Journal of Cardiac Failure Vol. 16 No. 6 2010

Review Article

Pulmonary Hypertension in Heart Failure

MAYA GUGLIN, MD, PhD,1 AND HAMMAD KHAN, MD1

Tampa, Florida

From the 1DepaManuscript rece

14, 2010; revisedReprint request

versity of South33618. Tel: 813-2

See page 470 fo1071-9164/$ - s� 2010 Elseviedoi:10.1016/j.ca

ABSTRACT

Background: Pulmonary hypertension occurs in 60% to 80% of patients with heart failure and is asso-ciated with high morbidity and mortality.Methods and Results: Pulmonary artery pressure correlates with increased left ventricular end-diastolicpressure. Therefore, pulmonary hypertension is a common feature of heart failure with preserved as wellas reduced systolic function. Pulmonary hypertension is partially reversible with normalization of cardiacfilling pressures. Pulmonary vasculature remodeling and vasoconstriction create a second component,which does not reverse immediately, but has been shown to improve with vasoactive drugs and especiallywith left ventricular assist devices.Conclusion: Many drugs used for idiopathic pulmonary arterial hypertension are being considered astreatment options for heart failureerelated pulmonary hypertension. This is of particular significance inthe heart transplant population. Randomized clinical trials with interventions targeting heart failurepatients with elevated pulmonary artery pressure would be justified. (J Cardiac Fail 2010;16:461e474)Key Words: Heart failure, pulmonary hypertension, pulmonary reversibility testing, pulmonary vascularresistance, left ventricular assist device, heart transplant.

Heart failure (HF) is the most common cause of pulmo-nary hypertension (PH). Elevated left heart filling pressures,whether from systolic dysfunction, diastolic dysfunction, orvalvular heart disease, can result in elevated pulmonary ar-tery pressures.1 The proportion of HF patients who alsohave PH varies depending on the subset of patients, but re-mains invariably high. In 1992, Abramson et al2 reportedthat 26% of their cardiomyopathy cohort had a systolic pul-monary artery (PA) pressure of 40 mm Hg or higher. In2001, Ghio et al3 found PH in more than 60% of their pa-tients with moderate or severe HF and left ventricular (LV)dysfunction. In 2009, Lam et al4 presented the Mayo Cliniccohort of HF patients with preserved systolic function,more than 80% of which had PH.

However, although the literature is abundant on the much lesscommon primary pulmonary arterial hypertension, it is

rtment of Cardiology, University of South Florida, Tampa.ived July 7, 2009; revised manuscript received Januarymanuscript accepted January 19, 2010.s: Maya Guglin, MD, PhD, Director, Heart Failure, Uni-Florida, 2A Columbia Drive Suite 5074, Tampa, FL59-0992; E-mail: mguglin@health.usf.edur disclosure information.ee front matterr Inc. All rights reserved.rdfail.2010.01.003

461

relatively scarce on PH in HF, or type 2 PH by the World HealthOrganization classification. This review will focus on PH in HF.

Definitions

PH is usually defined as a chronic elevation of a mean PApressure above 25 mm Hg, measured invasively by a PAcatheter.5 By echocardiography, PA systolic pressure iscommonly estimated from the velocity of tricuspid regurgi-tation. PH is considered mild if the PA systolic pressureis 35 to 45 mm Hg, moderate if it is 46 to 60 mm Hg,and severe if it is greater than 60 mm Hg.6

The driving pressure across the pulmonary circulation, orthe difference of mean PA pressure and pulmonary capil-lary wedge pressure, is referred to as the transpulmonarygradient (TPG).

Pulmonary vascular resistance (PVR) is derived by divid-ing the difference of mean PA pressure and left atrial pres-sure (pulmonary capillary wedge pressure) by the cardiacoutput. PVR index is used to correct PVR for body sizeand to avoid underestimation of PH in obesity.

The key feature differentiating PA hypertension and PHresulting from HF is elevated pulmonary capillary wedgepressure, which is present in HF and absent in pulmonaryarterial hypertension. The latest diagnostic algorithm ispresented by Hoeper et al (Fig. 1).7

Fig. 1. Diagnostic algorithm for PH.7 EF, ejection fraction; DHF, diastolic heart failure; PVR, pulmonary vascular resistance; PCWP,pulmonary capillary wedge pressure; PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; RHC, right heart catheterization;WU, Wood units.

462 Journal of Cardiac Failure Vol. 16 No. 6 June 2010

Pathophysiology

In HF, there are 2 major components of PH: hydrostaticand vasoreactive (Fig. 2). Hydrostatic, or the passive com-ponent, reflects the backward transmission of elevated LVend-diastolic pressure. Therefore, PA systolic pressure cor-relates tightly with pulmonary capillary wedge pressure and

Fig. 2. Pathophysiology of pulmonary hypertension in heart failure.

is roughly twice the wedge pressure.8 The reactive compo-nent represents vasoconstriction and remodeling of pulmo-nary vasculature.

Normally, the pulmonary vasculature is characterized bylow pressure, low resistance, and high distensibility. It canaccommodate a significant increase in blood flow witha minimal elevation of PA pressure. When this compensa-tory capacity is exceeded, PA pressure increases at firston exertion and then at rest. The right ventricle is very sen-sitive to changes in afterload. With chronic elevation inafterload, the right ventricle begins to fail. Excessive sym-pathetic adrenergic stimulation as well as activation of theendothelin and renin-angiotensin-aldosterone system con-tributes to the pathophysiology of right ventricularfailure.9e11 Right ventricular dilatation results in a leftwardshift of the septum causing a change in LV geometry, de-crease in LV distensibility, and thus contributing to thelow cardiac output state.12 The measured severity of PH de-pends, in part, on the performance of the right ventricle.Right ventricular failure as a result of cardiomyopathy, in-farct, or ischemia may occur at pulmonary pressures lowerthan 45 to 50 mm Hg; severe PH may never develop, de-spite an increase in PVR. An acute increase in pulmonaryvascular tone can also result in right ventricular failure asis seen in heart transplant recipients with PH and thus thereis the necessity to decrease PA pressure both before andafter heart transplant.

Structural changes occur at the capillary level includingswelling of the pulmonary capillary endothelial cells, thick-ening of the basal lamina, and proliferation of reticular andelastic fibrils. These structural changes contribute toward

Pulmonary Hypertension in Heart Failure � Guglin and Khan 463

increasing PVR, decreasing permeability of the vascularbed, and ultimately lower the possibility of developmentof pulmonary edema13 and increase the likelihood of rightventricular failure. These changes are mostly reversible ifthere is a successful reduction in cardiac filling pressures,although the reversal may take several months.14

Factors Determining PH

Although related to LV failure, PH in the context of HFdoes not seem to correlate with the severity of LV systolicdysfunction. On the contrary, it depends on the elevation offilling pressure echocardiographically determined by sever-ity of diastolic dysfunction.15e18

The E wave deceleration rate, E/A ratio,15,19 and ratio ofE/E0 have been shown to reflect end-diastolic pressure moreaccurately than other echocardiographic parameters.20 Ac-cording to the results of various studies, the restrictive fill-ing pattern,21 the E wave deceleration rate, and the degreeof mitral regurgitation were the strongest independent pre-dictors of PH.19 A reduction in PA systolic pressure duringtherapy is determined, to the great extent, by wedge pres-sure reduction.8 Moreover, the reversibility of PH was ap-parent only in those patients who exhibited improvementof diastolic dysfunction from the restrictive or pseudonor-mal to impaired relaxation pattern likely representing im-provement in filling pressures.

Among patients with normal systolic function, Neumanet al22 found a significant increase in PA pressure foreach step up in diastolic dysfunction grade. The mean PApressure was 31.1 6 6 mm Hg for normal diastolic func-tion, 35.6 6 10.2 mm Hg for grade 1 diastolic dysfunction(impaired relaxation), 38.9 6 10.6 mm Hg for grade 2(pseudo normal), and 55.1 6 11.4 mm Hg for grade 3 (re-strictive pattern) (P ! .001). Interestingly, pulmonary ve-nous hypertension has been shown to be highly associatedwith the metabolic syndrome in patients with normal LVsystolic function.23

Age strongly predicts PH as well.16 PH is highly prev-alent among patients with end-stage renal disease on he-modialysis. In 1 study, diastolic dysfunction was presentin three fourths of patients with PH and end-stage renaldisease. A higher PA pressure correlated with a higherflow through arteriovenous fistula and the brain natriureticpeptide level.24

In exercise, wedge pressure rises in parallel with PA meanpressure; both correlate well with maximal oxygen consump-tion, unlike resting cardiac index and resting systemic arterialmean pressure, which did not demonstrate correlation withPA pressure.25 However, according to other data, ejectionfraction, or degree of systolic dysfunction, is a determinantof PH on exercise. LV ejection fraction (P 5 .03) and mitraleffective regurgitant orifice (P 5 .008) were independentlyassociated with PA systolic pressure. Furthermore, dyspneaon exertion was more pronounced in patients with greaterexercise-related increase in PA systolic pressure.26

Compared with patients with idiopathic pulmonary arte-rial hypertension, patients with pulmonary venous hyper-tension have been found to have a higher frequency ofmetabolic syndrome.23

Clinical Significance

In patients with HF, PH is a predictor of poor outcome. Itis associated with increased short- and long-term mortal-ity2,27 in patients with both reduced and preserved LV ejec-tion fraction.28 Moreover, it was recently discovered thatPH is associated with poor prognosis and high mortality,not only in HF, but also in general population.29

Patients with a higher velocity of tricuspid regurgitation(greater than 2.5 m/s) had a 40% higher mortality rate anda 50% higher rate of HF admissions than those with normalpulmonary pressures.2 Shalaby et al30 demonstrated thatelevated baseline systolic PA pressure in patients who un-dergo cardiac resynchronization therapy independentlypredicted all-cause mortality or transplantation and HF ad-mission. A post-resynchronization decrease in pulmonarypressure was an independent positive prognostic marker. Inanother study, in which more than 1000 patients with cardio-myopathy were followed for an average of 4.4 years, meanPA pressure appeared to be 1 of the most important hemody-namic predictors of death.27 In a cohort of 400 patients withknown or presumed HF and PH, a Cox proportional-hazardsmodel apportioned a 9% increase in mortality per 5 mm Hgincrease in right ventricular systolic pressure.28

PH also impacts the exercise capacity in HF patients. Intreadmill exercise testing with hemodynamic monitoring,increased pulmonary vascular resistance was associatedwith significantly lower peak exercise oxygen consumption(VO2) and lower peak exercise cardiac output, suggestingthat PH impairs exercise performance in HF.31

Role of PH in Heart Transplantation

PH is a risk factor for early postoperative mortality inheart transplantation, mostly from fatal right ventricularfailure. According to data from the International Societyfor Heart and Lung Transplantation registry, approximately20% of early deaths after cardiac transplantation can be at-tributed to right ventricular failure.32 Several studies haveidentified increased PVR O2.5 Woods units (WU), whichis present in about 30% of heart transplant candidates, asan important risk factor for early death after transplant.Other groups reported a 2.5-fold increase in 3-month mor-tality in patients with a PVR O2.5 and an increase in 3-, 6-,and 12-month mortality with a TPG O15 mm Hg.33e35

Retrospectively studied transplant patients had a 1-yearmortality of 5.6% if their PVR and TPG were below theselevels and 24.4% if they exceeded these numbers before thetransplant.35

These and other observations are reflected in the listingcriteria for cardiac transplantation published by the Interna-tional Society for Heart and Lung Transplantation.

464 Journal of Cardiac Failure Vol. 16 No. 6 June 2010

According to them, PA hypertension and elevated PVRshould be considered as a relative contraindication to car-diac transplantation when the PVR is O5 WU or thePVR index O6 or the TPG exceeds 16 to 20 mm Hg. IfPA systolic pressure exceeds 60 mm Hg in conjunctionwith any 1 of the preceding 3 variables, the risk of rightHF and early death is increased. If the PVR can be reducedto !2.5 with a vasodilator but the systolic blood pressurefalls !85 mm Hg, the patient remains at high risk of rightHF and mortality after cardiac transplantation.36

The determination of TPG in combination with PVR isa more reliable predictor of early posttransplant survivalthan PVR alone.37 Butler et al reported that PA systolicpressure and TPGdbut not PVR pretransplantdwere asso-ciated with poor posttransplant survival.38

Interestingly, some investigators did not see the increasedrisk when performing transplants with PH. Tenderich et al39

could not confirm increased mortality in patients with ele-vated PVR. In their 83 patients with preoperative PVR$5 WU and TPG O15 mm Hg, 30-day mortality and cu-mulative survival after 1 and 5 years was not differentfrom patients with more favorable from the hemodynamicprofile.40 Addonizio et al41 transplanted 33 patients withPVR index $6, and 28 of them survived.

After heart transplantation, 80% of survivors normalizetheir PVR at 1 year,42e44 indicating that even ‘‘fixed’’ PHreverses eventually with adequate blood flow and normalfilling pressures. Similar favorable changes occur in LVassist device (LVAD) recipients.

Reversibility Tests

PH is considered reversible if PVR can decrease to #2.5WU with pharmacological testing, which is commonlydone as a part of the transplant evaluation process in anattempt to predict and improve outcomes. Patients with re-active PH can be considered suitable for orthotropic cardiactransplantation.

Different factors influence the reversibility of PH, which isless reversible in patients with ischemic versus nonischemiccardiomyopathy and in ex-smokers versus nonsmokers.45

Reversibility of PH translates into improved 30-day survivalrate after heart transplantation, but does not entirely elimi-nate the risk. Pharmacological tests to predict the reversibil-ity of PH do not always reflect the posttransplant response.Cardiopulmonary bypass and intraoperative blood productsmay lead to further increase in PVR, which might explainwhy even patients with ‘‘reversible’’ PH still have a markedlyhigher mortality compared with patients with normal PVR.34

According to Costard-Jackie et al,46 candidates for trans-plant with a PVR O2.5 WU had a 3-month posttransplantmortality rate of 17.9% versus 6.9% in patients with PVR#2.5 WU. However, if their PVR could be reduced to #2.5WU with nitroprusside without a significant drop in systemicblood pressure, their 3-month mortality after the transplantwas only 3.8%, as opposed to 40.6% in those who did not re-spond to nitroprusside and 27.5% in those who responded but

with a drop in systolic blood pressure to below 85 mm Hg. Af-ter these data were published in 1992, it became a commonpractice to conduct acute pharmacological testing in patientswith HF and PH before heart transplant.

Historically, sodium nitroprusside was used as a challengein the acute setting. Intravenous nitroprusside therapy is be-gun with a dose of approximately 1 mcg kg min and titrateduntil (1) PVR decreases to below 2.0 Wood units, (2) PA sys-tolic pressure decreases to below 50 mm Hg, or (3) meanblood pressure decreases to below 65 mm Hg.34

Currently, multiple other agents are used for PH revers-ibility testing. Table 1 has medications and doses used forthis purpose. It is difficult to say which agents are betterthan others because direct comparison of all of them ina randomized manner was never done. To a great extent,the choice of an agent depends on the experience of a partic-ular center.

An intravenous bolus of 0.1 mg of nitroglycerin can befollowed by increasing doses according to the criteriaused for nitroprusside.47 An intravenous bolus of milrinonefollowed by continuous infusion can be used acutely andcontinued for a prolonged time.48,49

Among patients participating in the study by Pambou-kian et al,49 none of those who responded to milrinone inpretransplant testing died after the transplant. Milrinonewas also tested as a nebulizer.50

Inhaled nitric oxide (NO) is a potent, rapidly acting, andselective pulmonary vasodilator that causes pulmonary vaso-dilatation with minimal systemic effects, thereby reducingTPG and PVR.51,52 Compared with nitroprusside, NO doesnot drop systemic pressure, although it can sometimes causean elevation in pulmonary capillary wedge pressure.53

Intravenous dipyridamole augments and prolongs the pul-monary vasodilator effects of inhaled NO in congestive HFpatients with severe PH; when administered in combinationwith NO inhalation, it can identify PH reversibility in poten-tial cardiac transplant recipients in whom no pulmonary va-sodilator response to inhalation of NO alone is observed.54

Prostaglandins are also used for PH reversibility testingwith good results. Prostacyclin is infused at a starting doseof 1 to 2 ng kg min and increased until a decrease in systolicarterial blood pressure, increase in heart rate, or side effectssuch as nausea and headache. Haraldsson and colleagues55

described a good selective dose-dependent decrease inPVR and TPG with inhaled prostacyclin with no effects onsystemic circulation. It effectively improves pulmonary he-modynamics, with an almost 50% reduction in PVR (P 5

.0003) and a doubling of PA compliance (P ! .0001), reflect-ing improvement in pulmonary vascular tone. Furthermore, itproduces a positive inotropic effect.56 Intravenous prosta-glandin E1 have also safely and successfully lowered PVRand TPG in 99% of patients without any significant sideeffects.57 In the Muenster experience, all patients with PH ex-perienced a successful reduction in PVR by using prostaglan-din E1 or prostacyclin; their 30-day and 10-year survivalrates after orthotopic cardiac transplantation were similarto patients without PH.58

Table 1. Pharmacologic Agents Used for Testing of Reversibility of PH

Agent Dose Route Author, Year

Milrinone 50 mcg/kg IV Givertz et al 1996,48 Pamboukian et al 1999,49 Botha 200968

Enoximone 0.5e2.5 mg/kg IV Murali et al 199164

Dobutamine 7.5e15 mcg/kg/min IV Murali et al 199164

Sodium nitroprusside 1e1.5 mcg/kg/min to maximally tolerated IV Murali et al 1991,64 Semigran et al 1994,53 Kieler-Jensen 1994,51

Pagano et al 1996,146 Weston et al 200160

Prostaglandin E1 O50 ng/kg/min IV von Scheidt et al 2006,57 Radovancevic 200563

Prostaglandin E1 !50 ng/kg/min IV Murali et al 1992,147 Murali et al 1991,64 Wasler 1993148

Prostacyclin 5e13 ng/kg/min IV Kieler-Jensen 1994,51 Pagano et al 1996,146 Trautnitz 1999149

Prostacyclin 50e1000 mcg Inhaled Weston et al 2001,60 Haraldsson et al 1998,62 Sablotzki et al 200261

Sildenafil 25e100 mg PO Angel Gomez-Sanchez et al 2004,67 Alaeddini et al 2004,66 Leporeet al 2005,83 De Freitas 2009150

Sildenafil 0.43 mg/kg IV Botha 200968

Sildenafil 0.05 mg/kg IV Botha 200968

Nitroglycerin 15e25 mcg/kg/min IV Murali et al 199164

Nitric oxide 5e80 parts per million Inhaled Kieler-Jensen N 1994,51 Lepore et al 2005,54,83 Mahajan et al2007,151 Haraldsson et al 1998,62 Pagano et al 1996,146 Sablotzkiet al 2002,61 Radovancevic et al 2005, 63 Semigran et al 1994,53

Fojon 2006,152 Loh 1994153

Dipyridamole 0.2-mg/kg bolus, then infusion of0.0375 mg/kg/min

IV Lepore et al 200554

Nesiritide Bolus 2 mcg/kg then 0.01 mcg/kg/min IV O’Dell et al 2005136

PO, orally; IV, intravenously.

Pulmonary Hypertension in Heart Failure � Guglin and Khan 465

Some evidence suggests that prostaglandins may be moreeffective than other agents in the acute reversal of PH. Pros-tacyclin, compared with sodium nitroprusside, induceda greater increase in cardiac output and decrease in systemicand pulmonary vascular resistances as well as lesser decreasein cardiac filling pressures.59 Inhaled prostacyclin effectivelyreversed PH in patients resistant to sodium nitroprusside,60

and caused a significantly greater reduction in PA pressureand an increase in cardiac output than inhaled NO.61,62 Otherdata have indicated that patients unresponsive to NO may beresponsive to prostaglandin E1 and vice versa.63

Murali et al64 compared nitroglycerin and nitroprussideto prostaglandin E1, dobutamine, and enoximone. All ofthe drugs significantly increased cardiac output and de-creased PVR. In addition, all of the drugs except dobut-amine significantly lowered PA pressure and wedgepressure. However, prostaglandin E1 was the only drugthat significantly lowered TPG. The magnitude of declinein PVR and TPG was greatest with prostaglandin E1.

In a retrospective comparison of vasopressors (dobutamine,dopamine, or combination of both) with vasodilators (nitro-glycerin, sodium nitroprusside) and prostacyclin, no signifi-cant difference in the magnitude of decrease of PA pressure,TPG, or PVR, although cardiac output increased more withprostacyclin. Similar proportion of patients (45% to 50%)demonstrated reversibility of PH with each intervention.65

Recently, oral sildenafil has been used to assess for revers-ibility of PH, reducing PA pressure in a dose-dependent fash-ion without significant change in mean pulmonary capillarywedge pressure, cardiac output, systemic vascular resis-tances, or mean blood pressure.66,67 It provided an evenstronger effect when used in combination with inhaled NO.54

In a randomized comparison of intravenous milrinoneand intravenous sildenafil, milrinone produced greater de-crease in mean PA pressure and wedge pressure, as well

as increase in heart rate. The reductions in systemic andpulmonary vascular resistance were similar.68

When an acute vasodilator challenge is unsuccessful,hospitalization with continuous inotropes or vasodilatorsand hemodynamic monitoring may be required. PVR maynormalize in days or weeks; it almost always eventuallynormalizes with LVADs.42

Treatment

PH resulting from LV failure can be improved using med-ications that improve LV function. LV unloading results indecreased PA pressure, which in turn leads to favorable ef-fects on systemic circulation. b-blockers that normally donot directly change pulmonary pressure may reverse PH,which was considered fixed after post-nitroprusside, be-cause of the improved LV function.69 Cardiac resynchroni-zation therapy increases cardiac output and decreasespulmonary capillary wedge pressure, thereby partially re-versing hemodynamic abnormalities that lead to secondaryPH in many HF patientsdsometimes to the point thatthey become eligible for cardiac transplantation.70 Manytreatment options available for pulmonary arterial hyperten-sion have been tested in PH secondary to HF, some of themsuccessfully. Clinical studies in HF population assessingagents used in treatment of pulmonary arterial hypertensionare summarized in Table 2. Studies in which patients wereexposed to a single dose of a drug are not included inTable 2.

Phosphodiesterase Inhibitors (Sildenafil)

Sildenafil is a specific phosphodiesterase type 5 inhibitorthat increases NO availability and NO-mediated vasodila-tion in HF.71 In HF, phosphodiesterase type 5 activity is

Table 2. Clinical Trials with PH Medications in HF Patients

Treatment, DurationStudy Acronym and

CharacteristicsPatients Population,

DurationPH is an Inclusion

Criterion Outcome

Bosentan114

500 mg twice dailyREACH-1

Double-blind, randomized,placebo controlled

n 5 370NYHA III/IV26 weeks

No Terminated early because of liver function test abnormalities

Bosentan154

62.5 mg twice daily for 4weeks, then 125 mg twicedaily

ENABLEPlacebo controlled,randomized

n 5 16001.5 years

No No improvement with bosentan

Darusentan109

varying daily doses: 10 mg,25 mg, 50 mg, 100 mg, 300mg or placebo

EARTHPlacebo controlled,randomized, parallel

n 5 642NYHA II-IV6 months

No No change in left ventricular end systolic volume

Tezosentan155

50 or 100 mg/hour IVRITZ-5

Placebo controlled,randomized, blinded

n 5 84Acute pulmonary edema24 hours

No No change in oxygen saturationOutcome worse with higher dose

Bosentan110

8e125 mgTwice a day

Multicenter, double-blind,randomized placebocontrolled

n 5 94NYHA III-IV, EF !35%20 weeksTreatmentþ30 days’ Follow-up

YesSystolicPAP O40 mm Hg

No difference in systolic PAP change, cardiac index shift, or any of theother 22 echocardiographic measurements.More patients in the bosentan arm experienced adverse and seriousadverse events

Epoprostenol93

4.0 ng.kg.min IVThe Flolan International

Randomized Survival Trial(FIRST)

n 5 471NYHA III-IV, EF !25%2 years

No Increased mortality rates and no improvement in quality of life withFlolan

Prostaglandin E197

10 ng/kg/min IV for a totalof 24 hours over 3consecutive days every 3months

Prospective controlled notrandomized36 months

n 5 22NYHA III-IV, EF !35%.

YesTricuspid regurgitantvelocity O3 m/s by echoconfirmed by right heartcatheterization

36 months’ survival: 72.7% in the PGE1 group and 56% in the controlgroup (NS). The mean EF increased from 25.78% to 32.1% in thePGE1 group and from 23.38% to 26.15 in the control group (P !.001); the NYHA mean class improved from 3.18 to 2.24 in thePGE1 group and from 3.46 to 3.38 in the control group (P ! 05).The PA pressure decreased from 57.7 to 40.8 mm Hg (P ! 001)

Prostacyclin98 continuous IVinfusion

Prospective controllednonrandomized

n 5 33NYHA III-IVEF !30%12 weeks

No Increase in 6-minute walk distance72 6 40 vs. -39 6 32 m, P 5 .033

Sildenafil77 25 mg, 3 times/day

Not controlled, notrandomized

n 5 40HF6 months

No Improved heart rate recovery (baseline: 17.5 6 3.5 beats per minuteversus post: 20.6 6 3.2 beats/min)

Sildenafil85 50 mg twice perday

Prospective, randomized n 5 46!65 years oldNYHA II-IIIEF !45%6 months

No Reduction of systolic PAP (from 33.7 to 23.9 mm Hg), decrease inventilation to CO2 production slope (from 35.5 to 29.8), andbreathlessness score (from 23.6 to 17.2Increase in peak VO2 (from 14.8 to 18.7 ml � min(-1) � kg(-1)),and ratio of VO2 to work rate changes (from 7.7 to 9.3 and 10.1). Allchanges were significant at P ! .01

Sildenafil86

25 to 75 mg orally 3 timesdaily

Prospective randomizedplacebo controlled12 weeks

n 5 34NYHA II-IV, EF !40%

YesMean PApressure O25 mm Hg bycatheter

The change in peak VO2 from baseline was greater in the sildenafilgroup (1.8 6 -0.7 mL � kg(-1) � min(-1)) than in the placebogroup (-0.27 mL � kg(-1) � min(-1); P 5 .02). Sildenafil reducedpulmonary vascular resistance and increased cardiac output withexercise (P ! .05 vs. placebo for both). Sildenafil improved in 6-minute walk distance (29 m vs. placebo; P 5 .047) and MinnesotaLiving With Heart Failure score (-14 versus placebo; P 5 .01).Subjects in the sildenafil group experienced fewer hospitalizationsfor HF

PH, pulmonary hypertension; HF, heart failure; PAP, pulmonary arterial pressure; IV, intravenously; NYHA, New York Heart Association; EF, ejection fraction.

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Pulmonary Hypertension in Heart Failure � Guglin and Khan 467

increased in the systemic and pulmonary vasculature and inthe kidney. It is partially responsible for natriuretic peptidedesensitization in HF, and many effects of phosphodiester-ase type 5 inhibition produce effects similar to brain natri-uretic peptide infusion.72

Basic studies suggest that phosphodiesterase inhibitionhas potentially favorable direct myocardial effects thatmay block adrenergic, hypertrophic, and proapoptotic sig-naling.73 Sildenafil protects cardiomyocytes against necro-sis and apoptosis in the ischemia-reperfusion model,74

and prevents LV dysfunction in the anthracycline-inducedcardiomyopathy model.75 In humans, it has been found toenhance endothelial function76 and improve arterial stiff-ness.77

Sildenafil increases myocardial contractility and reducesLV afterload,78 blunts adrenergic stimulation,79 and im-proves lung diffusion capacity as well as pulmonary hemo-dynamics at rest and during exertion. Measurements onright cardiac catheterization have shown that sildenafilacutely reduced resting and exercise pulmonary arterialpressure, systemic vascular resistance, and PVR while in-creasing the resting and exercise cardiac index (P ! .05for all) without altering mean arterial pressure, heart rate,or pulmonary capillary wedge pressure, thereby acting asa selective pulmonary vasodilator.80 These effects are sus-tained if sildenafil is used regularly.81 It also reduces fluidtransition to the alveolar interstitium.80,82 In addition, silde-nafil augmented and prolonged the hemodynamic effects ofinhaled NO in patients with HF and PH.83

In exercise, sildenafil improves exercise ventilation effi-ciency and aerobic performance,84 as well as heart rate re-covery after exercise.77 It increases peak VO2 and decreasesventilatory response to carbon dioxide output during a car-diopulmonary stress test.80,85 Sildenafil’s ability to augmentpeak VO2 is directly correlated with baseline resting PVRand indirectly correlated with baseline resting right ventric-ular ejection fraction.86

Some early concerns about potential arterial oxygen de-saturation with sildenafil have yet to be confirmed. Sildena-fil is usually well tolerated without desaturation orsignificant changes in heart rate or blood pressure.87 Theonly common side effect is flushing.85

Favorable physiologic effects of sildenafil translate intobetter outcomes in HF patients. A randomized, double-blind, placebo-controlled trial demonstrated that sildenafilin HF patients with severely reduced systolic function de-creased PA systolic pressure at 60 minutes and at 4 weekscompared with a placebo.88 Symptomatically, stable HF pa-tients on optimal therapy experienced less breathlessness af-ter adding sildenafil as their systolic PA pressure decreasedfrom 33.7 to 25.2 mm Hg and 23.9 mm Hg (P ! .01) in 3and 6 months, respectively.85 Sildenafil treatment has alsobeen associated with improvement in right ventricular sys-tolic function, 6-minute walk distance, and Minnesota Livingwith Heart Failure score.86

Sildenafil may be effectively used not only for acutehemodynamic testing of PH reversibility, but also for

treatment of secondary, irreversible PH in potential hearttransplant recipients because it allows patients who mayotherwise have been excluded because of PH to be trans-planted. In 1 study, 6 patients with PH nonresponsive to ni-troprusside were put on oral sildenafil. After 1 month, 3patients had normalized PVR and TPG and 2 patients be-came responsive to nitroprusside.89 Moreover, sildenafil ap-pears to not only make patients eligible for heart transplant,but also provide a smooth postoperative course in trans-planted patients. Six patients received 50 mg of sildenafilbefore the transplant, followed by 50 or 25 mg 3 timesper day after heart transplantation; good short-term out-comes occurred in 4 of them. Sildenafil treatment was dis-continued 10 to 14 days after surgery, using a stepwise dosereduction.90

After LVAD implantation, sildenafil provides additionalreduction of PA pressure and facilitates weaning from in-haled NO and inotropes, which can otherwise cause a re-bound PH.91 All these small studies provide a goodbackground for future randomized controlled clinical trialsin HF population with PH.

Prostaglandins

Prostaglandins are potent vasodilators that have beenused in the treatment of primary (arterial) PH. They havemultiple effects that seem to benefit HF patients. Availableprostaglandins include prostaglandin I2 (prostacyclin, epo-prostenol, Flolan) and prostaglandin E1. Although the for-mer is a potent systemic vasodilator with consequentdeleterious effects on ischemic myocardium, the latter isdegraded in the pulmonary vessels and has a systemic effectonly at high doses.92,93 Intravenous prostaglandin E1 re-duces atrial natriuretic peptide and norepinephrine 94 whileincreasing renal perfusion and diuresis.95

Despite their vasoactive properties, prostaglandins didnot perform well in the HF setting. The acute effects of in-travenous prostacyclin in HF patients include a decrease inpulmonary capillary wedge pressure and PVR and an in-crease in cardiac index; however, at the same time, theycan cause a drop in arterial pressure and systemic vascularresistance, with a subsequent rise in plasma epinephrine,norepinephrine, renin, and aldosterone concentrations.96

Some small nonrandomized trials provided encouragingresults with improved hemodynamics and symptoms, show-ing a trend toward better outcomes through intermittent in-fusion of prostaglandin E1.97 Epoprostenol (prostacyclin),added to a maximal conventional treatmentdincludingdobutamine in 30% of patientsdresulted in an increase in6-minute walk distance by 30 meters in 12 weeks whencompared with standard treatment only. Long-term out-comes were not studied.98

One case report described a longer successful use ofprostaglandins. Intravenous prostacyclin and dobutaminecombined with inhaled iloprost given for 21 days stabilizeda patient with PH for heart transplantation, which was un-complicated.99 A direct prospective and randomized

Table 3. Reversal of Pulmonary Hypertension with Left Ventricular Assist Devices

N Time, DaysMean PA Pressure

before, mm HgMean PA Pressure

after, mm Hg PVR before, WU PVR after, WU

Zimpfer et al 2007142 35 42 5.1 2.0Liden et al 2009144 11 239 4.3 2.0Etz et al 2007143 10 182 42 24 4.8 2.2Martin et al 2004137 6 64 21 5.7 2.0Salzberg et al 2005156 6 130 47 29 5.0 2.1Gallagher et al 1991157 16 61 3.8 1.5Nguyen et al 2001158 3 56 26 6.3 3.6Smedira et al 1996159 63 41 30 5.0 3.7

PA, pulmonary artery; PVR, pulmonary vascular resistance; WU, Wood units.

468 Journal of Cardiac Failure Vol. 16 No. 6 June 2010

comparison of prostaglandin E1 versus prostacyclin versuslow-dose dobutamine in patients awaiting heart transplanta-tion resulted in treatment failure in 13% of patients on pros-taglandin E1, 50% on prostacyclin, and 43% on dobutamine(P ! .05).100 Intermittent infusion of prostaglandin E1 hasbeen shown to decrease PA pressure in patients with ad-vanced HF.97

Some data indicate that prostaglandins can benefit short-term management of PH during the early postoperative pe-riod after cardiac transplantation. When 9 patients with PHafter cardiac surgery or heart transplantation and an ele-vated PVR treated with inotropic support were given in-haled prostacyclin, a dose-dependent decrease occurred inPVR and TPG (which decreased by 29% and 26%, respec-tively), right ventricular performance improved, and nochanges were evident in systemic vascular resistance.55 Inpatients with PH undergoing mitral valve surgery, inhalediloprost was superior to intravenous nitroglycerin for pre-venting acute right ventricular failure during weaningfrom cardiopulmonary bypass.102 Aerosolized iloprost ina patient after heart transplant with early postoperative rightventricular failure resulted in a decrease of PVR (-23.5%),whereas cardiac index (þ24.0%) and mixed venous satura-tion (þ9.0%) increased, without affecting systemic vascularresistance.101

However, in clinical trials, patients with severe HF anddecreased LV ejection fraction randomly assigned to epo-prostenol demonstrated a strong trend toward decreasedsurvival, despite improvements in cardiac index and pulmo-nary capillary wedge pressure. The Flolan InternationalRandomized Survival Trial was prematurely stopped be-cause of increased mortality in the epoprostenol arm.93

This increased mortality could have resulted from a positiveinotropic effect.56 It is important to realize though that PHwas not among inclusion criteria in the Flolan InternationalRandomized Survival Trial. Therefore, treatment with Flo-lan in this study did not target subset of patients with HFand PH, where the benefit from Flolan could be expected.

Endothelin-receptor Blockers

Endothelin, one of the most potent natural vasoconstric-tors, plays an important role in the regulation of vasculartone. Vasodilatation is in turn mediated by the release of

NO and prostacyclin. Studies in both experimental modelsand patients suggest that NO-dependent pulmonary vasodi-latation (which depends on endothelial functions) is im-paired in HF.102,103

Production of endothelin-1 is markedly increased in HF,correlating with both prognosis and symptoms.104

Endothelin-receptor blockage provides hemodynamic bene-fits in experimental and clinical HF. Endothelin receptorblockage after experimental myocardial infarction also re-duced PH and right ventricular hypertrophy.105

Elevated plasma endothelin levels in patients with HFcorrelate with PA pressures and PVR.106

Acute effects of intravenous bosentan in HF have in-cluded a reduction in mean arterial and pulmonary pres-sures, right atrial and wedge pressure, and PVR as wellas an increased cardiac and stroke volume index withoutchange in heart rate. Short-term oral therapy has demon-strated that oral bosentan provides similar but enhanced he-modynamic effects: PVR normalized and dyspneaimproved.107 In a multicenter, double-blind, placebo-controlled trial, Givertz et al109 demonstrated similarhemodynamic responses to sitaxsentan. However, vascularresistance also significantly decreased, which can createproblems in HF.108 And indeed, the outcomes of the useof endothelin antagonists in HF trials thus far have beendiscouraging.

In the randomized, double-blind, placebo-controlled En-dothelinA Receptor Antagonist Trial in Heart Failure (ie,EARTH), endothelin blockage with darusentan did not im-prove cardiac remodeling or clinical symptoms or outcomesin patients with chronic HF.109 In another multicenter,double-blind, randomized, and placebo-controlled trialcomparing bosentan to a placebo in HF patients with PH, nodifference emerged in PA pressure and cardiac indexdorany of the other 22 echocardiographic measurementsobtained. The frequency of adverse events requiringdrug discontinuation was higher in the bosentan group.110

In the Endothelin Antagonist Bosentan for Lowering Car-diac Events in Heart Failure (ie, ENABLE) study, treat-ment with bosentan increased the risk of worsening HF,necessitating hospitalization.111 In the Heart FailureET(A) Receptor Blockade Trial (ie, HEAT), short-termadministration of darusentan increased the cardiac index,but did not change pulmonary capillary wedge pressure,

Pulmonary Hypertension in Heart Failure � Guglin and Khan 469

PA pressure, PVR, or right atrial pressure. Systemic vas-cular resistance decreased significantly, and a trend towardmore adverse events (including death and early exacerba-tion of HF) was also evident.112

Tezosentan, an intravenous short-acting endothelin re-ceptor antagonist tested in the Value of Endothelin Recep-tor Inhibition With Tezosentan in Acute Heart FailureStudies (ie, VERITAS), neither improved dyspnea nor re-duced the incidences of death or worsening HF.113

Packer et al114 found that bosentan-treated HF patientshad an increased risk of HF during the first month of treat-ment, but a decreased risk of HF during the fourth, fifth,and sixth months of therapy when compared with a placebo.The major noncardiac adverse effects of bosentan includedan increase in hepatic transaminases (in 15.6% of patients)and a decrease in hemoglobin.

There may be still a place for short-term treatment withendothelin antagonists in the setting of pretransplant orearly posttransplant PH. Indeed, in 5 of 7 patients consid-ered ineligible for heart transplantation because of highPVR (post-nitroprusside infusion), bosentan therapy signif-icantly reduced PVR.115

However, in the only long-term randomized control trialwhere PH was in inclusion criterion, patients on bosentanexperienced more serious adverse events than controls.110

Inhaled NO

NO is synthesized endogenously from L-arginine and ox-ygen through a family of 3 NO synthasesdall of which areexpressed in the lungdand provides vasorelaxation andbronchodilation as well as the inhibition of mitochondrialrespiration, inhibition of platelet and leukocyte activation,and modulation of vascular smooth muscle cell prolifera-tion.116 Normal basal pulmonary resistance is maintainedin part by continuous local production of NO.117 Drugsthat generate NO, such as nitroglycerin and sodium nitro-prusside, can dilate the pulmonary vasculature, but theyalso cause systemic hypotension.

In 1991, Frostell et al118 described the decrease in PApressure with inhaled NO in experimental PH and foundthat doses up to 80 parts per million did not alter systemicblood pressure. In 1999, it was approved by the Food andDrug Administration for the treatment of hypoxemic infantswith PH.119 Since then, it has been widely used in adult car-diology as well.

Inhaled NO diffuses rapidly across the alveolar-capillarymembrane into the smooth muscle of pulmonary vesselsand provides effects similar to endogenous NOdnamely,vasodilatory, bronchodilatory, anti-inflammatory, and anti-proliferatory.120 Inhaled NO has facilitated the weaningoff of right ventricular assist devices in animal experi-ments.121 In addition, in cardiopulmonary stress test, NOhas been shown to improve oxygen consumption at the an-aerobic threshold.122

Inhaled NO in concentrations from 5 to 80 parts per millionhas been used for the treatment of PH in HF patients,

especially post-ventricular assist device placement and post-transplant. When inhaled NO was started before the termina-tion of cardiopulmonary bypass, patients had better 30-daysurvival rate and decreased incidence of right ventricular dys-function compared with the historical cohort.123 Their hemo-dynamics were also better,124e126 and the weaning frombypass was easier.127 After LVAD implantation, inhaledNO reduced PA pressure and increased LVAD flow.128

When several drugs (inhaled NO, intravenous prostacy-clin, prostaglandin E1, and sodium nitroprusside) were com-pared in posttransplant PH management, cardiac output,right ventricular end-diastolic volume, and central fillingpressures were highest, whereas systemic and pulmonaryvascular resistance were lowest with prostacyclin. Only in-haled NO induced a selective decrease in pulmonary vascularresistance, with no change in systemic vascular resistance.Cardiac output increased with NO, whereas mean pulmonaryarterial pressure, transpulmonary pressure gradient, and cen-tral venous pressure decreased, had the most pronouncedeffect at an inhaled concentration of 20 parts per million.92

Because of its short half-life, NO has to be administeredcontinuously; even brief interruptions may cause a dangerousrebound of PH, leading to a decreased cardiac output and sys-temic hypotension.129 The risk can be minimized by gradu-ally weaning the concentration of inhaled NO.119 Thedownregulation of endogenous NO synthesis or elevatedendothelin-1 levels by inhaled NO may be responsible forthis phenomenon.120 Inhaled NO also carries a small risk ofmethemoglobinemia, which is rarely an issue in adult popu-lation. Testing for methemoglobin regularly, Ardehali et al123

and Beck et al127 did not observe any abnormalities even after4 days of continuous NO. Some authors still advocate routinemethemoglobin checks especially in patients inhaling con-centrations of 80 parts per million,119 although we did notfind any mentioning of actual occurrence of methemoglobi-nemia in any reviewed papers.

Another potential side effect of inhaled NO is an increasein LV filling pressure in patients with HF from an increasedpulmonary venous return to a poorly compliant left ventricle,resulting in an acute pulmonary edema.53,130 This finding hasnot been confirmed by other authors. Thus, Sablotzki et al61

found no increase of pulmonary capillary wedge pressureduring NO inhalation. To the contrary, they observed a fallingtrend in wedge pressure with NO inhalation. In their study,the main disadvantage of NO inhalation was an increase inPA pressure and PVR in 4 patients (28.6%).

Some success has occurred with inhaled NO as a supple-ment to other treatments. Of particular interest is the com-bination of inhaled NO and sildenafil. After the Food andDrug Administration approved sildenafil for the treatmentof erectile dysfunction, reports of severe and possibly fatalhypotension in patients taking sildenafil and nitrates led tochanges in drug labeling that warned against the adminis-tration of nitrates in patients using sildenafil. An expertpanel of the American College of Cardiology/AmericanHeart Association concluded that concomitant use of silde-nafil and nitrates should be avoided unless the benefits are

470 Journal of Cardiac Failure Vol. 16 No. 6 June 2010

determined to far outweigh the risks.131 However, Parkeret al132 found that the actual risk is low. In HF patientswith PH, when sildenafil did not result in the desired mag-nitude of pulmonary vasodilation, adding systemic nitrates(oral isosorbide dinitrate) led to a reduction in mean PApressure of 11 mm Hg, whereas mean systemic arterialpressure decreased by only 3 mm Hg. The ratio of pulmo-nary vascular resistance to systemic vascular resistance wasreduced by 45%, suggesting some pulmonary selectivity ofthe combination. Treatment with sildenafil and nitrates wascontinued for 2 to 8 months, with no episodes of markedsystemic hypotension, syncope, or lightheadedness.133

Inotropes and Vasodilators

Milrinone, a type 3 phosphodiesterase inhibitor with vaso-dilating and positive inotropic properties, has been shown tolower PVR. Milrinone produces sustained inotropic effectwith increase in contractility and cardiac output and venousand pulmonary vasodilation with decrease in right and leftheart filling pressures and systemic and PVR without signif-icant change in TPG.48 In right ventricular failure due to re-sidual PH after the implantation of LVAD, milrinone causeda significant reduction in PVR and an increase in LVADflow.134 Inhaled milrinone also can be useful for decrease ofPA pressure in the postoperative setting, alone or in combina-tion with prostacyclin.135 Nesiritide decreases pulmonarycapillary wedge pressure and therefore decreases pulmonarypressure. A 31% decrease in wedge pressure was accompa-nied by 15.6% reduction in mean PA pressure.136

LVAD

When pharmacological interventions fail to decreasePVR sufficiently to allow heart transplantation, it can beachieved with LVADs, which reverse many pathologicalprocesses in HF, including PH.137 Unloading the left ventri-cle alleviates left atrial hypertension and decreases pulmo-nary capillary wedge pressure, thereby inducing a declinein the PA pressure. In addition, improved cardiac output re-duces hypoxia at the tissue level, resulting in less pulmo-nary vasoconstriction.

Initial anecdotal reports of normalization of ‘‘fixed’’ PHafter LVAD support138e140 have been replaced by case se-ries, as summarized in the Table 3.

Even in patients with fixed PH, long-term LVAD therapyusually results in normalization of pulmonary pressureswithin several months, and patients become eligible fortransplant, regardless of the type of LVAD used. Pulsatileand nonpulsatile flow devices appear equally effective inPH reduction.141e143 Subsequent heart transplantations re-sult in good outcomes.137

However, according to some data, LVAD before heart trans-plant in the presence of PHdalthough decreasing PVR from4.3 6 1.6 to 2.0 6 0.6WU, P ! .05ddid not provide betterlong-term outcomes. The 30-day survival rate in patientswho received LVADs pretransplant was 82% versus 91% in

patients with similar degree of PH who did not receive LVADs;the 4-year survival was 64% and 82%, respectively.144

Sometimes heterotopic heart transplant is used with thedonor heart functioning as an LVAD. This also leads to nor-malization of PA pressure.145

Conclusions

PH is highly prevalent in HF. It is associated with highmorbidity and mortality. PA pressure correlates with in-creased LV end-diastolic pressure and diastolic dysfunction,but not with LV ejection fraction.

Many drugs currently used for pulmonary arterial hyper-tension are being tested as treatment options for PH in HF.Although the short-term benefit of such therapies is well es-tablished in the peritransplant setting, the effects on long-term outcomes are unclear. Randomized clinical trialswith endothelin antagonists and prostaglandins did not tar-get HF patients with PH and are therefore inconclusive. Sil-denafil appears to be a promising agent based on smallstudies with surrogate outcomes. Randomized clinical trialsdesigned to elucidate its potential role would be justified.

Pulmonary hypertension in HF may be a potentially im-portant treatment target. Advances in its management couldpotentially improve the clinical outcomes in heart failurepopulation.

Disclosures

None.

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