© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Heart Rate Variability and Progression of Coronary Atherosclerosis
From the Division of Cardiology, Department of Medicine and Biocenter of Oulu, University of Oulu (H.V.H., V.J., K.E.J.A., M.J.I., J.M.K., H.K., A.Y.K.); Department of Medicine, University of Helsinki (M.S., M.S.N., M.H.F.); and Department of Medicine, University of Tampere, Finland (S.M., K.O.N.).
Correspondence to Heikki V Huikuri, MD, Division of Cardiology, Department of Medicine, University of Oulu, Kajaanintie 50, 90220 Oulu, Finland. E-mail HEIKKI.HUIKURI{at}oulu.fi
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Low heart rate (HR) variability is associated with increased risk of cardiovascular morbidity and mortality, but the causes and mechanisms of this association are not well known. This prospective study was designed to test the hypothesis that reduced HR variability is related to progression of coronary atherosclerosis. Average HR and HR variability were analyzed in 12-hour ambulatory ECG recordings from 265 qualified patients participating in a multicenter study to evaluate the angiographic progression of coronary artery disease in patients with prior coronary artery bypass surgery and low high-density lipoprotein cholesterol concentrations (<1.1 mmol/L). Participants were randomized to receive a placebo or gemfibrozil therapy. The progression of coronary atherosclerosis was estimated by quantitative, computer-assisted analysis of coronary artery stenoses from the baseline angiograms and from repeated angiograms performed an average of 32 months later. The progression of focal coronary atherosclerosis of the patients randomized to placebo therapy was more marked in the tertile with the lowest standard deviation of all normal to normal R-R intervals (SDNN, 74±13 ms; mean decrease in the per-patient minimum luminal diameter -0.17 mm; 95% confidence interval [CI], -0.23 to -0.12 mm) than in the middle tertile (SDNN, 107±7 ms; mean decrease -0.05 mm; 95% CI, -0.08 to -0.01 mm) or highest tertile (SDNN, 145±25 ms; mean change 0.01 mm; 95% CI, -0.04 to 0.02 mm) (P<0.001 between the tertiles). This association was abolished by gemfibrozil. SDNN was lower (P<0.001) and minimum HR was faster (P<0.01) in the patients with marked progression than in those with regression of focal coronary atherosclerosis. In multiple regression analysis including HR variability, minimum HR, demographic and clinical variables, smoking, blood pressure, glucose, lipid measurements and lipid-modifying therapy, progression of focal coronary atherosclerosis was independently predicted by the SDNN (ß=0.24; P=0.0001). Low HR variability analyzed from ambulatory ECG predicts rapid progression of coronary artery disease. HR variability provided information on progression of focal coronary atherosclerosis beyond that obtained by traditional risk markers of atherosclerosis.
Key Words: coronary artery disease • lipids • heart period • angiography
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Elevated heart rate (HR) and reduced HR variability are associated with an increased risk of cardiovascular morbidity and mortality in various populations,1 2 3 4 5 6 7 8 but the pathophysiological link between these associations is not well understood. Experimental studies on monkeys fed an atherogenic diet have demonstrated a relationship between resting HR and progression of coronary atherosclerosis,9 10 11 and there is also a strong relationship between HR and arterial stiffness,12 but there has been little evidence of any association between HR, or its variability, and human coronary atherosclerosis.
Progression of coronary artery stenoses in repeated coronary angiograms increases the risk of adverse cardiac events, suggesting that rapid progression predisposes patients to acute complications of coronary artery plaques and serves as a surrogate end point for clinical events.13 14 Lipid-modifying therapy has been shown to prevent the progression of coronary atherosclerosis, confirming that abnormalities in plasma lipid concentrations are strongly associated with the progression of coronary artery disease and the occurrence of adverse clinical events.14 However, lipid theory may not explain all aspects of coronary artery disease, eg, the rapid progression of discrete stenoses in specific coronary arterial regions, which is thought to result from an interplay of hemodynamic, metabolic, and hemostatic factors.15 16 17 18 To test the hypothesis that elevated HR and reduced HR variability are associated with the progression of human coronary atherosclerosis in patients with lipid abnormalities, we studied HR and its variability, measured by ambulatory ECG, and the angiographic progression of coronary artery disease in patients with reduced HDL cholesterol concentrations.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients and Study Protocol
Three-hundred and five men aged <70 years, randomized in a double-blind fashion to receive either slow-release gemfibrozil or a matching placebo in the Lopid Coronary Angiography (LOCAT) trial, underwent ambulatory ECG recordings before the baseline angiographic examination. The inclusion and exclusion criteria have been described in detail recently.19 In brief, all the patients had previously undergone coronary bypass surgery, and they also fulfilled the following inclusion criteria at two consecutive screening visits: HDL cholesterol
1.1 mmol/L, LDL
cholesterol 4.5 mmol/L, and serum
triglycerides 4.0 mmol/L. In addition, they had
blood pressure 160/95 mm Hg, body mass index 30
kg/m2, left ventricular ejection
fraction 
35%, no history of diabetes, fasting glucose concentration
<7.8 mmol/L, and no condition requiring therapy with calcium
channel blockers, ACE inhibitors, or diuretics.
Details of the entry criteria and screening process, clinical visits,
and laboratory analyses have been described
previously.19 20 All patients provided written informed
consent, and the study was approved by the ethics committees of the
participating hospitals. All the patients underwent comprehensive
clinical examinations, bicycle exercise tests, and received detailed
dietary counseling at the baseline stage. Fasting serum
triglycerides, cholesterol, HDL and LDL
cholesterol, and blood glucose were measured by methods
described previously.19 20
Coronary Angiography
Native coronary arteries and bypass grafts were imaged
at baseline and at the end of the trial (32±3 months after the
baseline angiogram) as described previously.19 20 21 The
images were analyzed with the Cardiovascular
Measurement System (Medis) by a single trained technical analyst. The
accuracy and reproducibility of the angiographic analyses have
been shown to be comparable to those reported previously by other
investigators.21 All angiographic analyses and
handling of the data were done by persons blinded to the treatment
group and ambulatory ECG data.
The progression of atherosclerosis was defined by measuring the change from the baseline to the follow-up angiogram in the average diameter of the coronary artery segments and the minimum luminal diameter of the discrete stenoses. Per-patient means of these variables were calculated in 3 types of native coronary segments, differing in their relation to the bypass grafts, ie, unaffected, graft affected (proximal to graft insertions and hemodynamically related), and graft-dependent (distal to graft insertions). Per-patient means were also calculated for the average and minimal diameters in all native segments. New lesions were defined as stenoses in the follow-up angiogram causing at least 20% diameter reduction that were not present on the baseline angiogram.
HR Variability Analyses
The prospective study of the effects of HR variability on
progression of coronary artery disease was performed by
recording ambulatory ECG after informed consent on the day
before the baseline coronary angiography, or 1 day after the
angiography. Patients with acute cardiovascular events,
ie, myocardial infarction, unstable angina pectoris, or stroke between
the baseline and repeat angiogram; patients with atrial fibrillation;
and those with technically inadequate ECG recordings were
excluded. After exclusions, 265 patients were included in the study.
Ambulatory ECG recordings were performed between 6
PM and 10 AM, including at least 4 hours awake
and 4 hours asleep.
The ECG data were sampled digitally and transferred from the Oxford Medilog scanner to a microcomputer for analysis of HR variability.22 All the R-R interval time series were first edited automatically, after which careful manual editing was performed by visual inspection of the R-R intervals. Each R-R interval time series was passed through a filter that eliminates premature beats and artifacts, and deletes the filling gaps, using previously described methods.22 23 Only recordings with qualified beats for at least a 12-hour period, and with >85% of qualified sinus beats, were included in the analysis of HR variability (n=265).
After editing of the R-R interval tachograms, the R-R interval spectra were generated. A Fast Fourier transform method was used to estimate the power spectrum densities of HR variability.23 Frequency domain measures of R-R interval variability were computed by integrating the point-power spectrum over the frequency intervals. The power spectra were quantified by measuring the areas in the following frequency bands: (1) <0.0033 Hz (ultra-low frequency power), (2) 0.0033 to <0.04 Hz (very low frequency power), (3) 0.04 to 0.15 Hz (low frequency power), and (4) 0.15 to <0.4 Hz (high frequency power). The standard deviation of all normal-to-normal R-R intervals (SDNN) was used as a time-domain measure of HR variability. The average HR was measured for each hour of the recording period, and the minimum, maximum, and average R-R intervals were calculated.
Statistical Analyses
The patients were divided into tertiles according to the
baseline HR variability, and ANOVA followed by Bonferroni post-hoc
analysis was used to compare the continuous variables
between these tertiles. ANCOVA was used for adjustments for possible
confounding effects of various variables on differences between the
groups. Pearson's correlation coefficients were used to estimate the
linear correlations between continuous variables. The
2 test was used to compare categorical
variables. Linear multiple regression analysis (stepwise
forward analysis, SPSS for Windows, version 6.0) was used to
assess the predictors of the progression of coronary
atherosclerosis. Data are presented as
mean±standard deviation (SD) in all Tables.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Relation of Baseline Characteristics to HR Variability
Patients were divided into tertiles according to baseline HR variability; SDNN was 74±13 ms in the lowest tertile, 104±7 ms in the middle tertile, and 145±25 ms in the highest tertile. Baseline demographic characteristics, history and symptoms of heart disease, cardiac medication, results of exercise tests, number of randomized patients, and laboratory data are shown in Table 1
. The blood glucose level was higher in
the tertile with the lowest SDNN than in the highest tertile, but no
other variable, eg, age, blood pressure, lipid values, duration of
coronary artery disease, medication, presence of angina
pectoris, ischemia during exercise test (Table 1), or
left ventricular ejection fraction (Table 2), differed across the tertiles.
|
|
Angiographic Progression of Coronary Artery
Disease
The progression of coronary artery stenoses, as
assessed from the per-patient decrease in the minimum luminal diameter
of all native vessels, was more marked in the patients with the lowest
SDNN than in the middle and highest tertile (Figure 1). This difference was observed as a
per-patient change in all native segments, -0.11 mm (95% CI,
-0.15 to -0.07 mm) in the lowest tertile, -0.06 mm (95%
CI, -0.09 to -0.04 mm) in the middle tertile, and -0.03 mm
(95% CI, -0.06 to 0.001 mm) in the highest tertile
(P<0.01 between the tertiles); the difference was evident
in both the native vessels without bypass grafts and the proximal
portions of grafted native vessels (Table 2
) but not in the
grafted distal coronary artery segments. The difference in the
per-patient change in minimal luminal diameter remained significant
among the HR variability tertiles after adjustments to all baseline
variables, including randomization to lipid-modifying therapy
(ANCOVA, F=4.7, P=0.01). In the total study group, a
significant correlation existed between the baseline SDNN and the
change in the minimum luminal diameter of all the native vessels
(r=0.26, P<0.001).
|
Twenty-four patients were found to have new coronary artery lesions in repeated coronary angiograms. There were no differences in HR or HR variability, ie, SDNN 110±26 versus 108±32 ms (not significant [NS]), between the patients with and without new stenoses.
Comparison of Placebo and Gemfibrozil Groups
The relationship between the progression of focal coronary
atherosclerosis and HR variability was observed only in
the patients randomized to placebo treatment (Figure 2), but no significant relationship was
observed in those receiving gemfibrozil therapy (Figure 3). Marked progression of focal
atherosclerosis was observed mainly in the patients
with the lowest SDNN in the placebo group, ie, decrease in the mean
per-patient minimal luminal diameter of all native segments -0.17
mm (95% CI, -0.23 to -0.12 mm) in the lowest tertile,
-0.05 mm (95% CI, -0.08 to -0.01 mm) in the middle
tertile, and only -0.01 mm (95% CI, -0.04 to 0.02 mm) in
the patients with highest HR variability (P<0.001 between
the tertiles; Figure 2). A significant correlation was observed
between the baseline SDNN and the change in the minimal luminal
diameter of all native vessels (r=0.44, P<0.001)
in the placebo group. In the gemfibrozil group, the per-patient change
in the minimum luminal diameter was -0.03 mm (95% CI, -0.07 to
0.02 mm) in the lowest SDNN tertile, -0.07 mm (95%
CI, -0.12 to -0.03 mm) in the middle tertile, and -0.05 mm
(95% CI, -0.11 to 0.01 mm) in the highest tertile, respectively
(NS; Figure 3); no correlation was observed between the SDNN and
the change in the minimum luminal diameter (r=0.08, NS).
|
|
Predictors of Progression of Coronary Atherosclerosis
The patients were also divided into tertiles according to the
per-patient change in the minimum luminal diameter of all
native-segment stenoses. Patients in the lowest tertile had a
marked progression of focal atherosclerosis (decrease
in the minimum luminal diameter -0.25±0.11 mm), minimal or no
progression was observed in the middle tertile (-0.05±0.04 mm), and
regression of focal atherosclerosis was observed in the
highest tertile (0.10±0.07). The progression of discrete
coronary stenoses was related to the time-domain
measures of HR variability, also when normalized by reference to the
averaged HR, and to all the spectral components of HR variability
(Table 3). Minimum HR (during sleep) was
also faster in the patients with marked progression of discrete
stenoses than in those with minimal progression or regression,
but the maximum HR (awake) did not differ between the groups.
|
In univariate analyses, the per-patient change in the minimum luminal diameters of the stenoses in all native vessels was related to SDNN (P<0.0001), triglyceride level (P=0.009), randomization to placebo or gemfibrozil (P=0.003), minimum HR (P=0.02), and to systolic and diastolic blood pressure (P=0.02 for both), but not to any other measured variable. In a multiple regression analysis, the change in the minimum luminal diameter was best predicted by the SDNN (ß=0.24, P=0.0001) and triglyceride level (ß=-0.16, P=0.009); no other variables entered the equation.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The main observation was that reduced HR variability, as analyzed from ambulatory ECG, predicted the progression of human coronary atherosclerosis. These data corroborate previous evidence on the significance of HR variability for clinical manifestations of coronary artery disease.1 2 3 4 5 6 7 The association between low HR variability and the progression of coronary artery disease was not explained by common risk factors for atherosclerosis, or by the severity of ischemic heart disease at the time of analysis of HR variability, supporting the view that there may be an independent relationship between HR variability and the progression of coronary atherosclerosis.
Despite the epidemiological evidence of an association between low HR variability and cardiovascular mortality,5 6 7 the causes and mechanisms of this association have not been well known. Follow-up and case-control studies in patients after myocardial infarction have suggested that low HR variability predicts the occurrence of arrhythmic events,24 25 but results in other populations suggest that reduced HR variability may also predict the occurrence of vascular events, such as angina pectoris, myocardial infarction, and coronary death.7 23 The present observations give an insight into the pathophysiology, and mechanisms for the observed clinical associations, showing that reduced HR variability is related to accelerated progression of coronary atherosclerosis, rather than being a consequence of severe ischemic heart disease itself.
Elevated casual HR has been shown to predict cardiovascular mortality in a number of large-scale prospective epidemiological studies.1 2 3 Ambulatory ECG recordings have shown that the minimum HR measured during a 24-hour period is even more closely related to cardiac events than the casual HR or 24-hour average HR,26 and blunted circadian rhythm of autonomic modulation of HR has been described in patients with coronary artery disease.22 In this study, the elevated minimum HR during sleeping hours, but not the maximum HR, was found to be related to the progression of coronary artery stenoses, also providing a possible explanation for the prior epidemiological and clinical observations.1 2 3
The observed associations between HR, HR variability, and progression of focal atherosclerosis may be explained by hemodynamic factors, effects of the autonomic nervous system, or a combination of these factors. The role of hemodynamic factors in the localized nature of coronary artery disease, ie, localization of coronary stenoses to specific proximal portions of the coronary arteries around the arterial branches, has been speculated upon in earlier studies, and it has been shown that hemodynamic factors may play an important role in the progression and regression of these lesions.8 15 The present observations support the concepts of these experimental findings by showing that reduced HR variability, and elevated minimum HR, predicted the progression of discrete coronary stenoses located in the proximal portions of native coronary vessels, but not the progression of diffuse disease, or the development of new coronary lesions. The lack of association between HR variability and progression of diffuse atherosclerosis may be explained by different impacts of hemodynamic factors on progression of focal and diffuse atherosclerosis, and by the interaction between bypass grafts and local hemodynamics. Hemodynamically mediated mechanisms of atherosclerosis may be more closely related to geometric aspects of vulnerable areas, ie, discrete lesions proximal to bypass grafts but not distal diffuse disease, which promote eddy formation, low shear, and increased exposure to blood-born elements that are atherogenic. Abnormal baroreflex-mediated HR fluctuation and elevated HR have also been associated with increased arterial stiffness,12 27 and frequency-dependent arterial stiffness may have influence on progression of atherosclerotic lesions.
The mechanism linking hemodynamic factors to the progression of discrete localized coronary lesions has been proposed to be the effects of blood flow dynamics on the arterial wall.28 Movements of atherogenic particles over the endothelium, and vascular smooth cell proliferation, are affected by the fluid velocity and flow characteristics in the vicinity of the endothelium.28 29 Recirculation and turbulence in the blood flow, and changes in shear stress, have been shown to result in morphological changes in the vascular endothelial cells and in intimal thickening, promoting accumulation of atherogenic particles within the endothelium.15 29 30 Enhanced pulsatile flow has been observed to foster turbulence and recirculation,31 and this has been proposed to be a mechanism whereby a fast HR accelerates the progression of discrete coronary stenoses in monkeys fed an atherogenic diet.9 A combination of fast HR during sleep and enhanced de novo synthesis of lipid particles observed during sleeping hours32 may accelerate the progression of human atherosclerosis. Loss or reduction of beat-to-beat variation in pulsatile flow, in addition to an elevated rate, may favor the localization of turbulence and recirculation to the same, specific anatomic segments of the arterial wall, further enhancing the atherosclerotic process in these localized areas.
The autonomic nervous system may also affect coronary atherosclerosis.9 33 Reduced HR variability and elevated HR result from altered cardiac autonomic regulation with sympathetic predominance and/or reduced vagal tone. Increased sympathetic tone with elevated catecholamine levels may have direct effects on vascular smooth muscle cells,34 or it may affect other factors promoting the progression of atherosclerosis.35 The combined effects of HR variability on local fluid dynamics and the effects of autonomic nervous system may contribute to the observed progression of focal coronary atherosclerosis, but further investigations will be needed to elucidate the exact mechanisms.
The present observations cannot confirm any direct causal relationship between reduced HR variability and the progression of coronary artery disease because we cannot exclude the possibility that low HR variability may be an indicator of other factors, not measured here, in relation to the progression of atherosclerosis. It is possible, for example, that there may be a genetic link between HR variability and atherogenesis, independent of hemodynamics or the autonomic nervous system. The present observations may likewise not be applicable to other populations with different risk factors for atherosclerosis because only male patients with previous bypass surgery and a specific lipid abnormality were included. Of potential interest for future research is the role of impaired HR variability in other populations, eg, in diabetic subjects or patients with heart transplants, because both groups commonly experience rapid progression of atherosclerosis and reduced HR variability.
HR variability was the strongest independent predictor of the progression of focal coronary atherosclerosis in this population, and lipid-modifying therapy seemed to prevent progression mainly in the tertile of patients with the lowest HR variability. Whether recordings of long-term ambulatory ECG and measurement of HR variability will help in selecting patients for more aggressive antiatherogenic therapy merits further investigation.
|
Acknowledgments |
|---|
The investigators participating in the Lopid Coronary Angioplasty trial were listed in the Appendix of Circulation. 1997;96:2137–2143. This study was supported by grants from Parke-Davis, a division of Warner Lambert; the Finnish Foundation for Cardiovascular Research; and by contract with the Finnish Life and Pension Insurance Companies, Helsinki, Finland.
Received August 27, 1998; accepted December 29, 1998.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Kannel WB, Kannel C, Paffenbarger RS, Cupples LA. Heart rate and cardiovascular mortality: The Framingham Study. Am Heart J. 1987;113:1489–1494.[Medline] [Order article via Infotrieve]
2. Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: The NHANES I Epidemilogical Follow-up Study. Am Heart J. 1991;121:172–177.[Medline] [Order article via Infotrieve]
3.
Mensink GBM, Hoffmeister H. The relationship between
resting heart rate and all-cause, cardiovascular and
cancer mortality. Eur Heart J. 1997;18:1404–1410.
4. Hjalmarson A, Gilpin EA, Kjekshus J, Schieman G, Nicord P, Henning H, Ross J Jr. Influence of heart rate on mortality after myocardial infarction. Am J Cardiol. 1990;65:547–551.[Medline] [Order article via Infotrieve]
5. Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ, and the Multicenter Post-Infarction Research Group. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256–262.[Medline] [Order article via Infotrieve]
6.
Bigger JT Jr, Fleiss JL, Steinman RC, Rolnitzky LM,
Klieger RE, Rottman JN. Frequency domain measures of heart period
variability and mortality after myocardial infarction.
Circulation. 1992;85:164–171.
7.
Tsuji H, Larson MG, Venditti FJ, Manders ES, Evans JC,
Feldman CL, Levy D. Impact of reduced heart rate variability on risk
for cardiac events: The Framingham Heart Study. Circulation. 1996;94:2850–2855.
8.
Filipovsky J, Ducimetiere P, Safar ME. Prognostic
significance of exercise blood pressure and heart rate in middle-aged
men. Hypertension. 1992;20:333–339.
9.
Beere PA, Glagov S, Zarins CK. Retarding effect of
lowered heart rate on coronary atherosclerosis.
Science. 1984;226:180–182.
10. Kaplan JR, Manuck SB, Adams MR, Weingard KW, Clarkson TB. Inhibition of coronary atherosclerosis by propranolol on behaviorally predisposed monkeys fed an atherogenic diet. Circulation. 1987;86:1364–1372.
11. Kaplan JR, Manuck SB, Clarkson TB. The influence of heart rate on coronary atherosclerosis. J Cardiovasc Pharm. 1987;10(suppl 2):S100–S102.
12. Sa Cunha R, Pannier B, Benetos A, Siche J-P, London GM, Mallion JM, Safar ME. Association between high heart rate and high arterial rigidity in normotensive and hypertensive subjects. J Hypertension. 1997;15:1423–1430.[Medline] [Order article via Infotrieve]
13.
Haskell WL, Alderman EL, Fair JM, Maron DJ, Mackey SF,
Superko HR, Williams PT, Johnstone IM, Champagne MA, Krauss RM,
Farquliar JW. Effects of intensive multiple risk factor reductions on
coronary atherosclerosis and clinical cardiac
events in men and women with coronary artery disease: The
Stanford Coronary Risk Intervention Project.
Circulation. 1994;89:975–990.
14.
Gotto AM Jr. Lipid lowering, regression and
coronary events: a review of the Interdisciplinary Council of
Lipids and Cardiovascular Risk Intervention, Seventh
Council Meeting. Circulation. 1995;92:646–656.
15. Schwartz CJ, Mitchell JRA. Observations on localization of arterial plaques. Circ Res. 1972;11:63–73.
16. Ip JH, Fuster V, Badimon L, Badimon J, Taubman MB, Chesebro JH. Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation. J Am Coll Cardiol. 1990;15:1667–1687.[Abstract]
17.
Asakura T, Karino T. Flow patterns and spatial
distribution of atherosclerotic lesions in human coronary
arteries. Circ Res. 1990;66:1045–1066.
18.
Hamsten A. Hemostatic function and coronary
artery disease. N Engl J Med. 1995;332:677–678.
19.
Frick MH, Syvänne M, Nieminen MS, Kauma H,
Majahalme S, Virtanen V, Kesäniemi YA, Pasternack A, Taskinen
M-R, for the Lopid Coronary Angiography Trial (LOCAT) Study
Group. Prevention of the angiographic progression of coronary
and vein-graft atherosclerosis by gemfibrozil after
coronary bypass surgery in men with low levels of HDL
cholesterol. Circulation. 1997;96:2137–2143.
20. Syvänne M, Taskinen M-R, Nieminen MS, Manninen V, Kesäniemi YA, Pasternack A, Nawrocki JW, Haber H, Frick MH. A study to determine the response of coronary atherosclerosis to raising low HDL cholesterol with a fibric-acid derivative in men after coronary bypass surgery: the rationale, design and baseline characteristics of the LOCAT study. Control Clin Trials. 1997;18:93–119.[Medline] [Order article via Infotrieve]
21. Syvänne M, Nieminen MS, Frick MH. Accuracy and precision of quantitative arteriography in the evaluation of coronary artery disease after coronary bypass surgery: a validation study. Int J Vasc Imaging. 1994;10:243–252.
22.
Huikuri HV, Niemelä MJ, Ojala S, Rantala A,
Ikäheimo MJ, Airaksinen KEJ. Circadian rhythms of frequency
domain measures of heart rate variability in healthy subjects and
patients with coronary artery disease: effects of arousal and
upright posture. Circulation. 1994;90:121–126.
23.
Huikuri HV, Mäkikallio TH, Airaksinen KEJ,
Seppänen T, Puukka, P, Räihä IJ, Sourander LB. Power
law relationship of heart rate variability as a predictor of mortality
in the elderly. Circulation. 1998;97:2031–2036.
24. Hartikainen JEK, Malik M, Staunton A, Poloniecki J, Camm AJ. Distinction between arrhythmic and nonarrhythmic death after acute myocardial infarction based on heart rate variability, signal-averaged electrocardiogram, ventricular arrhythmias and left ventricular ejection fraction. J Am Coll Cardiol. 1996;28:296–304.[Abstract]
25. Perkiömäki JS, Huikuri HV, Koistinen MJ, Mäkikallio T, Castellanos A, Myerburg RJ. Heart rate variability and dispersion of QT interval in patients with vulnerability to ventricular tachycardia and ventricular fibrillation after previous myocardial infarction. J Am Coll Cardiol. 1997;30:1331–1338.[Abstract]
26. Perski A, Olsson G, Laudon C, deFaire V, Theorell T, Hamsten A. Minimum heart rate and coronary atherosclerosis: independent relations to global severity and rate of progression of angiographic lesions in men with myocardial infarction at a young age. Am Heart J. 1992;123:609–616.[Medline] [Order article via Infotrieve]
27. Bergel DH, Brooks DE, MacDermott AJ, Robinson JL, Sleight P. Baroreceptor firing frequency and activation of carotid sinus vascular smooth muscle in dogs. J Physiol. 1978;275:37P–38P.
28. Caro CG, Fitz-Gerald JM, Schroter RC. Arterial wall shear and distribution of early atheroma in man. Nature. 1969;223:1159–1161.[Medline] [Order article via Infotrieve]
29.
Sprague EA, Steinbach BL, Nerem RM, Schwartz CJ.
Influence of laminar steady-state fluid-imposed wall shear stress on
the binding, internalization, and degradation of low-density
lipoproteins by cultured arterial
endothelium. Circulation. 1987;76:648–656.
30. Predel, HG, Yang Z, von Segesser L, Turina M, Bühler FR, Lüscher TF. Implications of pulsatile stretch on growth of saphenous vein and mammary artery smooth muscle. Lancet. 1992;340:878–879.[Medline] [Order article via Infotrieve]
31.
Yellin EL. Laminar-turbulent transition process in
pulsatile flow. Circ Res. 1966;19:791–804.
32. Jones PJH, Schoeller DA. Evidence for diurnal periodicity in human cholesterol synthesis. J Lipid Res. 1990;31:667–673.[Abstract]
33. Kukreja RS, Datta BN, Chakra-Varti RN. Catecholamine-induced aggravation of aortic and coronary atherosclerosis in monkeys. Atherosclerosis. 1981;40:291–298.[Medline] [Order article via Infotrieve]
34.
Yu S-M, Tsai S-Y, Guh J-H, Ko F-N, Teng C-M, Ou J-T.
Mechanisms of catecholamine-induced proliferation of
vascular smooth muscle cells. Circulation. 1996;94:547–554.
35. Dzau VJ, Sarbs FM. Regulation of lipoprotein metabolism by adrenergic mechanisms. J Cardiovasc Pharmacol. 1987;10(suppl 9):S2–S6.
This article has been cited by other articles:
 |
|
 |
|
  R. P. Sloan, P. A. Shapiro, R. E. DeMeersman, E. Bagiella, E. N. Brondolo, P. S. McKinley, I. Slavov, Y. Fang, and M. M. Myers The Effect of Aerobic Training and Cardiac Autonomic Regulation in Young Adults Am J Public Health, May 1, 2009; 99(5): 921 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Bhattacharyya, D. L. Whitehead, R. Rakhit, and A. Steptoe Depressed Mood, Positive Affect, and Heart Rate Variability in Patients With Suspected Coronary Artery Disease Psychosom Med, November 1, 2008; 70(9): 1020 - 1027. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Pizzi, L. Manzoli, S. Mancini, and G. M. Costa Analysis of potential predictors of depression among coronary heart disease risk factors including heart rate variability, markers of inflammation, and endothelial function Eur. Heart J., May 1, 2008; 29(9): 1110 - 1117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Bleil, P. J. Gianaros, J. R. Jennings, J. D. Flory, and S. B. Manuck Trait Negative Affect: Toward an Integrated Model of Understanding Psychological Risk for Impairment in Cardiac Autonomic Function Psychosom Med, April 1, 2008; 70(3): 328 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ohira, A. V. D. Roux, R. J. Prineas, M. A. Kizilbash, M. R. Carnethon, and A. R. Folsom Associations of Psychosocial Factors With Heart Rate and Its Short-Term Variability: Multi-Ethnic Study of Atherosclerosis Psychosom Med, February 1, 2008; 70(2): 141 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Fox, J. S. Borer, A. J. Camm, N. Danchin, R. Ferrari, J. L. Lopez Sendon, P. G. Steg, J.-C. Tardif, L. Tavazzi, M. Tendera, et al. Resting Heart Rate in Cardiovascular Disease J. Am. Coll. Cardiol., August 28, 2007; 50(9): 823 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Schubiner, B. Hassunizadeh, and R. Kaczynski A controlled study of autonomic nervous system function in adults with attention-deficit/hyperactivity disorder treated with stimulant medications: results of a pilot study. J Atten Disord, November 1, 2006; 10(2): 205 - 211. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Iellamo, A. Galante, J. M. Legramante, M. E. Lippi, C. Condoluci, G. Albertini, and M. Volterrani Altered autonomic cardiac regulation in individuals with Down syndrome Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2387 - H2391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Falcone, M. P. Buzzi, C. Klersy, and P. J. Schwartz Rapid Heart Rate Increase at Onset of Exercise Predicts Adverse Cardiac Events in Patients With Coronary Artery Disease Circulation, September 27, 2005; 112(13): 1959 - 1964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Gianaros, K. Salomon, F. Zhou, J. F. Owens, D. Edmundowicz, L. H. Kuller, and K. A. Matthews A Greater Reduction in High-Frequency Heart Rate Variability to a Psychological Stressor is Associated With Subclinical Coronary and Aortic Calcification in Postmenopausal Women Psychosom Med, July 1, 2005; 67(4): 553 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. K. Kim, S. P. McGorray, B. A. Bartholomew, M. Marsh, T. Dicken, S. Wassertheil-Smoller, J. D. Curb, A. Oberman, J. Hsia, J. Gardin, et al. Depressive Symptoms and Heart Rate Variability in Postmenopausal Women Arch Intern Med, June 13, 2005; 165(11): 1239 - 1244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Abuissa, J. H. O'Keefe Jr, W. Harris, and C. J. Lavie Autonomic Function, Omega-3, and Cardiovascular Risk Chest, April 1, 2005; 127(4): 1088 - 1091. [Full Text] [PDF]
|
|
|
|
|
|
A. Sajadieh, O. W. Nielsen, V. Rasmussen, H. O. Hein, S. Abedini, and J. F. Hansen Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease Eur. Heart J., March 1, 2004; 25(5): 363 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pelat, C. Dessy, P. Massion, J.-P. Desager, O. Feron, and J.-L. Balligand Rosuvastatin Decreases Caveolin-1 and Improves Nitric Oxide-Dependent Heart Rate and Blood Pressure Variability in Apolipoprotein E-/- Mice In Vivo Circulation, May 20, 2003; 107(19): 2480 - 2486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Curtis and J. H. O'Keefe Jr Autonomic Tone as a Cardiovascular Risk Factor: The Dangers of Chronic Fight or Flight Mayo Clin. Proc., January 1, 2002; 77(1): 45 - 54. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||