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Am J Physiol Heart Circ Physiol 291: H564-H569, 2006. First published February 24, 2006; doi:10.1152/ajpheart.00915.2005
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Determinants of coronary flow velocity reserve in healthy young men

Tuomas O. Kiviniemi,1 Amir Snapir,2 Markku Saraste,1 Jyri O. Toikka,1,4 Olli T. Raitakari,1 Markku Ahotupa,3 Jaakko J. Hartiala,1 Mika Scheinin,2 and Juha W. Koskenvuo1

1Department of Clinical Physiology, Nuclear Medicine and PET, Turku University Hospital; and the 2Department of Pharmacology and Clinical Pharmacology, University of Turku, and the 3MCA Research Laboratory, Department of Physiology, University of Turku, Turku, Finland; and the 4Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland

Submitted 24 August 2005 ; accepted in final form 21 February 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The objective of this study was to identify risk markers for attenuated coronary flow velocity reserve (CFVR) that exist in healthy young men without evident atherosclerotic risk factors. Coronary blood flow velocity was measured with transthoracic Doppler echocardiography at baseline and during adenosine infusion in 37 healthy nonsmoking men [mean age, 27 yr (SD 4.0)]. Body composition and distribution of fat tissue were assessed with anthropometric measures and regulation of fat metabolism by determination of adiponectin and leptin levels. Physical performance capacity was tested with ergospirometry. The mean body mass index was 23 kg/m2 (SD 1.9), waist-to-hip ratio was 0.84 (SD 0.04), and CFVR was 3.5 (SD 0.61). Obesity indexes at study outset, leptin, adiponectin, maximal load (Max load in W/kg) and maximal oxygen consumption (VO2 peak in ml·kg–1·min–1) in ergospirometry, rate-pressure product, and heart rate at rest were significantly associated with CFVR. In multivariate analysis, Max load (in W/kg) and waist-to-hip ratio were the only independent predictors of CFVR. We found no relationship between CFVR and serum lipids or body mass index. We conclude that abdominal fat accumulation and low aerobic fitness are independently associated with CFVR in men.

transthoracic Doppler echocardiography; physical capacity in ergospirometry; visceral adipose tissue

ALTERED VASODILATATION of coronary arteries is one of the first signs of atherosclerosis, appearing before any other clinical symptom (1). Impaired coronary reactivity has been detected in subjects with traditional atherosclerotic risk factors, such as hypercholesterolemia (28, 30), diabetes (29), and hypertension (22), but without evidence of complications of these diseases. Because atherosclerotic processes begin early in life, it is reasonable that markers of attenuated coronary reactivity could be already found in healthy young men.

Coronary flow velocity reserve (CFVR) is a measure of coronary artery integrity and cardiac microvascular function (1, 10). It is defined as the ratio between coronary blood flow velocities during and before pharmacologically induced vasodilatation. Adenosine induces its vasodilatory effect through direct actions on smooth muscle cells. The increased blood flow mediated by this vasodilatation induces shear stress on the artery wall that is followed by release of substances from endothelial cells that further dilate the artery. CFVR represents a combination of functions of the microcirculation and epicardial arteries.

Recent developments in transthoracic Doppler echocardiography (TTDE) allow the use of this tool in investigation of CFVR (4, 18–20, 32). Measurement of CFVR with TTDE has been found to correlate closely with measurements carried out with an intracoronary flow wire (4, 19), MRI (20), and PET (32). Previously, we have published intraobserver and interobserver variability and day-to-day variability of mean diastolic velocity-derived coronary flow reserve (CFR) measurements, which are 2.8% (SD 2.4), 2.6% (SD 1.8), and 6.1% (SD 4.3), respectively (32). Echocardiography-derived CFVR measurements appear to be more reproducible compared to PET measurements, as assessed with the coefficient of variation of a totally reproduced study: 6.1% vs. 19% (13, 32).

The purpose of this study was to determine whether body size, fat distribution, serum lipids, adipose tissue-derived hormones, hemodynamic variables, and ergospirometry variables in physiological range are predictors of coronary reactivity in healthy, young nonsmoking men.


   METHODS
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 METHODS
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Subjects. Thirty-seven healthy, young, nonsmoking Finnish men were included in the study. The study was carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association and was approved by the Ethics Committee of the Southwest Finland Health Care District. All subjects gave their written informed consent.

Echocardiography and coronary flow reserve measurements. Echocardiography and ergospirometry sessions were conducted on separate days. Experiments were carried out during morning hours after a 10-h overnight fast. Subjects were instructed to avoid caffeine for 10 h and alcohol for 36 h before the session. The same investigator performed all echocardiographic measurements. Echocardiography (including coronary flow velocity measurements) was carried out with an Acuson Sequoia C 256 instrument (Acuson, Mountain View, CA) with a 3.5-MHz transducer. A cannula was inserted in an antecubital vein for the infusion of adenosine (adenosin item 5 mg/ml, Item Development AB). Hyperemia was induced by infusion of adenosine at a rate of 0.14 mg·kg–1·min–1. Left anterior descending coronary artery blood flow velocity was recorded on a videotape for later analysis. During the session, the electrocardiogram was monitored continuously, and blood pressure was recorded at 2-min intervals with a digital blood pressure monitor (Omron HEM 706, Omron, Japan). In off-line analysis, mean diastolic velocity (MDV) was measured at baseline and during adenosine infusion (Fig. 1). CFVR was calculated as the ratio of MDV during hyperemia to MDV during baseline. All the coronary flow velocity measurements were carried out and analyzed by investigators who were blinded to the clinical data.


Figure 1
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  		Fig. 1. Coronary flow velocity at rest (left) and during adenosine infusion (right) by transthoracic echocardiography.

 
Ergospirometry. Ergospirometry was performed by using a bicycle ergometer starting from a load of 100 W, followed by increases of 30 W every 2 min. Pedaling frequency was kept >65 rpm during all load levels. Subjects were strongly encouraged to continue exercise until exhaustion. Volumes of oxygen consumed (VO2), carbon dioxide produced, and respiratory quantity breath-by-breath during exercise were calculated from minute ventilation and measured by using mass flow ventilometry and simultaneous mixing chamber analysis of expired gas fractions. The gas chromatograph and flow probes were calibrated before each test. Maximal oxygen consumption (VO2 peak in l/min), VO2 peak (in ml·kg–1·min–1), and maximal load (Max load in W/kg) were determined according to the guidelines of the American College of Sports Medicine (1995).

Measurements. Subjects' height and weight were measured by standard procedures. The waist circumference was measured at the level of the umbilicus in the late exhalation phase and the hip circumference at the level of the greater trochanter in the standing position. Four skinfolds (subscapular, triceps, biceps, and suprailiac) were measured on the left side of the body with a caliper (Harpenden Skinfold Caliper, model HSK-BI). and the fat percentage was estimated according to Durnin and Womersley (11).

Serum total cholesterol, HDL cholesterol, LDL cholesterol, oxidized-LDL cholesterol, apolipoprotein A1, apolipoprotein B, lipoprotein (a), triglyceride concentrations, fasting plasma glucose, adiponectin, and leptin concentrations were sampled.

Statistical analysis. Data are presented as means (SD) unless stated otherwise. Variables that did not follow the normal distribution (Shapiro-Wilk test) were log- or –1/x-transformed before analysis. Spearman correlation coefficients were calculated between CFVR and other study variables. Moreover, Spearman correlation coefficient was calculated between adiponectin, leptin, and Max load (in W/kg), waist-to-hip ratio, fat percentage, serum lipids, apolipoproteins (A1 and B), lipoprotein (a), and body mass index. The multivariate correlates of CFVR were assessed by multivariate linear regression modeling (stepwise manner, P ≤ 0.05 to enter, P ≥ 0.10 to remove), including Max load (in W/kg), waist-to-hip ratio, skinfold thickness suprailiac, VO2 peak (in ml·kg–1·min–1), waist circumference, fat percentage, rate pressure product at rest, VO2 peak (in l/min), skinfold thickness subscapularis, heart rate, leptin, and adiponectin in the model. Independence of waist-to-hip ratio from heart rate as a primary predictor of CFVR was tested by adjusting waist-to-hip ratio with heart rate in a multivariate linear regression model (enter manner, waist-to-hip ratio, and heart rate at rest as variables). Statistical analysis was performed with SPSS for Windows 11.0.1 (SPSS, Chicago, IL).


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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Coronary flow velocity reserve was measured successfully in all subjects. Adenosine infusion was generally well tolerated. Some of the subjects experienced mild transient discomfort that was relieved after the end of the infusion. None of the study subjects had clinical evidence of any cardiovascular disease or major risk factors, such as hypertension (blood pressure > 140/90 mmHg) (7), diabetes (fP-glucose > 6.7 mmol/l) (2), or severe hypercholesterolemia (fP-total cholesterol > 8.0) (9) in the physical and laboratory examinations. Characteristics of the subjects (Table 1) and the results of ergospirometry and coronary flow velocity measurements (Table 2) are presented.


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  		Table 1. Characteristics of the study population

 

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  		Table 2. Results of ergospirometry and coronary flow velocity measurements

 
Adiponectin levels and the ergospirometry variables Max load (in W/kg), VO2 peak (in ml·kg–1·min–1), and VO2 peak (in l/min) were statistically significant when correlated with CFVR. Waist-to-hip ratio, waist circumference, suprailiac and subscapular skinfold thickness and fat percentage at study outset, leptin, rate-pressure product, and heart rate at rest correlated inversely and were statistically significant with CFVR. Correlation coefficients between relevant variables and CFVR are presented in Table 3.


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  		Table 3. Correlation of variables of interest with CFVR (Spearman correlation)

 
Variables that correlated as statistically significant with CFVR (P ≤ 0.05) were entered as independent variables into a multivariate linear regression model. Different techniques, including stepwise forward selection, backward selection, and enter methods, gave identical results. All the models suggested that Max load (in W/kg) in ergospirometry and waist-to-hip ratio were the only independent predictors of CFVR. The results of this multivariate linear regression analysis are presented in Table 4. Correlations between waist-to-hip ratio and Max load (in W/kg) and CFVR are presented in Fig. 2.


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  		Table 4. Independent predictors of coronary flow velocity reserve: results of multivariate stepwise linear regression analyses

 

Figure 2
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  		Fig. 2. Correlation of waist-to-hip ratio (A) and maximal load (Max load in W/kg) in ergospirometry (B) with coronary flow velocity reserve (CFVR; n = 36 subjects in A).

 
The adipose tissue derived hormone leptin correlated with Max load (in W/kg), waist-to-hip ratio, fat percentage, body mass index, LDL cholesterol, oxidized LDL, and apolipoprotein B, whereas adiponectin did not. Subcutaneous adipose tissue distribution showed a stronger association with the leptin concentration than visceral adipose tissue. The correlation matrix is presented in Table 5. In addition, Max load (in W/kg) correlated with waist-to-hip ratio (R = –0.51, P = 0.002).


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  		Table 5. Spearman correlation coefficients of the adipose tissue derived hormones adiponectin and leptin with Max loadW/kg, waist-to-hip ratio, fat percentage and body mass index

 
Waist-to-hip ratio appeared to significantly predict CFVR before and after heart rate adjustment (beta = –0.51, P = 0.001; and beta = –0.44, P = 0.048, respectively) in a multivariate linear regression model with waist-to-hip ratio and heart rate as variables.


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
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This study provides evidence that Max load (in W/kg) and waist-to-hip ratio are associated with coronary reactivity in healthy, young, nonsmoking men. Waist-to-hip ratio also appeared as a significant predictor of coronary reactivity when other characteristics of body size, such as body mass index and fat percentage, were within the normal range. In the present study, we demonstrated that visceral adipose tissue attenuates and physical capacity enhances CFVR in physiological range in healthy young men.

Strong associations have been found previously between waist-to-hip ratio and impaired vascular reactivity in patients with hypercholesterolemia, Type 2 diabetes, and coronary artery disease (15) and in overweight healthy adults without evidence of other cardiovascular risk factors (3). In the latter study, waist-to-hip ratio was the only independent predictor of endothelial dysfunction, and the authors suggested that abdominal visceral adipose tissue would be directly linked to impaired vascular reactivity. Our study supports the finding of an inverse relationship between waist-to-hip ratio and coronary artery reactivity. This finding is strengthened in the current study by the results that other variables describing characteristics of adipose tissue, such as body fat percentage, adiponectin, and leptin concentrations, seemed to correlate with but were not independent predictors of CFVR.

Although the exact mechanism that links increased visceral adipose tissue with attenuated coronary reactivity remains unsolved, part of the association may be explained by peptide hormones secreted from adipose tissue. Adiponectin exerts anti-inflammatory and antiatherogenic effects by reducing monocyte attachment to endothelial cells, by inhibiting oxidized LDL uptake into macrophages, and by inhibiting vascular smooth muscle cell proliferation (24). Hypoadiponectinemia is associated with obesity (27) and increased risk for atherosclerosis (21). In previous studies (27), adiponectin levels have correlated inversely with visceral adipose tissue and waist-to-hip ratio. In our study, however, adiponectin levels were not associated with any measure of body adipose tissue distribution. One possible explanation for this finding might be that associations between adiponectin levels and obesity, fat distribution, or atherosclerosis do not exist in healthy young men of normal weight. Another possible explanation might be that our study was underpowered to detect this association. Leptin concentrations reflect body fat stores, and the hormone regulates energy intake and expenditure. A recent review concluded that leptin may serve as a regulator of cardiovascular functions and that elevated leptin levels (hyperleptinemia) may be a trigger for pathological processes in the cardiovascular system (31). The effects of leptin on vascular tone are complex, including nitric oxide and endothelin-1 production (31). In previous reports, elevated serum leptin concentrations were associated with increasing waist-to-hip ratio, fat percentage, and body mass index (27) and decreased coronary vasoreactivity (33). Our results support these findings. In the current study, leptin was also correlated with LDL cholesterol, oxidized LDL, apolipoprotein B, and Max load (in W/kg).

In the current study, Max load (in W/kg) appeared as an independent determinant of CFVR. It is well established that exercise and physical activity have cardioprotective effects (34). Low cardiorespiratory fitness has been associated with the development of cardiovascular disease (6), and it has been demonstrated that an exercise intervention improves coronary endothelial function in patients with coronary artery disease (16) and in healthy men (35). The independent role of exercise in the cardiovascular risk profile has previously been documented in healthy men (8). Our results support the finding of a relationship between physical capacity and coronary reactivity. This association is strengthened by an observation in a recent study (15) that exercise improves endothelial function independently of the reduction of other cardiovascular risk factors. A possible mechanism that leads to the correlation between physical capacity and coronary reactivity may be that exercise induces a recurrent intermittent increase in shear stress that leads to improved endothelial function (15). In our study, the association between CFVR and physical capacity was stronger than the association between CFVR and indexes of body adipose tissue distribution. These results are not in agreement with a previous report (8) in which the authors concluded that body fat and fat distribution are better predictors of coronary reactivity than fitness. This discrepancy may be explained by differences between the studies in sample size, subjects' age, fitness, and health status. Moreover, Max load (in W/kg) correlated with waist-to-hip ratio, and it is possible that one of these two variables is the cause and the other is the effect or that both are a result of a third factor that was not measured in our study.

Heart rate and rate pressure product at rest correlated negatively with CFVR. This is likely explained by an observation that subjects with lower heart rate have longer diastole and, therefore, lower baseline flow velocity than subjects with higher heart rate. Lower baseline flow velocity affects CFVR because it is defined as a ratio of hyperemia to baseline flow velocity. This raised a question as to whether heart rate at rest could explain the association between waist-to-hip ratio and CFVR. We tested this by adjusting waist-to-hip ratio by heart rate in a multivariate model. Elevated heart rate probably exaggerated the reduction in CFVR in subjects with higher waist-to-hip ratio. Nevertheless, there was an independent association between waist-to-hip ratio and reduced CFVR. This provides evidence that although waist-to-hip ratio is associated with baseline heart rate, it still has independent relevance as a predictor of CFVR.

Body mass index, serum total cholesterol, LDL cholesterol, oxidized-LDL cholesterol, apolipoprotein A1, apolipoprotein B, lipoprotein (a), or triglyceride concentrations were neither independent predictors nor correlated significantly with CFVR in healthy adults. These traditional coronary artery disease risk factors, when in the normal range, do not seem to affect coronary artery reactivity in healthy young men.

CFR is closely correlated between Doppler- and perfusion-derived methods, for example, echocardiography and PET, r = 0.94–0.98 (14, 25, 32) in healthy volunteers. Previously, decreased CFR values have been found to associate with elevated cardiovascular risk status (accumulation of risk factors in otherwise healthy subjects/burden score), hypercholesterolemia, hypertension, cardiomyopathy, and diabetes (1, 5, 22, 23, 29, 30). Moreover, risk factor modifications have had positive effect on echocardiography-derived CFVR in hypertension (17, 26). Also, in a previous study where patients were divided into percutaneous transluminal coronary angioplasty (PTCA) group (CFVR < 2.0) and the non-PTCA group (CFVR ≥ 2.0), the non-PTCA group had fewer major adverse cardiac events and angina symptoms than the PTCA group during the 15-mo follow-up period (12). However, the prognostic value of CFR has not been reported in longitudinal studies.

Study limitations. CFVR measurements are based on changes in blood flow velocity. Because coronary blood flow depends not only on flow velocity but also on artery diameter, changes in the diameter of the conduit artery during adenosine infusion may cause underestimation of true CFR. Causal relationships cannot be concluded in this cross-sectional study on a relatively small population.

In conclusion, the results of the current study suggest that abdominal fat accumulation and low aerobic fitness are independently associated with coronary reactivity in healthy men already at a young age.


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This study was supported by the Turku University Hospital Research Foundation and the Finnish Heart Foundation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. O. Kiviniemi, Dept. of Clinical Physiology, Nuclear Medicine and PET, Turku Univ. Hospital, Kiinamyllynkatu 4-8, FIN-20520 Turku, Finland (e-mail: tuoski{at}utu.fi)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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