Pulmonary Hypertension

Kazemi.toba,M.D.
 

Birjand University of Medical

Sciences
24th Ordibeheshte 1390
 Outline
 Introduction, definition
 Pathophysiology
 Diagnosis
 Laboratory Findings
 Idiopathic Pulmonary Arterial Hypertension
 Natural History
 Treatment
 Introduction
 Pulmonary hypertension:
 an abnormal elevation in pulmonary artery pressure
 result of left heart failure, pulmonary parenchymal or vascular disease,
thromboembolism, or a combination of these factors.
 Regardless the etiology of pul.htn, it is a feature of advanced disease.
 it is essential that the etiology underlying the pulmonary hypertension
be clearly determined before treatment.
 Cor pulmonale :
 RV enlargement secondary to any underlying cardiac or pulmonary
disease.
 Pulmonary hypertension is the most common cause of cor pulmonale.
Advanced cor pulmonale is associated with the development of RV
failure.
Cor pulmonale
 DEFINITION 
 The definition of pulmonary hypertension
(PH) is based upon right heart
catheterization measurements.
 PH is defined as a mean pulmonary artery
pressure greater than 25 mmHg at rest.
 A mean pulmonary artery pressure of 8 to
20 mmHg at rest is considered 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
resistance is influenced by several factors, including age
and the rapidity of the development of pulmonary
hypertension
 Acute:  RV afterload,  EDV,  EF, SV of RV
 Chronic: progressive systolic pressure overload of RV that
dilates and hypertrophies, gradual RV dysfunction
 venous return compromises RV preload and pulm blood
flow
 Coexisting hypoxemia can impair the ability of the
ventricle to compensate
Pathogenesis of Pulmonary Arterial
Hypertension

IRREVERSIBLE
NORMAL REVERSIBLE DISEASE DISEASE
 Symptoms of PH

 Dyspnea 60%
 Fatigue 19%
 Near syncope/syncope 13%
 Chest pain 7%
 Palpitations 5%
 Leg edema 3%
Physical Exam
 JVD
 Loud P2 (increases PAP)
 Left parasternal lift (RV heave=R sided
overload)
 murmur of TR
 S3 gallop (advanced RV failure)
 CLEAR lungs
Signs of Disease Severity
 Dyspnea at rest
 Low cardiac output with metabolic acidosis
 Hypoxemia
 Signs of right heart failure (large V wave on
jugularis vein, periph edema, hepatomegaly)
 Syncope (poor prognosis)
 Chest pain (2 to RV ischemia)
 Diagnosis

 CXR: Enlarged proximal pulmonary

vessels,”

 ECG: RAD, RAE, RVH most common

 Echo :Estimate PA pressure

Assess for shunts and valvular
disease; ventricular function
 ECG Findings

 Often
sugge
stive
of
RVH
and
RAE
RAE,RVH
 Chest X-ray Findings
 central Pul arterial and/or RV enlargement ,
distal “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  Mean PAP

disease (mmHg)
 Mild  25 - 40
 Moderate  41 - 55
 Severe  >55
 Right Heart Cath
 Essential for firm diagnosis:
 Helps to not dx people with PAH that do not have it!

 Vasoreactivity testing

 NO, Adenosine—drop in mPAP by 10 mmHg to

value < 40 mmHg

 Predicts CCB response

 Evaluate for septal defects

 Shed light on the issue of diastolic dysfunction

 Interpret data in context of patient’s volume status

 Lab Exam
 Selected labs
 ANA, RF, ESR
 LFTs, hepatitis serologies

 HIV antibody

 Drugs (cocaine)
Algorithm for investigation of suspected
PH
 Complications of PH
 Right-sided heart failure (cor pulmonale).

 Blood clots.

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

 Bleeding. Pulmonary hypertension can lead to bleeding into the lungs and
hemoptysis.
 Classification
Group 1 "Pulmonary arterial hypertension".
 1. Idiopathic (IPAH)
 2. Familial (FPAH)
 3. Associated with (APAH):
 Collagen vascular disease

 Congenital systemic-to-pulmonary shunts

 Portal hypertension

 HIV infection

 Drugs and toxins

 Other (thyroid disorders, glycogen storage disease, Gaucher disease,

hereditary hemorrhagic telangiectasia, hemoglobinopathies,

myeloproliferative disorders, splenectomy)
 4. Associated with significant venous or capillary involvement
 Pulmonary veno-occlusive disease (PVOD)

 Pulmonary capillary hemangiomatosis (PCH)

 5. Persistent pulmonary hypertension of the newborn

 Classification
 Group 2 : "Pulmonary venous hypertension".
Examples:
 1. Left-sided atrial or ventricular heart disease
 2. Left-sided valvular heart disease
 Group 3 PH — "Pulmonary hypertension associated with
disorders of the respiratory system or hypoxemia".
Examples:
 1. Chronic obstructive pulmonary disease
 2. Interstitial lung disease
 3. Sleep-disordered breathing
 4. Alveolar hypoventilation disorders
 5. Chronic exposure to high altitude
 6. Development abnormalities
 Classification
 Group 4 PH — "Pulmonary hypertension caused by chronic
thrombotic or embolic disease".
Examples:
 1. Thromboembolic obstruction of proximal pulmonary arteries
 2. Thromboembolic obstruction of distal pulmonary arteries
 3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign material)
 Group 5 PH — These patients have PH caused by
inflammation, mechanical obstruction, or extrinsic
compression of the pulmonary vasculature (eg, sarcoidosis,
histiocytosis X, lymphangiomatosis, compression of
pulmonary vessels by adenopathy, and fibrosing
mediastinitis).
Pulmonary Hypertension: Define Lesion
Post-Capillary PH
(PCWP>15 mmHg; PVR nl)
PAH
Respiratory Atrial Myxoma
Diseases Cor Triatriatum MV Disease
PE

VC RA RV PA PV LA LV
Ao
PC LVEDP
PV Systemic HTN
compression AoV Disease
PVOD
Pre-capillary
PH Myocardial Disea
PCWP<15 mmHg DCM,HCM,ischemic CM
PVR > 3 Wu RCM,Obesity , others
Idiopathic PH
 PPH
 uncommon,
 incidence : 2 cases per million.
 female predominance
 presenting in the 4th and 5th decades
 although the age range is from infancy to
>60 years.
 Familial PAH :20% of cases of IPAH
 autosomal dominant inheritance
 Natural History of PPH
 The natural history of IPAH is uncertain
 the disease is typically diagnosed late
 Prior to current therapies, a survival of 2–3 years from
the time of diagnosis
 Functional class remains a strong predictor of
survival,
 patients who are in NYHAfunctional class IV having a
mean survival of <6 months.
 The cause of death is usually RV failure, which is
manifest by progressive hypoxemia, tachycardia,
hypotension, and edema
Mediators of PH
 Prostacycline
 Thromboxane A2
 Endothelin-1
 Nitric Oxide (NO)
 Serotonin
 Adrenomedullin
 Vasoactive Intestinal Peptide (VIP)
 Vascular Endothelial Growth Factor
(VEGF)
 Prostacycline & Thromboxane A2
 Prostacycline
 Vasodilator

 Inhibits platelet activation

 Antiproliferative properties

 Thromboxane A2
 Vasoconstrictor
 Platelet agonist

 in PH balance shifted to Thromboxane A2

ENDOTHELIN-1
 Potent vasoconstrictor
 Stimulates proliferation of smooth muscle
cells in PA
 Plasma levels increased in PHT
 Level inversely proportional to pulmonary
blood flow & CO - ? Direct effect
NO & serotonin
 NO
 Vasodilator & inhibitor of platelet

activation & vascular SM proliferation

 Serotonin
 Vasoconstrictor promoting SM

hyperplasia & hypertrophy

 Elevated plasma levels/ reduced platelet

levels in PHT
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
 Classes of therapy
 Medical
 Diuretics
 Coumadin (IPAH, Anorexigen)
 Oxygen
 PAH specific therapy
 Surgical therapy
 Atrial septostomy
 Lung transplantation
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
Mainstay of treatment
 ANTICOAGULANTS
 Warfarin
 Anticoagulant therapy is advocated for all

patients with PAH .

 warfarin increases survival of patients with

PAH.
 The dose of warfarin is generally titrated to

achieve an INR of 2–3 times control.

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

mPA 10 mmHg

 mPA < 40 mmHg

Non - responder
Responder (<15%) and
candidate for CCB (no
Consider p.o. Bosentan
RHF)
Consider p.o. Sildenafil
Consider Inhaled Iloprost Hemodynamically-Monitored
Consider s.q. Treprostinil Trial of
Consider Continuously- Calcium Channel Blocker
Infused Epoprostenol Therapy
 Calcium Channel Blockers
 Patients who have substantial reductions in PAP in response to
vasodilators at the time of cardiac catheterization (a fall of 10
mmHg in mean PAP and a final mean pressure <40 mmHg)
should be treated with CCB.
 dramatic reductions in PAP, PVR,improved symptoms, regression
of RV hypertrophy
 improved survival documented to exceed 20 years
 patients require high doses (e.g., nifedipine, 240 mg/d, or
amlodipine, 20 mg/d).
 <20% of patients respond to CCB in the long term.
 should not be given to patients who are unresponsive, as they can
result in hypotension, hypoxemia, tachycardia, and worsening
right heart failure
 Endothelin Receptor Antagonists
 Bosentan :nonselective endothelin receptor antagonist
 approved treatment of PAH for patients who are NYHA
functional classes III and IV.
 bosentan improved symptoms and exercise tolerance
 Therapy is initiated at 62.5 mg bid for 1 month,then
increased to 125 mg bid .
 Because of the high frequency of abnormal hepatic
function tests associated with drug use, primarily an
increase in transaminases, it is recommended that liver
function be monitored monthly throughout the duration
of use.
 Bosentan is also contraindicated in patients who are on
cyclosporine or glyburide concurrently.
 PHOSPHODIESTERASE
INHIBITORS
 Sildenafil
 PDE type5 inhibitor

 Reduce metabolism of cGMP

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

compounds
 lowers pulmonary artery pressure and inhibits pulmonary
vascular growth
 sildenafil improves symptoms and exercise tolerance in PAH
 The recommended dose is 20 mg tid. The most common side
effect is headache
 Prostacyclins
 1-Iloprost
 IV or Inhaled

 is approved via inhalation for PAH patients

who are NYHA functional classes III and IV.

 improve symptoms and exercise tolerance

 Therapy can be given at either 2.5 or 5 mcg per

inhalation treatment.
 inhaler must be given by a dedicated nebulizer

 The most common side effects are flushing and

cough
 Because of the very short half-life (<30 min) it

is recommended to administer treatments as

 Prostacyclins
 2-Treprostinol
 is approved for the treatment of PAH patients

who are NYHA functional class III or IV

 improvement in symptoms, exercise tolerance,

and survival
 drug is administered iv

 requires placement of a permanent central

venous catheter and infusion through an

ambulatory infusion pump system.
 Side effects include flushing, jaw pain, and

diarrhea,
Subcutaneous Treprostinil
(Remodulin )


• SQ administration
• Longer half-life than
epoprostenol
• Pre-mixed
• Stable at room temperature
IV epoprostenol (flolan)
 Prostacyclins
 3- Treprostinil
 an analogue of epoprostenol,
 for patients with PAH &NYHA classes II–IV.
 Treprostinil has longer half-life than epoprostenol (4 h)
 is stable at room temperature,
 may be given iv or sc through a small infusion pump that
was originally developed for insulin.
 improvement in symptoms and exercise capacity.
 The major problem has been local pain at the infusion
site, which has caused many patients to discontinue
therapy.
 Side effects are similar to those seen with epoprostenol.
 Surgical Therapy
 Transplantation - lung / heart-lung
 Lung transplantation is considered for patients
who, while on an intravenous prostacyclin,
continue to manifest right heart failure.
 Acceptable results have been achieved with
heart-lung, bilateral lung, and single-lung
transplant.
 The availability of donor organs often influences
the choice of procedure
Functional classes
Good luck