Pulmonary Hypertension

Kazemi.toba,M.D.Kazemi.toba,M.D.  

Birjand University of Medical Birjand University of Medical SciencesSciences

2424thth Ordibeheshte 1390 Ordibeheshte 1390

Outline

Introduction, definitionIntroduction, definition PathophysiologyPathophysiology DiagnosisDiagnosis Laboratory Findings Laboratory Findings Idiopathic Pulmonary Arterial HypertensionIdiopathic Pulmonary Arterial Hypertension Natural HistoryNatural History TreatmentTreatment

Introduction Pulmonary hypertension:Pulmonary hypertension: an abnormal elevation in pulmonary artery pressurean abnormal elevation in pulmonary artery pressure result of left heart failure, pulmonary parenchymal or vascular disease, result of left heart failure, pulmonary parenchymal or vascular disease,

thromboembolism, or a combination of these factors. thromboembolism, or a combination of these factors. Regardless the etiology of pul.htn, it is a feature of advanced disease. Regardless the etiology of pul.htn, it is a feature of advanced disease. it is essential that the etiology underlying the pulmonary hypertension it is essential that the etiology underlying the pulmonary hypertension

be clearly determined before treatment.be clearly determined before treatment.

Cor pulmonale :Cor pulmonale : RV enlargement secondary to any underlying cardiac or pulmonary RV enlargement secondary to any underlying cardiac or pulmonary

disease. disease. Pulmonary hypertension is the most common cause of cor pulmonale. Pulmonary hypertension is the most common cause of cor pulmonale.

Advanced cor pulmonale is associated with the development of RV Advanced cor pulmonale is associated with the development of RV

failurefailure. .

Cor pulmonale

DEFINITION 

The definition of pulmonary hypertension The definition of pulmonary hypertension (PH) is based upon right heart (PH) is based upon right heart catheterization measurements.catheterization measurements.

PH is defined as a mean pulmonary artery PH is defined as a mean pulmonary artery pressure pressure greater than 25 mmHg at restgreater than 25 mmHg at rest..

A mean pulmonary artery pressure of 8 to A mean pulmonary artery pressure of 8 to 20 mmHg at rest 20 mmHg at rest is consideredis considered normal, normal,..

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

Pathophysiology

The ability of the RV to adapt to increased vascular The ability of the RV to adapt to increased vascular resistance is influenced by several factors, including resistance is influenced by several factors, including age age andand the rapidity of the development the rapidity of the development of pulmonary of pulmonary hypertension hypertension

Acute: Acute: RV afterload, RV afterload, EDV, EDV, EF, EF, SV of RVSV of RV Chronic: progressive systolic pressure overload of RV that Chronic: progressive systolic pressure overload of RV that

dilates and hypertrophies, gradual RV dysfunctiondilates and hypertrophies, gradual RV dysfunction venous return compromises RV preload and pulm blood venous return compromises RV preload and pulm blood

flowflow Coexisting hypoxemia Coexisting hypoxemia can impair the ability of the can impair the ability of the

ventricle to compensateventricle to compensate

NORMAL REVERSIBLE DISEASEIRREVERSIBLE

DISEASE

Pathogenesis of Pulmonary ArterialPathogenesis of Pulmonary ArterialHypertensionHypertension

Symptoms of PHSymptoms of PH

DyspneaDyspnea 60%60% FatigueFatigue 19%19% Near syncope/syncopeNear syncope/syncope 13%13% Chest painChest pain 7%7% PalpitationsPalpitations 5%5% Leg edemaLeg edema 3%3%

Physical Exam

JVDJVD Loud P2 (increases PAP)Loud P2 (increases PAP) Left parasternal Left parasternal liftlift (RV heave=R sided (RV heave=R sided

overload)overload) murmur of TR murmur of TR S3 gallop (advanced RV failure)S3 gallop (advanced RV failure) CLEARCLEAR lungs lungs

Signs of Disease Severity

Dyspnea at restDyspnea at rest Low cardiac output with metabolic acidosisLow cardiac output with metabolic acidosis HypoxemiaHypoxemia Signs of right heart failure (large V wave on Signs of right heart failure (large V wave on

jugularis vein, periph edema, hepatomegaly)jugularis vein, periph edema, hepatomegaly) Syncope (poor prognosis)Syncope (poor prognosis) Chest pain (Chest pain (22 to RV ischemia) to RV ischemia)

Diagnosis

CXR:CXR: Enlarged proximal pulmonary Enlarged proximal pulmonary vessels,”vessels,”

ECG:ECG: RAD, RAE, RVH most commonRAD, RAE, RVH most common

EchoEcho ::Estimate PA pressureEstimate PA pressureAssess for shunts and Assess for shunts and

valvular valvular disease; ventricular disease; ventricular functionfunction

ECG Findings

Often Often suggestsuggestive of ive of RVHRVH and and RAERAE

RAE,RVH

Chest X-ray Findings central central Pul arterial Pul arterial and/or and/or RV RV enlargement ,enlargement , distal distal

“pruning”“pruning”

. Note the dilated proximal pulmonary arteries with a relative lack of pulmonary vasculature in the periphery. No cardiomegaly is noted .

Chest roentgenogram from a patient with primary pulmonary hypertension showing the marked dilation of the main pulmonary arteries and right ventricular enlargement.

Pulmonary hypertension. Chest radiograph in a patient with secondary pulmonary hypertension reveals enlarged pulmonary arteries. This patient was found to have an atrial septal defect.

Severe right chamber dilation

Estimate PA pressure Assess for shunts and valvular disease ventricular function

secondary pulmonary hypertension

Severity of Pulmonary Hypertension

Degree of diseaseDegree of disease

MildMild

ModerateModerate

SevereSevere

Mean PAP (mmHg)Mean PAP (mmHg)

25 - 4025 - 40

41 - 5541 - 55

>55>55

Right Heart Cath Essential for firm diagnosis:Essential for firm diagnosis:

Helps to not dx people with PAH that do not have Helps to not dx people with PAH that do not have it!it!

Vasoreactivity testingVasoreactivity testingNO, Adenosine—drop in mPAP by 10 mmHg to NO, Adenosine—drop in mPAP by 10 mmHg to

value < 40 mmHgvalue < 40 mmHgPredicts CCB responsePredicts CCB response

Evaluate for septal defectsEvaluate for septal defects Shed light on the issue of diastolic dysfunctionShed light on the issue of diastolic dysfunction Interpret data in context of patient’s volume statusInterpret data in context of patient’s volume status

Lab Exam

Selected labsSelected labs ANA, RF, ESRANA, RF, ESR LFTs, hepatitis serologiesLFTs, hepatitis serologies HIV antibodyHIV antibody Drugs (cocaine)Drugs (cocaine)

Algorithm for investigation of suspected PH

Complications of PH Right-sided heart failure (cor pulmonale).Right-sided heart failure (cor pulmonale).

Blood clots.Blood clots.

Arrhythmia.Arrhythmia. Irregular heartbeats from the upper or lower chambers of the heart are Irregular heartbeats from the upper or lower chambers of the heart are complications of pulmonary hypertension. These can lead to palpitations, dizziness complications of pulmonary hypertension. These can lead to palpitations, dizziness or fainting and can be fatal. or fainting and can be fatal.

Bleeding.Bleeding. Pulmonary hypertension can lead to bleeding into the lungs and Pulmonary hypertension can lead to bleeding into the lungs and hemoptysis. hemoptysis.

ClassificationGroup 1 "Group 1 "Pulmonary arterial hypertension".Pulmonary arterial hypertension".

1. Idiopathic (IPAH)1. Idiopathic (IPAH) 2. Familial (FPAH)2. Familial (FPAH) 3. Associated with (APAH):3. Associated with (APAH):

Collagen vascular diseaseCollagen vascular disease Congenital systemic-to-pulmonary shuntsCongenital systemic-to-pulmonary shunts Portal hypertensionPortal hypertension HIV infectionHIV infection Drugs and toxinsDrugs and toxins Other (thyroid disorders, glycogen storage disease, Gaucher disease, Other (thyroid disorders, glycogen storage disease, Gaucher disease,

hereditary hemorrhagic telangiectasia, hemoglobinopathies, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)myeloproliferative disorders, splenectomy)

4. Associated with significant venous or capillary involvement4. Associated with significant venous or capillary involvement Pulmonary veno-occlusive disease (PVOD)Pulmonary veno-occlusive disease (PVOD) Pulmonary capillary hemangiomatosis (PCH)Pulmonary capillary hemangiomatosis (PCH)

5. Persistent pulmonary hypertension of the newborn5. Persistent pulmonary hypertension of the newborn

Classification Group 2 : "Group 2 : "Pulmonary venous hypertensionPulmonary venous hypertension".".

Examples: Examples: 1. Left-sided atrial or ventricular heart disease1. Left-sided atrial or ventricular heart disease 2. Left-sided valvular heart disease2. Left-sided valvular heart disease

Group 3 PH — "Pulmonary hypertension associated with Group 3 PH — "Pulmonary hypertension associated with disorders of the disorders of the respiratory system or hypoxemiarespiratory system or hypoxemia". ".

Examples:Examples: 1. Chronic obstructive pulmonary disease1. Chronic obstructive pulmonary disease 2. Interstitial lung disease2. Interstitial lung disease 3. Sleep-disordered breathing3. Sleep-disordered breathing 4. Alveolar hypoventilation disorders4. Alveolar hypoventilation disorders 5. Chronic exposure to high altitude5. Chronic exposure to high altitude 6. Development abnormalities6. Development abnormalities

Classification Group 4 PH — "Pulmonary hypertension caused by Group 4 PH — "Pulmonary hypertension caused by chronic chronic

thrombotic or embolic disease". thrombotic or embolic disease".

Examples:Examples: 1. Thromboembolic obstruction of proximal pulmonary arteries1. Thromboembolic obstruction of proximal pulmonary arteries 2. Thromboembolic obstruction of distal pulmonary arteries2. Thromboembolic obstruction of distal pulmonary arteries 3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign 3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign

material)material)

Group 5 PH — These patients have PH caused by Group 5 PH — These patients have PH caused by inflammation, mechanical obstruction, or extrinsic inflammation, mechanical obstruction, or extrinsic compression of the pulmonary vasculature compression of the pulmonary vasculature (eg, sarcoidosis, (eg, sarcoidosis, histiocytosis X, lymphangiomatosis, compression of histiocytosis X, lymphangiomatosis, compression of pulmonary vessels by adenopathy, and fibrosing pulmonary vessels by adenopathy, and fibrosing mediastinitis). mediastinitis).

VCVC RARA RVRV PAPA PVPVPCPC

LALA LVLV AoAo

Post-Capillary PH Post-Capillary PH

((PCWP>15 mmHg; PVR nlPCWP>15 mmHg; PVR nl))

Systemic HTNSystemic HTNAoV DiseaseAoV Disease

Myocardial DiseaseMyocardial DiseaseDCM,HCM,ischemic CMDCM,HCM,ischemic CMRCM,Obesity , othersRCM,Obesity , others

Atrial MyxomaCor Triatriatum

PV compression

PVOD

PAHPAHRespiratoryRespiratory

DiseasesDiseasesPEPE

Pulmonary Hypertension: Define LesionPulmonary Hypertension: Define Lesion

MV DiseaseMV Disease

LVEDP

Pre-capillary Pre-capillary PHPHPCWPPCWP<<15 15 mmHgmmHg

PVR PVR >> 3 Wu 3 Wu

Idiopathic PH PPHPPH uncommon, uncommon, incidence : 2 cases per million. incidence : 2 cases per million. female predominancefemale predominance presenting in the 4presenting in the 4thth and 5th decades and 5th decades although the age range is from infancy to although the age range is from infancy to

>60 years.>60 years. Familial PAH :20% of cases of IPAH Familial PAH :20% of cases of IPAH autosomal dominant inheritanceautosomal dominant inheritance

Natural History of PPH The natural history of IPAH is uncertainThe natural history of IPAH is uncertain the disease is typically diagnosed late the disease is typically diagnosed late Prior to current therapies, a survival of 2–3 years from Prior to current therapies, a survival of 2–3 years from

the time of diagnosisthe time of diagnosis Functional class remains a strong predictor of survival, Functional class remains a strong predictor of survival, patients who are in NYHAfunctional class IV having a patients who are in NYHAfunctional class IV having a

mean survival of <6 months. mean survival of <6 months. The cause of death is usually RV failure, which is The cause of death is usually RV failure, which is

manifest by progressive hypoxemia, tachycardia, manifest by progressive hypoxemia, tachycardia, hypotension, and edemahypotension, and edema

Mediators of PH

ProstacyclineProstacycline Thromboxane A2Thromboxane A2 Endothelin-1Endothelin-1 Nitric Oxide (NO)Nitric Oxide (NO) SerotoninSerotonin AdrenomedullinAdrenomedullin Vasoactive Intestinal Peptide (VIP)Vasoactive Intestinal Peptide (VIP) Vascular Endothelial Growth Factor (VEGF) Vascular Endothelial Growth Factor (VEGF)

Prostacycline & Thromboxane A2

ProstacyclineProstacycline VasodilatorVasodilator Inhibits platelet activationInhibits platelet activation Antiproliferative propertiesAntiproliferative properties

Thromboxane AThromboxane A22

VasoconstrictorVasoconstrictor Platelet agonistPlatelet agonist

in PH balance shifted to in PH balance shifted to Thromboxane AThromboxane A22

ENDOTHELIN-1

Potent vasoconstrictorPotent vasoconstrictor Stimulates proliferation of smooth muscle Stimulates proliferation of smooth muscle

cells in PAcells in PA Plasma levels Plasma levels increasedincreased in PHT in PHT Level Level inverselyinversely proportional to pulmonary proportional to pulmonary

blood flow & CO - ? Direct effectblood flow & CO - ? Direct effect

NO & serotonin

NONO Vasodilator & inhibitor of platelet Vasodilator & inhibitor of platelet

activation & vascular SM proliferationactivation & vascular SM proliferation SerotoninSerotonin

Vasoconstrictor promoting SM hyperplasia Vasoconstrictor promoting SM hyperplasia & hypertrophy& hypertrophy

Elevated plasma levels/ reduced platelet Elevated plasma levels/ reduced platelet levels in PHT levels in PHT

Goals of Therapy

Alleviate symptoms, improve exercise Alleviate symptoms, improve exercise capacity and quality of lifecapacity and quality of life

Improve cardiopulmonary Improve cardiopulmonary hemodynamics and prevent right hemodynamics and prevent right heart failureheart failure

Delay time to clinical worseningDelay time to clinical worsening Reduce morbidity and mortalityReduce morbidity and mortality

Classes of therapyClasses of therapy MedicalMedical

DiureticsDiuretics Coumadin (IPAH, Anorexigen)Coumadin (IPAH, Anorexigen) OxygenOxygen PAH specific therapyPAH specific therapy

Surgical therapySurgical therapy Atrial septostomyAtrial septostomy Lung transplantationLung transplantation

PAH Therapy: Life style considerations

Sodium restrictionSodium restriction

Abstinence from smokingAbstinence from smoking

Avoid high altitudeAvoid high altitude

<4,000 feet above sea level<4,000 feet above sea level

Avoid physical exertion in setting of Avoid physical exertion in setting of

pre- or frank syncope sxpre- or frank syncope sx

Avoid pregnancyAvoid pregnancy

Mainstay of treatment

ANTICOAGULANTS WarfarinWarfarin

Anticoagulant therapy is advocated for all Anticoagulant therapy is advocated for all patients with PAH .patients with PAH .

warfarin increases survival of patients with warfarin increases survival of patients with PAH. PAH.

The dose of warfarin is generally titrated to The dose of warfarin is generally titrated to achieve an INR of achieve an INR of 2–32–3 times control. times control.

Algorithm for Assessment of Vasoreactivity Algorithm for Assessment of Vasoreactivity in Patients with PAHin Patients with PAH

Right Heart Catheterization With Acute Vasoreactivity Testing (iNO, epoprostenol, adenosine)

Non - responderResponder (<15%) and candidate for CCB (no RHF)Consider p.o. Bosentan

Consider p.o. SildenafilConsider Inhaled IloprostConsider s.q. Treprostinil

Consider Continuously-Infused Epoprostenol

Hemodynamically-Monitored Trial of

Calcium Channel Blocker Therapy

mPA 10 mmHg mPA < 40 mmHg

Calcium Channel Blockers Patients who have substantial reductions in PAP in response to Patients who have substantial reductions in PAP in response to

vasodilators at the time of cardiac catheterization (a fall of 10 vasodilators at the time of cardiac catheterization (a fall of 10 mmHg in mean PAP and a final mean pressure <40 mmHg) mmHg in mean PAP and a final mean pressure <40 mmHg) should be treated with CCB.should be treated with CCB.

dramatic reductions in PAP, PVR,improved symptoms, dramatic reductions in PAP, PVR,improved symptoms, regression of RV hypertrophyregression of RV hypertrophy

improved survival documented to exceed 20 yearsimproved survival documented to exceed 20 years patients require high doses (e.g., nifedipine, 240 mg/d, or patients require high doses (e.g., nifedipine, 240 mg/d, or

amlodipine, 20 mg/d).amlodipine, 20 mg/d). <20% of patients respond to CCB in the long term.<20% of patients respond to CCB in the long term. should not be given to patients who are unresponsive, as they can should not be given to patients who are unresponsive, as they can

result in hypotension, hypoxemia, tachycardia, and worsening result in hypotension, hypoxemia, tachycardia, and worsening right heart failureright heart failure

Endothelin Receptor Antagonists BosentanBosentan :nonselective endothelin receptor antagonist :nonselective endothelin receptor antagonist approved treatment of PAH for patients who are NYHA approved treatment of PAH for patients who are NYHA

functional classes III and IV. functional classes III and IV. bosentan improved symptoms and exercise tolerance bosentan improved symptoms and exercise tolerance Therapy is initiated at 62.5 mg bid for 1 month,then Therapy is initiated at 62.5 mg bid for 1 month,then

increased to 125 mg bid .increased to 125 mg bid . Because of the high frequency of abnormal hepatic Because of the high frequency of abnormal hepatic

function tests associated with drug use, primarily an function tests associated with drug use, primarily an increase in transaminases, it is recommended that liver increase in transaminases, it is recommended that liver function be monitored monthly throughout the duration function be monitored monthly throughout the duration of use. of use.

Bosentan is also contraindicated in patients who are on Bosentan is also contraindicated in patients who are on cyclosporine or glyburide concurrently.cyclosporine or glyburide concurrently.

PHOSPHODIESTERASE INHIBITORS

SildenafilSildenafil PDE type5 inhibitorPDE type5 inhibitor Reduce metabolism of cGMPReduce metabolism of cGMP

Sildenafil should not be given to patients who are taking nitrate Sildenafil should not be given to patients who are taking nitrate compounds compounds

lowers pulmonary artery pressure and inhibits pulmonary lowers pulmonary artery pressure and inhibits pulmonary vascular growthvascular growth

sildenafil improves symptoms and exercise tolerance in PAHsildenafil improves symptoms and exercise tolerance in PAH The recommended dose is 20 mg tid. The most common side The recommended dose is 20 mg tid. The most common side

effect is headacheeffect is headache

Prostacyclins 1-Iloprost1-Iloprost

IV or InhaledIV or Inhaled is approved via inhalation for PAH patients who are NYHA functional is approved via inhalation for PAH patients who are NYHA functional

classes III and IV.classes III and IV. improve symptoms and exercise toleranceimprove symptoms and exercise tolerance Therapy can be given at either 2.5 or 5 mcg per inhalation treatment.Therapy can be given at either 2.5 or 5 mcg per inhalation treatment. inhaler must be given by a dedicated nebulizerinhaler must be given by a dedicated nebulizer The most common side effects are flushing and coughThe most common side effects are flushing and cough Because of the very short half-life (<30 min) it is recommended to Because of the very short half-life (<30 min) it is recommended to

administer treatments as often as every 2 h.administer treatments as often as every 2 h. TreprostinolTreprostinol

IV or s/c injectionIV or s/c injection No CYP inhibition - ? inductionNo CYP inhibition - ? induction t½ 2-4 hourst½ 2-4 hours

Prostacyclins 2-Treprostinol2-Treprostinol

is approved for the treatment of PAH patients who is approved for the treatment of PAH patients who are NYHA functional class III or IV are NYHA functional class III or IV

improvement in symptoms, exercise tolerance, and improvement in symptoms, exercise tolerance, and survival survival

drug is administered ivdrug is administered iv requires placement of a permanent central venous requires placement of a permanent central venous

catheter and infusion through an ambulatory catheter and infusion through an ambulatory infusion pump system.infusion pump system.

Side effects include flushing, jaw pain, and Side effects include flushing, jaw pain, and diarrhea, diarrhea,

Subcutaneous Treprostinil(Remodulin )

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

IV epoprostenol (flolan)

Prostacyclins 3-3- Treprostinil Treprostinil an analogue of epoprostenol, an analogue of epoprostenol, for patients with PAH &NYHA classes II–IV.for patients with PAH &NYHA classes II–IV. Treprostinil has longer half-life than epoprostenol (4 h)Treprostinil has longer half-life than epoprostenol (4 h) is stable at room temperature, is stable at room temperature, may be given iv or sc through a small infusion pump that may be given iv or sc through a small infusion pump that

was originally developed for insulin. was originally developed for insulin. improvement in symptoms and exercise capacity. improvement in symptoms and exercise capacity. The major problem has been local pain at the infusion site, The major problem has been local pain at the infusion site,

which has caused many patients to discontinue therapy. which has caused many patients to discontinue therapy. Side effects are similar to those seen with epoprostenol.Side effects are similar to those seen with epoprostenol.

Surgical Therapy TransplantationTransplantation - lung / heart-lung - lung / heart-lung

Lung transplantation is considered for patients Lung transplantation is considered for patients

who, while on an intravenous prostacyclin, who, while on an intravenous prostacyclin,

continue to manifest right heart failure. continue to manifest right heart failure.

Acceptable results have been achieved with Acceptable results have been achieved with

heart-lung, bilateral lung, and single-lung heart-lung, bilateral lung, and single-lung

transplant.transplant.

The availability of donor organs often influences The availability of donor organs often influences

the choice of procedurethe choice of procedure

Functional classes

Good luck