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1 Mini Forum for Hypertension Acta Cardiol Sin 2013;29:19 27 Effects of Anti-Hypertensive Monotherapy with Either Calcium Channel Blocker or Angiotensin Receptor Blocker on Arterial Stiffness, Central Hemodynamics, and Ventriculo-Arterial Coupling in Uncomplicated Hypertension Patients Heng-Hsu Lin, 1 Chia-Sung Wang, 2 Jiunn-Lee Lin, 3 Juey-Jen Hwang 3 and Lian-Yu Lin 3 Objectives: This study is designed to investigate the effects of anti-hypertensive monotherapy [either calcium channel blocker (CCB) or angiotensin receptor blocker (ARB)] on pulsatile hemodynamic parameters in patients with uncomplicated hypertension. Methods: This is a longitudinal observational study. For simplicity, we included patients with uncomplicated hypertension who received mono anti-hypertensive therapy with ARB or CCB. Hemodynamic parameters including central arterial pressure (CAP), aortic characteristic impedance (Zc), augmentation index (AI), brachial-ankle pulse wave velocity (bapwv), heart-ankle pulse wave velocity (hapwv), cardiac ultrasonographic parameters and ventriculo-arterial (VA) coupling were measured before, 1 month and 3 months after treatment. Results: A total of 74 subjects were included in our study for analysis from Systolic blood pressure (SBP), diastolic blood pressure (DBP), and central systolic arterial pressure (CSAP) were significantly reduced 1 and 3 months after initiation of therapy. Among the pulsatile hemodynamic parameters, only the bapwv was significantly reduced (from cm/s to cm/s to cm/s, p for trend = 0.016). The hapwv only decreased with borderline significance (from cm/s to cm/s to cm/s, p for trend = 0.041). The other pulsatile hemodynamic parameters remained unchanged before and after therapy. Subgroup analysis (age above or below 52 years) showed that the bapwv was significantly reduced only in the younger group. Conclusions: Among the pulsatile hemodynamic parameters, only the bapwv was effectively reduced by either CCB or ARB. The improvement of PWV was more evident in younger subjects. Key Words: Arterial stiffness Central arterial pressure Hypertension Pulse wave velocity Ventriculo-arterial coupling INTRODUCTION Received: October 8, 2012 Accepted: December 26, Cardiovascular Center, Far Eastern Memorial Hospital; 2 Department of Internal Medicine, En Chu Kong Hospital; 3 Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan. Address correspondence and reprint requests to: Dr. Lian-Yu Lin and Juey-Jen Hwang, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chuan-Shan S. Road, Taipei, Taiwan. Tel: ext ; Fax: ; Large conduit arterial pressures are pathophysiologically more relevant than peripheral pressure for the pathogenesis of cardiovascular diseases. 1 In the Anglo- Scandinavian Cardiac Outcomes Trial (ASCOT), the calcium channel blocker (CCB)/angiotensin-converting enzyme inhibitor (ACE-I) combination was more effective than a combination of -blocker and thiazide diuretic 19 Acta Cardiol Sin 2013;29:19 27

2 Heng-Hsu Lin et al. for decreasing cardiovascular events in hypertensive patients. 2 The Conduit Artery Function Evaluation (CAFÉ), a sub-study of the ASCOT, showed that such benefits may be attributed to a greater reduction of the central rather than the brachial systolic blood pressure (SBP) in subjects receiving CCB/ACE-I combination therapy. 3 The CAFÉ Study has provided an explanation for various clinical trials showing clinical benefits beyond peripheral blood pressure (BP) control by using new anti-hypertensive agents. 4,5 The elastic property of the large conduit arteries provides an important buffering function for the pulsatile pumping of the left ventricle. The amplitude of the pressure waves in the normal conduit arteries is only modestly increased by a given flow. Also, pressure waves travel along the normal conduit arteries at relatively low speeds, so that reflecting waves from the peripheral arteries return to the heart and augment the pressure waves in the diastolic period, which further minimizes pulse pressures. 6 In patients with advanced age or disease processes, stiffening of the large conduit arteries impairs the buffering function, increases pulse wave traveling speed, worsens ventriculo-arterial (VA) coupling, and is probably the major pathophysiology for the development of heart failure in the elderly. 7 Conventionally, the stiffness of the large arteries is assessed by pulse wave velocity (PWV). However, the brachial-ankle pulse wave velocity (bapwv) does not cover the central aorta where the major portion of the buffering function of the large conduit vessels originates, and the central aorta only contributes in minor part regarding the distance measured by heart-ankle pulse wave velocity (hapwv). Mitchell et al. reported that characteristic impedance (Zc), which was calculated by taking the ratio of change in pressure and change in flow of the proximal aorta during early systole before return of the reflected pressure wave, was an important determinant of left-ventricular load during ejection, and it was elevated out of proportion to the increase in PWV in subjects with systolic hypertension. 8 Thesamegroup also found that increased Zc arising from reduced aortic diameter is the main mechanism leading to elevated pulse pressure in the elderly. 9 These findings have supported the belief that Zc should be incorporated into the analysis of central hemodynamics. The effects of different anti-hypertensive drug classes on arterial stiffness and central arterial pressure have been investigated through numerous studies However, most of them used combination treatments and included subjects with multiple co-morbidities, which might complicate the analyses. A study based on monotherapy in subjects with uncomplicated hypertension has not been reported. Our intention was to study the effects of monotherapy on central hemodynamics, PWV and VA coupling in subjects with uncomplicated hypertension. METHODS Study population and intervention This is an observational study. Subjects with hypertension (defined as BP 140/90 mmhg noted in over 80% of examinations over past 2 months) were consecutively included from the outpatient clinic of National Taiwan University Hospital from Attending physicianswerefreetoprescribethefirst-lineanti-hypertensive medications for these subjects. We included subjects who received monotherapy with angiotensin receptor blocker (ARB) or CCB (all received amlodipine) for further study. For simplicity, all study subjects were in sinus rhythm, and patients with diabetes mellitus, dyslipidemia, stroke, heart failure, chronic renal failure, valvular heart disease, pacemaker implantation, or clinically significant peripheral vascular disease were all excluded. After we obtained informed consents, subjects were asked to discontinue their anti-hypertensive medications for one week before the baseline hemodynamic study. Subsequently, the dosages of the anti-hypertensive medications were adjusted every month to keep BP < 140/90 mmhg. Hemodynamic evaluation was repeated at 1 month and 3 months for each subject. The protocol was reviewed and approved by the Ethical Committee of the National Taiwan University Hospital. Pulse wave velocity, augmentation index The BP, PWV and augmentation index (AI) were measured for each subject in a supine position after 5 minutes of rest using an automatic waveform analyzer (Colin VP-2000, Omron Inc., Japan). The instrument simultaneously recorded right and left brachial and tibial Acta Cardiol Sin 2013;29:

3 Anti-Hypertensive Monotherapy in Uncomplicated Hypertension arterial pressure wave forms, lead I of the electrocardiogram, and a phonocardiogram. A carotid tonometry sensor incorporating an array of 15 micropiezoresistive transducers was coupled with this device to measure common carotid arterial pressure wave. Occlusion cuffs, which were connected to both plethysmographic and oscillometric sensors, were placed around both arms and ankles of subjects for pulse wave analysis and BP measurements. The time difference between the brachial and ankle arterial pressure wave was determined by the wave front velocity theory. The distance between the arm and ankle is calculated based on anthropometric data for the Japanese population. Finally, the bapwv is calculated by dividing the distance with the time difference. The hapwv was estimated by a similar method. The AI was examined by analysis of the right common carotid arterial pressure wave. The common carotid arterial pressure wave was measured by using a multi-element tonometry sensor and the pressure signal was digitized at 1200 Hz. After identification of the early and late systolic peaks and the inflection point that separated them, we measured the height of the shoulder and the height above the shoulder of the late systolic peak attributable to the return of wave reflections from reflecting sites. The ratio of the height above the shoulder to the carotid pulse pressure defined the AI, which is used to estimate the effect of wave reflections in central arteries. Echocardiographic parameters, central arterial pressure and characteristic impedance Two dimensional, echocardiographic left ventricular (LV) end diastolic volume (EDV) and end systolic volume (ESV) were measured by using the biplane Simpson's method, and the ejection fraction (EF) was then calculated (GE Vivid 7, GE Medical Systems, USA). The mean of three consecutive cardiac cycles was used for each measurement. The diameter of the left ventricular outflow tract from the trailing edge to the leading edge was measured, and the orifice area was calculated assuming a circular orifice. Left ventricular outflow tract velocity was measured by Doppler echocardiography and was analyzed off-line by a program written in MATLAB language (version 6.1; MathWorks Inc., Natick, Massachusetts, USA). About 3 flow spectra were signal-averaged using the ECG as a fiducial point. Each point on the flow velocity waveform was multiplied by orifice area to generate a volume flow waveform. All Doppler echocardiographic assessments were performed by a single echocardiographer. Right common carotid pressure wave was digitized at 1200 Hz and was analyzed off-line by MATLAB. Approximately 5 pressure waves were averaged by using the ECG as a fiducial point. Central arterial pressure (CAP)wasderivedfromrightcommoncarotidpressure wave by assuming equivalence of mean and diastolic blood pressure (DBP) at the carotid and brachial sites. 13 FromtheCAPwaveform,wealsocalculatedcentral pulse pressure (PPc) by subtracting CAP from DBP. The PPc could be further divided into two components (see Figure 1). The first is augmented pressure (AP) which was derived by timing PPc with AI. AP represented the magnitude of reflective pressure wave. The second is incident pressure (P1h) which was calculated by PPc minus AP. P1h represented the magnitude of forward pressure wave. ThetimedomainZcwasestimatedbyusingtheCAP and the volume flow waveforms as previously described. 14 Ventriculo-arterial coupling By using the end-systolic pressure-volume relation (Ees) to define LV chamber elastance and the endsystolicpressure-strokevolumerelationtodefineeffective arterial elastance (Ea), the interaction of Ea and Ees Figure 1. The figure illustrates how to calculate augmented pressure (AP), incident pressure (P1h) and their relationship to central pulse pressure (PPc) and augmented index (AI). 21 Acta Cardiol Sin 2013;29:19 27

4 Heng-Hsu Lin et al. (the ventriculo-arterial coupling) would be useful for characterizing LV pump function under varying loading conditions,andbothofwhichcouldbecalculatednoninvasively 7,15,16 (See Figure 2). Ees and Ea are often equal in absolute magnitude, a combination yielding optimal and efficient matching of heart and artery. However, the elderly patient displays marked increases in both elastances, with Ea reflecting vascular stiffening and Ees reflecting left ventricle stiffening. Higher ventricular and arterial stiffness has important implications to BP liability and loading sensitivity. A changed preload results in only a modest decline in SBP in younger individuals but a much greater change in older ones. In the present study, we derived Ees and Ea noninvasively by using the single beat method. 16 The VA coupling was expressed by Ea/Ees. 17 Statistics All data were expressed as mean standard deviation. Repeated measures analysis of variance (ANOVA) was performed to evaluate the therapeutic effects on various hemodynamic parameters. When ANOVA results were significant, post-hoc tests of the differences among serial hemodynamic parameters (baseline, 1 and 3 months after treatment) were performed by the least significant difference (LSD). Multiple linear regression analyses were used to determine the predictors for pulsatile hemodynamic parameters. A p value < 0.05 was considered significant. RESULTS A total of 74 patients were included in our study. Among them, 23 subjects received valsartan (80 to 160 mg dose daily), 11 received candesartan (4 to 8 mg daily),6receivedolmesartan(20to40mgdaily)and33 subjects received amlodipine (5 to 10 mg daily). Table 1 summarized the baseline demographics data, the hemodynamic parameters, and anthropometric parameters prior to, 1 month, and 3 months after the initiation of antihypertensive therapy. The anthropometric parameters including body mass index (BMI) and waist, LVEF and left ventricular mass (LVM) remained unchanged after 3 months of antihypertensive treatment. Both SBP and DBP were significantly decreased (from Figure 2. The figure illustrates the end-systolic elastance (Ees) and effective arterial elastance (Ea) on LV pressure-volume loop / mmhg to / mmhg to / mmhg, p for trend < 0.001) after 3 months of antihypertensive therapy. We found that the central systolic arterial pressure (CSAP) (from mmhg to mmhg to mmhg, p for trend < 0.001) and the PPc (from mmhg to mmhg to mmhg, p for trend = 0.010) also decreased significantly. Also shown in Table 1, the bapwvs were significantly decreased (from cm/s to cm/s to cm/s, p for trend = 0.016). The changes of hapwv had borderline significant difference during the treatment course (from cm/s to cm/s to cm/s, p for trend = 0.41). Other pulsatile arterial stiffness parameters including AI, AP, P1h, and Zc were not significantly changed after therapy. The VA coupling indicators, Ees, Ea and Ea/Ees also did not change during the three-month treatment. In Table 2, we divided our study subjects into two groups according to their median age (above or below 52 years old). In younger subjects, there were significant changes of SBP (from mmhg to mmhg to mmhg, p for trend < 0.001), DBP (from mmhg to mmhg to mmhg, p for trend = 0.001), CSAP (from mmhg to mmhg to mmhg, p for trend < 0.001), PPc (from mmhg to mmhg to Acta Cardiol Sin 2013;29:

5 Anti-Hypertensive Monotherapy in Uncomplicated Hypertension Table 1. Hemodynamic and anthropometric parameters before, 1 month and 3 months after initiation of antihypertensive therapy (N = 74) Baseline 1 mon 3 mon p for trend Age, yr Gender, M/F 42/32 BMI, kg/m Waist, cm SBP, mmhg * * < < DBP, mmhg * * < < CAP, mmhg * * < < PPc * * LVEF, % LVM, g bapwv, cm/s * * hapwv, cm/s * AI, % AP, mmhg P1h, mmhg Zc, dyne.sec/cm Ees, mmhg/cm Ea, mmhg/cm Ea/Ees AI, augmentation index; AP, augmented pressure; bapwv, brachail-ankle pulse wave velocity; BMI, body mass index; CAP, central arterial pressure; DBP, diastolic blood pressure; Ea, effective arterial elastance; Ees, end-systolic elastance; hapwv, heart-ankle pulse wave velocity; LVEF, left ventricular ejection fraction; LVM, left ventricular mass; SBP, systolic blood pressure; P1h, incident pressure wave; Zc, characteristic impedance. * p < 0.05 compared with baseline. mmhg, p for trend = 0.016) and bapwv (from cm/s to cm/s to cm/s, p for trend = 0.015). In older subjects, SBP (from mmhg to mmhg to mmhg, p for trend = 0.035), DBP (from mmhg to mmhg to mmhg, p for trend = 0.038) and CSAP (from mmhg to mmhg to mmhg, p for trend = 0.005) also declined significantly. But unlike younger patients, bapwv and PPc did not change after treatment. As for other hemodynamic parameters, there was no significant change after treatment in both groups. We tested the relative contribution of the basic demography, medical usage and the changes of SBP and DBP to the changes of pulsatile hemodynamic parameters after 3 months of treatment by multiple linear regression analyses. The results were shown in Table 3. The change of bapwv was significantly related to the change of SBP ( coeff. = , p = 0.006). There was of borderline significance in that the usage of CCB, in comparison with ARB, could reduce bapwv more evidently ( coeff. = , p = 0.034). The change of hapwv was positively associated with the change of SBP ( coeff. = , p = 0.004) and DBP ( coeff. = , p = 0.038). The change of CAP was significantly associated with male gender ( coeff. = , p = 0.015), the change of SBP ( coeff. = , p < 0.001), but inversely associated with the change of DBP ( coeff. = , p < 0.001). The change of PPc was significantly associated with the change of SBP ( coeff. = , p < 0.001) and male gender ( coeff. = , p = 0.015). Although the change of Zc was not associated with any of the independent variables, the Zc itself was only positively associated with elder age (data not shown). DISCUSSION In recent years, there has been an increasing inter- 23 Acta Cardiol Sin 2013;29:19 27

6 Heng-Hsu Lin et al. Table 2. Hemodynamic and anthropometric parameters before, 1 month and 3 months after initiation of antihypertensive therapy with age below and above 52 years old Baseline 1 mon 3 mon p for trend 52 years old (N: 37) SBP, mmhg * * DBP, mmhg * * CAP, mmhg * * bapwv, cm/s hapwv, cm/s AI, % PPc, mmhg AP, mmhg P1h, mmhg Zc, dyne.sec/cm Ees, mmhg/cm Ea, mmhg/cm Ea/Ees < 52 years old (N: 37) SBP, mmhg * *0 < < DBP, mmhg * * CAP, mmhg * * < < bapwv, cm/s * * hapwv, cm/s AI, % PPc, mmhg AP, mmhg P1h, mmhg Zc, dyne.sec/cm Ees, mmhg/cm Ea, mmhg/cm Ea/Ees AbbreviationsasTable1. * p < 0.05 compared with baseline. Table 3. Multiple linear regression analyses to find the determinants for changes of central hemodynamic and arterial stiffness parameters after 3 months of antihypertensive treatment bapwv hapwv CAP PPc Age coeff p value (0.664) (0.890) (0.176) (0.176) Gender coeff p value (0.846) (0.271) (0.015) (0.015) SBP coeff p value (0.006) (0.004) (< 0.001) (< 0.001) DBP coeff p value (0.583) (0.038) (0.404) (< 0.001) CCB Usage coeff p value (0.034) (0.503) (0.786) (0.786) R AbbreviationsasTable1. Acta Cardiol Sin 2013;29:

7 Anti-Hypertensive Monotherapy in Uncomplicated Hypertension est in the role of arterial stiffening in the development of cardiovascular disease. However, there is limited data concerning the effects of mono antihypertensive therapy on detailed pulsatile hemodynamic parameters in patients with uncomplicated hypertension. We found that modern antihypertensive agents (ARB and CCB) could not only reduce SBP and DBP, but also reduce CSAP effectively. This is consistent with the findings of the CAFÉ study, 3 which showed that the improved cardiovascular protective effects of the CCB/ACE-I combination may be attributed to a greater reduction of central rather than brachial systolic blood pressure. We found that the improvement of PWV was more evident in younger subjects after antihypertensive treatment while Zc and P1h remained unchanged. Our current study also showed that Zc is strongly correlated to age. Previous studies have demonstrated that aortic pressure waveform is a combination of forward pressure wave and reflective pressure wave. 18,19 Aortic systolic and pulse pressure rise with age and in hypertensive subjects because of aortic stiffening. There are two factors responsible for this: first, a larger forward pressure wave, because of increased aortic characteristic impedance (Zc); and second, a premature return of the reflected pressure wave from peripheral sites secondary to increased PWV. Zc governs the pressure-flow relationship in the proximal aorta until the first pressure wave reflection. Data presently available suggest that the major changes of aortic structure that cause age-related stiffening are degenerative and structural. 20,21 The underlying mechanism is probably that the aorta progressively stiffens with age due to cyclic strain, causing fracture of elastin lamellae in the tunica media and fibrous remodeling of the aortic wall. 20,21 Since these structural changes of the aorta are aging processes, it is plausible that they respond poorly to medical therapy. Wave reflection is another issue for management of hypertension. The guideline of the European Society of Hypertension for the management of arterial hypertension has indicated that PWV should be used as a surrogate marker for sub-clinical target organ damage. 22 A recent meta-analysis also supported this notion and suggested that PWV should be applied in clinical practice. 23 In our study, we found that PWV was significantly reduced within three months after the initiation of antihypertensive agents, and that this protective effect was diminished in older patients. Several studies have demonstrated that CCB and ACEI/ARB could reduce PWV effectively, thereby reducing arterial stiffness. 10,24,25 This finding probably resulted from a change in terminal peripheral resistance, and stiffness of small muscular conduit arteries after use of antihypertensive agents. Dilation of the muscular arteries, even without change in peripheral resistance, can also exert a substantial effect on wave reflection, and thereby reduce aortic systolic pressure (and late systolic ventricular loading) by up to 20 mmhg without a corresponding reduction in brachial or radial systolic pressure. 3,11,26 These could also explain why the CAFÉ study 3 found that the beneficial cardiovascular effects of new drugs may not be apparent from the measurement of peripheral blood pressure. One recent study had proven that age-related increase of wave reflection is important across the life span. 27 Because the aging process is already involved in elevating PWV, our study could not demonstrate the beneficial effect of monotherapy in terms of PWV for just three months in the older group. Our study also showed no significant change of VA coupling during antihypertensive therapy. Ea and Ees are reported to be increased in hypertensive patients compared with normotensive controls. 28,29 Normally Ea/Ees is matched for maximal efficiency at rest, and not for maximal cardiac work. In healthy humans, the optimal range of Ea/Ees to cardiac efficiency generally ranges from 0.50 to 0.73, 15,30 which is very close to the values of our patients. In contrast to our finding, one previous study has shown that ACEI, ARB, and CCB could improve VA coupling by decreasing Ea/Ees, while other anti-hypertensive agents such as diuretics, -blockers, and -blockers significantly increase Ea/Ees after 6- month active therapy. 31 Another study also showed that optimal brachial and CAP reduction shifts VA coupling from cardiac output maximization to ventricular mechanical efficiency optimization. 17 The discrepancy might be due to the relatively younger and uncomplicated natures of our patients, and whose VA coupling was normal before medical intervention. A relatively short treatment period, compared with previous studies, 17,31 might be another cause that resulted in negative findings on VA coupling in our study. There are some limitations to this study. First, the main limitation of this study is the small study popula- 25 Acta Cardiol Sin 2013;29:19 27

8 Heng-Hsu Lin et al. tion. Second, this is an observational study which lacks a control group. Another limitation is the relatively short treatment period (three months). Though some studies 32,33 reported that significant changes of PWV and Zc were observed by weeks of active therapy, a longer period of treatment is mandatory to detect some subtle functional and structural changes, and to provide further prognostic information. CONCLUSION In conclusion, we showed that in patients with uncomplicated hypertension, modern antihypertensive agents (either CCB or ARB) could effectively reduce arterial stiffness as assessed by bapwv, while Zc, and VA coupling parameters remain unchanged. The improvement of PWV was more evident in younger subjects. REFERENCES 1. Agabiti-Rosei E, Mancia G, O'Rourke MF, et al. Central blood pressure measurements and antihypertensive therapy: a consensus document. Hypertension 2007;50: Dahlof B, Sever PS, Poulter NR, et al. 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