`PULMONARY HYPERTEN SION
`CHF MAYflUNE 2003
`
`155
`
`Pulmonary Hypertension:
`New Perspectives
`
`
`The lr’l’orld Health Organization symposium oyj’ers a new
`treatment—oriented classification ofpulmonary hyperten—
`sion based on an improved understanding ofits potho—
`physiology. Regardless ofthe etiology, severe or unre—
`lie-aed pulmonary hypertension leads to right heart fail—
`ure. Symptoms and signs ofpidmonary hypertension are
`often subtle and nonspecific. As a result, a significant
`delay between the onset ofsymptoms and the diagnosis of
`pulmonaryI hypertntsion is common. lichocardiography
`with Dopplerflow is the most useful study to evaluate pa—
`tients suspected of having pulmonary hypertension. The
`suspected diagnosis ofpuimonary hypertension should
`then be confirmed by right heart catheterization. lfpre-
`sent, further evaluation may include oxygen assessment.
`pulmonary function testing, high resolution computed to—
`mography of the chest, and ventilation—perfusion lung
`scanning. Treatment ofpulmonary hypertension requires
`uncommon expertise. General measures include correc—
`tion of the underlying cause, reversal ofbyporemia and
`judicious use ofdiuretics. Advances in vasodilator thera—
`py have increased treatment options beyond calcium
`channel blockers and intravenous epoprostenol. Lung
`transplantation remains an optionfor select patients
`with pulmonary hypertension not responding to medical
`management.
`(CHF. 2003;9:l 55—162) 62an cm; lnc.
`
`Trenton D. Nauser, MDfl Steven W. Stiles, MD3
`From the Division offitlmonasy and Critical Care
`Medicine, Department of Veterans Afi'airs Medical Center,
`Kansas City, Mflfl and theDioision ofPulmonary and
`Critical Care Medicine, University ofKansas Medical
`Center, Kansas City, K52
`
`Addressfor conmptmdence:
`Trenton D. Nauser, MD, Eamon offlulmonary and Criti—
`cal Care Medicine, Kansas City Veterans with Medical
`Center, 480! East [almond Boulevard, Mnlicine Service
`(HI), Kansas City, MO 64128—2295
`E—mail: trentonmausequhnadmagov
`Manuscript received April 22, 2002;
`accepted May El, 2002
`
`The pulmonary circulation is normally a low-pres-
`sure, low—resis Lance circuit due to its large cross—
`seclional area and high capacitance. Pulmonary hy—
`pertension is defined as a mean pulmonary arterial
`pressure >25 mm Hg at rest or 30 mm Hg with cx~
`ercisc at catheterization. The significance of elevat—
`ed pulmonary arterial pressure is that it increases
`impedance to right ventricular ejection. This in—
`creased afterload, if severe or unrelieved, leads to
`right heart failure.
`Pulmonary hypertension has traditionally been
`divided into two forms: primary and secondary.
`The etiology of primary pulmonary hypertension
`{PPH} is unknown. In secondary pulmonary hypen
`tension, a myriad of rcspiralory. cardiac, and one
`trathoracic disorders presumably explain the pul~
`monaIy hypertension. However, pulmonary vascu—
`lar disease with clinical and pathologic features
`identical to PPH can occur in association with sev—
`eral conditions. As a result, this nomenclature be—
`comes unclear. Recenlly, a new diagnostic classifica—
`tion was proposed by a World Health Organization
`symposium (Table I).1 In this categorization, forms
`of pulmonary hypertension are grouped according
`to shared pathobiologic processes. For instance,
`pulmonary arterial hypertension refers to a disease
`spectrum that includes PPH and pulmonary hyper—
`tension that cannot be distinguished from PPH.
`
`Pathogenesis and Classification
`The pulmonary vasculature is the exclusive target of
`disease in PPH, although its pathogenesis remains
`speculative. The most widely accepted mechanism sug—
`gestslhatPPH isadiseaseofpredisposedmdividualsm
`whom various stimuli may initiate the development of
`pulmonary arteriopalhy. Vasooonstriction, vascular—wall
`remodelingand lhmmbosis insitu allplaya role.2
`Vascular tone is increased in PPH. A decrease in
`
`the ratio of the metabolites of the vasoclilalor prosta—
`cyclin to those of [he vasoconstrictor flirombaxane
`erdsts.2 Levels of the potent vasoconslrictor endothe—
`lin-l are increased.2 Impaired function and expres-
`sion of voltage—gated potassium channels on smooth
`muscle cells have been noted.2 This may initiate and
`maintain vasoconslriction. Vascular remodeling is
`
`Congestive Heart Failure (ISSN 152?—5299] is published bimonthly [Feb. AprilJune. Aug. Oct.. Dec} by CHFr |nc.,Three Parklands Drive, Darien,(_‘r 06820—3652. Copyright CE 2002 by
`l-ar cupifls In excess of 25 or l'ur cummulciul purposes, plum-0 conlucl Sarah Howell at. shuwflll@lfl]acq.cum or 201555.17” lxlDE.
`CHE Inc. All rights reserved. No part ofthl's publication may be reproduced or transmitted in any form or by anyI mca n5. electronic or mechanical. including photocopy. recordingmr
`any informalion storage and retrieval system, wilhouL permission in writing from the publishers. Thr.I ideas and opinions expressed in Congestive Heart Falluro do not necessarin
`rolled [hosts of the Editor and Publlshur.
`
`
`Liquidia's Exhibit 1059
`Page 1
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`Liquidia's Exhibit 1059
`Page 1
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`

`

`156
`
`
`PULMONARY HYPERTENSIDN
`CHF MAYQUNE 2003
`
`also a prominent feature of PPH. Intimal fibrosis and
`medial hypertrophy are well recognized. Production
`of extracellular matrix including collagen and elastin
`is increased.2 Thrombosis in situ is often found in
`
`the pulmonary arterioles.2 Platelet activity is en-
`hanced; levels of serotonin. plasminogen activator
`inhibitor and fibrinopeptide are elevated; and
`thrombomodulin levels are decreased.2
`
`PPH is rare, with an incidence of l to 2 cases per
`million people in the general population. The disease
`is most prevalent in the third and fourth decade of life
`where it is more common in women than men (ratio:
`1.7 to l).5 Falnilial PPH. an autosomal dominant dis—
`order with incomplete penetrance, accounts for 6% of
`all cases of PPH. The gene involved, BMPRZ, encodes
`a transfom'ling growth factor [3 type II receptor that
`influences angiogenesis and apclptosis.L1
`Entities other than PPH associated with pul—
`monary arterial hypertension include collagen vascuh
`lar disease, systemic arterial—to~pulmonary artery
`shunts. portal hypertension, human immunodeficien—
`cy virus (H IV) infection, and anorexic agents. The
`exact mechanism by which these risk factors lead to
`pulmonary arterial hypertension is unknown. Since
`only a minority of persons with these risk factors de-
`velop pulmonary hypertension, individual suscepti—
`bility is likely to have an important fiJnction.
`Many collagen vascular diseases have been associ-
`ated with pulmonary hypertension?F This includes
`systemic lupus erythematosus, scleroderma, CREST
`(calcinosis, Raynaud's phenomenon, esophageal dys-
`motility, sclerodactyly. and telangiectasias) syn—
`drome, rheumatoid arthritis, Sjogren's syndrome,
`dermatomyositisfpoly‘myositis, and mixed connective
`tissue disease. Pulmonary hypertension may be the
`presenting manifestation and can precede the diag
`nosis of autoimmune disease by several years. Most
`often pulmonary hypertension develops because of
`pulmonary fibrosis. However. in some cases the pul+
`monary interstitium is preserved and the pulmonary
`vessels have histologic features resembling PPH.
`Through vascular recruitment and distensibility,
`the pulmonary circulation can accommodate moder—
`ate increases in blood flow with minimal increase in
`
`pulmonary arterial pressure. However. when pul—
`monary blood flow is extreme and pulmonary vascu—
`lar capacity is reached, any further increase in flow
`will generate pulmonary hypertension. This occurs
`most commonly in congenital anomalies involving
`systemic to pulmonary shunts. Irreversible pathologic
`changes in the pulmonary vasculature similar to PPH
`may occur depending upon the quantity and duration
`of volume and pressure overload.
`Elevated pulmonary arterial pressure is not un-
`common in advanced liver disease.5 The mecha—
`
`nisms are at least threefold: l) a high pulmonary
`flow state due to a hyperdynarnic circulation; 2) vol-
`ume overload possibly related to impaired left ven—
`tricular contractility; and 3) a condition that leads
`to the histologic abnormalities identical to PPH.
`Only the third description should be labeled por—
`topulmonary hypertension.
`Chronic HIV infection is related to the develop-
`ment of pulmonary arterial hypertension.T Howev—
`er, no correlation exists between CD: counts or
`prior respiratory infections and its development.
`Pulmonary arterial hypertension does appear to be
`more rapidly progressive in patients with HIV than
`in those without this risk factor.
`
`The use of anorexic agents for more than three
`months is associated with a >30 times increased
`
`risk of pulmonary arterial hypertension}; Impor—
`tantly, pulmonary hypertension may present sever—
`al months after discontinuation of the agent.
`Aminorex. fenfluranline, dexfenfluraniine, and am—
`phetamines have all been implicated. The patho—
`genic mechanism of pulmonary hypertension asso—
`ciated with appetite suppressants is unclear, al—
`though alteration of the serotonin pathway has
`been proposed}!I Serotonin is known to be a potent
`pulmonary vasoconstrictor and stimulator of
`smooth muscle proliferation.
`Pulmonary venous hypertension is a potential
`consequence of any condition that impedes pul—
`monary venous drainage. Left ventricular dysfuncL
`tion and mitral valve disease result in pulmonary
`hypertension primarily by raising left atrial pres—
`sure and therefore obstructing pulmonary venous
`drainage. This necessitates an increase in pul-
`monary arterial pressure to maintain flow through
`the pulmonary circulation. More direct hindrance
`to pulmonary venous flow occurs in association with
`unusual conditions such as fibrosing mediastinitis
`and pulmonary venoocclusive disease.
`Alveolar hypoxia causes pulmonary vasoconstric—
`tion by a variety of actions on endothelium and
`smooth muscle. This increased pulmonary vascular
`resistance can be further compounded by reactive
`polycythemia. Chronic mountain sickness and sleep
`apnea syndromeslfl are illustrative of pulmonary
`hypertension associated with hypoxemia.
`Advanced interstitial lung disease or chronic ob—
`structive pulmonary disease (COPD) may cause pul—
`monary hypertension through hypoxia-induced
`vasoconstriction and obliteration of capillary beds.
`Acidosis, also a pulmonary vasoconstrictor, may
`augment the effects of hypoxia.“ As a result, acute
`exacerbations of COPD leading to hypoxia and un—
`compensated hypercarbia can markedly elevate
`pulmonary arterial pressure.
`
`Congestive Heart Failure tISSN BEEP—5299] is published bimonthly [Feb.. Aprillune. Aug“ Oct" Dec} by CHF. |nc..Three Parklands Drive.Darien.CT 06820—3652. Copyright 033 2002 by
`reflect those of the Editor and Publisher. For copies In excess of 25 or far Lommercial purposes. please contact Sarah Howell at. shuwflll@le1acq.cum or 203.656.1711xi06.
`CHF. Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means. electronic or mechanical. including photocopy. recording. or
`any information storage and retrieval system. WIthUL permission In writing from the publishers. The ideas and opinions expressed in Congestive Heart Failure do not necessarily
`
`
`Liquidia's Exhibit 1059
`Page 2
`
`Liquidia's Exhibit 1059
`Page 2
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`

`

`
`PULMONARY HYPERTENSION
`CHF MAYJJUNE 2003
`
`157
`
`Pulmonary hypertension may result from obstruc—
`Lion of flow through the pulmonary arterial tree after
`pulmonary embolism. Subsequent to pulmonary em—
`bolism, the normal right ventricle can sustain its out—
`put after an abrupt increase in mean pulmonaryr arter—
`ial pressure up to 50 mm Hg, A higher acute pressure
`increase will cause the right ventricle to fail. There—
`fore, a massive pulmonary embolus may cause right
`ventricular failure, but not severe pulmonary hyper—
`tension. A pulmonary arterial pressure 2’50 mm Hg
`suggests a chronic process with resultant right ventric—
`ular hypertrophy. Chronic thromboembolism can
`provoke severe pulmonary hypertension if thrombi
`fail to undergo recanalization or lysis. This occurs in
`(1% ofpatients with diromboembolic disease,12
`
`Clinical Manifestations
`Patients with pulmonary hypertension often present
`with nonspecific symptoms. These symptoms are
`often difficult to dissociate from symptoms due to a
`known underlying pulmonary or cardiac disorder.
`As a result, a significant delay between the onset of
`symptoms and the diagnosis of pulmonary hyper—
`tension is common.
`
`Dyspnea on exertion, fatigue, and syncope are
`the most common presenting symptoms. These re—
`flect an inability to increase cardiac output when
`appropriate. Chest pain is prevalent in pulmonary
`hypertension despite normal coronary arteries.
`This is likely due to angina from right ventricular
`ischemia or pain directly related to pulmonary
`artery stretching.
`Hemoptysis, due to the rupture of distended pul-
`monary vessels, is rare but potentially life—threaten—
`ing. Hoarseness may result from compression ofthe
`recurrent laryngeal nerve by the enlarged pul-
`monary artery. Raynaud‘s phenomenon occurs in
`approximately 2% of patients with PPH, but is
`more common in pulmonary hypertension related
`to connective tissue disease.5
`
`Physical examination abnormalities tend to be 10*
`calized to the cardiovascular system. A careful exam
`will often detect signs of both pulmonary hyperten—
`sion and right ventricular hypertrophy. Compatible
`findings include jugular venous distention, a right
`ventricular heave, an accentuated second heart sound
`in the pulmonic area. and a tricuspid insufficiency
`murmur. Hepatomegaly and peripheral edema are
`signs of advanced pulmonary hypertension.
`
`Diagnostic Assessment
`A high index of suspicion combined with a meticulous
`history and physical examination is paramount in die
`
`evaluation of patients with pulmonary hypertension.
`Careful attention should be given to prior medical
`conditions, all drug use {both legal and illegal), family
`history, and an extensive review of systems.
`The electrocardiogram {ECG} may demonstrate
`signs of right ventricular hypertrophy or right atrial
`enlargement in pulmonary hypertension. ECG find-
`ings include right axis deviation, P—pulmonale,
`right bundle branch block, and RES ratio >1 in lead
`V]. The higher the pulmonary artery pressure, the
`more sensitive is the ECG.13 Chest radiograph is in—
`ferior to ECG in detecting pulmonary hyperten—
`sion. Although insensitive, a right descending pul—
`monary artery diameter 2:16 nun on standard chest
`x—ray is specific for pulmonary hypertension.”
`Patients with symptoms, signs. ECG. or chest ra—
`diograph suggestive of pulmonary hypertension
`should undergo two~dimensional echocardiography
`with Doppler flow. Echocardiography is the most
`useful screening test to detect pulmonary hyperten-
`sionl‘1 and to exclude underlying congenital,
`valvular, or myocardial disease.
`Echocardiographic screening for pulmonary hy—
`pertension is based on identification of the tricus—
`pid regurgitant jet (TR), absent in normal individu—
`als. Measurement of TR velocity (mi’sec) provides
`an estimate of the backward flow between the right
`ventricle and right atrium. The modified Bernoulli
`equation [fip=4(TR2)] converts this flow measure~
`ment into a pressure gradient. By adding this pres—
`sure gradient to an estimate of right atrial pressure,
`the right ventricle peak systolic pressure is deter—
`mined. The right ventricle peak systolic pressure
`approximates pulmonary artery systolic pressure
`obtained by catheterization.“1
`All patients with suspected pulmonary hyperten—
`sion on echocardiography should undergo compre-
`hensive evaluation to clarify the etiology. The goal
`of this diagnostic approach is to identify or exclude
`treatable causes, keeping in mind the differential
`diagnosis {Table I). Initial laboratory evaluation in—
`cludes a complete blood count, pmthrombin time,
`partial thromboplastin time, hepatic profile and
`serologic studies for collagen vascular disease if
`suggested by history or physical examination. Spe—
`cific autoantibodies might include antinuclear and
`anti—DNA (systemic lupus erythematosus), anti—Scl—
`70 and antinucleolar (scleroderma), anticen—
`tromere [CREST syndrome), rheumatoid factor
`{rheumatoid arthritis], anti—Ro and anti-La (Sjo—
`gren's syndrome), antiAJo—l (dermatomyositis,If
`polymyositis} and anti—U: RNP (mixed connective
`tissue disease). HIV testing should be considered in
`all patients. especially those with a compatible
`history or risk factors.
`
`Congestive Heart Failure (ISSN 152?—5299] is published bimonthly [Feb.. Aprildune. thug.I Oct.I Dee} by CHF, |nc..Three Parklands Drive,Darien.CT 06820—3652. Copyright fl 2002 by
`reflect those of the Editor and Publisher. For Copies In excess Lil 25 or fur Lummurcial purposes. please contact Sarah Howell at shuwflllfi’lmacqcum or 203.656.1711x105.
`CHF. Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any Form or by an):I means. electronic or mechanical. including photocopy. recording. or
`any information storage and retrieval system. without permission In WIllJI’lQ from the publishers. The ideas and opinions expressed in Congestive Heart Failure do not necessarily
`
`
`
`Liquidia's Exhibit 1059
`Page 3
`
`Liquidia's Exhibit 1059
`Page 3
`
`

`

`15B
`
`PULMONARY HYPERTENSION
`
`CHF MAY! NE 2003
`
`Arterial blood gas analysis should be performed
`to exclude hypoxia and acidosis as contributors to
`pulmonary hypertension. Importantly, normal rest-
`ing oxygenation does not exclude exertional or
`nocturnal oxygen desaturation. Approximately 20%
`of patients with COPD and normal awake arterial
`oxygen tensions have nocturnal, nonapneic oxygen
`desaturation.” Exertional oxygen desaturation is
`also common. These episodes are ameliorated with
`supplemental oxygen. Consequently, exercise and
`sleep oximetry should be completed in all patients
`with pulmonary hypertension. A formal overnight
`polysomnog'ram is indicated ifthe clinical presenta—
`tion suggests sleep apnea.
`Pulmonary function tests are necessary to establish
`airflow obstruction or restrictive pulmonary physiolo-
`gy. Unless hypoxia is present. pulmonary hyperten—
`sion cannot be attributed to these disorders unless
`
`pulmonary function is severely reduced. Computer—
`ized tomographic scanning of the chest with high-res—
`olution images is usefiJl to exclude occult interstitial
`lung disease and mediastinal fibrosis when pulmonary
`function tests and chest radiograph are nondiagnostic.
`If the cause of the pulmonary hypertension re~
`mains unexplained, chronic thromboembolism
`should be excluded as it can mimic PPH clinically.
`Fortunately, the ventilation-perfusion lung scan is a
`reliable method of differentiating chronic throm—
`boembolic pulmonary hypertension from PPH. One
`or more segmental or larger perfusion defects is a
`sensitive marker of embolic obstruction. The venti—
`
`lation—perfusion scan is either normal or demon—
`strates patchy subsegmental abnormalities in PPH.l6
`If the ventilation—perfusion scan is suggestive of
`chronic thromboembolism, pulmonary angiography
`can be safely performed in order to confirm the diag—
`nosis, define the extent of disease, and consider pos—
`sible surgical thromboendanerectomy.” The role of
`helical computerized tomography of the pulmonary
`arteries remains unclear. Helical computerized to—
`mography has high specificity but undefined sensi—
`tivity for the diagnosis of pulmonary embolism.“3
`Complete cardiac catheterization should be per—
`formed in all patients undergoing an evaluation of
`pulmonary arterial hypertension, and remains the
`gold standard for its diagnosis and quantification.
`Cadleterization is particularly useful in die diagnosis
`of occult systemic to pulmonary shunts, congenital
`heart disease. and distal pulmonary artery stenosis.
`
`Prognosis
`The median duration of survival after diagnosis of
`PPH is 2.8 years,'9 but this is highly variable. In pa+
`
`tients without hemodynamic evidence of right ven-
`tricular dysfunction. survival >10 years is possible
`with new treatment methods. The lIii-minute walk
`
`test is predictive of mortality in patients with PPH
`and is useful for following a response to therapyfi’o
`Prognosis in patients with od'Jer forms of pulmonary
`hypertension depends on the underlying disease as well
`as right ventricular function. For instance, patients with
`COPD and moderate airflow obstruction have a 3-year
`mortality of 50% after the onset of right ventricular fail—
`ure.“ Survival is influenced similarly in patients with
`interstitial lung disease and pulmonary hypertension.
`
`Therapeutics
`The treatment of pulmonary hypertension is complex
`and potentially dangerous. Patients benefit from refer—
`ral to centers that specialize in the management of this
`problem. Table II lists possible treatment options for
`patients with pulmonary hypertension.
`
`General Measures
`A primary goal in the management of pulmonary hy—
`pertension is the early recognition and treatment of
`Ihe underlying disease while it is still potentially re—
`versible. To illustrate, pulmonary arterial hyperten-
`sion associated with autoimmune disease may respond
`to corticosteroids or other immunosuppressive agents.
`Ifno permanent arteriolar vascular disease exists, abo—
`lition of a systemic to pulmonary shunt by corrective
`surgery restores pulmonary blood flow and pressure
`to normal. Mild to moderate portopulmonary hyper—
`tension does not appear to alter outcome after ortho-
`topic liver transplantation.22 Antiretroviral therapy
`may exert a beneficial effect on the course of pul—
`monary hypertension in the setting of HIV infection
`in some patients.23 Improvement or resolution of pul—
`monary hypertension may be seen following discon—
`tinuation of anorexic medications, although this is un-
`commonF"1 Left ventricular dysfunction should be
`treated with afterload reducing agents. digoxin,
`diuretics, and revascularization ifappropriate.
`Because hypoxia is a potent pulmonary vasocon—
`strictor. identification and reversal of hypoxemia is
`a cornerstone of therapy for pu[monary hyperten—
`sion. Low~flow supplemental oxygen selectively di4
`lates the pulmonary vasculature and prolongs sur—
`vival in hypoxemic patients.25
`A lots.r sodium diet and judicious use of diuretics can
`be helpful in reducing volume overload in patients with
`pulmonary hypertension and right ventricular failure.
`However, because the right heart is dependent upon
`preload, care should be taken to avoid excessive dilue—
`sis and further reduction in cardiac output.
`
`
`
`Congestive Heart Failure (ISSN 152?—5299] is published bimonthly [Feb.. Aprildune. hug.I Oct. Dec} by CHF. |nc.. Three Parklands Drive. Dariendj 06820—3652. Copyright fl: 2002 by
`CHI'. Inc. All rights reserved. No part of this publication may be reproduced or transmitted in an).r form or by anyI means. electronic or mechanical. including photocopy, recording. 01
`am.I information storage and retrieval system. without permission in writing from the publishers. The ideas and opinions expressed. in Congestive Heart Failure do not necessarin
`reflect those of the Editor and Publisher. For copies. In excess til 25 or for commercial purposes. pluase contact Sarah Howull at showflll@lnjacq.ctirri or 201555.171 1x106.
`
`
`Liquidia's Exhibit 1059
`Page 4
`
`Liquidia's Exhibit 1059
`Page 4
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`

`

`
`PULMONARY HYPERTENSION
`CHF MAYflUNE 2003
`
`
`159
`
`Table I. The World Health Organization Diagnostic
`Classification of Pulmonary Hypertension
`
`I'L'LMONARTAR’I‘ERLXI.H‘rTI-LRTENSION
`Primary Fulfill-1113f? hl'Pf-‘flflflSiOll
`590T3d'l'3
`Related to:
`Familial
`{Iollagen vascular disease
`Congenital systemic to pulmonary shunts
`Portal hypertension
`HIV Infection
`Drugsi'toxins
`Anorexigens
`Ollier
`Persisteiitpulmcuary hypertension ofthenewborn
`Other
`PL'IMONARY VENOL'S H‘i'PI-IRTENSION
`Left—sided atria] or ventricular heart disease
`left—sided valvular heart disease
`
`Extrinsic compression of central pulmonary veins
`Fibrosing mcdiastinills
`Adcnoparhyitumors
`Pulmonaiy “.11”de disease
`Ollicr
`I'Lqmofimu' Hfi-ER'HNSIQNAsg-iocmTl-‘D WTl'l-I DISORDERS
`OF THE RESPIRATORTSYSTIfl-{ANWOR HtTOXI-IML-t
`Chronic obstruclive pulmonary disease
`Interstitial lung diSt‘flM‘
`Sleep disordered breathing
`Alveolar hypovcntilation disorders
`Chronic exposure to high altitude
`Neonatal lung disease
`Alveolar—capillary dysplasia
`DIhcr
`PL'IMONARY H‘r'l'I-IRTENSION DL'E 1o CHRONIC
`”I‘HROMBQ‘i-ic mango]; EMEOLIC 013F351;
`'Ihromboenibolic obstruction of proximal
`pulmonary arteries
`Obstruction of distal pulmonary arteries
`Pulmonary embolism (thrombus, tumor,
`“"3 andfor parasnes. foreign material)
`ln-situ thrombosis
`Sickle cell disease
`PL'LMONARY HvPI-Ji'n-ZN Sl-DN Dt'r. To DISORDERS
`DTRECTLY AFFECTING THE PULMONARY VASCULA'I'L'RE
`inflammatory
`Schistosoriiiasis
`Sarcoidosis
`Other
`Pulmonary capillary heriiangiomatosis
`
`
`
`Medical Therapy
`Oral calcium channel blockers may alleviate pul+
`monary vasoconstriction and prolong life in approxi—
`mately 209’:- of patients with PPH. Unfortunately,
`there is no simple way to predict who will respond.
`Consequently, it is imperative to evaluate pulmonary
`vasoreactivity during right heart catheter'ization prior
`to selecting long—term therapy. The most suitable
`drugs for testing acute vasodilator response are po-
`tent, short acting, and titratable. Prostacyclin, adeno-
`sine, or nitric oxide can all be used for acute vasodila—
`tor testing. A minimal acceptable response would be a
`reduction in mean pulmonary artery pressure of 10
`mm Hg associated with either no change or an in—
`crease in cardiac output.1 Long-term therapy with
`high—dose oral calcium channel blockers can produce
`sustained hemody'namic responses and increase sur-
`vival in patients with acute vasoreactivityfifi However,
`oral calcium channel blockers can have pronounced
`systemic hypotensive reflects. Patients who do not have
`an acute vasodilator response are unlikely to benefit
`.
`.
`.
`from chronic oral calctum antagonists.
`Epoprostenol (prostacyclin) is the single most im—
`portant advance in the treatment of PPH. It may
`also be effective in select patients with pulmonary
`arterial hypertension related to collagen vascular
`disease, congenital heart disease and portopul—
`monary hypertensionFF-za Epoprostenol is a potent,
`shortsacting vasodilator and inhibitor of platelet ags
`gregation that is produced by vascular endothelium.
`PPH patients treated with continuous intravenous
`infusion of epoprostenol have improved exercise ca—
`P3515“ qualltY 0f l'fe: hemOlem‘CS!_and long'l'fl'm
`survlval compared to those treated With convention—
`al therapy.” Lack of an acute vasodilator response
`to epoprostenol does not preclude a longmterm ben—
`efit. Allhough the delivery system for continuous in;
`fusion is complex. most patients are able to learn
`hovi.r to prepare and infuse the drug. Dose—related
`side effects are common and include flushing,
`headache, jaw pain, nausea, foot pain and diarrhea.
`As tachyphylaxis develops, the dose of epoprostenol
`is slowly increased. Titration involves balancing the
`.
`.
`symptoms of drug excess against those of inade-
`quately treated pulmonary hypertension. Abrupt
`cessation of long-term infusion is poorly tolerated
`and potentially catastrophic.
`The side effects and inconvenience of continuous
`
`intravenous epoprostenol infusion make other
`routes of administration attractive. Subcutaneous,
`inhaled. and oral forms of prostacyclin analogs are
`being evaluated.
`Treprostinil is a stable prostacyclin analog ad—
`ministered subcutaneously through an ambulatory
`
`
`
`HIV=human immunodeficiency virus
`Reproduced with permission of the World Health
`Organization from Rich 5. ed. Executive stunmary from
`Ihe World Symposium on Primary Pulmonary Hyper—
`tension 1998; September 6—]0, 1998; cosponsored b5 the
`
`World Health Organization. Evian, France'
`
`.Dct.. Dee} by CHFr |nc..Three Parklands Drive.Darien.CT 06820-3652. Copyright at 2002 by
`Conga
`3 in any form 01 by anyI means. electronic or mechanical. including photocopy. recording. 0:
`Chi. Ir
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`Liquidia's Exhibit 1059
`Page 5
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`Liquidia's Exhibit 1059
`Page 5
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`lfil]
`
`PULMONARY HYPERTENSION
`
`CHF MAY! NE 2003
`
`microinfusion pump. In a 12-week, lnulticenter,
`double—blind, randomized. placebo-controlled trial.
`treprostinil improved 6-minute walk distance and
`pulmonary hemodynamics in patients with pul—
`monary arterial hypertension?!“ Although signifi—
`cant, the improvement appeared modest compared
`to previous results obtained with intravenous
`epoprostenol. Infusion site pain occurred in 85% of
`the treatment group and prevented some individu—
`als from receiving adequate doses.
`Inhaled aerosolized iloprost, another prostacyclin
`analog. may offer a new therapeutic option for pa—
`tients with pulmonary arterial hypertensionfill-E'"2
`Preferential pulmonary vasodilation and improve—
`ment in right ventricular function in patients with
`PPH has been demonstrated over a l—year period.S2
`Unfortunately, the short duration of action requires
`frequent inhalations. This therapy appears to be well
`tolerated. Side effects such as coughing are usually
`minor and transient. No comparison with continuous
`infusion of epoprostenol has been made.
`Beraprost is a prostacyclin analog that is suitable
`for oral administration due to its prolonged activity.
`Small, prospective uncontrolled studies confirm sub-
`stantial and persistent improvements in exercise ca—
`pacity and pulmonary hemodynarnics in patients with
`PPH and chronic thromboembolic pulmonary hyper—
`tension.53:34 Side effects are similar to intravenous
`
`epoprostenol, although catheter—related problems are
`avoided. Optimal dosing is not yet known.
`Recently the Food and Drug Administration ap—
`proved bosentan, an oral endodtelin-l receptor an—
`tagonist for the treatment of pulmonary arterial hy-
`pertension. Interest in endothelin antagonists has
`increased after elevated levels of endothelin—1 were
`
`noted in plasma and lung tissue of patients with
`pulmonary hypertension. Endothelin—l has potent
`vasoconstrictive, proliferative and profibrotic ell
`fects. Although it remains unclear whether endothe—
`lin—l causes pulmonary hypertension or is simply a
`mediator,55 results of clinical trials are encourag—
`ing. In a 12—week study, 32 patients with New York
`Heart Association (NYHA) functional class III,
`PPH, or pulmonary hypertension due to scleroder—
`ma were randomized to oral bosentan or placebo.56
`Patients receiving bosentan had significantly im4
`proved 5—minute walk distance and cardiopul—
`monary hemodynamics. Improvement in pul—
`monary vascular resistance was not associated with
`a reduction in systemic blood pressure. A multicen—
`ter, randomized, placebo-controlled trial estab-
`lished the efficacy of bosentan in improving exer—
`cise capacity in a larger number of patients with
`pulmonary anerial hypertension.“ Potential for se—
`rious liver injury exists with bosentan therapy.
`
`Serum aminotransferase levels must be measured
`
`prior to initiation of treatment and monthly there—
`after. If increased aminotransferase levels are seen,
`reduction in dose or cessation of treatment may be
`appropriate depending on the degree of elevation.
`Several important questions regarding bosentan re—
`main to be answered. For instance, its effect on sur-
`vival and the role of the agent with concomitant
`epoprostenol therapy are unknown.
`Another endogenous vasodilator, nitric oxide, is
`approved for persistent pulmonary hypertension of
`the newborn. Experience in adults has been limited
`to testing acute vasodilator response in PPH and
`short—term therapy in critically ill patients. Long—
`term administration in PPH has been described in
`
`anecdotal reports.33-39 In contrast to intravenous
`epoprostenol, inhaled nitric oxide decreased pul—
`monary vascular resistance without affecting systemic
`vascular resistance. Controlled clinical trials are nec—
`
`essary to define the role of inhaled nitric oxide.
`Studies are also exploring the potential of silde—
`nafil in pulmonary hypertension.“ Sildenafil,
`known best as a treatment for erectile dysfunction,
`is a potent inhibitor of phosphodiesterase-E, which
`is plentiful in vascular, tracheal, and visceral
`smooth muscle in addition to corpora cavernosa.
`Phosphodiesterase—5 inhibitors increase the level of
`cyclic guanosine monophosphate, which in turn re—
`laxes smoodt muscle.
`
`Chronic anticoagulation is recommended to pre—
`vent thrombosis and has been shown to prolong life
`in PPH.25-'“ Patients are prone to dtromboembolism
`because of sluggish pulmonary blood flow, dilated
`right heart chambers, venous insufficiency, and re