CLINICAL STUDIES
Verapamil acutely reduces ventricular-vascular stiffening and improves aerobic exercise performance in elderly individuals
Chen-Huan Chen, MDa,1,
Masaru Nakayama, MD, PhDa,
Maurice Talbot, RNa,
Erez Nevo, MD, DSca,
Barry Fetics, BEa,
Gary Gerstenblith, MDa,
Lewis C. Becker, MDa and
David A. Kass, MDa
a Division of Cardiology, Department of Medicine and Department of Biomedical Engineering, Johns Hopkins University Medical Institutions, Baltimore, Maryland, 21287, USA
Manuscript received June 26, 1998;
revised manuscript received December 1, 1998,
accepted January 20, 1999.
Reprint requests and correspondence: Dr. David A. Kass, Halsted 500, Division of Cardiology, The Johns Hopkins Hospital, 600 N Wolfe Street, Baltimore, Maryland 21287
dkass{at}eureka.wbme.jhu.edu
 |
Abstract
|
|---|
OBJECTIVES
We tested the hypothesis that acute intravenous verapamil acutely enhances aerobic exercise performance in healthy older individuals in association with a combined reduction of ventricular systolic and arterial vascular stiffnesses.
BACKGROUND
Age-related vascular stiffening coupled with systolic ventricular stiffening may limit cardiovascular reserve and, thus, exercise performance in aged individuals.
METHODS
Nineteen healthy volunteers with mean age 70 ± 10 years underwent maximal-effort upright ergometry tests on two separate days after receiving either 0.15 mg/kg i.v. verapamil or 0.5 N saline in a double-blind, randomized, crossover study.
RESULTS
Baseline vascular stiffness, indexed by arterial pulse-wave velocity (Doppler) and augmentation index (carotid tonometry) declined with verapamil (–5.9 ± 2.1% and –31.7 ± 12.8%, respectively, both p < 0.05). Preload-adjusted maximal ventricular power, a surrogate for ventricular end-systolic stiffness, also declined by –9.5 ± 3.6%. Peripheral resistance and peak filling rate were unchanged. With verapamil, exercise duration prior to the anaerobic threshold (AT) increased by nearly 50% (260 ± 129 to 387 ± 176 s) with a corresponding 13.4 ± 4.7% rise in oxygen consumption ( O2) at that time (both p < 0.01). Total exercise duration prolonged by +6 ± 2.7% (p < 0.05) with no change in maximal O2. Baseline cardiodepression from verapamil reversed by peak exercise with net increases in stroke volume and cardiac output (p < 0.05).
CONCLUSIONS
Acute intravenous verapamil reduces ventriculovascular stiffening and improves aerobic exercise performance in healthy aged individuals. This highlights a role for heart-arterial coupling in modulating exertional capacity in the elderly, suggesting a potentially therapeutic target for aged individuals with exertional limitations.
|
Abbreviations and Acronyms
| | AI | = augmentation index | | AT | = anaerobic threshold | | Ea | = effective arterial elastance | | EDV | = end-diastolic volume | | Ees | = end-systolic elastance | | EF | = ejection fraction | | ESV | = end-systolic volume | | Pes | = end-systolic pressure | | PFREDV | = peak filling rate/EDV | | Psys | = arterial systolic pressure | | PWRmax | = maximal power | | PWV | = pulse wave velocity | | SV | = stroke volume | | O2· | = maximal oxygen consumption |
|
Aerobic capacity declines with age (1), with exertional fatigue and frailty often occurring in the absence of cardiac or peripheral vascular ischemia (2). Several age-related cardiovascular changes may contribute to such altered exercise physiology (1). One potentially important factor is arterial stiffening (3–5), which increases pulsatile and nonpulsatile components of vascular load (5) imposed on the heart, resulting in systolic hypertension and enhanced systolic wave reflections (1,3–5). We recently reported that left ventricular systolic stiffness (i.e., end-systolic elastance, [Ees]) also increases with age, matching cardiac function to the altered arterial load (6). Coupling a stiff heart in systole with a stiff arterial system impedes the transfer of increased stroke volume (SV) from heart to artery without concomitant substantial increases in pressure load, which in turn can feed back to inhibit cardiac ejection. Furthermore, a less stiff heart and vasculature can better accommodate reduced end-systolic volumes (ESV), whereas stiffer properties may contribute to a greater reliance on preload reserve in the elderly (7,8).
If combined ventricular-vascular stiffening limits exertional tolerance, then agents such as verapamil, which lower both end-systolic stiffness (9) and arterial stiffness (10), might improve exercise capacity. In particular, more effective ventricular-to-vascular interaction could enhance SV and cardiac output reserve, prolonging aerobic exercise duration. The present study tested this hypothesis in healthy elderly subjects.
|
Methods
|
|---|
Control subjects.
Twenty-four healthy volunteers aged 50 to 90 years were recruited from the general public. Control subjects with coronary or peripheral vascular ischemia, significant valvular regurgitation or stenosis, prior myocardial infarction, atrial fibrillation and those unable to withhold vasoactive medications for at least 24 h prior to study were excluded. Informed consent was obtained from each subject and the protocol approved by the Joint Committee on Clinical Investigation of the Johns Hopkins Medical Institutions. Three control subjects developed significant asymptomatic electrocardiographic ST segment depression with regional wall motion abnormalities on radionuclide ventriculography during exercise, while two subjects failed to complete the protocol (allergic reaction to verapamil, failure to return for follow-up). Data are reported from the remaining 19 subjects, comprised of 10 men and 9 women with a mean age 67.4 ± 10.5 years (range 50–84). Three individuals had hypertension treated with an angiotensin converting enzyme inhibitor, angiotensin II receptor blocker, or alpha1-blocker. No subject was treated with a Ca2+-channel blocker.
Study design.
We used a double-blind, randomized, placebo-controlled crossover design. Verapamil (0.15 mg/kg) or saline control (0.5 N NaCl-D5W) was injected i.v. in 5 mL over 5 min. Baseline cardiac and vascular properties were obtained (detailed below) in the supine position prior to and 15 min after the infusion. Maximal effort upright bicycle ergometry was then performed. Cardiac volumes, arterial pressures and several derived indexes of cardiovascular function were measured immediately before and during each stage of exercise. Each control subject returned for a second study one to seven days later, using the identical protocol but with the alternative agent.
Vascular measurements.
Carotid tonometry, transcutaneous Doppler flow velocity and noninvasive calibrated central arterial pressure assessed arterial vascular properties. Carotid applanation tonometry was performed with a hand-held transducer (SPC-350, Millar Instruments, Houston, Texas) (11). Signals were digitized at 200 Hz, and the ratio of pressure rise after the midlate systolic inflection to the total pulse pressure (augmentation index [AI]) (12,13) was determined. The inflection point was identified from zero-crossing timings of the fourth derivative of the pressure signal (14). Doppler flow signals (2.0 MHz nonimaging transducer, CFM 800, Vingmed Sound, Norway) were measured in the ascending aorta or right carotid artery and right femoral artery along with simultaneous electrocardiogram. The time from the R wave of the QRS complex to the foot of each flow wave (15,16) was subtracted to yield propagation time, and aortic pulse wave velocity (PWV) was the external distance between the suprasternal notch and right femoral pulse divided by this time.
Noninvasive calibrated central arterial pressures were measured using an improved version of a previously validated device (17). This system consisted of a computer-controlled sphygmomanometric arm cuff with an internal transducer to measure cuff pressure, dual microphones over the brachial artery at the antecubital fossa and an electrocardiographic monitor. The cuff was inflated above systolic pressure and then deflated at 2 to 3 mm Hg/beat. During deflation, Korotkoff sounds were recorded and the time delay between the ECG-R wave and the Korotkoff sound determined as a function of cuff pressure. This time delay combined cardiac electromechanical delay, flow transit time from aorta to brachial artery and the time for arterial pressure to exceed cuff pressure. This last component declined with cuff pressure, so plotting cuff pressure versus time delay produced the upstroke portion of the arterial waveform. A prior version of this system employed a Doppler transducer to signal the onset of brachial flow (17); however, maintaining persistent flow signals during exercise was problematic. In contrast, detection of Korotkoff sounds was less sensitive to exact dual microphone positioning and was more reliable during exercise.
The effective arterial elastance (Ea) was also determined as a measure of total vascular load. Both mean and pulsatile components of arterial impedance are manifest in Ea, and it has been shown to quantify influences of vascular loading on heart function in intact patients better than does mean resistance (18). Effective arterial elastance is equal to the ratio of end-systolic pressure (Pes) to SV. End-systolic pressure may be estimated by 0.9·arterial-systolic pressure (Psys) (18), so that Ea = 0.9·Psys/SV. Psys was arterial systolic pressure. Stroke volume was determined from radionuclide ventriculography.
Cardiac measurements.
Gated technetium99m pertechnetate radionuclide ventriculography blood pool scans were obtained in the left anterior oblique orientation at 32 frames/cycle at rest in the supine position before and after drug administration. Scans were gated at 16 frames/cycle during exercise. Time-activity curves from identified regions of interest were calibrated for ventricular volume using a count-based method with peripheral blood sampling to determine counts per mL of a reference volume and with correction for attenuation of left ventricular counts (19). In addition to providing ESV, end-diastolic volume (EDV), SV and ejection fraction (EF), time-activity curves were fit to a four-term Fourier series that was analytically differentiated to yield flow (20).
Left ventricular power equalled the product of ascending aortic pressure and ventricular systolic flow. Signals were adjusted so the onset of flow and the arterial end-diastolic pressure were synchronous. Maximal power (PWRmax) was the peak pressure-flow product. Maximal power varies with preload volume but is relatively insensitive to arterial load (20,21), and PWRmax/EDV has been shown to be both pre- and afterload insensitive in normal sized hearts (22). Importantly, changes in preload-adjusted PWRmax correlate with those of chamber end-systolic stiffness (20) (i.e., Ees), but unlike Ees, PWRmax can be measured noninvasively during exercise (22). In the present study, PWRmax/EDV was used as a surrogate for Ees changes.
Cardiopulmonary exercise testing.
Maximal effort upright bicycle exercise was performed, starting at a 25 W, and increasing 25 W every three minutes until exhaustion. Standard 12-lead electrocardiographic monitoring was performed. Breath-by-breath levels of oxygen consumed (O2) and carbon dioxide produced (CO2) were measured (CPX, MedGraphics, St. Paul, Minnesota). Maximal oxygen consumption at the anaerobic threshold (AT) (23) was determined by the V-slope method (24) and peak O2 defined as the mean value over 15 s prior to termination of exercise. Exercise capacity was assessed by total exercise duration, time-to-reach AT, O2 at the AT and maximal O2. Gated blood pool acquisitions were obtained during the last 2.5 min of each 3-min exercise load, and noninvasive central arterial pressures were recorded during the last minute of each stage.
Statistical analysis.
Data are presented as mean ± SD. Within subject effects comparing verapamil to saline infusion before and after infusion at rest and during exercise, between intervention studies and their interaction (i.e., different responses between verapamil vs. placebo) were tested by a repeated measures one-way analysis of variance. Post-hoc tests between individual means were then performed using Tukey’s test for multiple comparisons. Differences of baseline hemodynamics and exercise capacity between the two studies were compared by Student’s two-tailed paired t test.
|
Results
|
|---|
Baseline data and response to verapamil.
Table 1 provides baseline data for each of the two sequential studies. There were no significant differences in any parameter. Arterial systolic pressure averaged 140 ± 10 mm Hg and arterial pulse pressure 66.7 ± 19.7 mm Hg, consistent with age-related vascular changes (25).
Figure 1 compares the effects of verapamil with saline control on resting cardiovascular function. Verapamil lowered AI of the carotid pulse, slightly increased LV volumes and lowered PWRmax. Augmentation index declined from 25 ± 1 to 19 ± 14% (–32 ± 13%, p < 0.05), PWV declined from 905 ± 192 to 847 ± 173 cm/sec (–5.9 ± 2.1%, p < 0.05), and PWRmax/EDV declined from 6.04 ± 1.19 to 5.38 ± 1.13 watts/mL (–9.5 ± 3.6%, p < 0.05). Compared with saline, verapamil also lowered Psys (141 ± 16 to 136 ± 16 mm Hg) but not mean pressure, Ea (1.38 ± 0.21 to 1.35 ± 0.18 mm Hg/mL), EF (69 ± 8 to 67 ± 7%) and raised EDV (135 ± 19 to 139 ± 23 mL) and ESV (42 ± 14 to 47 ± 15 mL). Verapamil did not significantly change heart rate (66 ± 11 vs. 65 ± 10 min–1), SV (93 ± 13 vs. 92 ± 14 mL), cardiac output (6.1 ± 0.92 vs. 5.95 ± 0.91 L/min), mean arterial resistance (1271 ± 182 vs. 1269 ± 209 dynes·sec·com–5) or peak filling rate/EDV (PFREDV, 2.99 ± 0.72 vs. 2.87 ± 0.59 sec–1).
View larger version (29K):
[in this window]
[in a new window]
|
Figure 1 Effects of intravenous verapamil versus 0.5N NaCl on resting cardiovascular hemodynamics. A. Example showing reduction of carotid pulse augmentation index (left panel), increases in left ventricular (LV) volumes (middle) and decline in peak ventricular power (right). Dotted curves are control and solid curves are post verapamil. B. Group data showing effects of verapamil on supine hemodynamics at rest. Open bars show saline data and solid bars verapamil. * = p < 0.05; ** = p < 0.01 between studies. Error bars are SEM.
|
|
Hemodynamic responses to intravenous verapamil during exercise.
All subjects achieved 90% predicted heart rate and/or peak VO2 plateau. Despite initial cardiodepression from verapamil reflected by reduced PWRmax/EDV and EF and higher ESV, exercise reserve was similar in both treatment and saline control studies (Fig. 2, Table 2). Arterial load was lower throughout exercise (total peripheral resistance:–9%, Ea:–7%), whereas EDV and SV were significantly increased (Fig. 2). Improved cardiac output and EDV was not accompanied by enhanced diastolic filling, as verapamil tended to lower PFREDV during exercise (p = 0.08). Systolic pressure rose similarly during exercise in both studies. Cardiac output was slightly greater with verapamil (+6% averaged over exercise, Table 2, p < 0.05) despite slightly slower heart rates (–4%, p < 0.05).
View larger version (27K):
[in this window]
[in a new window]
|
Figure 2 Summary hemodynamic data for vascular and ventricular loading between saline and verapamil studies. Open circles denote saline and solid circles verapamil effects. Pre-D and Post-D indicate before and after infusion under supine rest condition. Pre-EX = pre-exercise in upright position; EX1 = stage-1 exercise (25W); EXmax = matched maximal exercise level (100W). There was a consistent increase in end-diastolic volume (EDV) during exercise. The increase in end-systolic volume (ESV), however, diminished during exercise to match saline controls. Arterial load (effective arterial elastance Ea and total peripheral resistance TPR) was lower with verapamil while stroke volume was greater. * = p < 0.05; ** = p < 0.01 between studies. Error bars are SEM.
|
|
Effect of intravenous verapamil on exercise tolerance.
Hemodynamic differences during exercise were accompanied by significant improvement in aerobic exercise performance. Exercise duration prior to achieving the AT increased from 260 ± 129 to 387 ± 176 s (+43.4 ± 16%, p = 0.007) with verapamil, and O2 at this time rose from 11.2 ± 2.8 to 12.5 ± 3.8 mL/min/kg (+13.2 ± 4.6%, p = 0.018). Total exercise time increased modestly from 803 ± 300 to 845 ± 293 sec (+5.8 ± 2.8%, p = 0.06) whereas maximal O2 remained unchanged (+2 ± 3%, p = NS).
Subgroup analysis.
While PFREDV did not significantly change with verapamil in the total study group, individual responses varied according to baseline value. Control subjects with slower early diastolic filling displayed increases with verapamil whereas filling rates declined in patients with higher resting values. This dependence was given by:  PFREDV=–0.35xPFREDV,Basal+0.93, r = 0.58, p = 0.009. To test if improved early filling related to enhanced exercise capacity, patients were subdivided into those with a baseline PFREDV  3.0 s–1 (mean 2.4 ± .44, n = 10) and those with higher initial values (mean 3.6 ± 0.4, n = 9). Verapamil increased PFREDV by 11 ± 17% in the first group but reduced it by –12 ± 11% in the latter group (p < 0.003). However, none of the exercise performance variables significantly differed between subgroups.
In contrast, exercise duration was greater in patients in whom both ventricular and vascular stiffness declined (reflected by PWRmax/EDV, Ea, PWV and AI). In 13 subjects with reductions in both parameters from verapamil, exercise duration increased 8.6 ± 11.4% whereas the remaining subjects had less change in duration (–0.08 ± 12.4%, p < 0.05 by Mann-Whitney U test).
|
Discussion
|
|---|
This is the first study to report that acute i.v. verapamil reduces ventricular-vascular stiffening and improves exercise capacity in healthy elderly individuals. Enhanced performance principally reflected an ability to exercise longer and reach a higher O2 prior to the anaerobic threshold. There was far less change in overall exercise duration or maximal O2. This suggests that exercise efficiency was improved rather than absolute capacity. Importantly, these changes occurred without an increase in cardiac per minute-work. Verapamil lowered preload-corrected PWRmax (a surrogate for ventricular chamber systolic stiffness) and reduced vascular stiffness as evidenced by AI, PWV and Ea. These data support the hypothesis that age-related arterial and ventricular stiffening may partially limit exercise performance even in healthy individuals and that this capacity can improve from interventions that diminish this stiffening.
Comparison with prior studies.
Prior studies regarding the effects of verapamil on cardiac function and exercise capacity in nonhypertrophied hearts have mostly employed oral therapy and highlighted influences on diastolic filling. For example, Arrighi et al. (26) administered verapamil for 3 to 4 days to middle-aged and older individuals and found enhanced early diastolic filling whereas this was not observed in younger subjects. That such changes might translate into better exercise capacity was suggested by Petrella et al. (27) who compared acute (4-h) to chronic (12-week) effects of oral verapamil in normotensive and hypertensive elderly subjects. They also observed enhanced diastolic filling (i.e., reduced isovolumic relaxation time, increased E:A ratio) associated with higher maximal O2 in both groups. Interestingly, similar results were achieved with acute and chronic treatment. Setaro et al. (28) treated elderly patients with symptomatic heart failure, EF > 45% and abnormal baseline PFREDV (<2.5) with five weeks of oral verapamil. They reported a 30% rise in PFREDV and 33% increase in exercise duration.
Our study demonstrates that exercise performance can be enhanced by even acute i.v. verapamil in elderly individuals, and that this response does not require increasing early diastolic filling rates. The lack of an overall change in PFREDV likely reflected heterogeneity of basal values in our study group, consistent with prior data (26). Acute i.v. verapamil also induces more pronounced systolic cardiodepression (9) and can have variable effects on relaxation (29) and thus, early peak filling while arterial load reduction may be less pronounced. This is consistent with the finding that pulsatile load, rather than mean resistive load, was mainly lowered by i.v. verapamil at baseline while contractility indexed by PWRmax/EDV fell approximately 10%.
Ventricular-vascular stiffening.
By lowering both vascular and ventricular systolic stiffness, verapamil may facilitate cardiac-arterial interaction, increasing functional reserve by providing more effective transfer of blood from the heart to periphery. It seems remarkable that the changes in both ventricular and vascular stiffnesses by verapamil were modest, yet improvement in aerobic exercise capacity was substantial. However, when volume is transferred into or out of stiff chambers there are correspondingly greater changes in accompanying pressures. Increasing cardiac SV during exercise would therefore be associated with a greater rise in arterial systolic pressure, and, in a closed-system, this can feedback and amplify inhibition of net cardiac ejection. With verapamil, both PWRmax/EDV declined and ESV increased, yet they reached similar values at peak exercise as with saline controls, suggesting increased reserve. Such recovery during exercise of basal contractile depression from verapamil has been previously proposed (30) but never as directly shown as in the present study employing cardiac-specific power indexes.
Exercise-induced increases in contractile function are thought to decline in aged hearts (7). This is thought to be partly due to lower beta-adrenergic responses, but it could also stem from age-dependent changes in basal ventricular end-systolic stiffness (Ees) (6). Since acute contractile reserve is linked to further increases in Ees (i.e., increasing slope of the end-systolic pressure-volume relation [31]), a higher baseline value of Ees limits further change and thus systolic reserve. By lowering basal contractile function but not inhibiting increases during exercise, verapamil may restore some of this reserve.
Verapamil also reduced effective ventricular afterload (Ea) during exercise due both to a decline in heart rate and fall in pulsatile and resistive vascular loading. This further enhanced cardiac ejection. Our hypothesis that the major cardiovascular effect from i.v. verapamil was more effective cardiac output transfer (with similar total cardiac per min-work) is supported by the type of exercise changes observed, i.e., aerobic exercise duration and O2. Prior studies performed in younger patients (mean age 52 years) treated for  1 month with oral verapamil have also displayed reduced heart rates and arterial load during exercise similar to that observed in the present study yet, without any improvement in exercise performance. The effects of verapamil on improving ventricular-arterial interaction likely depend upon the baseline state (i.e., age-dependent), as was the case for its effects on PFREDV in the present and earlier studies (26).
Methodological limitations.
Ventricular end-systolic stiffness (Ees) was not directly measured as there are no current methods to do this noninvasively during exercise. PWRmax/EDV was used as it is measurable during exercise, minimally load-dependent (32), and prior studies have shown that relative changes correlate with Ees (20,21) with the data including effects from i.v. verapamil (20).
Effective arterial elastance was based on an estimate of Pes which, while validated at rest and with preload reduction in patients of varying ages (18), nonetheless has not be verified during exercise. Effective arterial elastance has been reported to decline in younger individuals undergoing supine exercise (33) whereas it rose in the present study. This may reflect differences in systolic pressure augmentation during exercise in older versus younger individuals, faster heart rates with upright versus supine exercise and methodologic differences from using dicrotic notch pressure to estimate Pes.
Clinically occult coronary artery disease is a concern for any investigation of asymptomatic elderly individuals in whom invasive coronary arteriography cannot be justified. Beneficial effects of verapamil on exercise tolerance in patients with coronary artery disease are well known (34–36). We cannot entirely rule this factor out, although we did identify several patients with silent ECG changes associated with wall motion abnormalities during the initial stress testing, and these subjects were excluded from further testing and analysis. None of the remaining patients demonstrated these changes.
Conclusions.
We demonstrated that aerobic exercise capacity is acutely enhanced in elderly healthy individuals by intravenous verapamil. The dose of verapamil principally lowered basal pulsatile vascular load and ventricular systolic contractile function—reflecting reductions of systolic ventricular and vascular stiffening. Such changes may improve the functional coupling of the heart with the systemic vascular system, enhancing reserve capacity. While this study was performed in healthy individuals, the results may apply to those with baseline exertional intolerance. Heart failure symptoms in the elderly are often associated with preserved systolic function (37), and vascular stiffening is well-documented in elderly heart failure patients (38). Combined vascular and ventricular-systolic stiffening would further constrain reserve function. Reducing ventricular-vascular stiffening may therefore be a logical therapeutic target, particularly in elderly patients with limited exertional capacity.
|
Footnotes
|
|---|
This study was supported by NIA grant AG:12249 (DAK), Colin Research Fellowship Award (BF) and Fogarty Foundation Grant (EN).
1 Dr. Chen-Huan Chen was a Clinical Research Fellow on leave from the Division of Cardiology, Department of Medicine, Veterans General Hospital-Taipei and National Yang-Ming University, R.O.C. 
|
References
|
|---|
1. Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev. 1993;73:413–467[Free Full Text]
2. Landahl S, Steen B, Svanborg A. Dyspnea in 70-year old people. Acta Medica Scandinavica. 1980;207:225–230[Medline]
3. Kelly RP, Hayward C, Avolio AP, O’Rourke MF. Noninvasive determination of age-related changes in the human arterial pulse. Circulation. 1989;80:1652–1659[Abstract/Free Full Text]
4. Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, O’Rourke MF. Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation. 1983;68:50–58[Abstract/Free Full Text]
5. Nichols WW, O’Rourke MF, Avolio AP, et al. Effects of age on ventricular-vascular coupling. Am J Cardiol. 1985;55:1179–1184[CrossRef][Medline]
6. Chen C-H, Nakayama M, Nevo E, Fetics BJ, Maughan WL, Kass DA. Coupled systolic-ventricular and vascular stiffening with age implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol. 1998;32:1221–1227[Abstract/Free Full Text]
7. Fleg JL, O’Connor F, Gerstenblith G, et al. Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Phys. 1995;78:890–900[Abstract/Free Full Text]
8. Stratton JR, Levy WC, Cerqueira MD, Schwartz RS, Abrass IB. Cardiovascular responses to exercise. Effects of aging and exercise training in healthy men. Circulation. 1994;89:1648–1655[Abstract/Free Full Text]
9. Kass DA, Wolff MR, Ting CT, et al. Diastolic compliance of hypertrophied ventricle is not acutely altered by pharmacologic agents influencing active processes. Ann Intern Med. 1993;119:466–473[Abstract/Free Full Text]
10. Carosella L, Menichelli P, Alimenti M, et al. Verapamil disposition and cardiovascular effects in elderly patients after single intravenous and oral doses. Cardiovasc Drugs Ther. 1989;3:417–425[CrossRef][Medline]
11. Chen CH, Ting CT, Nussbacher A, et al. Validation of carotid artery tonometry as a means of estimating augmentation index of ascending aortic pressure. Hypertension. 1996;27:168–175[Abstract/Free Full Text]
12. Kelly RP, Karamanoglu M, Gibbs H, Avolio AP, O’Rourke MF. Noninvasive carotid pressure wave registration as an indicator of ascending aortic pressure. J Vasc Med Biol. 1989;1:241–247
13. Murgo JP, Westerhof N, Giolma JP, Altobelli SA. Aortic input impedance in normal man: relationship to pressure wave forms. Circulation. 1980;62:105–116[Free Full Text]
14. Takazawa K, Tanaka N, Takeda K, Kurosu F, Ibukiyama C. Underestimation of vasodilator effects of nitroglycerin by upper limb blood pressure. Hypertension. 1995;26:520–523[Abstract/Free Full Text]
15. Eliakim M, Saponikov D, Weinman J. Pulse wave velocity in healthy subjects and in patients with various disease states. Am Heart J. 1971;82:448–457[CrossRef][Medline]
16. Avolio AP, Deng FQ, Li WQ, et al. Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Circulation. 1985;71:202–210[Abstract/Free Full Text]
17. Sharir T, Marmor A, Ting CT, et al. Validation of a method for noninvasive measurement of central arterial pressure. Hypertension. 1993;21:74–82[Abstract/Free Full Text]
18. Kelly RP, Ting CT, Yang TM, et al. Effective arterial elastance as index of arterial vascular load in humans. Circulation. 1992;86:513–521[Abstract/Free Full Text]
19. Links JM, Becker LC, Shindledecker JG, et al. Measurement of absolute left ventricular volume from gated blood pool studies. Circulation. 1982;65:82–91[Free Full Text]
20. Sharir T, Feldman MD, Haber H, et al. Ventricular systolic assessment in patients with dilated cardiomyopathy by preload-adjusted maximal power. Validation and noninvasive application. Circulation. 1994;89:2045–2053[Abstract/Free Full Text]
21. Kass DA, Beyar R. Evaluation of contractile state by maximal ventricular power divided by the square of end-diastolic volume. Circulation. 1991;84:1698–1708[Abstract/Free Full Text]
22. Marmor A, Jain D, Cohen LS, Nevo E, Wackers FJT, Zaret BL. Left ventricular peak power during exercise: a noninvasive approach for assessment of contractile reserve. J Nucl Med. 1993;34:1877–1885[Abstract/Free Full Text]
23. Wasserman K. Determinants and detection of anaerobic threshold and consequences of exercise above it. Circulation. 1987;76:VI29–VI39
24. Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Phys. 1986;60:2020–2027[Abstract/Free Full Text]
25. Franklin SS, Gustin WIV, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure: The Framingham Heart Study. Circulation. 1997;96:308–315[Abstract/Free Full Text]
26. Arrighi JA, Dilsizian V, Perrone-Filardi P, Diodati JG, Bacharach SL, Bonow RO. Improvement of the age-related impairment in left ventricular diastolic filling with verapamil in the normal human heart. Circulation. 1994;90:213–219[Abstract/Free Full Text]
27. Petrella RJ, Nichol PM, Cunningham DA, Paterson DH. Verapamil improves left ventricular filling and exercise performance in hypertensive and normotensive elderly individuals. Can J Cardiol. 1994;10:973–981[Medline]
28. Setaro JF, Zaret BL, Schulman DS, Black HR, Soufer R. Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance. Am J Cardiol. 1990;66:981–986[CrossRef][Medline]
29. Bonow RO, Ostrow HG, Rosing DR, et al. Effects of verapamil on left ventricular systolic and diastolic function in patients with hypertrophic cardiomyopathy: pressure-volume analysis with a nonimaging scintillation probe. Circulation. 1983;68:1062–1073[Abstract/Free Full Text]
30. Atterhog JH, Ekelund LG. Haemodynamic effects of intravenous verapamil at rest and during exercise in subjectively healthy middle-aged men. Eur J Clin Pharm. 1975;8:317–322[CrossRef][Medline]
31. Suga H, Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res. 1973;32:314–322[Abstract/Free Full Text]
32. Nakayama M, Chen CH, Nevo E, Fetics B, Wong E, Kass DA. Optimal preload-adjustment of maximal ventricular power index varies with cardiac chamber size. Am Heart J. 1998;136:281–288[CrossRef][Medline]
33. Asanoi H, Kameyama T, Ishizaka S, Miyagi K, Sasayama S. Ventriculoarterial coupling during exercise in normal human subjects. Int J Cardiol. 1992;36:177–186[CrossRef][Medline]
34. Carlens P. Effect of intravenous verapamil on exercise tolerance and left ventricular function in patients with severe exertional angina pectoris. J Cardiovasc Pharmacol. 1981;3:1–10[Medline]
35. Silke B, Goldhammer E, Sharma SK, Verma SP, Taylor SH. An exercise hemodynamic comparison of verapamil, diltiazem, and amlodipine in coronary artery disease. Cardiovasc Drugs Ther. 1990;4:457–463[CrossRef][Medline]
36. Patton JN, Vlietstra RE, Frye RL. Randomized, placebo-controlled study of the effect of verapamil on exercise hemodynamics in coronary artery disease. Am J Cardiol. 1984;53:674–678[CrossRef][Medline]
37. Rich MW. Epidemiology, pathophysiology, and etiology of congestive heart failure in older adults. J Am Geriatr Soc. 1997;45:968–974[Medline]
38. Carroll JD, Shroff S, Wirth P, Halsted M, Rajfer SI. Arterial mechanical properties in dilated cardiomyopathy. Aging and the response to nitroprusside. J Clin Invest. 1991;87:1002–1009[Medline]
This article has been cited by other articles:
|
|
|
|
 
P. D. Chantler, E. G. Lakatta, and S. S. Najjar
Arterial-ventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercise
J Appl Physiol,
October 1, 2008;
105(4):
1342 - 1351.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Senzaki, Y. Iwamoto, H. Ishido, S. Masutani, M. Taketazu, T. Kobayashi, T. Katogi, and S. Kyo
Ventricular-Vascular Stiffening in Patients With Repaired Coarctation of Aorta: Integrated Pathophysiology of Hypertension
Circulation,
September 30, 2008;
118(14_suppl_1):
S191 - S198.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Tanaka and D. R. Seals
Endurance exercise performance in Masters athletes: age-associated changes and underlying physiological mechanisms
J. Physiol.,
January 1, 2008;
586(1):
55 - 63.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. A. Borlaug, V. Melenovsky, S. D. Russell, K. Kessler, K. Pacak, L. C. Becker, and D. A. Kass
Impaired Chronotropic and Vasodilator Reserves Limit Exercise Capacity in Patients With Heart Failure and a Preserved Ejection Fraction
Circulation,
November 14, 2006;
114(20):
2138 - 2147.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T Weber, J Auer, M F O'Rourke, C Punzengruber, E Kvas, and B Eber
Prolonged mechanical systole and increased arterial wave reflections in diastolic dysfunction
Heart,
November 1, 2006;
92(11):
1616 - 1622.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Kass
Ventricular Arterial Stiffening: Integrating the Pathophysiology
Hypertension,
July 1, 2005;
46(1):
185 - 193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Najjar, S. P. Schulman, G. Gerstenblith, J. L. Fleg, D. A. Kass, F. O'Connor, L. C. Becker, and E. G. Lakatta
Age and gender affect ventricular-vascular coupling during aerobic exercise
J. Am. Coll. Cardiol.,
August 4, 2004;
44(3):
611 - 617.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Vlachopoulos, K. Hirata, and M. F O'Rourke
Effect of sildenafil on arterial stiffness and wave reflection
Vascular Medicine,
November 1, 2003;
8(4):
243 - 248.
[Abstract]
[PDF]
|
|
|
|
|
|
|
D. Chemla, I. Antony, Y. Lecarpentier, and A. Nitenberg
Contribution of systemic vascular resistance and total arterial compliance to effective arterial elastance in humans
Am J Physiol Heart Circ Physiol,
July 11, 2003;
285(2):
H614 - H620.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Bonapace, A. Rossi, M. Cicoira, L. Franceschini, G. Golia, L. Zanolla, P. Marino, and P. Zardini
Aortic Distensibility Independently Affects Exercise Tolerance in Patients With Dilated Cardiomyopathy
Circulation,
April 1, 2003;
107(12):
1603 - 1608.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. R. Peterson, M. R. Rinder, K. B. Schechtman, R. J. Spina, K. L. Glover, D. T. Villareal, and A. A. Ehsani
Peak exercise stroke volume: associations with cardiac structure and diastolic function
J Appl Physiol,
March 1, 2003;
94(3):
1108 - 1114.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kawaguchi, I. Hay, B. Fetics, and D. A. Kass
Combined Ventricular Systolic and Arterial Stiffening in Patients With Heart Failure and Preserved Ejection Fraction: Implications for Systolic and Diastolic Reserve Limitations
Circulation,
February 11, 2003;
107(5):
714 - 720.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. G. Lakatta and D. Levy
Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises: Part II: The Aging Heart in Health: Links to Heart Disease
Circulation,
January 21, 2003;
107(2):
346 - 354.
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. G. Hundley, D. W. Kitzman, T. M. Morgan, C. A. Hamilton, S. N. Darty, K. P. Stewart, D. M. Herrington, K. M. Link, and W. C. Little
Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance
J. Am. Coll. Cardiol.,
September 1, 2001;
38(3):
796 - 802.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. F. O'Rourke
Diastolic heart failure, diastolic left ventricular dysfunction and exercise intolerance
J. Am. Coll. Cardiol.,
September 1, 2001;
38(3):
803 - 805.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Zieman, G. Gerstenblith, E. G. Lakatta, G. O. Rosas, K. Vandegaer, K. M. Ricker, and J. M. Hare
Upregulation of the Nitric Oxide-cGMP Pathway in Aged Myocardium : Physiological Response to l-Arginine
Circ. Res.,
January 19, 2001;
88(1):
97 - 102.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Bertella, P. Valentini, and R. Valentini
Heart rate-lowering drugs such as verapamil improve aerobic exercise performance in healthy elderly individuals: a new way to look at left ventricular diastolic function in the elderly
J. Am. Coll. Cardiol.,
May 1, 2000;
35(6):
1697 - 1697.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Nussbacher, G. Gerstenblith, F. C. O'connor, L. C. Becker, D. A. Kass, S. P. Schulman, J. L. Fleg, and E. G. Lakatta
Hemodynamic effects of unloading the old heart
Am J Physiol Heart Circ Physiol,
November 1, 1999;
277(5):
H1863 - H1871.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods