Pph

Pulmonary HTN Dr. Micha kassirer, MD ”Dept. Internal medicine ”D



Pulmonary Hypertension Normal Pulmonary artery pressure at sea level: Systolic 18-25 Diastolic 6-10 MPAP 12-16.



Pulmonary Arterial Hypertension: PASP >20 MPA > 25 (>35 with exercise) and PAOP (PCWP) < 15 mm Hg.



Prevalence of pulmonary vascular bed decreases with age: mild PH (MPA>20) 13% at age 45 and 28% above age 75.

Severity of Pulmonary Hypertension Degree of disease

Mean PAP (mmHg)

Mild

25 - 40

Moderate

41 - 55

Severe

>55

Hemodynamic and clinical squeal Increased pressure load on RV  Significant variability exists on RVH/RV dilatation  Right ventricular failure is present when an increased preload (RA pressure) is required to maintain adequate cardiac output  Once RV failure is present, prognosis is comparable to advanced CHF (NYHA class III/IV) 

Pathophysiology  

Primary Secondary: Hypoxic Vasoconstriction Vasculature obliteration / lung parenchyma Volume overload – L → R shunt Pressure overload – LV disease

Pulmonary Hypertension: Define Lesion Post-Capillary PH (PCWP>15 mmHg; PVR nl) PAH Respiratory Diseases PE

VC

RA

RV

PA

Atrial Myxoma Cor Triatriatum

PC

PV

LA

LV

Ao

↑LVEDP PV compression PVOD

Pre-capillary Mixed PH PH PCWP<15 mmHg

MV Disease

Systemic HTN AoV Disease

Myocardial Disease Dilated CMP-ischemic/non-isc. Hypertrophic CMP Restrictive/infiltrative CMP Obesity and others

Etiologic classification of pulmonary hypertension 

FLOW = ΔP / PVR



RVCO = MPAP



MPAP



MPAP = CO * PVR + PCWP

-

-

PCWP / PVR

PCWP = RVCO * PVR







MPA = CO * PVR + PCWP Pulmonary venous hypertension-most common cause Usually due to leftsided heart disease (valvular, coronary or myocardial),  obstruction to blood flow downstream from the pulmonary veins. Reversibility is variable, dependent on lesion, and variable also in time to regression--

MPA = CO *PVR PCWP 



Hypoxia induced pulmonary vasoconstriction and anatomical destruction of the vascular bed due to high pulmonary resistance and ultimately RV failure. The mechanisms of pulm HTN are unclear-include vasoconstriction due to alveolar hypoxia or neurohumoral activation

+

MPA = CO *PVR PCWP 

Chronic thrombotic and embolic diseases   



Chronic thromboembolic disease* Tumor emboli Sickle Cell Disease**

Pulmonary parenchymal disease  



Airway (emphysema, chronic bronchitis) Interstitial lung disease, pneumoconioses, fibrosis Mechanism may be related to hypoxemia, obliterative remodeling.

+

MPA = CO *PVR PCWP 

Pulmonary vascular disease      



Collagen Vascular disease (SLE, P.nodosa, SS, RA, polymyositis) Portal Hypertension HIV Toxins--anorexigens(Aminorex and fenfluramine), cocaine and methamphetamines Pathologically indistinguishable from iPAH(PPH) Familial PAH

Inflammatory diseases  



+

Sarcoidosis Schistosomiasis / Filariasis

Pulmonary capillary hemangiomatosis (microangiopathy/endothelial proliferation)

MPA = CO *PVR PCWP Pulmonary hypertension due to left-to-right shunts initially have high .pulmonary blood flow Over time this progressesincreased pulmonary vascular resistance and reversal of the shunt ((Eisenmenger complex



Acyanotic -ASD/VSD -PDA



Increased pulmonary blood flow: beriberi, *hyperthyroid, myeloma

+

Aortopulmonary septal defect Partial anomalous PV drainage

Cyanotic 

Okura, et al. High output heart failure as* a cause of pulmonary hypertension. Intern Med 33: 363, 1994

Total anomalous PV drainage Single atrium Single ventricle Persistent truncus Transposition of great vessels

CLINICAL SUBGROUPS 1.

PULMONARY ARTERIAL HYPERTENSION Idiopathic, Familial, Related to CVD, CHD, HIV, drugs, toxins, other

 PULMONARY HYPERTENSION WITH LEFT HD Atrial or ventricular heart disease, Valvular heart disease

3. PH WITH LUNG DISEASE AND HYPOXEMIA COPD, ILD, OSAHS, other

4. PH D/T THROMBEMBOLIC DISEASE 5. MISCELLANEAOUS Sarcoidosis, hystiocytosis, pulmonary vessels compression

Clinical Evaluation of PAH 

Symptoms: Insidious onset of shortness of breath 

Often results in delayed diagnosis

Chest pain Fatigue Syncope/presyncope with exertion Peripheral edema or ascites Raynaud’s in about 10% (worse prognosis) Hemoptysis (rare)

Physical Findings in Pulm HTN  







clear lungs Cor pulmonale: hepatomegaly, pulsatile liver, ascites, peripheral edema no clubbing (if present implicates CHD) hoarseness of voice (Ortner syndrome) stigmata of secondary causes of PAH:

Physical Findings in Pulm HTN     



Accentuated P2 Wide of fixed S2 splitting Right ventricular S4, S3 RV heave along left sternal border Elevated JVP, with Large A waves from stiff RV Systolic murmur of TR

Assessment of Disease Severity     

History, History, History Etiology Effort tolerance 6 minute walk Hemodynamics (Pressure and Flow) 



PAM, CO, and RA (right heart failure)

Response to acute vasodilator challenge   

Inhaled NO IV prostacyclin IV adenosine

IPAH/FPAH Epidemiology and Natural History Predictors of Prognosis NYHA Class I and II III IV

Median Survival 5 years 2.5 years 6 months

5-year survival: 27% NYHA Class III/IV

Predictors of Poor Prognosis  

Poor exercise capacity (6 MWD) Cardiopulmonary hemodynamics   

   

High right atrial pressure Low cardiac index High mean pulmonary artery pressure

Enlarged right atrium on echo Pericardial effusion on echo Absence of anticoagulant use Absence of initial acute vasodilator response

Laboratory work-up         

History, History, History….. ABG Collagen vascular disease screen HIV Coagulation studies (esp. D-dimer) Pulmonary Function test Imaging: CXR, CT-angio, HRCT Cardiac evaluation: TTE + contrast / TEE Rt. Heart catheterization

CHEST X-Ray Clear lung fields

Interstitial markings

Pulmonary function tests

Consider parenchymal lung disease or venoocclusive disease

Obstructive pattern

Restrictive pattern

Normal pattern

Secondary to COPD

Possible PAH

Possible interstitial lung disease

Arterial Blood Gases Normocapnea or hypocapnea

Perfusion lung scan Segmental or larger defects

hypercapnea

Consider hypoventilation syndrome Normal or patchy non-segmental defects

Pulmonary angiogram

Normal

Thromboembolic disease

Without primary cardiac disease

Cardiac Catheterization

Echocardiogram

primary cardiac disease

Rt. And Lt. Heart catheterization • O2 Step-up in R.A.

• Qp/Qs • Wedge pressure • Acute vaso-reactive testing •Coronary angiography •

84%

Idiopathic Pulmonary Fibrosis: Significance of PAH

Lettieri, et al Chest 2006

Eisenmenger’s Syndrome   



PAM = PVR*CO (PBF) + PWP If PBF is doubled, a proportionate (half) reduction in PVR maintains PAM If PBF increased, the reserve capacity of pulmonary vascular elastance is exceeded  rise in PAM pulmonary hypertension Higher PBFhigher PVR in post-tricuspid shunting (VSD, PDA)higher PA pressures shunt reversal (balanced or RL)

Reversibility of Pulmonary Vascular Disease in CHD 

  

Extent of reversibility of obstructive vascular disease varies after correction of hyperkinetic lesion Reversible: Medial hypertrophy and vasoconstriction Irreversible: Plexiform lesions and necrotizing arteritis High risk/benefit for surgical closure:  

PVR>SVR and high grade arteriopathy present Prohibitively high risk when balanced or RL shunts present, when high RA pressures or RV failure present

At-Risk Populations for PAH

Populations

Prevalence/Incidence

IPAH1 CTD2 Systemic Sclerosis CREST syndrome UNCOVER3 CHD4

million/1-2 30% 50% (newly identified 11%) 27% Up to 50% of patients with large VSDs develop Eisenmenger syndrome, often associated with PAH

HIV5

1/200

SCD6

20-40%

Drugs/Toxins7

Direct relationship with anorexigens (amphetamines, cocaine); L-tryptophan may also be associated with PAH

Rich et al. CHEST 1989; 2 Braunwald et al. Heart Disease, 6th ed.; 3 Wigley et al. Arth Rheum 2005 4 Simmoneau et al. JACC 2004; 5 Speich et al. CHEST 1991; 6 Lin et al. Curr Hematol Rep 2005. 7 Rich et al. CHEST 2000. 1

Pathogenesis of Pulmonary Arterial Hypertension

NORMAL

REVERSIBLE DISEASE

IRREVERSIBLE DISEASE

PAH: Pathophysiology Dilated RV- Intact pericardium ↑ RAP

⇓

↑ Intrapericardial pressure (IPP)

⇓

↓ LV transmural filling pressure= LVEDP-IPP + Shift of IV septum toward LV

⇓

↓ LV preload and ↓ LV distensibility

⇓

↓↓ Systemic Cardiac Output

IPAH/FPAH Epidemiology and Natural History Predictors of Prognosis NYHA Class I and II III IV

Median Survival 5 years 2.5 years 6 months

5-year survival: 27% NYHA Class III/IV

Predictors of Poor Prognosis  

Poor exercise capacity (6 MWD) Cardiopulmonary hemodynamics   

   

High right atrial pressure Low cardiac index High mean pulmonary artery pressure

Enlarged right atrium on echo Pericardial effusion on echo Absence of anticoagulant use Absence of initial acute vasodilator response

IPAH/FPAH (PPH): Progressive disorder associated with high mortality rate PAH Survival-NIH registry data 1980’s 100

Percentage Surviving

Time from sx to dx: 2.5 yrs Median: 2.8 yrs 50% survival at 2.5 yrs

80

60

68% 48%

40

50% mortality at 2.5 years if left untreated

20

34%

0

0

0.5

1

1.5

2

2.5

Years of Followup

3

3.5

4

Adapted from: D’Alonzo GE, Barst RJ, Ayres SM. Survival in patients with PPH: Results from a National Prospective Registry. Ann Internal Med. 1991; 115: 343-349

4.5

5

Goals of Therapy 



 

Alleviate symptoms, improve exercise capacity and quality of life Improve cardiopulmonary hemodynamics and prevent right heart failure Delay time to clinical worsening Reduce morbidity and mortality

PAH Therapy: Life style considerations 

Sodium restriction



Abstinence from smoking



Avoid high altitude  <4,000

feet above sea level



Avoid physical exertion in setting of pre- or frank syncope sx



Avoid pregnancy

PAH: Therapy 

Pharmacologic 

Vasodilators/Vasoremodeling therapy (CCB, oral bosentan, inhaled iloprost; SQ/IV treprostinil; IV epoprostenol, oral sildenafil)



Supplemental O2



Anticoagulation (INR≈ 2-3)



Diuretics (↓excessive preload)



Digoxin



IV inotropes (low dose dobutamine, dopamine 1-2 mcg/kg/min)

}

Rx for RV failure

Algorithm for Assessment of Vasoreactivity in Patients with PAH Right Heart Catheterization With Acute Vasoreactivity Testing (iNO, epoprostenol, adenosine)

Non - responder

Consider p.o. Bosentan Consider p.o. Sildenafil Consider Inhaled Iloprost Consider s.q. Treprostinil Consider Continuously-Infused Epoprostenol

mPA ↓10 mmHg ↓ mPA < 40 mmHg

Responder (<15%) and candidate for CCB (no RHF)

Hemodynamically-Monitored Trial of Calcium Channel Blocker Therapy

Strategies to Prevent and Treat Right Heart Failure 

Reduce RV wall stress (↓MVO2, ↓ischemia) 

Reduce RV afterload 







Pulmonary vasodilators (O2, CCB, ERA’s, prostanoids, nitric oxide) Anticoagulation to prevent thrombosis

Reduce RV preload and TR (diuretics: loop, aldosterone antagonists)

Improve RV inotropy  

Chronically: digoxin Acutely: • IV epoprostenol, IV treprostinil • low dose IV dobutamine or dopamine

Invasive Treatment of Advanced RV Failure 

Atrial septostomy +/- ECMO  Improve

LV filling and systemic C.O

Surgical Therapy 

Transplantation - lung / heart-lung  Reserved

for patients who continue to deteriorate with poor QOL despite aggressive pharmacologic therapy

1

year survival - 65-70%

5

year survival - 40-50%

PAH: Randomized Control Trials of Approved Agents Class of Drug

/Study Drug

N Etiol *Class

Design

PositiveResul ts

Dis-advantages

ET-1 Antagonist

BREATHE-1 / OralBosentan placebo

213 PAH III,IV

-Double Blind wk-16

MWD 6 Symptoms Clinical Worsening CPH

Hepatic toxicity ;(11% (transient, reversible

PDE-5 Inhibitor

SUPER Sildenafil Citrate ,(20 (or 80 mg tid 40

278 IPAH,CT CHD II, III

Doubleblind, placebo wks 12

MWD 6 CPH Symptoms

Headache, flushing, dyspepsia

Prostacyclin analogue

Inhalational /Iloprost Placebo

203 PH III-IV

Doubleblind week-12

Composite Endpoint MWD, sx 6

Administration to 9 times daily 6

Prostacyclin analogue

/ SQTreprostinil SQ placebo

470 PAH II-IV

Doubleblind wk-12

MWD 6 Symptoms CPH

Pain, erythema at infusion site Side effects

/ IVEpoprostenol Conventional Rx

81 PPH III,IV

-Open Label wk-12

MWD 6 Symptoms CPH Survival

Indwelling central line Pump (infection,malf) Side effects

Prostacyclin

Targets for Therapy in PAH

Humbert et al. New Engl J Med 2004

Endothelin isincreased in IPAH and PAH associated with other Diseases Congenital Scleroderma

IrET-1 (pg/ml)

10

8 6 4 2 0

Non-PPH

PPH

Stewart et al., Ann Inter Med,1991

P<0.05

10 8 6 4

LcSSc Non-PAH

LcSSc PAH

Vancheeswaran et al., J. Rheum, 1994

Heart Disease Delta ET-LI (PV-RV) (pg/ml)

P<0.001

Concentration of ET-1(pg/ml)

IPAH

P<0.001

5 4 3 2 1 0

Non-PH

PH

Yoshibayashi et al., Circulation, 1991

Endothelin is a Key *Pathogenic Mediator Proliferation

Vasoconstriction

 Vascular Smooth Muscle  Fibroblasts

Hypertrophy  Cardiac/Vascular

ET

Fibrosis  Fibroblast Proliferation   Extracellular Matrix Proteins  ↓ Collagenase Production

 Direct Or Via Facilitation Of Other  Vasoconstrictor Systems (Renin  Angiotensin System, Sympathetic)

Inflammation    

 Vascular Permeability Neutrophil / Mast Cell Activation Promotes Cellular Adhesion  Cytokine Production

*Based on observations reported from in-vitro, in-vivo, or animal models. The clinical significance in humans is unknown. Clozel. Ann Med. 2003

∆ Walk Distance (meters)

BREATHE-1: 6-Minute Walk Test Change From Baseline at Week 16 60

Placebo (n = 69)

Bosentan (n = 144)

40 20

P = 0.0002

Mean ± SEM

0

-20 -40 Baseline

Week 4

62.5 mg bid

Week 8

Week 16

125 or 250 mg bid Rubin L et al. NEJM 2002

BREATHE-1:Time to Clinical

*Worsening Event-Free (%)

100

95% 89% p = 0.0015

p = 0.0038 75%

75

63%

50 25

Bosentan (n = 35) Placebo (n = 13)

Bosentan (n = 144) Placebo (n = 69)

0 0

4

8

12

16

20

24

28

Time (weeks) * Time to clinical worsening = Shortest time to either death, premature withdrawal or hospitalization due to PHT worsening, or initiation of epoprostenol therapy

BREATHE-1 Trial: Bosentan in PAH

Recommended Laboratory Monitoring with Bosentan • Liver function testing 

Prior to initiation of treatment

 Monthly

• Hemoglobin Prior to initiation of treatment  After 1 month, then every 3 months 

• HCG Prior to initiation of treatment  Monthly 

Phosphodiesterase-5 )inhibitors )PDE5-I

Baseline Characteristics: Sildenafil Trial

Sildenafil: Outcomes

PROSTENOIDS

Recently Approved Therapy Inhalational Iloprost (Ventavis®) Approved for WHO Class III, IV patients with PAH

Properties:  Selective pulmonary vasodilator  Vasodilatory potency similar to PGI2  Exerts preferential vasodilation in wellventilated lung regions  Longer duration of vasodilation than PGI2 (30-90 vs 15 min)

Ventavis® (iloprost) Inhalation Solution : Dosage and Administration  



Indicated for inhalation via the Prodose® AAD® system only 2.5 mcg initial dose  increase to 5 mcg if 2.5 mcg dose is tolerated  maintain at maximum tolerable dose (2.5 mcg or 5 mcg) 6-9 inhalations daily during waking hours; 8-10 minutes each

Inhalational Iloprost (AIR) Olschewski et al, NEJM 2002, 347:322-9

Inhaled Placebo N=203 NYHA III or IV PAH, CTPH

2.5 or 5.0 ug (6 or 9 x/d, median 30ug/d)

Inhaled Iloprost Baseline

12 weeks 1o End-point

ILOPROST Results: 10% ↑6-min walk Primary endpoint met (17% vs 5%;p=0.007) & improved NYHA Class 6-min walk distance improved (36 m, p=0.004) w/o clinical deterioration NYHA class improved (p=0.03) or death Dyspnea improved (p=0.015) Minimal improvement in cardiopulmonary hemodynamics

Subcutaneous Treprostinil  ( (Remodulin

•SQ administration •Longer half-life than epoprostenol •Pre-mixed •Stable at room temperature

FLOLAN 

 

 

Sodium epoprostenol (Flolan)--shortlived relatively locally acting vasodilator, t1/2 3-5 minutes. Most potent effect --⇑ cardiac output in patients with PAH ⇓Resting heart rate, ⇓mean right atrial pressure, and a marked improvement in survival. Abrupt cessation can be fatal Contraindicated in veno-occlusive disease

IV epoprostenol (flolan)

PPH Study N=81 NYHA Class III or IV

Randomization Epoprostenol + Conventional Therapy

Screening

Baseline Dose Ranging

Conventional Therapy 12 weeks

Epoprostenol Improved: • Exercise Capacity mean rx effect 47 m, p<0.003 • Cardiopulmonary Hemodynamics rx effect: PA m ≈ 7 mmHg CI ≈ 0.5 L/m/m2 PVR ≈ 6 Wu • Dyspnea • NYHA Class • Survival Barst RJ et al. NEJM, 334: 296-301, 1996.

Barst RJ et al. NEJM, 334: 296-301, 1996.

PAH: Therapy ( Epoprostenol (Flolan 



Adverse effects 2˚ delivery system 

Pump malfunction



Catheter related infections



Thrombosis

Drug-induced side effects 



Flushing, headache, jaw pain, diarrhea, nausea, myalgias, arthralgias Thrombocytopenia



Tolerance



Cost 

Outpatient cost up to $100,000 per year

Conclusion  

 



Pulmonary arterial hypertension is a progressive disease with significant morbidity and mortality Right heart failure is an important development which clearly prognosticates and marks disease progression Treatment of right heart failure is essential Therapies with proven benefit in transpulmonary hemodynamics, functional class and exercise tolerance include ET-1 receptor antagonism (bosentan), prostanoids, and oral sildenafil. Continuous IV Flolan is reserved for advanced (class IV) disease where there is a proven survival benefit