Sildenafil Inhibits -Adrenergic–Stimulated Cardiac Contractility in Humans
http://www.100md.com
《循环学杂志》
the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
Abstract
Background— Sildenafil inhibits phosphodiesterase 5 (PDE5A) to elevate intracellular cGMP and to induce vasodilation. This effect has led to its use for treating erectile dysfunction. Although its influence on rest heart function has appeared minimal, recent animal studies suggest that sildenafil can have potent effects on hearts stimulated by -adrenergic or pressure overloads. We therefore tested whether sildenafil blunts dobutamine-stimulated cardiac function in humans.
Methods and Results— Thirty-five healthy volunteers underwent a randomized, double-blind, placebo-controlled study in which cardiac function was assessed in response to dobutamine before and after oral sildenafil (100 mg, n=19) or placebo (n=16). Echo Doppler and noninvasive blood pressure data yielded load-independent contractility indexes (maximal power index and end-systolic elastance), ejection fraction, and measures of diastolic function. In the initial dobutamine test, systolic and diastolic function improved similarly in both treatment groups (eg, peak power index rose 80±28% in the placebo group and 82±31% in the sildenafil group; P=NS). However, in subjects who then received sildenafil, their second dobutamine response was significantly blunted, with peak power, ejection fraction, and end-systolic elastance changes reduced by 32±34%, 66±64%, and 56±63%, respectively (each P<0.001 versus the initial response). This contrasted to the placebo group, which displayed similar functional responses with both dobutamine tests. Sildenafil treatment did not significantly alter diastolic changes induced by dobutamine compared with results with placebo.
Conclusions— PDE5A inhibition by sildenafil blunts systolic responses to -adrenergic stimulation. This finding supports activity of PDE5A in the human heart and its role in modifying stimulated cardiac function.
Key Words: contractility pharmacology phosphodiesterase 5 receptors, adrenergic, beta sildenafil
Introduction
Sildenafil (Viagra, Pfizer) is an orally active inhibitor of phosphodiesterase 5 (PDE5A), an enzyme that degrades the cellular messenger cGMP.1 cGMP plays a key role in relaxing vascular tone and is a primary mediator of the effects of nitric oxide and natriuretic peptides.2 Sildenafil and other drugs in its class (tadalafil, vardenafil) enhance intracellular cGMP levels in the corpus cavernosum, making them effective treatments for erectile dysfunction.3 Recent studies have revealed the importance of PDE5A in other organ systems,4,5 including the pulmonary vasculature, where PDE5A inhibition appears to benefit patients with chronic pulmonary hypertension.6,7
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cGMP also regulates cardiac function, and its synthesis in response to nitric oxide or natriuretic peptides counters adrenergic stimulation and blunts the development of cardiac hypertrophy.8–10 PDE5A is expressed at low levels in the myocardium.11–13 Its inhibition by sildenafil or other agents has not been thought to directly affect heart function because these drugs induce only a slight decline in arterial pressure and have no apparent effect on cardiac ejection fraction or output at rest14,15 or during exercise.16,17 However, recent animal studies have found that that despite low expression levels, PDE5A can exert potent localized regulation over adrenergic stimulation,18,19 and its chronic inhibition markedly limits and reverses cardiac hypertrophy and remodeling stimulated by pressure overload.20 If translatable to humans, these results might pave the way for novel and potentially important uses for PDE5A inhibitors.
Accordingly, the present study was designed to test whether sildenafil pretreatment suppresses -adrenergic–stimulated cardiac contractility in the healthy human subjects. We performed a randomized, double-blind, placebo-controlled, noninvasive hemodynamic study using dobutamine stress testing before and after administration of oral sildenafil or placebo.
Methods
Forty healthy volunteers were recruited from the general population in response to advertisements posted in the surrounding community. Subjects were screened by medical history, physical examination, and transthoracic echocardiogram. We excluded individuals with heart disease, atherosclerosis, hypertension, diabetes mellitus, pulmonary hypertension, renal or hepatic disease, smoking, or pregnancy or under treatment with nitrates, adrenergic-blocking drugs, or medicines known to interfere with sildenafil pharmacokinetics. Informed consent was obtained from all subjects, and the protocol was approved by the Joint Committee on Clinical Investigation of the Johns Hopkins Medical Institutions.
The study design followed a randomized, double-blind, placebo-controlled protocol, using a 3:2 assignment ratio that favored sildenafil. All subjects were instructed to fast for >6 hours before study. An intravenous cannula was placed in the forearm, and 15 to 20 minutes later, initial baseline (B1) measurements of blood pressure, ECG, and echo Doppler assessment of heart function were obtained in the supine position. Intravenous dobutamine (5 μg · kg–1 · min–1) was then administered for 5 minutes to achieve a stable response, and measurements were repeated (D1). Dobutamine was discontinued, and a 15-minute period was provided to return to the baseline state. Subjects then received either 100 mg oral sildenafil or placebo. After 75 minutes (mean time to peak level),21 a blood sample was obtained to confirm sildenafil level. Data were again recorded for a second baseline (B2) and during a second dobutamine infusion (D2) using the same protocol as for the first test.
Heart Function Analysis
Systolic function was determined by cardiac-specific indexes that combined measurements of pressure, dimension, and flow. Arterial pressure was determined by an oscillometric arm cuff (Dinemap, Critikon); 2D echo Doppler measurements were made with an Agilent Sonos 5500 (Philips) with a 3-MHz probe. All echo Doppler measurements were digitally acquired to optical disk and analyzed offline by a single blinded investigator. Each measurement reflected the average of at least 3 separate beats. Aortic flow was equal to the velocity time integral from pulsed-wave Doppler in the left ventricular outflow tract multiplied by cross-sectional diameter.22 Stroke volume and peak and mean flow were determined from this waveform. Cardiac output was the product of heart rate and stroke volume. Systemic vascular resistance was the ratio of mean arterial pressure (one third pulse pressure plus diastolic blood pressure) to cardiac output.
Cardiac contractility was assessed by several load-independent indexes. The primary outcome variable was peak power index (maximal power divided by end-diastolic volume), which reflects heart contractile state independently of afterload and preload as previously demonstrated.23–25 Maximal power was approximated by the product of peak aortic flow and systolic pressure, which strongly correlates with the maximal instantaneous product of pressure and flow (y=1.08x+0.002; r2=0.97, P<0.0001; based on analysis of reported invasive data from patients with a broad range of heart conditions25). Load-independent secondary outcome contractility parameters were mean ventricular power index and the ratio of end-systolic pressure to volume, an approximation for ventricular end-systolic elastance.
Other secondary outcome variables included routine measures of cardiac systolic and diastolic function. Ejection fraction was determined from cardiac end-diastolic and end-systolic volumes determined by Simpson’s method using apical 4- and 2-chamber views. End-diastolic volume was equal to stroke volume (from Doppler) divided by ejection fraction, with end-systolic volume equal to the difference between the former and latter. Pulsed-wave Doppler spectra of transmitral inflow and tissue Doppler imaging of the lateral mitral annular (E') velocities were used to assess diastolic function.26 The ratio of E/E' was determined as a surrogate marker of left ventricular filling pressures as previously validated.27 Isovolumic relaxation time was measured by continuous-wave Doppler as the time between aortic flow cessation and the onset of mitral inflow.
Plasma Sildenafil Levels
Plasma sildenafil and its metabolite desmethylsildenafil were measured in each subject by liquid chromatography and mass spectrometry (SFBC Analytical Labs).
Statistical Analysis
Sample size estimates were set to detect a >20% decline in peak left ventricular power index in response to dobutamine, with =0.05 and 80% power. In prior animal studies, dobutamine-stimulated power declines &50% with PDE5A inhibition, and for humans, dobutamine increases power by >100% from a baseline of &300 mm Hg/s.23 To detect a 20% decline in this response (60 mm Hg/s) with an SD of 50 mm Hg/s (from prior data), we estimated a sample size of 15 placebo control subjects and 23 sildenafil-treated subjects.
All statistical analyses were performed with Systat software. Results are expressed as mean±SD. Hemodynamic data were analyzed with a 3-way repeated-measures ANOVA (RMANOVA), with the 3 grouping factors being the presence or absence of dobutamine, placebo versus sildenafil, and first versus second dobutamine challenge study. The primary test was a between-group analysis of whether sildenafil (versus placebo) altered the disparity between the first and second dobutamine responses which was determined by a 3-way interaction term that included each grouping factor. This model also included a term testing for an overall effect of sildenafil (versus placebo) that did not relate solely to the relative changes in dobutamine response. Within-group analysis was also performed with a 2-tailed Student paired t test to assess individual dobutamine responses (ie, D1–B1; D2–B2), and 2-way ANOVA was used to test whether the study drug altered this response within each group. Categorical variables were compared by use of the 2 test.
Results
Free plasma sildenafil concentration was 44±29 nmol/L in the active treatment group and 22±18 nmol/L for its metabolite desmethylsildenafil (50% of parent drug level is anticipated).21 In 4 subjects who received sildenafil, plasma concentrations were very low (all <6 nmol/L; mean, 3.6 nmol/L) at the time of study, 10-fold below the group average. Each of these subjects also had low metabolite levels, arguing against rapid metabolism to explain the subtherapeutic concentrations. Because testing our hypothesis required establishing a therapeutic sildenafil level, these subjects were excluded from analysis. One additional subject was excluded because the blood sample was lost. There were no adverse events during the study.
Baseline Analysis and Sildenafil Effect
There were no baseline differences between the placebo- and sildenafil-treated groups with respect to age (30±6 versus 30±8 years, respectively; P=0.95), gender (50% versus 79% female; P=0.1), body mass index (23.9±3.5 versus 22.9±2.5 kg/m2; P=0.45), or cardiac function indexes (Table 1). Changes between the first and second baseline data for placebo and sildenafil treatment groups are also provided in Table 1. There was a slight decline in arterial pressures and systemic vascular resistance, along with a tandem increase in ejection fraction in subjects given sildenafil. Contractility also rose slightly in this group, which might have reflected a reflex response to the vasodilation, a direct effect, or slight residual dobutamine effects. Importantly, intergroup analysis found no significant influence of drug treatment (sildenafil versus placebo) on baseline contractility or diastolic function changes (B2–B1, RMANOVA) but only on arterial resistance, with borderline changes in diastolic arterial pressure and ejection fraction.
Sildenafil Blunts Dobutamine-Stimulated Contractility
Importantly, changes in contractile response were not due to altered vascular loading. The dobutamine-mediated drop in peripheral resistance was not modified by sildenafil (P=0.66; Figure 3), and there were no differences between groups in cardiac preload (end-diastolic volume) at all stages of the study (data not shown). End-systolic volumes declined with dobutamine, which also was blunted in the sildenafil group compared with placebo (P=0.03, data not shown). With the first dobutamine test, heart rate rose only modestly on average in both groups (3.5±7.7 and 6.7±2.2 bpm, placebo and sildenafil, respectively; Figure 3) and even declined in some subjects. The latter effect probably was related to the low dose used, which generates more contractile than chronotropic effect but can elicit a reflex response to the rise in pressure and flow. After sildenafil, heart rate increased more with dobutamine (14.5±4.7 bpm; P<0.01), but this increase did not reach statistical significance compared with the placebo group response (P=0.1 by RMANOVA).
Effects on Diastolic Function
Discussion
This study reports the first direct evidence that sildenafil directly influences cardiac function in healthy humans, suppressing -adrenergic–stimulated systolic function while having minimal effect under resting conditions. Importantly, this inhibitory effect did not depend on afterload or cardiac preload changes. The findings are significant because the use of PDE5A inhibitors appears poised for expansion from their current use for erectile dysfunction to the treatment of pulmonary hypertension and possibly other diseases in which cardiovascular interactions could play a more important role.4–7 Recent evidence that chronic PDE5A inhibition can suppress and even reverse pressure load–induced hypertrophy20 has raised interest in the potential clinical cardiac effects of these drugs. The present study provides a critical proof of principle that PDE5A inhibition can modify cardiac stress response in humans.
PDE5A inhibitors were first developed to treat ischemic heart disease; it was known that PDE5A was expressed in coronary arteries, and its inhibition was hypothesized to augment coronary flow. Studies with sildenafil in dogs28 and humans14 confirmed modest flow increases in normal and diseased coronary arteries; however, little discernible clinical benefit for symptomatic angina was observed.5 After subjects enrolled in these early trials reported salutary effects on erectile function, however, a new and novel use was discovered, leading to the introduction of sildenafil in 1998 as the first approved oral treatment for erectile dysfunction.3
PDE5A inhibitors have potent effects on other vascular beds and tissues,4,5 paving the way for new therapeutic indications for their chronic use. Sildenafil reduces pulmonary arterial resistance and may be effective in the treatment of pulmonary hypertension.6,7 It also improves endothelial function, a marker of nitric oxide bioavailability and overall vascular health, in smokers29 and patients with heart failure.30 Animal studies have shown that sildenafil impressively reduces infarct size via an ischemic preconditioning-like effect.31,32
After an early case report suggested that PDE5A inhibitors might increase the risk of heart attack,33 several studies attempted to define the cardiac effects of this class of drugs. In a study of 14 men with coronary artery disease, Herrmann et al14 reported that 100 mg oral sildenafil slightly reduced resting systemic and pulmonary pressures but had no effect on heart rate, left ventricular filling pressures, or cardiac output. In a subsequent study, men with known or suspected coronary disease underwent supine bicycle exercise testing; sildenafil again slightly lowered blood pressure but did not alter baseline or exercise-stimulated heart rate, blood pressure, exercise duration, or functional reserve.16 Other investigations found modest improvement in exercise performance17 or prolongation of the time required to reach ischemic ST-segment depression.34
Direct analysis of cardiac effects has been obtained in vitro, but these results remain limited and conflicting. PDE5A gene expression is present in human heart,12,19 although protein expression and enzyme activity have been questioned.11,13,35 Recent evidence has found that although gene and protein expression is indeed low, PDE5A is compartmentalized within the myocyte, and its inhibition can alter heart and myocyte function. This is not observed under resting conditions, but only when the heart is stimulated, eg, by -adrenergic agonists18,19 or pressure overload.20 -Adrenergic stimulation coactivates adenylate cyclase to increase cAMP and guanylate cyclase to generate cGMP.8 The former activates protein kinase A, which enhances contractility by targeting calcium handling and myofilament interaction, whereas the latter acts as a "brake" to oppose this effect. This is achieved in part by activating dual-substrate PDEs that break down cAMP36 and protein kinase G, which counteracts multiple cAMP/protein kinase A effects within heart cells.8,9,37
The present study followed a protocol similar to that used recently in animals,19 revealing for the first time an antiadrenergic efficacy of PDE5a inhibition in humans. Cardiac function was studied both at rest and during adrenergic stimulation using various parameters specific to the heart and less dependent on changes in cardiac loading.23,25 Although second baseline contractility was slightly (but significantly) higher in the group receiving sildenafil, this did not explain the findings because the peak response was itself significantly lowered. We cannot rule out a possible role of receptor desensitization resulting from sildenafil, although the prior evidence supporting a primary role of intracellular cGMP/PKG signaling19 supports a more distal mechanism. We used a dobutamine stress test rather than exercise because it provided a more targeted assessment of adrenergic regulation by sildenafil. Indeed, even healthy subjects acutely administered -blockers have been shown to display no change in overall exercise stress test performance or maximal cardiac output despite clear effects on adrenergic-stimulated contractility.38 The cardiac power index provides a sensitive load-independent index of contractility23–25 that is influenced minimally by arterial or venous vasodilation.23
Unlike systolic changes, dobutamine-stimulated diastolic function was not significantly blunted by sildenafil treatment when compared between groups. However, within-group analysis did show that sildenafil-treated subjects had an attenuated rise in early ventricular filling and relaxation (E and E' velocities, respectively) and greater increase in atrial filling (A velocity). Although this could reflect a slight diminution in diastolic function, it also is consistent with a blunted contractile response and thus increased end-systolic volumes with dobutamine infusion in the presence of sildenafil. This decline in net ventricular ejection could limit early diastolic recoil (suction) effects that contribute to early rapid filling of the heart. This in turn would result in augmented filling during atrial systole, particularly because end-diastolic volumes were similar in both groups. The E/E' velocity ratio has been shown to correlate well with left ventricular diastolic pressure.27 E/E' was similar in both groups at baseline or with dobutamine; importantly, there was no evidence that left ventricular diastolic pressure increased with sildenafil despite blunted systolic augmentation. The sample size may also have contributed to the lack of diastolic effects because noninvasive measures of diastole can have greater variance.
Sildenafil has been reported to increase sympathetic nerve activity without altering heart rate or blood pressure,39 which could have played a role in the slight rise in basal contractility at second baseline in subjects receiving sildenafil. Such activity might be anticipated to downregulate adrenergic stimulation, thereby blunting a dobutamine response. However, the changes were small, consistent with slight increases in plasma catecholamines with sildenafil (&70 pg/mL),40 &3 to 4 orders of magnitude lower than that expected from dobutamine. Furthermore, there was no statistical difference in the between-group analysis. Sildenafil has also been reported to decrease vagal inhibition on heart rate41 and in 1 study increased heart rate by &10% after a single dose.42 This finding may explain the enhanced heart rate response to dobutamine after sildenafil in our study. However, a higher heart rate per se would be expected to increase contractility by the force-frequency relationship, whereas we observed the opposite to be true in the sildenafil group.
This study has several limitations. We tested an acute intervention; the chronic impact of sildenafil on adrenergic stimulation or other forms of myocardial stress response remains to be determined. In addition, this effect may vary in patients with cardiac disease or chronically elevated sympathetic stimulation. Second, we did not randomize the order of therapy, which would have required us to perform studies on separate days. Rather, we used a parallel placebo design to control for potential differences between the first and second dobutamine tests. Importantly, the principal analysis focused on between-group disparities between the 2 tests. Third, our analysis relied on noninvasive functional analysis, which can have greater variability than invasive data. This also required making some simplifying assumptions such as substituting arm cuff pressure to approximate central arterial pressure, using a zero-volume axis intercept for the end-systolic PV relation, and estimating peak power. However, prior clinical data support these assumptions, and it is important to note that they were applied identically to both study groups and all stages of the protocol in a blinded fashion, which should limit bias. Of the 24 subjects randomized to sildenafil, &16% achieved very low free plasma levels. Variability in absorption of 30% to 40% is reported with sildenafil,21 but the levels in these subjects were far lower than the group average, suggesting that these patients may have had an additional factor such as nonreported eating before the test.
In summary, we report that sildenafil can potently suppress adrenergic-stimulated contractility in the intact human heart. Sildenafil and other agents in this class are safe and effective for the treatment of erectile dysfunction in healthy individuals,3 patients with coronary disease,14,16 and those with heart failure,17 and the present results should not alter this clinical use. However, the data do refute the notion that PDE5A inhibitors have no effect on the human heart and reveal a significant interaction in the presence of catecholamine stimulation. Blunting of adrenergic stimulation might prove beneficial for other disorders in which neurohormonal stimulation is enhanced such as hypertension, left ventricular hypertrophy, and heart failure. Future studies are needed to test this. From the present findings, such studies for testing chronic effects of PDE5A inhibition on cardiac structure and function appear justified.
Acknowledgments
This work was funded by NIH/NIA grants RO1-AG-18324-03, T32 HL-07227-29, and HL-47511 (D.A.K.), T32HL07227 (B.A.B.), and by the Peter Belfer Foundation (D.A.K.).
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Abstract
Background— Sildenafil inhibits phosphodiesterase 5 (PDE5A) to elevate intracellular cGMP and to induce vasodilation. This effect has led to its use for treating erectile dysfunction. Although its influence on rest heart function has appeared minimal, recent animal studies suggest that sildenafil can have potent effects on hearts stimulated by -adrenergic or pressure overloads. We therefore tested whether sildenafil blunts dobutamine-stimulated cardiac function in humans.
Methods and Results— Thirty-five healthy volunteers underwent a randomized, double-blind, placebo-controlled study in which cardiac function was assessed in response to dobutamine before and after oral sildenafil (100 mg, n=19) or placebo (n=16). Echo Doppler and noninvasive blood pressure data yielded load-independent contractility indexes (maximal power index and end-systolic elastance), ejection fraction, and measures of diastolic function. In the initial dobutamine test, systolic and diastolic function improved similarly in both treatment groups (eg, peak power index rose 80±28% in the placebo group and 82±31% in the sildenafil group; P=NS). However, in subjects who then received sildenafil, their second dobutamine response was significantly blunted, with peak power, ejection fraction, and end-systolic elastance changes reduced by 32±34%, 66±64%, and 56±63%, respectively (each P<0.001 versus the initial response). This contrasted to the placebo group, which displayed similar functional responses with both dobutamine tests. Sildenafil treatment did not significantly alter diastolic changes induced by dobutamine compared with results with placebo.
Conclusions— PDE5A inhibition by sildenafil blunts systolic responses to -adrenergic stimulation. This finding supports activity of PDE5A in the human heart and its role in modifying stimulated cardiac function.
Key Words: contractility pharmacology phosphodiesterase 5 receptors, adrenergic, beta sildenafil
Introduction
Sildenafil (Viagra, Pfizer) is an orally active inhibitor of phosphodiesterase 5 (PDE5A), an enzyme that degrades the cellular messenger cGMP.1 cGMP plays a key role in relaxing vascular tone and is a primary mediator of the effects of nitric oxide and natriuretic peptides.2 Sildenafil and other drugs in its class (tadalafil, vardenafil) enhance intracellular cGMP levels in the corpus cavernosum, making them effective treatments for erectile dysfunction.3 Recent studies have revealed the importance of PDE5A in other organ systems,4,5 including the pulmonary vasculature, where PDE5A inhibition appears to benefit patients with chronic pulmonary hypertension.6,7
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cGMP also regulates cardiac function, and its synthesis in response to nitric oxide or natriuretic peptides counters adrenergic stimulation and blunts the development of cardiac hypertrophy.8–10 PDE5A is expressed at low levels in the myocardium.11–13 Its inhibition by sildenafil or other agents has not been thought to directly affect heart function because these drugs induce only a slight decline in arterial pressure and have no apparent effect on cardiac ejection fraction or output at rest14,15 or during exercise.16,17 However, recent animal studies have found that that despite low expression levels, PDE5A can exert potent localized regulation over adrenergic stimulation,18,19 and its chronic inhibition markedly limits and reverses cardiac hypertrophy and remodeling stimulated by pressure overload.20 If translatable to humans, these results might pave the way for novel and potentially important uses for PDE5A inhibitors.
Accordingly, the present study was designed to test whether sildenafil pretreatment suppresses -adrenergic–stimulated cardiac contractility in the healthy human subjects. We performed a randomized, double-blind, placebo-controlled, noninvasive hemodynamic study using dobutamine stress testing before and after administration of oral sildenafil or placebo.
Methods
Forty healthy volunteers were recruited from the general population in response to advertisements posted in the surrounding community. Subjects were screened by medical history, physical examination, and transthoracic echocardiogram. We excluded individuals with heart disease, atherosclerosis, hypertension, diabetes mellitus, pulmonary hypertension, renal or hepatic disease, smoking, or pregnancy or under treatment with nitrates, adrenergic-blocking drugs, or medicines known to interfere with sildenafil pharmacokinetics. Informed consent was obtained from all subjects, and the protocol was approved by the Joint Committee on Clinical Investigation of the Johns Hopkins Medical Institutions.
The study design followed a randomized, double-blind, placebo-controlled protocol, using a 3:2 assignment ratio that favored sildenafil. All subjects were instructed to fast for >6 hours before study. An intravenous cannula was placed in the forearm, and 15 to 20 minutes later, initial baseline (B1) measurements of blood pressure, ECG, and echo Doppler assessment of heart function were obtained in the supine position. Intravenous dobutamine (5 μg · kg–1 · min–1) was then administered for 5 minutes to achieve a stable response, and measurements were repeated (D1). Dobutamine was discontinued, and a 15-minute period was provided to return to the baseline state. Subjects then received either 100 mg oral sildenafil or placebo. After 75 minutes (mean time to peak level),21 a blood sample was obtained to confirm sildenafil level. Data were again recorded for a second baseline (B2) and during a second dobutamine infusion (D2) using the same protocol as for the first test.
Heart Function Analysis
Systolic function was determined by cardiac-specific indexes that combined measurements of pressure, dimension, and flow. Arterial pressure was determined by an oscillometric arm cuff (Dinemap, Critikon); 2D echo Doppler measurements were made with an Agilent Sonos 5500 (Philips) with a 3-MHz probe. All echo Doppler measurements were digitally acquired to optical disk and analyzed offline by a single blinded investigator. Each measurement reflected the average of at least 3 separate beats. Aortic flow was equal to the velocity time integral from pulsed-wave Doppler in the left ventricular outflow tract multiplied by cross-sectional diameter.22 Stroke volume and peak and mean flow were determined from this waveform. Cardiac output was the product of heart rate and stroke volume. Systemic vascular resistance was the ratio of mean arterial pressure (one third pulse pressure plus diastolic blood pressure) to cardiac output.
Cardiac contractility was assessed by several load-independent indexes. The primary outcome variable was peak power index (maximal power divided by end-diastolic volume), which reflects heart contractile state independently of afterload and preload as previously demonstrated.23–25 Maximal power was approximated by the product of peak aortic flow and systolic pressure, which strongly correlates with the maximal instantaneous product of pressure and flow (y=1.08x+0.002; r2=0.97, P<0.0001; based on analysis of reported invasive data from patients with a broad range of heart conditions25). Load-independent secondary outcome contractility parameters were mean ventricular power index and the ratio of end-systolic pressure to volume, an approximation for ventricular end-systolic elastance.
Other secondary outcome variables included routine measures of cardiac systolic and diastolic function. Ejection fraction was determined from cardiac end-diastolic and end-systolic volumes determined by Simpson’s method using apical 4- and 2-chamber views. End-diastolic volume was equal to stroke volume (from Doppler) divided by ejection fraction, with end-systolic volume equal to the difference between the former and latter. Pulsed-wave Doppler spectra of transmitral inflow and tissue Doppler imaging of the lateral mitral annular (E') velocities were used to assess diastolic function.26 The ratio of E/E' was determined as a surrogate marker of left ventricular filling pressures as previously validated.27 Isovolumic relaxation time was measured by continuous-wave Doppler as the time between aortic flow cessation and the onset of mitral inflow.
Plasma Sildenafil Levels
Plasma sildenafil and its metabolite desmethylsildenafil were measured in each subject by liquid chromatography and mass spectrometry (SFBC Analytical Labs).
Statistical Analysis
Sample size estimates were set to detect a >20% decline in peak left ventricular power index in response to dobutamine, with =0.05 and 80% power. In prior animal studies, dobutamine-stimulated power declines &50% with PDE5A inhibition, and for humans, dobutamine increases power by >100% from a baseline of &300 mm Hg/s.23 To detect a 20% decline in this response (60 mm Hg/s) with an SD of 50 mm Hg/s (from prior data), we estimated a sample size of 15 placebo control subjects and 23 sildenafil-treated subjects.
All statistical analyses were performed with Systat software. Results are expressed as mean±SD. Hemodynamic data were analyzed with a 3-way repeated-measures ANOVA (RMANOVA), with the 3 grouping factors being the presence or absence of dobutamine, placebo versus sildenafil, and first versus second dobutamine challenge study. The primary test was a between-group analysis of whether sildenafil (versus placebo) altered the disparity between the first and second dobutamine responses which was determined by a 3-way interaction term that included each grouping factor. This model also included a term testing for an overall effect of sildenafil (versus placebo) that did not relate solely to the relative changes in dobutamine response. Within-group analysis was also performed with a 2-tailed Student paired t test to assess individual dobutamine responses (ie, D1–B1; D2–B2), and 2-way ANOVA was used to test whether the study drug altered this response within each group. Categorical variables were compared by use of the 2 test.
Results
Free plasma sildenafil concentration was 44±29 nmol/L in the active treatment group and 22±18 nmol/L for its metabolite desmethylsildenafil (50% of parent drug level is anticipated).21 In 4 subjects who received sildenafil, plasma concentrations were very low (all <6 nmol/L; mean, 3.6 nmol/L) at the time of study, 10-fold below the group average. Each of these subjects also had low metabolite levels, arguing against rapid metabolism to explain the subtherapeutic concentrations. Because testing our hypothesis required establishing a therapeutic sildenafil level, these subjects were excluded from analysis. One additional subject was excluded because the blood sample was lost. There were no adverse events during the study.
Baseline Analysis and Sildenafil Effect
There were no baseline differences between the placebo- and sildenafil-treated groups with respect to age (30±6 versus 30±8 years, respectively; P=0.95), gender (50% versus 79% female; P=0.1), body mass index (23.9±3.5 versus 22.9±2.5 kg/m2; P=0.45), or cardiac function indexes (Table 1). Changes between the first and second baseline data for placebo and sildenafil treatment groups are also provided in Table 1. There was a slight decline in arterial pressures and systemic vascular resistance, along with a tandem increase in ejection fraction in subjects given sildenafil. Contractility also rose slightly in this group, which might have reflected a reflex response to the vasodilation, a direct effect, or slight residual dobutamine effects. Importantly, intergroup analysis found no significant influence of drug treatment (sildenafil versus placebo) on baseline contractility or diastolic function changes (B2–B1, RMANOVA) but only on arterial resistance, with borderline changes in diastolic arterial pressure and ejection fraction.
Sildenafil Blunts Dobutamine-Stimulated Contractility
Importantly, changes in contractile response were not due to altered vascular loading. The dobutamine-mediated drop in peripheral resistance was not modified by sildenafil (P=0.66; Figure 3), and there were no differences between groups in cardiac preload (end-diastolic volume) at all stages of the study (data not shown). End-systolic volumes declined with dobutamine, which also was blunted in the sildenafil group compared with placebo (P=0.03, data not shown). With the first dobutamine test, heart rate rose only modestly on average in both groups (3.5±7.7 and 6.7±2.2 bpm, placebo and sildenafil, respectively; Figure 3) and even declined in some subjects. The latter effect probably was related to the low dose used, which generates more contractile than chronotropic effect but can elicit a reflex response to the rise in pressure and flow. After sildenafil, heart rate increased more with dobutamine (14.5±4.7 bpm; P<0.01), but this increase did not reach statistical significance compared with the placebo group response (P=0.1 by RMANOVA).
Effects on Diastolic Function
Discussion
This study reports the first direct evidence that sildenafil directly influences cardiac function in healthy humans, suppressing -adrenergic–stimulated systolic function while having minimal effect under resting conditions. Importantly, this inhibitory effect did not depend on afterload or cardiac preload changes. The findings are significant because the use of PDE5A inhibitors appears poised for expansion from their current use for erectile dysfunction to the treatment of pulmonary hypertension and possibly other diseases in which cardiovascular interactions could play a more important role.4–7 Recent evidence that chronic PDE5A inhibition can suppress and even reverse pressure load–induced hypertrophy20 has raised interest in the potential clinical cardiac effects of these drugs. The present study provides a critical proof of principle that PDE5A inhibition can modify cardiac stress response in humans.
PDE5A inhibitors were first developed to treat ischemic heart disease; it was known that PDE5A was expressed in coronary arteries, and its inhibition was hypothesized to augment coronary flow. Studies with sildenafil in dogs28 and humans14 confirmed modest flow increases in normal and diseased coronary arteries; however, little discernible clinical benefit for symptomatic angina was observed.5 After subjects enrolled in these early trials reported salutary effects on erectile function, however, a new and novel use was discovered, leading to the introduction of sildenafil in 1998 as the first approved oral treatment for erectile dysfunction.3
PDE5A inhibitors have potent effects on other vascular beds and tissues,4,5 paving the way for new therapeutic indications for their chronic use. Sildenafil reduces pulmonary arterial resistance and may be effective in the treatment of pulmonary hypertension.6,7 It also improves endothelial function, a marker of nitric oxide bioavailability and overall vascular health, in smokers29 and patients with heart failure.30 Animal studies have shown that sildenafil impressively reduces infarct size via an ischemic preconditioning-like effect.31,32
After an early case report suggested that PDE5A inhibitors might increase the risk of heart attack,33 several studies attempted to define the cardiac effects of this class of drugs. In a study of 14 men with coronary artery disease, Herrmann et al14 reported that 100 mg oral sildenafil slightly reduced resting systemic and pulmonary pressures but had no effect on heart rate, left ventricular filling pressures, or cardiac output. In a subsequent study, men with known or suspected coronary disease underwent supine bicycle exercise testing; sildenafil again slightly lowered blood pressure but did not alter baseline or exercise-stimulated heart rate, blood pressure, exercise duration, or functional reserve.16 Other investigations found modest improvement in exercise performance17 or prolongation of the time required to reach ischemic ST-segment depression.34
Direct analysis of cardiac effects has been obtained in vitro, but these results remain limited and conflicting. PDE5A gene expression is present in human heart,12,19 although protein expression and enzyme activity have been questioned.11,13,35 Recent evidence has found that although gene and protein expression is indeed low, PDE5A is compartmentalized within the myocyte, and its inhibition can alter heart and myocyte function. This is not observed under resting conditions, but only when the heart is stimulated, eg, by -adrenergic agonists18,19 or pressure overload.20 -Adrenergic stimulation coactivates adenylate cyclase to increase cAMP and guanylate cyclase to generate cGMP.8 The former activates protein kinase A, which enhances contractility by targeting calcium handling and myofilament interaction, whereas the latter acts as a "brake" to oppose this effect. This is achieved in part by activating dual-substrate PDEs that break down cAMP36 and protein kinase G, which counteracts multiple cAMP/protein kinase A effects within heart cells.8,9,37
The present study followed a protocol similar to that used recently in animals,19 revealing for the first time an antiadrenergic efficacy of PDE5a inhibition in humans. Cardiac function was studied both at rest and during adrenergic stimulation using various parameters specific to the heart and less dependent on changes in cardiac loading.23,25 Although second baseline contractility was slightly (but significantly) higher in the group receiving sildenafil, this did not explain the findings because the peak response was itself significantly lowered. We cannot rule out a possible role of receptor desensitization resulting from sildenafil, although the prior evidence supporting a primary role of intracellular cGMP/PKG signaling19 supports a more distal mechanism. We used a dobutamine stress test rather than exercise because it provided a more targeted assessment of adrenergic regulation by sildenafil. Indeed, even healthy subjects acutely administered -blockers have been shown to display no change in overall exercise stress test performance or maximal cardiac output despite clear effects on adrenergic-stimulated contractility.38 The cardiac power index provides a sensitive load-independent index of contractility23–25 that is influenced minimally by arterial or venous vasodilation.23
Unlike systolic changes, dobutamine-stimulated diastolic function was not significantly blunted by sildenafil treatment when compared between groups. However, within-group analysis did show that sildenafil-treated subjects had an attenuated rise in early ventricular filling and relaxation (E and E' velocities, respectively) and greater increase in atrial filling (A velocity). Although this could reflect a slight diminution in diastolic function, it also is consistent with a blunted contractile response and thus increased end-systolic volumes with dobutamine infusion in the presence of sildenafil. This decline in net ventricular ejection could limit early diastolic recoil (suction) effects that contribute to early rapid filling of the heart. This in turn would result in augmented filling during atrial systole, particularly because end-diastolic volumes were similar in both groups. The E/E' velocity ratio has been shown to correlate well with left ventricular diastolic pressure.27 E/E' was similar in both groups at baseline or with dobutamine; importantly, there was no evidence that left ventricular diastolic pressure increased with sildenafil despite blunted systolic augmentation. The sample size may also have contributed to the lack of diastolic effects because noninvasive measures of diastole can have greater variance.
Sildenafil has been reported to increase sympathetic nerve activity without altering heart rate or blood pressure,39 which could have played a role in the slight rise in basal contractility at second baseline in subjects receiving sildenafil. Such activity might be anticipated to downregulate adrenergic stimulation, thereby blunting a dobutamine response. However, the changes were small, consistent with slight increases in plasma catecholamines with sildenafil (&70 pg/mL),40 &3 to 4 orders of magnitude lower than that expected from dobutamine. Furthermore, there was no statistical difference in the between-group analysis. Sildenafil has also been reported to decrease vagal inhibition on heart rate41 and in 1 study increased heart rate by &10% after a single dose.42 This finding may explain the enhanced heart rate response to dobutamine after sildenafil in our study. However, a higher heart rate per se would be expected to increase contractility by the force-frequency relationship, whereas we observed the opposite to be true in the sildenafil group.
This study has several limitations. We tested an acute intervention; the chronic impact of sildenafil on adrenergic stimulation or other forms of myocardial stress response remains to be determined. In addition, this effect may vary in patients with cardiac disease or chronically elevated sympathetic stimulation. Second, we did not randomize the order of therapy, which would have required us to perform studies on separate days. Rather, we used a parallel placebo design to control for potential differences between the first and second dobutamine tests. Importantly, the principal analysis focused on between-group disparities between the 2 tests. Third, our analysis relied on noninvasive functional analysis, which can have greater variability than invasive data. This also required making some simplifying assumptions such as substituting arm cuff pressure to approximate central arterial pressure, using a zero-volume axis intercept for the end-systolic PV relation, and estimating peak power. However, prior clinical data support these assumptions, and it is important to note that they were applied identically to both study groups and all stages of the protocol in a blinded fashion, which should limit bias. Of the 24 subjects randomized to sildenafil, &16% achieved very low free plasma levels. Variability in absorption of 30% to 40% is reported with sildenafil,21 but the levels in these subjects were far lower than the group average, suggesting that these patients may have had an additional factor such as nonreported eating before the test.
In summary, we report that sildenafil can potently suppress adrenergic-stimulated contractility in the intact human heart. Sildenafil and other agents in this class are safe and effective for the treatment of erectile dysfunction in healthy individuals,3 patients with coronary disease,14,16 and those with heart failure,17 and the present results should not alter this clinical use. However, the data do refute the notion that PDE5A inhibitors have no effect on the human heart and reveal a significant interaction in the presence of catecholamine stimulation. Blunting of adrenergic stimulation might prove beneficial for other disorders in which neurohormonal stimulation is enhanced such as hypertension, left ventricular hypertrophy, and heart failure. Future studies are needed to test this. From the present findings, such studies for testing chronic effects of PDE5A inhibition on cardiac structure and function appear justified.
Acknowledgments
This work was funded by NIH/NIA grants RO1-AG-18324-03, T32 HL-07227-29, and HL-47511 (D.A.K.), T32HL07227 (B.A.B.), and by the Peter Belfer Foundation (D.A.K.).
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