Pulmonary Hypertension: Another Use for Viagra®

Kathleen Tong, MD Director, Heart Failure Program

Assistant Clinical Professor

University of California, Davis

Disclosures

• I have no financial conflicts

A Real Disclosure

• I will be discussing off label use of phosphodiesterase-5 inhibitors

Goals

• Define pulmonary hypertension

• Elucidate WHO groups

• Treatments for pulmonary hypertension

• Approach to pulmonary hypertension, from a cardiologist’s perspective

• Right ventricular failure

Pulmonary Hypertension (PH)

• Sustained elevations of pulmonary artery pressure (mPAP) of ≥25 mm Hg at rest (normal : 8-21 mm Hg)

– Usually measured by right heart catheterization

• By echo the pulmonary artery systolic pressure (PASP) may be estimated

– PASP >36 mm Hg

• Definition does not suggest etiology

Badesch, et al. JACC 2009

Pulmonary Hypertension

• Etiologies are many

• Classification system has evolved

• Most recent classification was published in 2009

• Grouped based on histologic findings, response to treatment and etiology

– Five WHO groups

Revised Clinical Classification of PH Endorsed by the World Health Organization (WHO)

1. Pulmonary arterial hypertension (PAH)

2. Pulmonary hypertension with left heart disease

3. Pulmonary hypertension associated with lung diseases and/or hypoxemia

4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease

5. Pulmonary hypertension with multiple etiologies

Etiologies of Group 1 PH: PAH

• Idiopathic (IPAH) – Formerly Primary Pulmonary Hypertension

• Heritable PAH

• Associated PAH

• Connective tissue disease

• HIV infection

• Congenital heart disease

• Drugs/toxins - METHAMPHETAMINE

• Portal hypertension

• Many others

Rare disease: Prevalence is 15/million; 50,000 to 100,000 in the U.S.

Simonneau G, et al. J Am Coll Cardiol 2009:54:S43-S54.

Etiologies of Group 1 PH: PAH

• Idiopathic (IPAH) – Formerly PPH

• Heritable PAH

• Associated PAH

• Connective tissue disease

• HIV infection

• Congenital heart disease

• Drugs/toxins

• Portal hypertension

• Many others

Rare disease: Prevalence is 15/million; 50,000 to 100,000 in the U.S.

Simonneau G, et al. J Am Coll Cardiol 2009:54:S43-S54.

VERY RARE US Prevalence is 50,000-100000

Aorta

Group 1: PAH

RA VEINS PA PV RV LA LV

PRESSURES HIGH PRESSURES LOW/NORMAL • PCWP • LVEDP

Normal

PAH

PC

“PRE-CAPILLARY”

Therapeutic Targets for PAH

Therapeutic Targets for PAH

• Bosentan • Ambrisentan

• Inhaled NO • PDE 5 Inhibitors

• Sildenafil • Tadalafil

• Infusion • Epoprostenol • Treprostinil

• Inhaled • Treprostinil • Iloprost

• Oral • None FDA

approved

Group 2 PH

• Pulmonary hypertension due to left sided heart disease

• Most commonly seen group

• Left sided pump failure

– Diastolic heart failure • Hypertension

• Infiltrative disorders

– Systolic heart failure • Ischemic cardiomyopathy

• Viral cardiomyopathy

• Valvular disease

– Mitral

– Aortic

Aorta

Group 2

RA VEINS PA PV RV LA LV

PRESSURES NORMAL

PRESSURE NORMAL

PC

Aorta

Group 2

RA VEINS PA PV RV LA LV

PRESSURES HIGH

PASSIVE PRESSURE ELEVATION

Mean PA Pressure – Wedge Pressure >10-15 OR the PVR is < 3

PVR = (Mean PAP – Wedge) Cardiac Output

PC

“POST-CAPILLARY”

Aorta

Group 2

RA VEINS PA PV RV LA LV

PRESSURES HIGH

PRESSURE ELEVATION “Out of Proportion” Or FIXED PULMONARY HYPERTENSION

Mean PA Pressure – Wedge Pressure >10-15 OR the PVR is > 3

PVR = (Mean PAP – Wedge) Cardiac Output

PC

Group 2: Treatment

• Treatment is disease/condition specific

– Systolic heart failure: beta blocker, ACE I, diuretics, spironolactone, CRT, LVAD

– Aortic Stenosis: Aortic valve replacement

– Mitral regurgitation: Mitral valve repair

– Ischemic cardiomyopathy: PCI or CABG

• Overall goal is to decrease left sided filling pressures

Can you have mixed Group 2 and Group 1?

• Group 1 is very rare

• PH “out of proportion” usually represents longstanding left sided congestion

– Group 1 drugs (ET antagonists, prostacyclin analogs) have not shown benefit and may be harmful in Group 2 PH except…

– PDE 5 inhibitors (RCT of 34 patients) associated with improved exercise capacity and quality of life with no safety issues

GD Lewis. Circulation. 2007

Group 3 PH

• Associated with lung diseases and/or hypoxemia

• COPD

• Sleep apnea

• Interstitial lung disease

– Idiopathic pulmonary fibrosis

Aorta

Group 3

RA VEINS PA PV RV LA LV

PRESSURES HIGH PRESSURES NORMAL/MILDLY • PCWP • LVEDP

PC

O2

Group 3

• Up to 50% of people with COPD have PH

– Mostly mild

– 1 to 2% of people with COPD and PH have severe PH or “out of proportion” PH

– Presence of PH is associated with poorer survival in Group 3 patients

Group 3: Treatment

• Directed toward the underlying disease

– OSA: CPAP, etc

– COPD: Smoking cessation, inhaler therapy, lung reduction surgery, oxygen

– ILD: ?????, oxygen

• Lung transplantation for end stage disease

• Group 1 therapies generally not used

– Can increase V/Q mismatch, impair oxygenation

Group 4

• Chronic thromboembolic pulmonary hypertension (CTEPH)

– Due to nonresolving thromboemboli in pulmonary arterial tree causing obstruction

Aorta

Group 4: CTEPH

RA VEINS PA PV RV LA LV

PRESSURES HIGH PRESSURES LOW/NORMAL • PCWP • LVEDP

PC

Group 4

• Diagnosis

– V/Q Scan: Negative or low prob rules out CTEPH

– PE protocol chest CT does not rule out CTEPH

– PA angiography is gold standard

Group 4: Treatment

• Anticoagulation

• Pulmonary endarterectomy

• Prostacyclin analogs, PDE 5 inhibitors, and ERAs may be of use

– Some favorable data for hemodynamics

– Functional capacity and survival benefit unclear

Group 5

• Pulmonary hypertension with multiple etiologies

• Treat underlying cause

Aorta

Group 5

RA VEINS PA PV RV LA LV

PRESSURES HIGH PRESSURES HIGH

PC

O2

Diagnostic Approach

Diagnostic Approach

Diagnostic Approach

• Referral is often initiated because of an echo

– RVSP/PASP is estimated from the tricuspid valve regurgitant jet

• Occasionally, referral comes from a heart catheterization

– PAP elevated

• No referral; found upon file review

Diagnostic Approach

• History and Physical

– Age, past medical history, symptoms, sleep history, physical exam findings

• Suspect left sided disease

– Echo: diastolic function, valve function, ejection fraction

• Suspect lung disease: PFTs, V/Q scan, CT chest, sleep study

Suspect PAH?

• History of methamphetamine use, connective tissue disease, family history, HIV, cirrhosis

Clues from the Echo

• Group 2

– Low LVEF

– Enlarged LA

– Diastolic dysfunction • E/e’

• E:a’

• Pulmonary veins

– LV > RV

– LVH

• Group 1/3/4

– LVEF preserved, LV small and underfilled

– Septal flattening

– RV enlargement

Right Heart Catheterization

• “Table of Truth”

– Assess hemodynamics

• RA, PA, PCWP, CO (venous access)

• LVEDP if needed (arterial access)

– Maneuvers

• Exercise – if PA pressures low, to unmask PH

• Nipride – if PCWP is high to assess for “fixed” PH

• Pulmonary vasodilator trial – to assess for CCB sensitive PAH

Case 1

• 57 year old man

• Referred for PH eval

• Hx of AF (ablated)

• HTN on HCTZ only

• Rapidly progressing dyspnea on exertion

Case 1

• RA 12

• PA 49/21 (31)

• PCW 19

• TPG 12

• PVR ~ 3 WU

• GROUP 2 – Infiltrative cardiomyopathy from primary amyloidosois

Case 1

• He underwent heart transplantation last month at UCSF

Case 2

• 45 yo woman

• Presenting with months of progressive, severe dyspnea, edema, and presyncope

• Mother has PAH

Case 2

• RA 30

• PA 106/59 (76)

• LVEDP 10

• TPG 66

• PVR ~ 20 WU

• Neg V/Q scan, no parenchymal lung disease

• GROUP 1: PAH

Case 2

• Started on remodulin infusion during her initial admission

• Ambrisentan added later in her clinical course

PH and Right Ventricular Dysfunction

Pulmonary hypertension

Pressure overload

Adaptive RV hypertrophy

Maladaptive RV hypertrophy & fibrosis

RV dilation & systolic failure

Tricuspid regurgitation

Inter-ventricular septal shift

Left ventricular failure

RV Compensated

RV Decompensated

De Marco, T. Advances PAH. 2005;4:16-26.

Strategies to Prevent and Treat Right Heart Failure

• Reduce RV wall stress

– Reduce afterload • Pulmonary vasodilators (O2, CCB, ERA’s, prostanoids, nitric oxide)

– Reduce preload • Diuretic; mechanical volume removal

• Improve RV inotropy

– Chronically: digoxin (controversial)

– Acutely:

low dose IV dobutamine or dopamine

De Marco, T. Advances PAH. 2005;4:16-26.

Invasive Treatment of RV Failure

• Atrial septostomy

– Improve LV filling and systemic cardiac output

• Mechanical circulatory support

• Lung or heart/lung transplantation

– 1 yr survival: 70%; 5 yr survival: 50%

– Reserved for pts with poor QOL despite optimal therapy

Summary

• Therapeutic options for PH are predicated on understanding

the classification and ascertaining the etiology

– Most common etiologies of PH are chronic respiratory

diseases and left sided heart disease

• Right ventricular failure is often the mechanism of death for

severe PH patients

• PAH is a subset of PH for which we have compiled effective

evidence-based therapies

• Treatment of other forms of PH are dependent on the

underlying cause

THE END