ± 0.08: p < 0.001). An RH-PAT index <1.35 was found to have a sensitivity of 80% and a specificity of 85% to identify patients with coronary endothelial dysfunction.
CONCLUSIONS: Digital hyperemic response, as measured by RH-PAT, is attenuated in patients with coronary microvascular endothelial dysfunction, suggesting a role for RH-PAT as a noninvasive test to identify patients with this disorder.
|
Abbreviations and Acronyms
| | CAD = coronary artery disease | | CBF = coronary blood flow | | L-NAME = N-nitro-L-arginine methyl ester | | NO = nitric oxide | | PAT = peripheral arterial tonometry | | RH-PAT = reactive hyperemia peripheral arterial tonometry | | ROC = receiver operating characteristic |
|
Endothelial dysfunction represents an early stage of coronary artery disease (CAD) (1). The presence of endothelial dysfunction in coronary or peripheral vessels constitutes an independent predictor of cardiovascular events (2). Given that endothelial dysfunction is reversible, early detection of this disorder may have therapeutic and prognostic implications (2).
Assessment of coronary endothelial function may be considered the "gold standard" of endothelial function testing (3). However, because endothelial dysfunction is not confined to the coronary arteries, less invasive techniques for the assessment of peripheral vascular endothelial function have been developed (4,5). Although these methods are widely used research tools, their operator dependency or complexity preclude their use in clinical practice (2,5). Thus, in order to promote endothelial function testing as a screening method for individuals at increased cardiovascular risk, techniques to easily assess endothelial function are needed.
Reactive hyperemia peripheral arterial tonometry (RH-PAT) is a noninvasive technique to assess peripheral microvascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia (6,7). This study was designed to investigate the relationship between coronary and peripheral microvascular endothelial function and to assess the value of RH-PAT as a tool to identify individuals with coronary endothelial dysfunction.
|
Methods
|
|---|
Patients.
This study was approved by the Mayo Clinic Institutional Review Board. Ninety-four consecutive patients, who were referred for coronary angiography to exclude CAD and were found to have no significant epicardial coronary stenoses (<30% diameter), were studied prospectively. Exclusion criteria included prior myocardial infarction; percutaneous coronary intervention; coronary artery bypass graft surgery; unstable or variant angina; an ejection fraction  50%; valvular heart disease; peripheral vascular disease; uncontrolled arterial hypertension; allergy to latex; and/or significant endocrine, hepatic, renal, or inflammatory disease. Cardiovascular medications were withheld for at least 48 h before cardiac catheterization. Coronary and RH-PAT studies were performed in the fasting state.
Assessment of coronary vasoreactivity.
After diagnostic coronary angiography and exclusion of significant CAD, measurements of endothelium-dependent and endothelium-independent coronary flow reserve were performed as previously described (3,8,9). According to previous studies, normal coronary endothelial function was defined as an increase in coronary blood flow (CBF) of >50% in response to the maximum dose of acetylcholine (8,9).
RH-PAT.
The principle of peripheral arterial tonometry (PAT) has been recently described (6,7). Briefly, this system (Itamar Medical Ltd., Caesarea, Israel) comprises a finger probe to assess digital volume changes accompanying pulse waves.
The RH-PAT measurements and cardiac catheterization were performed on the same day; RH-PAT studies were carried out at least 3 h after cardiac catheterization in a thermoneutral environment. According to previous studies (6), a blood pressure cuff was placed on one upper arm (study arm), while the other arm served as a control (control arm). Peripheral arterial tonometry probes were placed on one finger of each hand for continuous recording of the PAT signal. After a 10-min equilibration period, the blood pressure cuff was inflated to suprasystolic pressures for 5 min. Then the cuff was deflated, while PAT recording continued for 10 min (Fig. 1). A total of 19 patients with normal coronary endothelial function and 17 patients with coronary endothelial dysfunction agreed to take 0.4-mg nitroglycerin sublingually to assess endothelium-independent PAT response. In these patients nitroglycerin was given 10 min after cuff deflation, and 10 min later PAT recording was stopped.
View larger version (29K):
[in this window]
[in a new window]
|
Figure 1 Representative reactive hyperemia peripheral arterial tonometry recordings of subjects with normal and abnormal reactive hyperemic response. Normal response is characterized by a distinct increase in the signal amplitude after cuff release compared with baseline.
|
|
The RH-PAT data were analyzed by a computer in an operator-independent manner as previously described (6). As a measure of reactive hyperemia, RH-PAT index was calculated as the ratio of the average amplitude of the PAT signal over a 1-min time interval starting 1 min after cuff deflation divided by the average amplitude of the PAT signal of a 3.5-min time period before cuff inflation (baseline). Subsequently, RH-PAT index values from the study arm were normalized to the control arm. The choice to use the average 1-min PAT signal starting 1 min after cuff deflation to describe the magnitude of reactive hyperemia was based on the observation that this time interval provided the best information regarding detection of coronary endothelial dysfunction as determined by receiver operating characteristic (ROC) curve analysis as well as the best correlation with CBF response to acetylcholine. Hyperemic response to nitroglycerin was similarly assessed; average PAT signal amplitude of four consecutive 1-min periods starting at 5 min after administration of sublingual nitroglycerin was calculated. Peripheral arterial tonometry response to nitroglycerin was then calculated as the ratio of the PAT amplitude of the 1-min interval during which peak average PAT signal was recorded divided by the amplitude of the baseline PAT signal (nitroglycerin-PAT index).
Determination of reproducibility of RH-PAT measurements was described earlier (6).
Statistical analysis.
Results are expressed as mean values ± SEM. Fisher exact test and unpaired t test or analysis of variance was used to compare differences between groups. The ROC curve analysis was done to identify the RH-PAT index value for optimal discrimination between presence/absence of coronary endothelial dysfunction. Simple linear regression and multivariable analysis using a backward stepwise regression model were utilized for evaluation of possible associations between RH-PAT index and various clinical variables and cardiovascular risk factors. Multivariable analysis included all variables that were tested in univariable analysis. The ROC curve analysis was done by SPSS statistical software (SPSS Inc., Chicago, Illinois). All other analyses were done by StatView statistical data analysis software (SAS Institute, Cary, North Carolina). Statistical significance was accepted for p < 0.05.
|
Results
|
|---|
A total of 94 patients were studied; 39 had normal coronary endothelial function, and 55 had coronary endothelial dysfunction (Table 1).
Average RH-PAT index was higher in individuals with normal coronary endothelial function than in those with coronary endothelial dysfunction (1.78 ± 0.08 vs. 1.27 ± 0.05; p < 0.001).
Linear regression analysis identified a significant relationship between RH-PAT index and CBF response to acetylcholine (r = 0.405, p < 0.001). In addition, univariable analysis revealed significant relationships between RH-PAT index and body mass index as well as high-density lipoprotein cholesterol levels (Table 2). However, multivariable analysis identified CBF response to acetylcholine as the only independent predictor of RH-PAT index (p = 0.006).
By ROC curve analysis, an RH-PAT index of 1.35 was identified as the best discriminating value between individuals with normal and abnormal coronary endothelial function (Fig. 2). For an RH-PAT index value <1.35, the sensitivity and specificity for the detection of coronary endothelial dysfunction were 80% and 85%, respectively. When the patients were divided based on this cutoff value, a significant difference in the average CBF response to acetylcholine was found between patients with an RH-PAT index of  1.35 and those with a value of <1.35 (70.0 ± 11.9% vs. 6.5 ± 8.7%; p < 0.001). In contrast, there was no difference in the endothelium-independent coronary flow reserve to adenosine between these two groups (3.0 ± 0.1 vs. 3.1 ± 0.1; p = 0.711); PAT response to nitroglycerin was similar in patients with normal and abnormal coronary endothelial function (nitroglycerin-PAT index 1.42 ± 0.13 and 1.33 ± 0.13; p = 0.628).
View larger version (22K):
[in this window]
[in a new window]
|
Figure 2 Receiver operating characteristic curve for the reactive hyperemia peripheral arterial tonometry (RH-PAT) index to identify patients with normal coronary endothelial function. An RH-PAT index of 1.35 discriminates best between presence/absence of coronary endothelial dysfunction. AUC = area under the curve.
|
|
|
Discussion
|
|---|
This study demonstrates that patients with coronary microvascular endothelial dysfunction have a lower peripheral hyperemic response, as measured by RH-PAT, than those with normal coronary endothelial function, suggesting a potential role for RH-PAT as a noninvasive test to identify individuals with coronary endothelial dysfunction.
Reactive hyperemia peripheral arterial tonometry represents a noninvasive technique for measuring digital reactive hyperemia, which is partly mediated by endothelium-derived nitric oxide (NO) (10). Thus, the magnitude of reactive hyperemia may serve as an index of peripheral microvascular endothelial function. Indeed, an excellent correlation between forearm blood flow response to reactive hyperemia and that to intra-arterial infusion of acetylcholine was demonstrated (11).
Reactive hyperemia peripheral arterial tonometry measures digital pulse volume at rest and during reactive hyperemia. Although digital pulse volume is modulated by various local, systemic, and environmental factors, this parameter is also affected by the bioavailability of NO and, therefore, also depends on endothelial function (12). The role of endothelium-derived NO in the RH-PAT response was investigated in a preliminary study, in which RH-PAT testing was performed before and during brachial artery infusion of N-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, in healthy volunteers (7). In this study, L-NAME reduced RH-PAT index significantly by 61%. Taken together, measuring reactive hyperemia by RH-PAT provides a noninvasive means for assessing peripheral microvascular endothelial function.
Average RH-PAT index was significantly lower in individuals with coronary endothelial dysfunction. Moreover, and similar to a study by Anderson et al. (13), we found a significant correlation between RH-PAT index and the CBF response to acetylcholine. This moderate correlation may be secondary to the differential response of vascular beds to different stimuli. Therefore, defining a cutoff value may represent a more accurate method to compare endothelial function between peripheral and coronary vessels. Indeed, using ROC curve analysis, we found a sensitivity of 80% and a specificity of 85% for an RH-PAT index <1.35 to identify patients with coronary endothelial dysfunction.
The similar PAT response to nitroglycerin in individuals with normal and abnormal coronary endothelial function supports the concept that the RH-PAT index represents a measure of endothelial function. This is underscored by the similar endothelium-independent coronary flow reserve in both groups when patients were divided based on an RH-PAT index of 1.35.
To minimize the impact of confounding factors on the RH-PAT results, a two-pronged approach was used. First, the reactive hyperemic response was referenced to a baseline derived from the same finger in order to eliminate local finger-related effects. Second, the effect of systemic factors was minimized by normalizing the RH-PAT value of the study arm to the corresponding PAT signal of the control arm. Other factors affecting peripheral vascular tone, like temperature, were less of a concern in our study because environmental conditions during testing were kept equal for all patients.
The present study has several limitations. Only patients with chest pain undergoing cardiac catheterization were included. Similar to a previous study (8), distribution of traditional risk factors was similar among patients with normal and abnormal coronary endothelial function. This may explain the absence of a significant relationship between traditional risk factors and RH-PAT index and may also suggests the possibility of a selection bias that may limit translation of the results to a general population. Another potential limitation pertains to the definition of coronary endothelial dysfunction used. The role of coronary endothelial dysfunction as an independent risk factor for cardiovascular events is well established (2). Thus, our definition of coronary endothelial dysfunction was based on previous studies demonstrating the adverse prognostic impact of an increase in CBF to acetylcholine of <50% (8,9). Finally, our results cannot be transferred to patients with heart failure or autonomous nervous system dysfunction who may show alterations of the peripheral circulation. Given these limitations, our results require independent confirmation and further validation in different populations.
In summary, our study demonstrates that digital reactive hyperemia, as measured by RH-PAT, is attenuated in patients with coronary endothelial dysfunction compared with individuals with normal coronary endothelial function. This suggests a role for RH-PAT as a noninvasive tool to identify patients during the early stage of CAD.
|
Footnotes
|
|---|
Supported by the National Institutes of Health (HL-63911 and HL-69840), the Mayo Foundation, and an unrestricted grant from Itamar Medical Ltd.
|
References
|
|---|
- Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s Nature 1993;362:801-809.[CrossRef][Medline]
- Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk Arterioscler Thromb Vasc Biol 2003;23:169-175.
- Hasdai D, Lerman A. The assessment of endothelial function in the cardiac catheterization laboratory in patients with risk factors for atherosclerotic coronary artery disease Herz 1999;24:544-547.[Medline]
- Anderson TJ, Gerhard MD, Meredith IT, et al. Systemic nature of endothelial dysfunction in atherosclerosis Am J Cardiol 1995;7571B–4B.
- Anderson TJ. Assessment and treatment of endothelial dysfunction in humans J Am Coll Cardiol 1999;34:631-638.[Free Full Text]
- Bonetti PO, Barsness GW, Keelan PC, et al. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease J Am Coll Cardiol 2003;41:1761-1768.[Abstract/Free Full Text]
- Gerhard-Herman M, Creager MA, Hurley S, et al. Assessment of endothelial function (nitric oxide) at the tip of a finger Circulation 2002;102(Suppl II):851.
- Al Suwaidi J, Hamasaki S, Higano ST, Nishimura RA, Holmes Jr. DR, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction Circulation 2000;101:948-954.[Abstract/Free Full Text]
- Targonski PV, Bonetti PO, Pumper GM, Higano ST, Holmes Jr. DR, Lerman A. Coronary endothelial dysfunction is associated with an increased risk of cerebrovascular events Circulation 2002;107:2805-2809.
- Meredith IT, Currie KE, Anderson TJ, Roddy MA, Ganz P, Creager MA. Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide Am J Physiol 1996;270:H1435-40.
- Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Kajiyama G, Oshima T. A noninvasive measurement of reactive hyperemia that can be used to assess resistance artery endothelial function in humans Am J Cardiol 2001;87:121-125.[CrossRef][Medline]
- Noon JP, Haynes WG, Webb DJ, Shore AC. Local inhibition of nitric oxide generation in man reduces blood flow in finger pulp but not in hand dorsum skin J Physiol 1996;490:501-508.[Medline]
- Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial function in the human coronary and peripheral circulations J Am Coll Cardiol 1995;26:1235-1241.[Abstract]
This article has been cited by other articles:
|
|
|
|
 
M. A. Black, D. J. Green, and N. T. Cable
Exercise prevents age-related decline in nitric-oxide-mediated vasodilator function in cutaneous microvessels
J. Physiol.,
July 15, 2008;
586(14):
3511 - 3524.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Celermajer
Reliable Endothelial Function Testing: At Our Fingertips?
Circulation,
May 13, 2008;
117(19):
2428 - 2430.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. M. Hamburg, M. J. Keyes, M. G. Larson, R. S. Vasan, R. Schnabel, M. M. Pryde, G. F. Mitchell, J. Sheffy, J. A. Vita, and E. J. Benjamin
Cross-Sectional Relations of Digital Vascular Function to Cardiovascular Risk Factors in the Framingham Heart Study
Circulation,
May 13, 2008;
117(19):
2467 - 2474.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. V. Brauner, L. Forchhammer, P. Moller, L. Barregard, L. Gunnarsen, A. Afshari, P. Wahlin, M. Glasius, L. O. Dragsted, S. Basu, et al.
Indoor Particles Affect Vascular Function in the Aged: An Air Filtration-based Intervention Study
Am. J. Respir. Crit. Care Med.,
February 15, 2008;
177(4):
419 - 425.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. V. Joffe, R. Y. Kwong, M. D. Gerhard-Herman, C. Rice, K. Feldman, and G. K. Adler
Beneficial Effects of Eplerenone Versus Hydrochlorothiazide on Coronary Circulatory Function in Patients with Diabetes Mellitus
J. Clin. Endocrinol. Metab.,
July 1, 2007;
92(7):
2552 - 2558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Barac, U. Campia, and J. A. Panza
Methods for Evaluating Endothelial Function in Humans
Hypertension,
April 1, 2007;
49(4):
748 - 760.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Deanfield, J. P. Halcox, and T. J. Rabelink
Endothelial Function and Dysfunction: Testing and Clinical Relevance
Circulation,
March 13, 2007;
115(10):
1285 - 1295.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. Kuvin, A. Mammen, P. Mooney, A. A. Alsheikh-Ali, and R. H. Karas
Assessment of peripheral vascular endothelial function in the ambulatory setting
Vascular Medicine,
February 1, 2007;
12(1):
13 - 16.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Nohria, M. Gerhard-Herman, M. A. Creager, S. Hurley, D. Mitra, and P. Ganz
Role of nitric oxide in the regulation of digital pulse volume amplitude in humans
J Appl Physiol,
August 1, 2006;
101(2):
545 - 548.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A. Elesber, H. Solomon, R. J. Lennon, V. Mathew, A. Prasad, G. Pumper, R. E. Nelson, J. P. McConnell, L. O. Lerman, and A. Lerman
Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis
Eur. Heart J.,
April 1, 2006;
27(7):
824 - 831.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Schroeter, C. Heiss, J. Balzer, P. Kleinbongard, C. L. Keen, N. K. Hollenberg, H. Sies, C. Kwik-Uribe, H. H. Schmitz, and M. Kelm
(-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans
PNAS,
January 24, 2006;
103(4):
1024 - 1029.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Digital Diagnosis of Coronary Artery Disease
DOC News,
February 1, 2005;
2(2):
22 - 22.
[Full Text]
|
|
|
|
Top
Abstract
Methods