Peter J. Osmond

Hemodynamic and central blood pressure differences between carvedilol and valsartan added to lisinopril at rest and during exercise stress

There is little information about the hemodynamic and exercise-response implications of renin-angiotensin system blocker combinations. After a 3-week lisinopril (L; 40 mg/day) run-in, carvedilol (C; 20 then 40 mg/day) or valsartan (V; 160 then 320 mg/day) was added to L for 4 weeks each in a forced-titration, random order-entry crossover study in 30 subjects. Arterial tonometry (central pressures and time-tension index, TTI); impedance cardiography (steady-state hemodynamics), and ultrasound (carotid flow) were performed at rest and during supine bicycle exercise at 30 and 60 watts. At rest, both V and C lowered TTI similarly (7% to 9%, P = .05 compared with L, in part because they lowered blood pressure (3 to 7/3 to 4 mm Hg). V lowered central systolic pressure, augmentation pressure (AP), and systemic vascular resistance (SVR, all P < .02); C lowered heart rate but not central systolic pressure or SVR. During exercise, V persistently lowered central systolic pressure, AP, and SVR, whereas C did not. Neither drug affected exercise responses or carotid blood flow. Adding V or C to an angiotensin-converting enzyme inhibitor reduced cardiac workload by different mechanisms: vasodilation and reduced central blood pressure with V and lower heart rate with C.

7B.05: DIFFERENTIAL EFFECTS NEBIVOLOL AND VALSARTAN ALONE AND IN COMBINATION ON 24-HOUR AMBULATORY RATE-PRESSURE PRODUCT, STROKE LOAD, AND BLOOD PRESSURE-HEART RATE VARIABILITY.

Objective: Beta-blockers are antihypertensive drugs indicated for treatment of cardiomyopathies but little is known about their effects on cardiac workload in the ambulatory setting. We compared the effects of the beta-blocker nebivolol (N), the angiotensin receptor blocker valsartan (V) and combined V/N on 24-hour ambulatory central rate-pressure product (ACRPP, an index of myocardial oxygen consumption rate), stroke load (SL) and blood pressure-heart rate variability (SD and coefficient of variation). Design and method: Subjects with hypertension (SBP>140 or DBP>90, n = 26 including 21 blacks) were studied in a 3-way, double-blind, randomized crossover study. After 4 weeks of each drug (V 320, N 40, or V/N 320/40 mg daily), ambulatory pulse wave analysis (IEM MobilOGraph) was performed every 20 min for 24-hour with primary (ACRPP) and secondary endpoints analyzed by sequential paired t-analysis. SL = ACRPP/heart rate. Results: The table displays the main results. All 3 treatments resulted in similar brachial and central BP values. Addition of N to V resulted in lower ACRPP: 24-hour and daytime by 11 and 14% (p < 0.001 each) and nighttime by 4% (p < 0.02). This effect was driven largely by the heart-rate slowing effects of N (by 15–18%, p < 0.001 each). SL, however, was lower with V than either N or V/N (about 10%, p < 0.001 each). Variability (standard deviation and coefficient of variation) of ACRPP and heart rate were lower with N and V/N than V. Separate analysis of blacks revealed values very similar to those of the entire treatment group. Conclusions: We conclude that 24-hour ambulatory hemodynamic monitoring is feasible in clinical trials. The rate-slowing effects of nebivolol (both N and V/N) cause lower ambulatory cardiac oxygen consumption compared to V alone but at the same time, N and V/N cause an increase in stroke load. Absolute and relative heart rate variability is higher with V than N or V/N. These results are driven primarily by the effects in blacks. Figure. No caption available.

[PP.20.10] SYSTEMIC HEMODYNAMIC COUNTER-REGULATION IN HYPERTENSION AND AGING: IMPACT OF HEART RATE

Objective: To focus on the impact of heart rate on systemic hemodynamics. Design and method: Blood pressure (BP), heart rate (HR), cardiac output (CO), stroke volume index (SVI), systemic vascular resistance (SVR) and SVR index (SVRI) were analyzed in 3 sub studies. Sub study A: 24-hour PWA (MobilOGraph, IEM, Stolberg, DE) was performed in a convenience sample (n = 65) stratified into 3 groups by systolic BP levels (<120, 120–139, > 139 mmHg) and separately stratified by age (<55, > 55 years). Sub study B: Each individual PWA was analyzed for within-individual trends in stroke volume index (SVI); these were compared to the trends obtained from comparing inter-individual means. Sub study C: Laboratory supine hemodynamics and echocardiographic parameters measured in a reference population developed in our laboratory (n = 76) stratified by age and blood pressure. Results: BP was independent of HR in all 3 sub studies, overall and for each BP or age subgroup. There were very strong inverse correlations between SVI- HR and SVRI- HR in sub studies A and C (p < 0.001 each), and within each BP subgroup in sub study A (see Figure 1). In sub studies A and C, the regression lines for SVRI- HR exhibited a parallel upward-rightward shift in proportion to the increase in mean BP for the group. Inverse SVR-HR curves were similar to the corresponding SVR-cardiac output relationships. In older individuals, strong inverse relationships of (SV-HR or SVI-HR and SVR-HR or SVRI- HR) were also present but when their individual 24-hour hemodynamic studies were analyzed (Sub study B), there was a trend toward flattening of the slope of the SVI- HR relationship with age (p = .052). Figure. No caption available. Conclusions: Heart rate is a major determinant of systemic hemodynamic counter-regulation between and within individuals. The strong inverse relationships between heart rate and both stroke volume and systemic vascular resistance must be considered in hemodynamic analyses of hypertension and cardiovascular diseases. Rate-volume counter-regulation deserves further study.

[PP.33.10] AMBULATORY HEMODYNAMIC TRENDS IN HYPERTENSION AND AGING

Objective: To compare 24-hour ambulatory blood pressure monitoring with existing laboratory methods, and to investigate the impact of BP and age on systemic hemodynamics. Design and method: Cardiac output (CO) and systemic vascular resistance (SVR) were analyzed in 3 sub studies. Sub study A: 24-hour PWA (MobilOGraph, IEM, Stolberg, DE) was performed in a convenience sample (n = 66) stratified into 3 groups by systolic BP levels (<120, 120–139, >139 mmHg) and separately stratified by age (<55, >/ = 55 years). Sub study B: Each individual PWA was analyzed for within individual trends in CO and SVR. These trends were compared to the trends obtained from Sub study A. Sub study C: supine hemodynamics and echocardiographic parameters measured in a reference population developed in our laboratory (n = 78) were compared to 24-hour PWA means(Sub study A). Results: BP was independent of CO in all 3 sub studies, overall and for each BP subgroup. Thus, there are very strong inverse relationships between 24-hour SVR and 24-hour CO for each BP group (p < 0.000 each) in each sub study, with a parallel upward-rightward shift of the respective SVR-CO isobars as BP increases. Figure 1 (left panel) shows the SVR-CO isobars for each BP group in Sub study A. Nearly identical relationships were also found in sub studies B and C. Figure 1 (right panel) demonstrates respective SVR-CO isobars for younger and older individuals, demonstrating only a rightward shift in the SVR-CO isobar. Figure. No caption available. Conclusions: 1) Hemodynamic analysis using 24-hour ambulatory PWA is feasible. 2) Sustained hypertension is associated with an upward-rightward shift of the SVR-CO isobar in proportion to the degree of BP elevation, indicating that the underlying hemodynamic abnormality in hypertension at any stage is both inappropriately high CO and inappropriate high SVR. 3) Age effects on hemodynamics are more complex.

77 VARIABLE INFLUENCE OF REFLECTED PRESSIRE WAVES ON ARM CUFF BLOOD PRESSURES IN NORMAL AND HYPERTENSIVE INDIVIDUALS

Background: The systolic pulse contour at any point along the arterial tree is the sum of the forward- and backward-traveling pressure waves at that point. In the aorta, the first systolic pressure peak (P1, the forward wave) is augmented in late systole by the returning pressure wave (P2). In the arm, there is variable amplification of P1, and P2 does not usually augment peak pressure. Methods: We investigated whether reflected pressure waves contribute to the measured peak systolic BP in the arm using standard oscillometric cuff BP measurements and radial tonometry (OMRON Hem9000AI or Sphygmocor) after 5 minutes of rest. Radial augmentation index [(P2-P1)/(P1-diastolic BP)] was calculated and a simple classification system [figure] was developed to describe P1 (forward wave) and P2 (reflected wave) relationships: Figure. No caption available. Results: Results by JNC7 hypertension stage and waveform type are shown in the table (n, %): Table. No title available. In Type B individuals (5.7%), peripheral P2 augmentation ≥ 5mmHg occurred in 43 individuals (3.5%). A model was constructed for prediction of radial AI: age>gender>1/heart rate>diastolic BP>1/height>systolic BP; multiple r = 0.738 (p<0.000). Conclusions: (1) In contrast to the aorta, reflected pressure waves in the brachial artery do not usually contribute to measured arm cuff systolic BP but reflected waves may influence the diagnosis or staging of hypertension in some people; (2) radial AI and reflected wave amplitude are related to age and BP as well as gender, heart rate, and height.

1003 IMPACT OF MEASUREMENT SITE, AGE AND BLOOD PRESSURE ON VARIATION IN PULSE WAVE VELOCITY

Background: Pulse wave velocity (PWV), a lumped arterial stiffness parameter, depends on arterial size and wall elastance, and is affected by aging and hypertension. Carotid-femoral (cf) PWV is commonly used but other PWV relationships to aging and hypertension are less well described. Methods: All subjects had supine Omron oscillometric blood pressure (BP) cuff and Colin VP2000 measurements of heart-carotid (hc), heart-femoral (hf), femoral-ankle (fa), cf and brachial-ankle (ba) PWV. The associations among PWVs, age and BP were assessed by Pearson regression coefficients and by ranking the slopes of the corresponding regression equations. Results: Ranges in 98 subjects were: age 17-83 years; systolic BP (SBP) 87-220/diastolic BP (DBP) 51-143 mmHg. PWVs were [mean (SD)]: hc 770(337), hf 941(352), cf 1180(542), fa 917(175) and ba 1288(349) cm/sec. PWV values between sites were highly inter-correlated (p < 0.000 each). The table demonstrates r-values for PWVs with age and BP components [SBP, pulse pressure (PP) and mean arterial pressure (MAP) and DBP]. The order of slope values of PWV-age relationships was: cf>hf>hc>ba>fa (range 20 to 4.5 cm/sec/yr, cf vs. fa), while all PWV-BP components followed the order: cf>ba>hf>hc>fa. Conclusions: (1) PWV values are strongly inter-correlated; (2) sensitivity to age is greatest in proximal (hc, hf, cf) and lowest in distal (fa, ba) arterial regions; (3) PWVs of muscular arteries are most sensitive to BP increases; (3) SBP more closely predicts PWV than does MAP, PP or DBP; and (4) cfPWV is most sensitive to age and BP but also has the highest variability. Table. No title available.

1004 LACK OF VARIATION IN TIMING OF FORWARD AND REFLECTED PRESSURE WAVES AT DIFFERENT AGES AND BLOOD PRESSURE LEVELS

Background: It is widely believed that reflected pressure waves return in early diastole in younger people with elastic arteries and in late systole in older people with stiffer arteries. Methods: We studied a convenience sample of 229 men (42%) and women (58%) age 15-79 with systolic BP 87-212 mmHg. Each had radial tonometry (Sphygmocor) in the sitting position with brachial-ankle pulse wave velocity (PWV, Colin VP2000). Results: The ensemble radial waveform from this group [figure] demonstrates timing (T, in ms) and amplitude of pressure (P, in mmHg) landmarks: T1/P1 = forward wave, Tr = foot of reflected wave, T2/P2 = peak of primary reflected wave, ED = ejection duration, and DP1/DT1 = early diastolic pressure peak; the table demonstrates the mean, standard deviation, and range of values for each landmark (ms): Figure. No caption available. Inverse correlations between PWV and Tr (r = -0.41, p < 0.002) or T2 (r = -0.51, p < 0.000) were present but in all cases, T2 occurred late systole, with remarkable consistency of waveform patterns across all ages and systolic BP levels. PWV correlated most strongly with P2 amplitude (r = 0.83, p < 0.000). Conclusions: The timing of the forward wave (∼100 ms), primary reflected wave (∼200 ms), and early diastolic pressure (∼400 ms) peaks is relatively fixed, irrespective of age and blood pressure. This predictability strongly suggests that these pressure landmarks are conserved physiologic phenomena, perhaps designed to support antegrade cerebrovascular flow.

556 AMBULATORY RATE-PRESSURE PRODUCT DIFFERENCES BETWEEN CARVEDILOL AND VALSARTAN ADDED TO LISINOPRIL

Background: Guidelines recommend combining &bgr;-blockers and ACE inhibitors in high-risk heart disease but not in the initial treatment of hypertension. The mechanism of this benefit however, has not been determined. Methods: After 3 weeks of lisinopril (L, 40 mg/day) run-in, 30 subjects entered a single-blinded, forced-titration, crossover study where carvedilol (C, 20 then 40 mg/day) or valsartan (V, control renin-angiotensin blocker, 160 then 320 mg/day) were added to L for 4 weeks. Ambulatory blood pressure (ABP) and heart rate (HR) monitoring (Spacelabs 90207) was performed at the end of each period. Rate-pressure product (RPP, systolic BP x HR, an indicator of cardiac O2 consumption), was measured over 24-hour, daytime (6 AM to midnight) and night-time (midnight to 6 AM) periods. Variability (standard deviation, SD, and range) of RPP, BP and HR were calculated. Results: Mean 24-hour systolic BP was ∼8 mmHg lower when V or C was added to L (p < 0.01 each). HR was consistently lower with C (8 beats/min/24 hours, p < 0.000) and slightly increased with V (∼2 beats/min, pNS). Consequently, C lowered RPP to a greater degree than V during daytime, night-time, and 24-hour (∼8 vs ∼2%) periods (p < 0.000 each). Additionally, RPP variability (SD but not range) was consistently lower with C than V (p < 0.000). Conclusion: When added to lisinopril, carvedilol reduces the mean and variability (SD) of 24-hour cardiac workload (and heart rate) to a greater degree than valsartan. We speculate that these effects may contribute to outcome benefits observed with &bgr;-blocker-ACE inhibitor combinations.