CLINICAL RESEARCH: ENDOTHELIAL FUNCTION
Increased Ambulatory Pulse Pressure Is a Strong Risk Factor for Coronary Endothelial Vasomotor Dysfunction
Yoshihide Ichigi, MD,
Hajime Takano, MD, PhD,
Ken Umetani, MD, PhD,
Kenichi Kawabata, MD, PhD,
Jyun-ei Obata, MD, PhD,
Yoshinobu Kitta, MD,
Yasushi Kodama, MD,
Akira Mende, MD,
Takamitsu Nakamura, MD,
Daisuke Fujioka, MD,
Yukio Saito, MD and
Kiyotaka Kugiyama, MD, PhD*
Department of Internal Medicine II, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Manuscript received August 18, 2004;
revised manuscript received January 18, 2005,
accepted January 25, 2005.
* Reprint requests and correspondence: Dr. Kiyotaka Kugiyama, Department of Internal Medicine II, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Nakakoma-gun, Yamanashi, 409-3898 Japan. (Email: kugiyama{at}yamanashi.ac.jp).
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Abstract
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OBJECTIVES: This study was aimed to determine the relationship between pulse pressure (PP) and coronary vasomotor dysfunction, a predictor of coronary events.
BACKGROUND: Pulse pressure is a strong risk factor for coronary artery disease (CAD). However, the mechanisms by which an increase in PP affects the pathogenesis of CAD are unclear.
METHODS: Ambulatory blood pressure (BP) monitoring for 24 h was performed in 103 consecutive patients with normal coronary angiograms (51 hypertensive and 52 normotensive; age 42 to 70 years). The relationship between changes in coronary arterial diameter and blood flow during an intracoronary infusion of acetylcholine (ACh) (5, 10, 50 µg/min), and BP parameters, and other traditional risk factors was evaluated using univariate and multivariate linear regression analyses.
RESULTS: With multivariate analyses, the 24-h PP showed an inverse correlation with the epicardial coronary dilator response to ACh independently of other covariates including age, smoking, and 24-h systolic BP in normotensive as well as hypertensive patients. Furthermore, multivariate analysis showed that the 24-h PP was inversely and independently correlated with the increase in coronary blood flow in response to ACh. The dilator response of epicardial coronary arteries to nitrate was not significantly correlated with 24-h PP.
CONCLUSIONS: Increased 24-h PP is independently associated with endothelial vasomotor dysfunction in conduit and resistance coronary arteries irrespective of the presence of hypertension. Increased ambulatory PP may have an intimate relation to coronary endothelial vasomotor dysfunction.
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Abbreviations and Acronyms
| | ACh = acetylcholine | | BP = blood pressure | | DBP = diastolic blood pressure | | HR = heart rate | | NO = nitric oxide | | PP = pulse pressure | | SBP = systolic blood pressure |
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Pulse pressure (PP), calculated as the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP), has been previously reported to be a stronger cardiovascular risk factor than SBP alone, especially in elderly hypertensive patients (1). Even in normotensive subjects, an increase in PP remains a powerful and independent predictor of cardiovascular risk, particularly for myocardial infarction (2). However, the underlying mechanisms by which an increase in PP plays a role in pathogenesis of coronary artery disease remain unclear. A recent report (3) showed that an increase in PP was associated with endothelial vasomotor dysfunction, an independent predictor of future coronary events, in the resistance vessels downstream from the brachial artery in hypertensive patients. However, there is no information on the effects of PP on endothelial vasomotor functions in human coronary arteries in normotensive or hypertensive patients. Furthermore, the relationship between PP and endothelial vasomotor function in the coronary arteries may not be similar to the brachial artery because of the predominant role of DBP in the coronary circulation. Thus, the objective of this study was to determine whether an increase in PP might be associated with endothelial vasomotor dysfunction in the conduit and resistance vessels in the coronary circulation in both normotensive and hypertensive subjects.
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Methods
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Study patients.
Study subjects consisted of a consecutive series of 103 patients. Characteristics of the study subjects are shown in Table 1. They underwent diagnostic coronary angiography for atypical chest pain (95 subjects) or ST-segment depression at rest or during exercise without chest pain (8 subjects) in Yamanashi University Hospital between January 2002 and January 2004. They fulfilled all of the following inclusion criteria: 1) angiographically normal coronary arteries (<5% narrowing after nitrate administration) and no coronary spasm (<50% decrease in epicardial coronary diameter from baseline and neither chest pain nor ischemic electrocardiographic change) after the intracoronary infusion of acetylcholine (ACh); 2) normal left ventriculography; 3) no left ventricular hypertrophy, verified by both electrocardiography and echocardiography; and 4) no history of myocardial infarction, congestive heart failure, valvular heart disease, secondary hypertension, stroke, renal dysfunction (serum creatinine concentration >2.0 mg/dl) or other serious diseases. All medications that could have affected coronary vasomotor reactivity and blood pressure (BP) were withdrawn  3 days before the study. Hypertension was defined according to Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure-VI criteria (4): the averaged values of two or more BP measurements obtained on at least two separate occasions were >140 mm Hg SBP or >90 mm Hg DBP, with waking ambulatory BP measurements >135/85 mm Hg or sleeping ambulatory BP measurements >120/75 mm Hg. Written informed consent was obtained from all study subjects before the study. The study was approved by the ethics committee at our institution.
Protocol for coronary angiography.
After baseline angiography, incremental doses of ACh (5, 10, and 50 µg/min) were infused directly into the left coronary artery through the Judkins catheter for 2 min with a 5-min interval between each dose (5). Hemodynamic measurements and coronary angiography were repeated before and during each of the ACh infusions. After an additional 15 min, intracoronary injection of isosorbide dinitrate (1 mg) was performed; 2 min after that, coronary angiography was performed in multiple projections in all study subjects.
Ambulatory BP measurements.
Systolic BP, DBP, PP, and heart rate (HR) during daily activities were measured every 30 min for 24 h, by the oscillometric method, using a noninvasive ambulatory BP monitoring system (TM-2425, A&D, Tokyo, Japan) (6). The daytime and nighttime mean values of SBP, DBP, PP, and HR during the 24-h period were analyzed after reviewing the patients’ diaries. We defined daytime as the period from the time they awoke to the time they went to sleep, and nighttime as the period during which they were sleeping (7). The daytime, nighttime, and 24-h SBP, DBP, PP, and HR were the averages of all of the values obtained at 30-min intervals. Non-dipper hypertension was defined by the absence of the fall (>10%) in the nighttime mean SBP, and/or in DBP from the respective daytime values (7).
Quantitative coronary angiography and the measurement of coronary blood flow.
A quantitative coronary angiographic study was performed in all of the study subjects with the Judkins technique in the morning when the patients were fasting, in the same manner as described previously (5). Measurement of luminal diameter of the left anterior descending coronary artery at the midsegment was performed quantitatively by use of a computer-assisted coronary angiographic analysis system (Cardio 500, Kontron Instruments, Munich, Germany) by two observers blinded to the study protocol. Responses of the coronary artery diameter to infusions of ACh and nitrates were expressed as percent changes from baseline diameter measured on angiograms taken just before each infusion.
Blood flow velocity was measured in a subgroup of 56 consecutive subjects using a 0.014-inch wire equipped with a Doppler crystal at its tip (Flow Wire, Cardiometrics, Mountain View, California), which was advanced through the Judkins catheter and carefully positioned in a straight proximal segment of the left anterior descending coronary artery to obtain a stable flow velocity signal (5). The stable peak flow velocity signals at baseline and during a 2-min infusion of ACh at doses of 5 and 10 µg/min were used for the analysis (Flow Map, Cardiometrics). Coronary blood flow (ml/min) was estimated from coronary blood flow velocity and arterial diameter by the following formula: 0.5 x averaged peak velocity (cm/min) x cross-sectional area (cm2). The response of coronary blood flow to intracoronary infusions of ACh was expressed as a percentage change from the baseline blood flow just before ACh infusion.
Statistical analysis.
Results are expressed as the mean ± SD or percentage. The mean values of continuous variables were compared between the two groups using an unpaired t test and frequencies were compared by chi-square analysis. Comparison of continuous variables among more than three groups was performed using one-way analysis of variance. Linear regression analysis was used to determine the relationship between the coronary responses and all continuous variables. Multivariate linear regression analyses were also used to determine the relationship between coronary responses and 24-h ambulatory PP; independent covariates included any continuous variable that was significantly correlated with the coronary responses in the univariate analysis. In addition, the multivariate analysis also included any categorical risk factor that led to a significant difference in coronary responses when patients with and without the traditional risk factors were compared using an unpaired t test. The categorical variables were coded using the following dummy variables: 0 for the absence of the risk factor; or 1 for the presence of the risk factor. When correlation between coronary flow response and risk factors was analyzed in the multivariate analysis, only data from all patients were used because there were too few patients tested for coronary flow response in the various subgroups. A confidence level of p < 0.05 was considered statistically significant. Analyses were partially assessed using StatView 5.0 (SAS Institute, Cary, North Carolina).
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Results
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Comparisons of clinical characteristics and parameters among all study patients, hypertensive patients, and normotensive patients.
None of the clinical characteristics or parameters except the BP parameters was significantly different among the three groups, all patients, hypertensive patients, and normotensive patients (Table 1).
Correlations of epicardial coronary diameter responses with clinical characteristics and BP parameters.
Intracoronary infusion of ACh constricted the coronary arteries in a majority of patients and dilated the arteries in a small number of patients, resulting in an overall constrictor response. Using univariate linear regression analysis, age and 24-h ambulatory PP and SBP had a significant and inverse correlation with the dilator responses of epicardial coronary arteries to ACh at a dose of 50 µg/min in all patients (Fig. 1, Table 2). Age and ambulatory PP and SBP also showed a significant correlation in the subgroup of normotensive patients, as shown in Table 2. As shown in Table 3, smokers had an impaired dilation or an enhanced constriction of epicardial coronary arteries to ACh as compared with nonsmokers in all three of the study groups (Table 3). Using multivariate linear regression analysis after adjustment for age, smoking status, and ambulatory SBP as covariates, 24-h ambulatory PP remained significantly and inversely correlated with the coronary diameter response to ACh at a dose of 50 µg/min in all patients, the hypertensive patients, and the normotensive patients (Table 4). Ambulatory PP also was independently correlated with the diameter responses to ACh at 5 and 10 µg/min in all patients as well as normotensive patients (standardized regression coefficient, 5 µg/min; –0.47 and –0.53, respectively; p < 0.05 in both; 10 µg/min; –0.44 and –0.47, respectively; p < 0.05 in both). The dilator response to nitrates was not significantly correlated with 24-h ambulatory PP in either all patients or just the normotensive patients (r = –0.1, p = NS; r = –0.12, p = NS, respectively).
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Figure 1 Correlations of 24-h ambulatory pulse pressure (PP) with percent (%) changes of epicardial coronary dilator responses to acetylcholine (50 µg/min) in all the study patients, hypertensive patients, and normotensive patients.
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Table 2. Relationships of Coronary Risk Factors (Continuous Variables) With the Percent (%) Changes in Diameter of Epicardial Coronary Arteries and Coronary Blood Flow Response to ACh Using Univariate Linear Regression Analysis
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Table 3. Comparisons of Percent (%) Changes in Diameter of Epicardial Coronary Arteries and Coronary Blood Flow Response to ACh Using Categorical Variables to Classify Patients
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Table 4. Multiple Linear Regression Analysis for the Association of Risk Factors With Relative Changes in Epicardial Coronary Diameters and Coronary Flow Response to ACh
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Correlation of coronary flow responses with clinical characteristics and BP parameters.
Coronary blood flow was increased in response to ACh infusion in all patients studied. Using univariate linear regression analysis, age and ambulatory 24-h PP and SBP had a significant and inverse correlation with percent increase of coronary flow in response to ACh at doses of 5 µg/min in all patients (Fig. 2, Table 2). Age and ambulatory PP also had a significant correlation in the subgroup of the normotensive patients (Table 2). Diabetic patients had an impaired increase of coronary flow to ACh as compared with nondiabetic patients in all of the three study groups (Table 3). In all of the patients, 24-h ambulatory PP remained significantly and inversely correlated with the percent increase of flow in response to ACh at doses of 5 µg/min using multivariate linear regression analysis after adjustment for age, ambulatory SBP, and diabetes (these covariates were significantly related to the flow response in the univariate linear regression analysis or the unpaired t test) (Table 4). Also, the independent and inverse correlation of 24-h ambulatory PP with the percentage increase of flow in response to ACh at doses of 10 µg/min was observed in all of the patients (standardized regression coefficient = –0.45, p < 0.05).
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Figure 2 Correlations of 24-h ambulatory pulse pressure (PP) with percent (%) changes of coronary blood flow responses to acetylcholine (5 µg/min) in all the study patients, hypertensive patients, and normotensive patients.
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Discussion
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The present study assessed the relation between PP and endothelial vasomotor function in human coronary arteries. Multivariate analyses indicated that increased ambulatory PP had a significant and independent correlation with abnormal vasomotor reactivity in both the conduit and resistance vessels in the coronary circulation, as demonstrated by impaired dilation or enhanced constriction of epicardial coronary arteries and by the impairment of the coronary blood flow increase in response to an intracoronary infusion of ACh. The epicardial coronary diameter responses to nitrates were not significantly correlated with ambulatory PP. Thus, the present results indicate that an increase in ambulatory PP has an independent association with endothelium-dependent vasomotor dysfunction in conduit and resistance coronary vessels in the coronary circulation.
The present study further showed that increased PP also had a significant and independent association with epicardial coronary vasomotor dysfunction in a subgroup of normotensive patients. This may be related to previous findings (2) that an increase in PP is a strong predictor of cardiovascular disease, especially myocardial infarction, independently of other BP parameters. However, prospective studies are required to determine the value of ambulatory PP for the prediction of future cardiac events in patients with preclinical hypertension in order to confirm the results of the present study. In contrast to the usefulness of ambulatory PP in the present study, office PP did not have a significant association with coronary endothelial vasomotor dysfunction. This is consistent with previous reports (1,8,9) that found 24-h ambulatory PP monitoring superior to office PP measurement for predicting cardiovascular disease because ambulatory PP may more accurately reflect the dynamic interaction between the heart and the central stiff arteries during all of the patient’s activities.
We and others (10,11) have previously shown that coronary vasomotor regulation largely depends on endothelial nitric oxide (NO) activity. Thus, the decrease in coronary endothelial NO activity may be the underlying mechanism for the coronary endothelial vasomotor dysfunction in the present patients with increased ambulatory PP. The decrease in arterial NO might cause coronary artery spasm (12) and induction of various proatherothrombogenic molecules in the arterial walls (13), resulting in a high incidence of myocardial infarction.
Pulse pressure is largely determined by three hemodynamic factors: arterial stiffness, stroke volume, and wave reflections (14). Among these factors, an increase in arterial stiffness most importantly contributes to the effects of an elevated PP on the risk of cardiovascular disease. An increase in extracellular matrix formation causes arterial stiffness, especially in central arteries, and it might largely contribute to the increase in PP in patients with age and hypertension (15). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers attenuate extracellular matrix formation in addition to reducing SBP (15). Therefore, these drugs could reduce arterial stiffness, thereby effectively reducing PP as well as SBP.
In conclusion, increased 24-h ambulatory PP has a strong and independent association with endothelial vasomotor dysfunction in the conduit and resistance vessels in the coronary circulation in normotensive as well as hypertensive patients. Increased ambulatory PP may have an intimate relation to coronary endothelial vasomotor dysfunction.
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Footnotes
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This study was supported by grants-in-aid for (B)(2)-15390244, Priority Areas (C) "Medical Genome Science 15012222" from the Ministry of Education, Culture, Sports, Science, and Technology; Health and Labor Sciences Research Grants for Comprehensive Research on Aging and Health (H15-Choju-012); and the Smoking Research Foundation, Tokyo, Japan.
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Abstract
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