Association of premature ventricular complexes with central aortic pressure indices and pulse wave velocity

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1 Association of premature ventricular complexes with central aortic pressure indices and pulse wave velocity Ju-Yi Chen, MD, a,b Wei-Chuan Tsai, MD, a Yung-Ling Lee, PhD, c Cheng-Han Lee, MD, a Liang-Miin Tsai, MD, a Ting-Hsing Chao, MD, a Yi-Heng Li, PhD, a Jyh-Hong Chen, PhD, a and Li-Jen Lin, MD a Tainan, Taiwan Background Although premature ventricular complex (PVC) occurs frequently, its predisposing factors have rarely been studied. We examined the connection between PVC and aortic stiffness. Methods We recruited 200 consecutive patients (b50 years, 95 men, mean age 36 ± 10 years) who received a 24-hour ambulatory electrocardiography examination for palpitation and PVC loads. Muscular artery pulse wave velocity (PWVm) and 4 main aortic pressure indices augmented pressure, augmentation index (AI x ), AI x corrected for a steady heart rate of 75 beat/min, and the extra workload were measured, and atherosclerosis risk was evaluated. Results Eighty-three (42%) patients had no PVC loads; 58 (29%) patients had low loads (b24 beat/d), and 59 (29%) had high loads ( 24 beat/d). Only age and hyperlipidemia were significantly associated with PVC loads. Using a multivariate logistic regression model adjusted for potential confounders, we found that AI x (odds ratio [OR] 1.88, 95% CI , P =.005); augmented pressure (OR 1.57, 95% CI , P =.042); AI x corrected for a steady heart rate of 75 beat/min (OR 1.82, 95% CI , P =.007); and PWVm (OR 1.53, 95% CI , P =.021) were independent factors for PVC loads. Conclusion Increased central aortic pressure indices as well as PWVm were associated with increased PVC loads in young patients undergoing 24-hour ambulatory electrocardiography. Central aortic properties probably contributed to the occurrence of PVC. (Am Heart J 2008;155:500.e1-500.e6.) From the a Division of Cardiology, Department of Internal Medicine, National Cheng Kung University, Hospital, Tainan, Taiwan, b Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, and c Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. Submitted October 11, 2007; accepted November 20, Reprint requests: Li-Jen Lin, MD, Division of Cardiology, Department of Internal Medicine National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan 704, Taiwan. linl@mail.ncku.edu.tw /$ - see front matter 2008, Published by Mosby, Inc. doi: /j.ahj Premature ventricular complex (PVC), common both in healthy and in diseased patients, is associated with an increased risk of ventricular arrhythmias or sudden death in patients with myocardial infarction or congestive heart failure. 1 The possible mechanisms for PVC are myocardial ischemia, myocardial infarction, hypertensive cardiomyopathy, left ventricular systolic or diastolic dysfunction, and left ventricular remodeling. 2-7 However, the predisposing factors for PVC in apparently healthy individuals have not been fully elucidated. Many risk models for cardiovascular disease, such as the Framingham coronary risk model, have been used in an attempt to identify those who would benefit most from preventive treatment. 8 Such models are based primarily on age, sex, blood pressure, smoking status, cholesterol, and diabetes mellitus. Still, a large proportion of individuals are not identified before they have developed cardiovascular disease. 9 Noninvasive tests to detect individuals with atherosclerosis or arterial stiffness, preferably before they develop cardiovascular disease, may improve the selection of candidates for preventive treatments. High PVC loads may be associated with Cornell voltage estimates of left ventricular mass 10 and the left ventricular mass index derived from echocardiography. 11 This effect is independent of many of the known causal predictors of PVC. 7 We also know that left ventricular hypertrophy (LVH) detected using conventional echocardiography is associated with atherosclerotic plaque in the aorta in patients with previous stroke or transient ischemic attack. 12 It was recently shown that aortic augmented pressure (AG) is associated with left ventricular mass. 13 In hemodialysis patients, atherosclerosis is associated with LVH, and the presence of aortic plaques is an independent factor related to the left ventricular mass index. 14 Pulse wave analysis, a noninvasive test and expressed as a central augmentation index (AI x ), suggests that atherosclerosis in the aorta and peripheral arteries may be detected as high aortic stiffness, even before patients develop cardiovascular disease We hypothesized that high PVC loads might be associated with aortic stiffness in young individuals. To study the connection between aortic stiffness and PVC

2 500.e2 Chen et al American Heart Journal March 2008 loads, from February 2005 through December 2005, we evaluated 200 consecutive individuals who underwent 24-hour ambulatory electrocardiographic (ECG) recordings because of palpitation and measured their central aortic pressure indices and muscular artery pulse wave velocity (PWVm) using applanation tonometry. Figure 1 Methods Study population We prospectively recruited 200 consecutive young patients (95 men, all b50 years [mean age 36 ± 10 years]) who received an ambulatory 24-hour ECG examination to evaluate palpitation. All the patients were apparently healthy and without peripheral vascular occlusion diseases, finger deformities, coronary artery disease, myocardial infarction, left ventricular dysfunction, congestive heart failure, critical valvular heart diseases, or chronic atrial fibrillation. The traditional risk factors for coronary artery disease diabetes mellitus, hypertension, hypercholesterolemia, and current smoking were all carefully evaluated in each patient. Diabetes mellitus was diagnosed if the fasting plasma glucose concentration was N125 mg/dl on 2 separate occasions or if the patient was being treated with insulin or oral hypoglycemic agents. Hypertension was diagnosed if blood pressure was N140/90 mm Hg on 3 occasions or if the patient was taking any antihypertension medication. Hypercholesterolemia was defined as a total serum cholesterol concentration 200 mg/dl or as using lipidlowering therapy. Smokers were defined as those who habitually smoked cigarettes ( 20 cigarettes per day) at the start of this study. A family history of premature coronary artery disease (CAD) was defined as patients whose parents, siblings, or grandparents had premature CAD before the age of 55 years in men and 65 years in women. Antihypertension drugs were also carefully reviewed in hypertensive patients. All patients were asked to refrain from taking their medications for 1 day before each test and consuming coffee, smoking, and eating at least 2 hours before data collection. All patients gave written informed consent for this study, and the study protocol was approved by the human research committee of our hospital. Pulse wave analysis using applanation tonometry Before any testing, all measurements (including blood pressure and heart rate) were made with the patient supine for 20 minutes in a quiet, temperature-controlled laboratory at 26 C ± 1 C. The right radial and carotid pulse waves were detected directly using a piezoresistive pressure transducer (Millar SPT 301; Millar Instruments, Houston, TX) coupled to an electronic sphygmometer (SphygmoCor Px Aortic BP Waveform Analysis System; AtCor Medical Pty Ltd, West Ryde, NSW, Australia). The timing of these waveforms was compared with that of the R wave on a simultaneously recorded ECG. The carotid-to-radial PWVm was calculated by dividing the transit time by the distance between these 2 pulses. Central aortic pressure indices were obtained at the same time by transforming the radial arterial waveform. The principle of this noninvasive method consists in registering a pulse waveform at the radial artery and deriving it at the ascending aorta using a mathematical transformation, expressed as the central AI x. The systolic part of Aortic pressure wave synthesized from the measured radial artery pressure wave (applanation tonometry) using a generalized transfer function. AI x =(P s P i )/(P s P d ). P s, Peak systolic pressure; P i, inflection point that indicates the beginning upstroke of the reflected pressure wave; P d, minimum diastolic pressure. the central aortic waveform is characterized by 2 pressure peaks. The first peak is caused by left ventricular ejection, and the second peak is a result of wave reflection. Two aortic pressure indices were measured: AG and AI x. Augmented pressure represents the difference between the second and first systolic peaks of the central pressure waveform (Figure 1). The AI x is defined as the percentage of the central pulse pressure attributed to the reflected pulse wave and, therefore, reflects the degree to which central aortic pressure is augmented by wave reflection (Figure 1). 15 AI x75 is defined as the AI x corrected for a steady heart rate of 75 beat/min. 16 Δtr is defined as the systolic duration of the reflected pressure wave. 17 The extra workload (E w ) due to wave reflection is wasted energy that the left ventricle must generate during ejection and can be estimated as 2.09 tr(ag) (Figure 1). 17 Twenty-four-hour ambulatory electrocardiography Twenty-four-hour Holter recordings were taken using a standard 3-channel flash card recorder (RZ153; Rozinn Electronics, Glendale, NY). The ECG signal was digitized and stored using a commercially available personal computer based system. All recordings were visually scanned and analyzed using the RZ153. Low and high PVC loads were defined as b or 24 beats of premature atrial contraction per day, respectively, detected using an ambulatory electrocardiograph. Twelve-lead electrocardiography Patients underwent a standard 12-lead ECG recorded at 25 mm/s and 1 mv/cm standardization with equipment (Page Writer 200i; Hewlett-Packard Company, Palo Alto, CA), whose frequency response characteristics met the recommendations of the American Heart Association. The Sokolow-Lyon voltage criteria were used to assess LVH in electrocardiography. The voltage amplitude

3 American Heart Journal Volume 155, Number 3 Chen et al 500.e3 Table I. Clinical characteristics of patients PVC loads: factors No (n = 83) Yes (n = 117) P Male (%) 42 (50.6) 53 (45.3).459 Age (y) 34.0 ± ± Body weight (kg) 61.9 ± ± Body height (cm) ± ± Body mass index (kg/m 2 ) 23.1 ± ± Systolic blood ± ± pressure (mm Hg) Diastolic blood 68.0 ± ± pressure (mm Hg) Mean blood 85.0 ± ± pressure (mm Hg) Pulse pressure (mm Hg) 49.0 ± ± Heart rate (beat/min) 70.0 ± ± Background Diabetes mellitus 0 (0.0) 5 (4.3).056 Hypertension 7 (8.4) 20 (17.1).077 Hyperlipidemia 8 (9.6) 31 (26.5).003 Current smoker 27 (32.5) 31 (26.5).354 Chronic renal failure 1 (1.2) 1 (0.9).806 Hyperthyroidism 2 (2.4) 7 (6.0).230 Family history of CAD 3 (3.6) 6 (5.1).827 Angiotensin-converting 2 (2.4) 4 (3.4).882 enzyme inhibitors Angiotensin II 3 (3.6) 7 (6.0).746 receptor blockers Statins 6 (7.2) 12 (1.3).642 β-adrenergic blockers 2 (2.4) 5 (4.3).671 Calcium-channel blockers 1 (1.2) 4 (3.4).586 Left ventricle hypertrophy 0 (0.0) 8 (6.8).054 in 12-lead ECG Applanation tonometry PWVm (m/s) 8.2 ± ± Δtr (ms) ± ± E w (dyne-s/cm 2 ) ± ± AG (mm Hg) 3.4 ± ± AI x (%) 10.1 ± ± 14.7 b.001 AI x75 (%) 7.7 ± ± 15.0 b.001 Data are means ± SD or number (percentage). sum (S-wave in V1 + max [R-wave in V5 or R-wave in V6]) was calculated, and ECG LVH was defined as a sum 3.5 mv. Statistical analysis Differences between patients with and without PVC loads were compared using Student t test for continuous variables and the χ 2 test for categorical variables. The differences between different PVC load groups were tested using 1-way analysis of variance and post hoc tests. Multiple logistic regression analyses were used to assess the independent factor for the occurrence of PVC loads. Statistical significance was set at P b.05. All analyses were done using SPSS software, version 11.5 for Windows (SPSS Inc, Chicago, IL). Results Correlation between PVC loads and aortic stiffness indices Of the 200 patients, 117 (59%, 53 men, mean age 37 ± 10 years) had PVC loads. Age (37 ± 10 vs 34 ± 11 years, P =.010); PWVm (8.6 ± 1.1 vs 8.2 ± 1.0 m/s, P =.002); Figure 2 The correlation of the PWVm and PVC loads in the entire study population. AG (6.0 ± 5.6 vs 3.4 ± 6.0 mm Hg, P =.002); AI x75 (15.3% ± 15.0% vs 7.7% ± 14.7%, P b.001); AI x (18.0% ± 14.7% vs 10.1% ± 15.2%, P b.001); and E w (3321 ± 3130 vs 1947 ± 3416 dyne-s/cm 2, P =.004) were significantly higher in patients with PVC loads (Table I). More patients with PVC loads had a history of hyperlipidemia (26.5% vs 9.6%, P =.003). There were no differences in sex, other risk factors, ECG findings, or drug history between patients with or without PVC loads (Table I). We further divided the 117 patients with PVC loads into low- and high-load groups. We took the median number (24 beat/d) as a cutoff point. The low-load group (b24 beat/d) contained 58 (29%) patients and the high-load group ( 24 beat/d) 59 (29%) patients. Muscular artery pulse wave velocity (8.2 ± 1.0 vs 8.6 ± 1.0 vs 8.7 ± 1.1 m/s) (Figure 2); AG (3.4 ± 6.0 vs 4.9 ± 5.1 vs 7.0 ± 5.9 mm Hg); AI x75 (7.7% ± 14.7% vs 13.8% ± 15.8% vs 16.9% ± 14.1%); AI x (10.1% ± 15.2% vs 15.8% ± 15.5% vs 20.0% ± 13.5%) (Figure 3); and E w (1947 ± 3416 vs 2772 ± 2849 vs 3860 ± 3320 dyne-s/cm 2 ) were significantly higher with PVC loads (Table II). We did multivariate logistic regression analyses, adjusted by age, sex, heart rate, mean blood pressure, and a history of diabetes mellitus and hyperlipidemia, to access an independent predictor of PVC loads. Odds ratios (ORs) are expressed for a change in each factor by 1 SD. The AI x (OR 1.88, 95% CI , P =.005); AI x75 (OR 1.82, 95% CI , P =.007); AG (OR 1.57, 95% CI , P =.042); and PWVm (OR 1.53, 95% CI , P =.021) were all independent predictors of PVC loads. However, E w was only marginally statistically significantly (P =.075) associated with PVC loads (OR 1.13, 95% CI ).

4 500.e4 Chen et al American Heart Journal March 2008 Figure 3 Table II. Applanation tonometry data PVC loads: factors No (n = 83) Low (n = 58) High (n = 59) Applanation tonometry PWVm (m/s) 8.2 ± ± ± 1.1 Δtr (ms) ± ± ± 20 E w (dyne-s/cm 2 ) ± ± ± 3320 AG (mm Hg) 3.4 ± ± ± 5.9 AI x (%) 10.1 ± ± ± 13.5 AI x75 (%) 7.7 ± ± ± 14.1 Data are means ± SD. P b.05, compared with group with no PVC. P b.01, compared with group with no PVC. P b.001, compared with group with no PVC. Table III. Independent aortic stiffness predictors of PVC loads Factors ORs 95% CI P The correlation of AI x and PVC loads in the entire study population. Reproducibility of pulse wave velocity and the AI x The intraclass correlation coefficient between the 2 separate measurements of PWVm and the AI x were high (r = 0.959, P b.01, and r = 0.978, P b.01). There were no significant differences between the 2 measurements (6.37 ± 1.05 vs 6.29 ± 1.00 m/s, P =.276; mean difference 0.09 ± 0.35 m/s and 14.20% ± 10.22% vs 14.40% ± 11.08%, P =.396; mean difference 0.12% ± 0.08%). The coefficient of variation was 5.8%, calculated using a previously reported method. 19 Discussion In the present study, we showed that central aortic pressure indices and PWVm were independently associated with the occurrence of PVC loads in young persons undergoing 24-hour ambulatory ECG recordings for palpitation. To the best of our knowledge, this is the first report showing that central aortic properties in addition to the left ventricle contributed to PVC loads. Although the exact mechanisms for the linkage between PVC loads and aortic stiffness are unknown, one of the possible mechanisms is the association of PVC loads with atherosclerosis. Many studies have shown that aortic stiffness is a risk factor for cardiovascular events. 20,21 Physiologically, the stiffness of the large arteries depends on 3 main factors: structure elements within the arterial wall, such as elastin and collagen; distending pressure; and vascular smooth muscle tone. Noninvasive tests to detect individuals with atherosclerosis or aortic stiffness, preferably before they develop cardiovascular disease, may improve our ability to select patients for preventive treatments. Arterial pulse wave velocity PWVm (m/s) E w (dyne-s/cm 2 ) AG (mm Hg) AI x (%) AI x75 (%) Odds ratios are adjusted by age, sex, heart rate, mean blood pressure, diabetes mellitus, and hyperlipidemia and are expressed for a change in each factor by 1 SD. provides a more direct surrogate of arterial stiffness, 22,23 and the AI x provides a composite measure of aortic elasticity plus muscle artery stiffness and wave reflection. 24 The AI x, measured using pulse wave analysis, is used as a surrogate measure of aortic stiffness. The AI x should be interpreted as a global index of wave reflections and left ventricular additional load but not as a direct index of aortic stiffness. Age, sex, and blood pressure are known determinants of the AI x. 25,26 The central AI x is related to arterial properties through changes in pulse wave velocity. Increased aortic stiffness increases pulse wave velocity and causes the early return of the reflected wave from peripheral reflecting sites to the heart during systole, when the ventricle is still ejecting blood. 27 Central AI x is related to arterial stiffness of both elastic and muscular arteries. 27 This mechanism augments ascending aortic systolic and pulse pressures, an effect that increases aortic wall stress and potentiates the development of atherosclerosis. 27 Because both pulse wave velocity and the AI x are influenced by age, sex, heart rate, blood pressure, a history of hypertension, diabetes mellitus, and hypercholesterolemia, 25 we had to adjust these factors when doing a multivariate logistic regression analysis to find the independent predictors of PVC loads in the present study (Table III). In recent years, carotid-radial PWVm has been increasingly measured as an alternative to aortic PWV because it is easier to gain access to the vessels concerned, and the measures are simpler to perform than the standard

5 American Heart Journal Volume 155, Number 3 Chen et al 500.e5 assessment of carotid-femoral PWV. Noninvasive measures of carotid-radial PWVm correlate with the extent of coronary artery plaque volume and may be a useful noninvasive surrogate marker for the extent of coronary atherosclerosis. 28 Because aortic stiffness is greater in patients with CAD, and because it increases with CAD severity, there is a possibility that increased aortic stiffness in turn increases the elevation of left ventricular wall stress and then PVC loads. 29 Pulse wave velocity and the AI x are also related to the extent of coronary obstruction in patients with chronic kidney disease. 30 One investigation of the relation between pulse wave velocity and the quantity of coronary artery calcium in a community-based sample of adults without a prior history of heart attack or stroke found (1) that pulse wave velocity was related to subclinical coronary atherosclerosis independently of conventional risk factors and (2) that it might be a biomarker of cardiovascular risk in asymptomatic individuals. 31 Therefore, our population with high central aortic stiffness indices and pulse wave velocity might have had high PVC loads because of subclinical CAD. Pulse wave analysis for measuring arterial stiffness was valuable for predicting cardiac hypertrophy in untreated mild-to-moderate essential hypertension. 32 Augmented pressure and the AI x, assessed using radial artery applanation tonometry and pulse wave analysis, were predictors of left ventricular mass index independently of age and blood pressure measurements during 24-hour monitoring. 32 It should be noted that both wave reflection amplitude and the AI x can increase without an increase in central artery systolic pressure. These changes in pressure components increase left ventricular afterload and myocardial oxygen demand, a combination that causes an undesirable mismatch between the ventricle and arterial system (that is, ventricular/vascular coupling). 21 Indices of pulse wave analysis are better predictors of left ventricular mass reduction than cuff pressure. 13 Furthermore, high central pressure increases circumferential arterial wall stress, which causes a breakdown of medial elastin and increases the possibility of endothelial damage and the development of atherosclerosis. The E w due to wave reflection is wasted (pressure) energy the ventricle must generate during ejection and can be estimated as E w. In the present study, we found, using multivariate logistic regression analyses controlled by age, sex, heart rate, and mean blood pressure, that both PWVm and aortic stiffness indices were still significantly associated with the occurrence of PVC loads in young persons. Extra workload was only marginally associated with PVC loads. A small proportion of patients in our study population had hypertension (27/200, 13.5%). However, LVH according to ECG criteria was only marginally significantly different between different PVC load groups (Table I). It is interesting that the patients in the present study without LVH according to ECG voltage criteria also had an increased AI x, PWVm, and PVC loads, indicating increased aortic stiffness. The PVC loads might be an earlier marker than LVH for aortic stiffness in young persons. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-adrenergic receptor antagonists, and statins effectively lower blood pressure and improve arterial stiffness Drug impacts on PVC loads and arterial stiffness were insignificantly different between our study subgroups. This result connoted that PVC loads might be a surrogate marker for aortic stiffness in the early stage of atherosclerosis in a young population. Although patients with frequent PVCs may be asymptomatic or mildly symptomatic, high PVC loads might be an important marker for early aortic stiffness, which suggests that PVC load studies might be useful for guiding the aggressiveness of drug therapy in low-risk young persons. Optimal treatment of arterial stiffness and its complications should include a consideration of aortic stiffness, augmentation of aortic pressure, E w, and the loads of PVCs, all of which should be reduced to the lowest possible level. Study limitations First, our study was limited by a cross-sectional rather than a longitudinal design. However, after we used multivariate logistic regression analyses that considered all possible confounders, aortic stiffness indices were still significantly associated with PVC loads in patients undergoing 24-hour ambulatory electrocardiography. Second, we did not measure the left ventricular systolic (by ejection fraction) and diastolic performances (by tissue Doppler) or left ventricular mass and index, using echocardiography. Those measurements might have provided a reason why increased aortic stiffness leads to abnormal left ventricular systolic or diastolic performances that led to PVC loads in this study population. Finally, pulse wave velocity may be associated with sympathetic nervous activity. 36 We did not obtain the measurement of heart rate variability from 24-hour ambulatory ECG recordings. Conclusions High aortic stiffness indices may be surrogate markers of PVC loads in young patients undergoing 24-hour Holter electrocardiography due to palpitation. 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