PULMONARY

HYPERTENSION

Antonello Picerno
DEFINITION

Pulmonary Hypertension include a spectrum of

diseases, involving the
pulmonary vasculature, and defined as an
elevation in pulmonary arterial pressures:
Mean pulmonary artery pressure (PAPm)
>25 mmHg, assessed by right heart
catheterization

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CLASSIFICATION

1. PULMONARY ARTERIAL HYPERTENSION (PAH)

2. PULMONARY HYPERTENSION SECONDARY TO LEFT HEART DISEASE

3. PULMONARY HYPERTENSION DUE TO LUNG DISEASE, CHRONIC HYPOXIA

4. CHRONIC ARTERIAL OBSTRUCTION

5. PULMONARY HYPERTENSION WITH UNCLEAR OR MULTIFACTORIAL

MECHANISMS

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1. PULMONARY ARTERIAL
HYPERTENSION (PAH)

-Idiopathic
-Heritable (BMPR2, ALK1, SMAD9, caveolin 1,
KCNK3 mutations)
-Drug- and toxin-induced (e.g.,
methamphetamine use )
-Associated conditions: Connective tissue
disease, HIV infection, Portal hypertension,
Congenital heart diseases, Schistosomiasis
-Pulmonary veno-occlusive disease (PVOD),
pulmonary capillary hemangiomatosis (PCH)
-Persistent pulmonary hypertension of the
newborn

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2. PULMONARY HYPERTENSION
SECONDARY TO LEFT HEART
DISEASE

- Left ventricular systolic dysfunction

-Left ventricular diastolic dysfunction
-Valvular heart disease
-Congenital/acquired left heart inflow/outflow
tract obstruction and congenital
cardiomyopathy
-Congenital/acquired pulmonary venous
stenosis

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3. PULMONARY HYPERTENSION
DUE TO LUNG DISEASE,
CHRONIC HYPOXIA

-Chronic obstructive pulmonary disease

(COPD)
-Interstitial lung disease
-Mixed restrictive and obstructive pattern
pulmonary diseases
-Sleep-disordered breathing
-Alveolar hypoventilation disorders
-Chronic exposure to high altitude
-Developmental abnormalities

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4. CHRONIC ARTERIAL
OBSTRUCTION

-Chronic thromboembolic pulmonary

hypertension (CTEPH)
-Other pulmonary artery obstructions:
*Angiosarcoma or other tumor within the
blood vessels
*Arteritis
*Congenital pulmonary artery stenosis
*Parasitic infection (hydatidosis)

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5. PULMONARY HYPERTENSION
WITH UNCLEAR OR
MULTIFACTORIAL MECHANISMS

-Hematologic diseases: chronic hemolytic

anemia (including sickle cell disease)
-Systemic diseases: sarcoidosis, pulmonary
Langerhans cell histiocytosis:
lymphangioleiomyomatosis,
neurofibromatosis, vasculitis
-Metabolic disorders: glycogen storage
disease, Gaucher disease, thyroid diseases
-Others: pulmonary tumoral thrombotic
microangiopathy, fibrosing mediastinitis,
chronic kidney failure, segmental pulmonary
hypertension .
 PATHOGENESIS
Pulmonary pressure is physiologically regulated through the intervention of factors that cause vasoconstriction and
factors that cause vasodilation.

Vasoconstrictor Factors Vasodilator factors

• Thromboxane • Prostacyclin

• Endothelin-1
• Nitric Oxide
• Hypoxia

• Histamine, Serotonin

The group 1 PH originates from an imbalance between factors with vasodilator action and factors with
vasoconstrictor action.
Pulmonary hypertension is characterized by variable and sometimes pathologic vasoconstriction and by endothelial
and smooth muscle proliferation, hypertrophy, and chronic inflammation, resulting in vascular wall remodeling.
PATHOGENESIS

The increased pulmonary vascular pressure that results from

vascular obstruction further injures the endothelium.
Injury activates coagulation at the intimal surface, which may
worsen the hypertension.
Thrombotic coagulopathy due to platelet dysfunction, increased
activity of plasminogen activator inhibitor type 1 and fibrinopeptide
A, and decreased tissue plasminogen activator activity may also
contribute.
Platelets, when stimulated, may also play a key role by secreting
substances that increase proliferation of fibroblasts and smooth
muscle cells such as platelet-derived growth factor (PDGF),
vascular endothelial growth factor (VEGF), and transforming growth
factor-beta (TGF-β).
Focal coagulation at the endothelial surface should not be
confused with chronic thromboembolic pulmonary hypertension.
PATHOGENESIS
SYMPTOMS

-Shortness of breath
-Fatigue
-Chest pain
-Palpitations (heartbeat rate increased)
-Right-sided abdominal pain
-Poor appetite
-Lightheadedness
-Fainting
-Swelling (legs/ankles)
-Cyanosis
SIGNS

In advanced disease, signs of right heart

failure may include:
- Right ventricular heave
- Widely split 2nd heart sound
- Accentuated pulmonic component of S2
- Pulmonary ejection click
- Right ventricular 3rd heart sound (S3)
- Tricuspid regurgitation murmur
- Jugular vein distention
- Liver congestion and peripheral edema are
common late manifestations.
DIAGNOSIS
COMMON EXAMS:

- Chest radiograph
- Electrocardiogram
- Pulmonary function tests
- Arterial blood gases
- Echocardiography
CHEST X RAY
The most common x-ray finding in
pulmonary hypertension is:
-enlarged hilar vessels that rapidly prune
into the periphery
-a right ventricle that fills the anterior
airspace on lateral view

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 ECG

Possible alterations:

- Right axis deviation (negative qrs in lead

1,positive Qrs in aVR)

- R > S in V1, (normally v1>v6 R increasing,

S decreaseing)
-Possible S1Q3T3.
Both the signs suggesting right ventricular
hypertrophy

Pulmonary hypertension demonstrating evidence of right-axis deviation >120° (A), right ventricular
- Peaked P waves (suggesting right atrial
hypertrophy (B), right atrial enlargement (C) and right ventricular strain (D) dilation) in lead 2
ECHOCARDIOGRAPHY
Transthoracic echocardiography is used to
image the effects of PH on the heart and
estimate PAP (Pulmonary artery Pressure)
from continuous wave Doppler measurements.
The estimation of systolic PAP is based on the
peak tricuspid regurgitation velocity.
All forms of PH may demonstrate a
hypertrophied and dilated right ventricle with
elevated estimated pulmonary artery systolic
pressure.
Important additional information can be
gleaned about specific etiologies of PH, such
as valvular disease, left ventricular systolic
and diastolic function, shunts, other cardiac
diseases.
Doppler echocardiography can suggest the
presence of pulmonary hypertension, but right
heart catheterization remains the gold
standard.
EXAMS TO EXCLUDE OTHER DISEASE

-HRCT scan imaging is a widely available tool

that can provide important information on
vascular, cardiac, parenchymal and mediastinal
abnormalities.
-Contrast CT angiography of the PA is helpful in
determining whether there is evidence of CTEPH
-A ventilation/perfusion (V/Q), or
ventilation/perfusion scintigraphy, lung scan
should be performed in patients with PH to look
for CTEPH
-MRI
- Lung biopsy

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RIGHT HEART CATHETERIZATION

Pressure measurements with a Swan-Ganz

catheter inserted through the right side of the
heart provide the most definite assessment.

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TREATMENT
Treatment varies according to the cause of pulmonary
hypertension.
For PH secondary forms (PH groups 2-5) it is essential
to cure the underlying pathology.
The current treatment strategy for PAH patients can be
divided into three main steps:

1. The initial approach includes general measures,

supportive therapy (oral anticoagulants, diuretics,
O2, digoxin), acute vasoreactivity testing for the
indication of chronic CCB therapy.
2. Use of high-dose CCB in vasoreactive patients or
drugs approved for PAH in non-vasoreactive
patients
3. In the case of an inadequate response, the role of
combinations of approved drugs and lung
transplantation are proposed.

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TREATMENT: FIRST LINE

Some good practice recommended to PH

patients:

-encouraging physical activity and supervised

rehabilitation
-avoid pregnancy, birth control and post-
menopausal hormonal therapy
-infection prevention, psychosocial support,
adherence to treatments, genetic counselling.

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SUPPORTIVE THERAPY
-Oral anticoagulants (warfarin, novel oral anticoagulants)
Abnormalities in coagulation and fibrinolytic pathways have also been
reported. This, together with the non-specific increased risk factors for
venous thromboembolism, including heart failure and immobility,
represents the rationale for oral anticoagulation in PH

-Diuretics (thiazide, thiazide-like diuretics, loop diuretics, MRA)

It is important with diuretic use to monitor renal function and blood
biochemistry in patients to avoid hypokalaemia and the effects of
decreased intravascular volume leading to pre-renal failure

-O2 therapy
Specially in patients with lung disorders and hypoxia benefit from
supplemental oxygen as well as treatment of the primary disorder.

-Digoxin
It may be given also to slow ventricular rate in patients with PAH who
develop atrial tachyarrhythmias.

-Iron Supplements

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SPECIFIC DRUG THERAPY
-CALCIUM CHANNEL BLOCKER
(nifedipine and diltiazem)
Only in case of vasoreactive PH

Vascoactivity test:
During right hearth catheterization, those patients whose
mean pulmonary artery pressure falls by more than 10 mm
Hg to less than 40 mm Hg, when challenged with
adenosine, epoprostenol, or nitric oxide, are considered
vasoreactive.

-PROSTACYCLIN ANALOGUES AND PROSTACYCLIN

AGONISTS
Epoprostenol, Iloprost, Selexipag

-PHOSPHODIESTERASE TYPE 5 INHIBITORS AND

GUANYLATE CYCLASE STIMULATORS
sildenafil, tadalafil and vardenafil

-ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan, Ambrisentan
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LUNG TRANSPLANTATION

Lung transplantation offers the only hope of cure but has high
morbidity because of rejection (bronchiolitis obliterans syndrome)
and infection.
The 5-year survival rate is 50%.

Lung transplantation is reserved for patients with New York Heart

Association class IV disease (defined as dyspnea associated with
minimal activity, leading to bed to chair limitations) or complex
congenital heart disease in whom all therapies have failed and
who meet other health criteria to be a transplant candidate

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RECOMMENDATIONS BY ESC

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REFERENCES:

▪ Kasper, D., Fauci, A., Hauser, S., Longo, D., Jameson, J. and Loscalzo, J.,
2015. Harrison's Principles of Internal Medicine . New York: McGraw-Hill
Professional Publishing.

▪ Nazzareno Galiè, Marc Humbert, Jean-Luc Vachiery, Simon Gibbs, Irene Lang,
Adam Torbicki, Gérald Simonneau, Andrew Peacock, Anton Vonk Noordegraaf,
Maurice Beghetti, Ardeschir Ghofrani, Miguel Angel Gomez Sanchez, Georg
Hansmann, Walter Klepetko, Patrizio Lancellotti, Marco Matucci, Theresa
McDonagh, Luc A. Pierard, Pedro T. Trindade, Maurizio Zompatori, Marius
Hoeper, ESC Scientific Document Group, 2015 ESC/ERS Guidelines for the
diagnosis and treatment of pulmonary hypertensionE uropean Heart Journal,
Volume 37, Issue 1, 1 January 2016, Pages 67–
119, https://doi.org/10.1093/eurheartj/ehv317

▪ MSD Manual Professional Edition. 2021. Pulmonary Hypertension - Pulmonary

Disorders - MSD Manual Professional Edition. [online] Available at:
<https://www.msdmanuals.com/professional/pulmonary-disorders/pulmonary-
hypertension/pulmonary-hypertension#v922016> [Accessed 30 November
2021]

▪ Gelzinis, T., 2021. Pulmonary Hypertension in 2021: Part I—Definition,

Classification, Pathophysiology, and Presentation.
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