REVIEW PAPER

Phosphodiesterase Inhibitors, Congestive Heart Failure, and SuddenDeath: Time for Re-Evaluation

Amit Varma, MD; Keyur B. Shah, MD; Michael L. Hess, MD

From the Department of Internal Medicine ⁄ Cardiology, CHF and Heart Transplant, Virginia Commonwealth University Health System, Richmond, VA

A 42-year-old diabetic man was admitted with systolicheart failure and pulmonary hypertension being treatedwith sildenafil for the previous year. With an increase increatinine, he experienced 3 episodes of ventriculartachycardia and ventricular fibrillation. Withdrawal of thephosphodiesterase (PDE) inhibitor resulted in no furtherepisodes of dysrhythmias. The basic pharmacology of PDEinhibitors is presented and the use of PDE-3 inhibitors forthe treatment of heart failure causing an increase in sud-den death is also reviewed. There have been several cases

of sudden death associated with sildenafil use and with itsincreasing use in patients with severe pulmonary hyperten-sion and decompensated heart failure. The authors alsoreviewed the electrophysiologic effects of PDE-5 inhibitorsassociated with their use. The crossover between PDE-3and PDE-5 inhibitors is also discussed and caution isurged when contemplating the use of PDE-5 inhibitors inpatients with systolic heart failure and pulmonary hyperten-sion. �2012 Wiley Periodicals, Inc.

RC was a 42-year-old man originally referred to theheart failure (HF) service of our institution with a doc-umented primary cardiomyopathy with a left ventricu-lar ejection fraction (LVEF) of 20% and edema to thelevel of his thighs in late 2008. His medical historywas pertinent for meningococcemia in 1997 and anembolic stroke in 2005, with complete recovery ofmotor function. His comorbidities included obesity(body mass index �45) and insulin-dependent diabetesmellitus. Electrocardiography (ECG) showed a normalsinus rhythm with left bundle branch block and QRSduration of 140 ms. A right heart catheterizationrevealed significant elevations in right-sided pressureswith a pulmonary artery systolic pressure (PASP) of90 mm Hg, pulmonary capillary wedge pressure(PCWP) of 25 mm Hg, and pulmonary vascular resis-tance of 8 WU. He was treated with nesiritide andeventually initiated on an oral regimen of thrice-dailyhydralazine and isosorbide dinitrate in addition toangiotensin-converting enzyme inhibitors and b-block-ers. After management of his acute decompensatedHF, a left ventricular lead and biventricular pacemakerwere implanted. He was readmitted several monthslater with anasarca and similar right-sided pressures,and was started on sildenafil 20 mg 3 times daily forpulmonary hypertension with increased pulmonaryvascular resistance.

Several months later during a hospital admission foracute renal failure related to intravenous antibioticsfor nonhealing foot wounds, the patient developed

sustained ventricular tachycardia (VT) followed byventricular fibrillation (VF) and pulseless cardiacarrest. Cardiopulmonary resuscitation was performedand electrical defibrillation was successful. He was in-tubated and transferred to the coronary intensive careunit. Sildenafil therapy was continued. Three dayslater, another episode of VT was pace-terminated. Hewas eventually stabilized on amiodarone therapy andtransferred to the telemetry floor. The patient subse-quently had a third episode of sustained VT that wasalso pace-terminated. Sildenafil was withdrawn andthere have been no further episodes of ventricular dys-rhythmias, although he has had multiple subsequentadmissions for HF.

A phosphodiesterase (PDE) is any enzyme thatbreaks a phosphodiester bond. More germaine to ourdiscussion is the family of enzymes, which are cyclicnucleotide phosphodiesterases that degrade the phos-phodiester bond in the secondary messenger moleculescyclic adenosine monophosphate (cAMP) and cyclicguanosine monophosphate (cGMP). These cyclicnucleotides regulate the duration, localization, andamplitude of cyclic nucleotide signaling at the subcel-lular level and are important regulators of signal trans-duction. Multiple subtypes of these cyclic nucleotidephosphodiesterases (PDE 1–11) were isolated in theearly 1970s and were shown to be selectively inhibitedby a variety of drugs, not only in the brain, but also incardiovascular tissue.1–4 A PDE inhibitor is a drug thatblocks one or more of the subtypes of PDE specificallywith reference to cardiovascular tissue, PDE-3 andPDE-5. This inhibition increases the intracellular levelsof either cAMP (PDE-3) or cGMP (PDE-5).

PDE-3 INHIBITORSDrugs that show selectivity to inhibition of PDE-3, eg,milrinone, vesnarinone, and flosequinan, lead to anintracellular increase in the concentration of cAMP.cAMP mediates the phosphorylation of protein

Address for correspondence: Michael L. Hess, MD, Department ofInternal Medicine ⁄ Cardiology, CHF and Heart Transplant, VirginiaCommonwealth University Health System, 1200 East Broad Street,Box 980204, Richmond, VA 23298E-mail: mhess@mcvh-vcu.edu

Manuscript received: January 17, 2012; revised: February 3, 2012;accepted: February 17, 2012DOI: 10.1111/j.1751-7133.2012.00293.x

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kinases, activates cardiac calcium channels, andincreases calcium influx from the sarcoplasmic reticu-lum, which thereby increases cardiac contractility. Thisincrease in cAMP and activation of calcium channelsalso increases automaticity.5 This demonstration of thepositive inotropic actions of the PDE-3 inhibitors ledto the development of clinical analogs, which led to aflurry of research papers extolling their benefit.6 Inrandomized placebo-controlled clinical trials, amrinonewas found to be of no significant benefit over placebo.This led to the development of more potent PDE-3inhibitors, eg, milrinone, enoximone, flosequinan, andvesnarinone.

In a 16-week controlled trial of enoximone, investi-gators could find no improvement in symptoms orexercise capacity and unexpectedly found a worse sur-vival rate with enoximone including sudden cardiacdeath.7 Unfortunately, there was no ECG monitoringin this study. Milrinone underwent a double-blind con-trolled trial with a mean duration of 6.1 months.8 Notonly did they find an increase in mortality, but theyalso found an increase in hypotension and syncope(P<.002) compared with placebo. Flosequinan had amuch more sordid course. Based on an improvementin exercise time and quality of life, the Food and DrugAdministration approved the drug before survival datawere available. Soon after release, however, the highdose was withdrawn from the market due to anincrease in mortality. The low dose continued on themarket, but further study revealed that even the lowdose increased mortality and the drug was withdrawn.Finally, vesnarinone, a complex inotrope but with pre-dominantly PDE-3 inhibition, was originally found tohave a U-shaped survival curve with an increase insurvival in the 30- and 60-mg doses, but an increase inmortality at 6 months with the 120-mg dose.9 As aresult of these findings, a survival trial was conductedwith 3833 patients, and vesnarinone was also found toincrease mortality that was probably related to anincrease in sudden cardiac death.10 A meta-analysispublished in the Cochrane Database analyzed 21 ran-domized controlled trials that included 8408 patients,4 specific PDE inhibitor derivatives, and 8 differentPDE inhibitor molecules. When compared with pla-cebo, they found that PDE inhibitors were associatedwith a significant 17% increase in mortality, with arelative risk of 1.17 (95% confidence interval, 1.06–1.30; P<.001) and an increase in cardiac death, sud-den death, arrhythmias, and vertigo.11 This effect wasindependent of vasodilator use, New York Heart Asso-ciation (NYHA) HF class, or type of PDE-3 inhibitorused.

PDE-5 INHIBITORSThis now brings us to the 21st century and to PDE-5inhibitors with sildenafil (Viagra; Pfizer, New York,NY) being the prototype drug, which inhibits the deg-radation of cGMP by PDE-5. It must be noted thatwhile sildenafil preferentially inhibits PDE-5, it is not

truly selective, especially at high doses. Sildenafil isprimarily metabolized by the cytochrome P450 enzymeCYP3A4 and somewhere between 13% and 15% isrenally excreted. Thus, the potential exists for adversedrug reactions with other drugs that inhibit CYP3A4such as the human immunodeficiency virus proteaseinhibitors, ketoconazole and organonitrates. Also, inpreliminary safety trials, it was noted that healthyelderly patients older than 65 had an 84% highersteady-state plasma concentration than their youngercounterparts secondary to reduced drug clearance.PDE-5 is present in the vascular smooth muscle of thepulmonary vasculature and therefore has become aneffective treatment modality for patients with pulmo-nary arterial hypertension. However, compared withour knowledge of the clinical pharmacology of a singledose of sildenafil for erectile dysfunction (ED), little isknown about the clinical pharmacology of chronic,long-term therapy and very little information is avail-able in patients with congestive HF (CHF) and ⁄ orchronic kidney disease (CKD) and hepatic dysfunction.PDE-5 inhibitors are effective and widely used thera-peutic agents for ED. Since 2005, sildenafil has alsobeen approved for the treatment of PAH and, in 2009,we saw the approval of the long-acting PDE-5 inhibi-tor tadalafil for these patients as well. PDE-5 inhibi-tors have a number of contraindications and sideeffects, while renal and ⁄ or hepatic dysfunction orconcomitant use of drugs that inhibit CYP3A4 can allcreate a scenario of supratherapeutic plasma levels.

There have been several cases of sudden cardiacdeath associated with sildenafil use, and with itsincreasing use in patients with PAH and numerouspublished and ongoing studies evaluating its use indiastolic HF, we decided to review the electrophysio-logic effects of PDE-5 inhibitors as well as any clinicalcase reports of ventricular arrhythmias associated withtheir use.

POTENTIAL MECHANISMS INCARDIOMYOCYTES ANDELECTROPHYSIOLOGIC EFFECTSIn a clinical study by Alpaslan and colleagues,12 36patients with ED, 21 of whom also had coronaryartery disease, QT dispersion with corrected anduncorrected QT intervals were measured before and 1and 4 hours after ingestion of 50-mg sildenafil using astandard 12-lead ECG. They found no change in meanheart rate, no prolongation of QT interval, and noincrease in QT dispersion. In another study, tadalafil(single, high dose of 100 mg [5-fold the maximumtherapeutic dose for ED]), investigators compared itsuse with placebo and an active control, ibutilide, in 99healthy men (mean age, 30 years).13 They found thatplacebo and high-dose tadalafil produced equivalenteffects on the QT interval, whereas ibutilide producedan increase of 6.9 ms and 8.9 ms compared withtadalafil and placebo, respectively.13 A double-blind,placebo- and positive-controlled, period-balanced,

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6-way crossover study evaluated the therapeutic andsupratherapeutic oral doses of vardenafil (10 mgand 80 mg, respectively) and sildenafil (50 mg and400 mg, respectively), therapeutic doses of moxifloxa-cin (400 mg), and placebo in 58 healthy men (meanage, 53 years).14 Six replicate, 12-lead ECGs wererecorded at 3 time points before and 5 time pointsafter dosing. Therapeutic and supratherapeutic dosesproduced only small, clinically insignificant increasesin the QTcF (measured by Fridericia formula) andrevealed shallow dose-response curves to QTc relation-ship for each PDE-5 inhibitor. As expected, moxifloxa-cin increased the absolute QTc by a mean of 8 ms.These clinical studies have shown that with singletherapeutic or supratherapeutic doses in healthypatients (no CKD or CHF), there is no QTc-prolong-ing effect of PDE-5 inhibitors.

A number of investigators have also performed ani-mal studies using both isolated heart models andwhole-cell patch clamp techniques in ventricular myo-cytes to study the effects of PDE-5 inhibitors on repo-larization, albeit the results on the exact mechanismremain controversial. In 2000, Geelen and colleagues15

used isolated guinea pig hearts measuring monophasicaction potentials and whole-cell patch clamp in humanEther-a-go-go Related Gene (hERG) transfectedHEK293 cells. They found a 15% increase in actionpotential duration (APD) during pacing at a basiccycle length of 250 ms and a 6% increase at a basiccycle length of 150 ms. The hERG-transfectedHEK293 cells showed a concentration-dependentblock of the rapid component (IKr) of the delayed rec-tifier potassium current compared with control. There-fore, they concluded that sildenafil prolonged cardiacrepolarization by blocking (IKr), the hERG current,and therefore its electrophysiologic effects are similarto that of other class III antiarrhythmics15 (Table).

In 2002, Chiang and colleagues used guinea pigsand canine Purkinje fibers to investigate the effects oftherapeutic and supratherapeutic doses of sildenafil onrepolarization. Dosages used to achieve therapeuticserum concentrations were those typically found inpatients being treated for ED. They found that APDwas not affected at therapeutic doses, but shortened atsignificantly higher doses in both the papillary muscleand Purkinje fibers.16 Sildenafil had no effect on the

rapid (IKr) or slow (IKs) components of the delayedrectifier potassium currents at any dose concentration.Sildenafil did dose-dependently block the L-type cal-cium current (ICa,L) in ventricular myocytes (Table).They went on to show that the QTc-prolonging effectproduced by sotalol or amiodarone could be reversedby administering supratherapeutic concentrations ofsildenafil.16 There are several possible explanations asto why in this study sildenafil had an APD-shorteningeffect. At significantly high plasma levels, sildenafil cancross-react with PDE-3 and increase intracellularcAMP levels, which, in turn, can enhance IK- andcAMP-dependent Cl) channels. Furthermore, theyshowed that sildenafil had a blocking effect on ICa,L

with higher plasma concentrations, which depressesthe plateau of the action potential.17 One study thatsupports the results from the Geelen study evaluatedwhether tadalafil, vardenafil, or sildenafil could inhibitthe hERG (IKr) channel and found a dose-dependentreduction in the hERG current amplitude over a largeconcentration range of 0.1 lM to 100 lM. They con-cluded, however, that at clinically therapeutic plasmalevels, none of these PDE-5 inhibitors could potentlyinhibit the hERG channel.18

The effect of sildenafil on VF and VT in the preclini-cal setting has also been investigated. Swissa and col-leagues19 evaluated the effects of sildenafil with andwithout the use of nitric oxide (NO) donors on pro-moting VT or VF in isolated swine right ventriclesafter rapid pacing. Sildenafil at lower concentrationswith or without an NO donor could not induceVT ⁄ VF. However, higher concentrations of sildenafilwith an NO donor did produce a dramatic increase inVT ⁄ VF. Investigators have also evaluated the effects ofsildenafil at supratherapeutic levels on VF threshold.Also using a swine model, high-dose sildenafil wasassociated with a reduction in the VF threshold whencompared with normal doses and placebo.20 Thesefindings are similar to another study by the samegroup which showed that supratherapeutic levels ofsildenafil decreased the defibrillation efficacy byincreasing the defibrillation threshold 19% by voltageand 38% by total energy compared with placebo.21

This indicates that for each shock delivered, a highershock strength would be required to restore a perfus-ing rhythm.

TABLE. PDE-5 Inhibitors and Electrophysiologic Effects

Study Drug(s) Used hERG (IKr) Channel IKs Channel ICa,L Channel Ip,Na Channel Effect on APD

Geelen et al15 Sildenafil Concentration-

dependent block

Not tested Not tested Not tested Prolonged

Chiang et al16 Sildenafil No effect No effect Concentration-

dependent block

No significant

effect

Shortened

Dustan Sarazan

et al18

Sildenafil,

vardenafil,

tadalafil

Concentration-

dependent block

Not tested Not tested Not tested Not tested

Abbreviations: APD, action potential duration; hERG, Ether-a-go-go Related Gene.

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These preclinical studies are largely at odds on theexact mechanism of action in the ventricular myocyte.Two studies15,18 support the notion that the APD isprolonged via a dose-dependent blocking effect on thehERG (IKr) channel, whereas the other has shown thatthe ICa,L channel is blocked, also in a dose-dependentmanner, thus shortening the APD.16 However, allstudies did show that at clinically relevant plasma con-centrations, no significant effect on cardiac repolariza-tion was seen. The VT ⁄ VF studies indicate that invarious in vivo and ex vivo swine models, suprathera-peutic concentrations of sildenafil may reduce the effi-cacy of defibrillation, that significantly more energymay be required during shock delivery to restore per-fusion, and that the myocardium may be more suscep-tible to VT ⁄ VF, especially in the presence of NOdonors. Further studies are needed before any firmconclusion on the exact electrophysiologic mechanismof PDE-5 inhibitors can be made.

SILDENAFIL AND HFSince the approval of sildenafil for the treatment PAH,numerous clinical trials have been ongoing, and somerecently published, on the treatment of PAH with HF,either with concomitant right ventricular failure orpreserved LVEF. In a 6-month study, patients with sta-ble CHF were treated with sildenafil 50 mg twice dailyor placebo (each arm, n=23 patients).22 At 3 and6 months, PASP, ergoreflex effect on ventilation, andventilation to carbon dioxide production slope wereall significantly decreased, while peak oxygen con-sumption and brachial artery flow–mediated dilation,an indicator of improved endothelial function, bothincreased. This same group recently published anotherstudy in which 44 patients with HF signs and symp-toms, PASP >40 mm Hg, but preserved LVEF >50%(diastolic dysfunction), were given placebo or sildenafil50 mg 3 times daily.23 At 6 months they found thatpatients treated with sildenafil had a significant reduc-tion in right atrial pressure (54�7.2%), a 42%�13%reduction in mean pulmonary artery pressure,improved PCWP, and isovolumetric relaxation time,and showed that these improvements were preservedat 1 year. Currently, larger randomized controlled tri-als are being conducted in patients with diastolic HFand are looking to evaluate the benefits of chronicPDE-5 use, such as the PhosphodiesteRasE-5 Inhibi-tion to Improve Quality of Life and Exercise Capacityin Diastolic Heart Failure (RELAX) trial.24

PDE-5 INHIBITORS AND VENTRICULARARRHYTHMIAS IN PATIENTSIn 1998, Shah25 first reported two patients with a his-tory of coronary artery disease who had VT associatedwith sildenafil use. In a few cases, sildenafil has alsobeen associated with atrial fibrillation in susceptiblepatients.26,27 One case reports that a 41-year-old manhad sustained monomorphic VT after taking 100 mgof sildenafil.28 He was not taking any other medica-

tion, had no history of cardiac disease, and no familyhistory of sudden cardiac death or long QT syndrome.Cardiac work-up of ischemia was unremarkable. Anelectrophysiologic study was performed and revealedthat stimulation at the right ventricular apex and out-flow tract induced 10 beats of nonsustained VT withalternating morphology. The patient subsequently hadanother electrophysiologic study done after 100 mg ofsildenafil and this time nonsustained VT of 24 beatswith identical morphology to the VT from admissionwas induced and subsequently an automated implant-able cardioverter-defibrillator (AICD) was placed.

Sildenafil citrate at supratherapeutic plasma concen-trations may increase the inducibility of ventricular ar-rhythmias in patients with systolic HF, CKD, andhepatic dysfunction and in those patients particularlyvulnerable to drug accumulation. At what plasma con-centration does the myocardium become susceptibleremains unknown and the exact electrophysiologicmechanism remains speculative as the few preclinicalinvestigations have been discordant. One groupshowed that sildenafil may accelerate cardiac repolari-zation and shorten the APD through blocking theICa,L.16 Conversely, another laboratory showed thatAPD and cardiac repolarization is actually prolonged,primarily through blocking the fast component (IKr) ofthe delayed rectifier potassium current.15 Preclinicalresearch is still needed before any conclusion can bemade on any mechanism, but enough data do existshowing that at extremely high (tens to hundred times)unbound plasma concentration levels, the myocardiumlikely becomes more vulnerable to ventricular arrhyth-mias. Furthermore, sildenafil increases sympatheticmodulation through its reflexive vasodilatory actionand such an increase in sympathetic activation in HFpatients could also be a mechanism for fatal ventricu-lar arrhythmias. Additionally, sildenafil, vardenafil,and tadalafil all have variable levels of PDE-5 selectiv-ity and, at higher plasma concentrations, have somecross-reactivity with PDE-3, thereby increasingintracellular cAMP levels, which also increasesautomaticity.

DISCUSSIONWe would hypothesize that our case represents thetypical case of a patient hospitalized with NYHA classIII or IV HF, and World Health Organization (WHO)group II PAH who was not a candidate for mechanicalassist device or cardiac transplantation. We proposethat, similar to a large number of patients in the PDE-3 inhibitor studies, our patient with low LVEF, PAH,and CKD experienced 3 episodes of sudden death.Based on our case and discussion, we would like topose several important questions regarding the use ofPDE-5 inhibitors in patients with CHF. There are noaccepted guidelines on their use in patients withdecompensated HF. These suggestions are the guide-lines we have established for our own program: (1)Should PDE-5 inhibitors be used in patients with CHF

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and preserved LVEF? The literature and our ownexperience support the safety and efficacy of PDE-5inhibitors in this patient population. (2) Should PDE-5inhibitors be used at all in patients with low LVEFand WHO group II PAH especially with CKD? Wewould not begin these patients on PDE-5 inhibitorsbut rather a combination of hydralazine and isordilwith dosing guidelines from the African AmericanHeart Failure Trial (A-HeFT).29 (3) Should patientswith a low ejection fraction and PAH have an AICDplaced? We bring these patients into the hospital and,using PDE-3 inhibitors or nesiritide, attempt to reducepulmonary vascular resistance and then place anAICD. Furthermore, we would like to raise severalimportant questions for the HF specialist regarding theuse of PDE-5 inhibitors in CHF. (1) Should PDE-5inhibitors be used at all in patients with WHO groupII PAH and low LVEF, especially those with CKD? (2)Should patients with reactive PAH and low LVEF havean AICD in place prior to starting a PDE-5 inhibitor?After all, the patient with systolic dysfunction isalready at risk for sudden death. It also raises theproblem of placing an AICD in a patient with severePAH and the increased risk of the procedure. (3)There is discussion that the original doses of the PDE-3 inhibitors were too high. Perhaps the starting doseof sildenafil at 20 mg, thrice daily is also too high? Inany event, with the lessons learned from the PDE-3 tri-als, the ventricular dysrhythmia potential of thepatient with low LVEF and the known pharmacologiceffects of sildenafil, great caution should be used instarting a patient with low LVEF and pulmonaryhypertension on sildenafil. Therefore, we should pro-ceed with great caution and care when and if wedesign clinical trials in HF using PDE-5 inhibitors,paying very close attention to electrical activity andventricular dysrhythmias.

Disclosures: The authors disclose that they have no conflicts of interest.

References1 Corbin JD, Francis SH. Pharmacology of phosphodiesterase-5 inhibi-

tors. Int J Clin Pract. 2002;56:453–459.2 Corbin JD, Francis SH. Phosphodiesterase type 5 as a pharmacologic

target in erectile dysfunction. Urology. 2002;60(2 suppl 2):4–11.3 Uzunov P, Weiss B. Separation of multiple molecular forms of cyclic

adenosine 3050 monophosphate phosphodiesterase in rat cerebellumby polyacrylamide gel electrophoresis. Biochem Biophys Acta.1972;284:220–226.

4 Fertel R, Weiss B. Properties and drug responsiveness of cyclicnucleotide phosphodiesterases of rat lung. Mol Pharmacol. 1976;12:678–687.

5 Morgan JP, Gwathmey JK, DeFeo TT, et al. The effects of amrinoneand related drugs on intracellular calcium in isolated mammaliancardiac and vascular smooth muscle. Circulation. 1986;73(3 pt 2):III65–III77.

6 Hastillo A, Hess M, Taylor DO. Amrinone. In: Massarelli F, ed. Car-diovascular Therapeutics, 1st ed. Philadelphia, PA: W.B. Saunders;1996:300–315.

7 Uretsky BF, Jessup M, Konstam MA, et al. Multicenter trial of oralenoximone in patients with moderate to moderately severe congestiveheart failure. Lack of benefit compared with placebo. EnoximoneMulticenter Trial Group. Circulation. 1990;82:774–780.

8 Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinoneon mortality in severe chronic heart failure. The PROMISE StudyResearch Group. N Engl J Med. 1991;325:1468–1475.

9 Feldman AM, Bristow MR, Parmley WW, et al. Effects of vesnari-none on morbidity and mortality in patients with heart failure.Vesnarinone Study Group. N Engl J Med. 1992;329:149–155.

10 Cohn JN, Goldstein SO, Greenberg BH, et al. A dose-dependentincrease in mortality with vesnarinone among patients with severeheart failure. Vesnarinone Trial Investigators. N Engl J Med. 1998;339:1810–1816.

11 Amsallem E, Kasparian C, Haddour G, et al. Phosphodiesterase IIIinhibitors for heart failure. Cochrane Database Syst Rev. 2005;CD002230.

12 Alpaslan M, Onrat E, Samli M, et al. Sildenafil citrate does notaffect QT intervals and QT dispersion: an important observation fordrug safety. Ann Noninvasive Electrocardiol. 2003;8:14–17.

13 Beasley CM Jr, Mitchell MI, Dmitrienko AA, et al. The combineduse of ibutilide as an active control with intensive electrocardio-graphic sampling and signal averaging as a sensitive method to assessthe effects of tadalafil on the human QT interval. J Am Coll Cardiol.2005;46:678–687.

14 Morganroth J, Ilson BE, Shaddinger BC, et al. Evaluation of varde-nafil and sildenafil on cardiac repolarization. Am J Cardiol.2004;93:1378–1383.

15 Geelen P, Drolet B, Rail J, et al. Sildenafil (Viagra) prolongs cardiacrepolarization by blocking the rapid component of the delayed recti-fier potassium current. Circulation. 2000;102:275–277.

16 Chiang CE, Luk HN, Wang TM, et al. Effects of sildenafil on car-diac repolarization. Cardiovasc Res. 2002;55:290–299.

17 Roden DM. Acquired long QT syndrome and the risk of proarrhyth-mia. J Cardiovasc Electrophysiol. 2000;11:938–940.

18 Dustan Sarazan R, Crumb WJ Jr, Beasley CM Jr, et al. Absence ofclinically important hERG channel blockade by three compoundsthat inhibit phosphodiesterase-5 – sildenafil, tadalafil, and vardenafil.Eur J Pharmacol. 2004;502:163–167.

19 Swissa M, Ohara T, Lee MH, et al. Sildenafil-nitric oxide donorcombination promotes ventricular tachyarrhythmias in the swine rightventricle. Am J Physiol Heart Circ Physiol. 2002;282:H1787–H1792.

20 Kanlop N, Shinlapawittayatorn K, Sungnoon R, et al. Sildenafil cit-rate on the inducibility of ventricular fibrillation and upper limit ofvulnerability in swine. Med Sci Monit. 2008;14:BR205–BR209.

21 Shinlapawittayatorn K, Sungnoon R, Chattipakorn S, et al. Effects ofsildenafil citrate on defibrillation efficacy. J Cardiovasc Electrophysi-ol. 2006;17:292–295.

22 Guazzi M, Samaja M, Arena R, et al. Long-term use of sildenafil inthe therapeutic management of heart failure. J Am Coll Cardiol.2007;50:2136–2144.

23 Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hyperten-sion in heart failure with preserved ejection fraction: a target ofphosphodiesterase-5 inhibition in a 1 year study. Circulation.2011;124:164–174.

24 Evaluating the effectiveness of sildenafil of improving health out-comes and exercise ability in people with diastolic heart failure –The RELAX Study. 2011; Available at: http://www.clinicaltrials.gov/ct2/show/NCT00763867?term=NCT00763867&rank=1. AccessedNovember 29, 2011.

25 Shah PK. Sildenafil in the treatment of ED. N Engl J Med.1998;339:699.

26 Awan GM, Calderon E, Dawood G, et al. Acute, symptomatic atrialafter sildenafil citrate therapy in a patient with hypertrophic obstruc-tive cardiomyopathy. Am J Med Sci. 2000;320:69–71.

27 Hahn IH, Hoffman RS. Aroused to atrial fibrillation? Am J EmergMed. 2000;18:642.

28 Rasmussen JG, Toft E, Frøbert O. Ventricular tachycardia afteradministration of sildenafil citrate: a case report. J Med CaseReports. 2007;1:65.

29 Franciosa JA, Taylor AL, Cohn JN, et al. African American HeartFailure Trial (A-HeFT): rationale, design and methodology. J CardFail. 2002;8:128–135.

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