DPT IV Exam 2 (PAH w/shatnawi)

pulmonary hypertension (PH)

a general term used to describe the elevation of pressure within the pulmonary circulation from any cause

pulmonary arterial hypertension (PAH)

mean pulmonary arterial pressure (mPAP)

> 20 mmHg at rest

pulmonary capillary wedge pressure (PCWP)

≤15 mmHg

pulmonary vascular resistance (PVR)

≥3 Wood units

mean pulmonary arterial pressure (mPAP)

the average pressure in the pulmonary arteries during a cardiac cycle (systolic and diastolic)

pulmonary capillary wedge pressure (PCWP)

the measure of pressure in the left atrium

group I PH

PAH (all are pulmonary arterial based)

group II PAH

PH with left heart disease

group III PAH

PH with associated lung diseases

group IV PAH

PH due to chronic thrombotic/embolic disease

group V PAH

PH of unclear multifactorial mechanisms

what is required for the diagnosis of PAH?

the absence of other disease of the heart and lungs

what are the three general categories/causes of PAH?

idiopathic (no known etiology)

identifiable genetic component

associated with a number of conditions/drugs/toxins/stimuli (ex. amphetamines, methamphetamine)

multiple hit hypothesis of PAH

combination of genetic and one or more other genetic or environmental factors or comorbidities

what are the primary vascular changes that result in elevated pressure in PAH?

due to increased resistance to blood flow resulting from narrowing or obliteration of small pulmonary arteries

PAH pathophysiology processes including: vasoconstriction, inflammation, vascular proliferation, and thrombosis

role of vasoconstriction contributing to elevated pressure in PAH

due to an imbalance between vasoconstriction and vasodilation

role of inflammation contributing to elevated pressure in PAH

activation of leukocytes and other inflammatory mediators

role of vascular proliferation contributing to elevated pressure in PAH

chronic insult leads to remodeling resulting in significant hypertrophy of the smooth muscle layer and the formation of fibrous lesions around the vessels

role of thrombosis contributing to elevated pressure in PAH

decrease in blood flow, imbalance of clotting and anti-clotting mechanisms results in thrombosis; increased vWF and PAI-1 as well as decreased tPA and thrombomodulin

what are the genetic factors associated with PAH pathophysiology?

5-hydroxytryptamine transporter (5HTT) polymorphism

nitric oxide synthase (NOS) polymorphism

carbamyl-phosphate synthetase (CPS) polymorphism

decreased KV 1.5 potassium channel expression

bone morphogenic protein receptor mutation (BMPR2)

activin receptor-like kinase mutation (ALK-1)

role of 5-hydroxytryptamine transporter (5HTT) polymorphism contributing to PAH

smooth muscle cell proliferation

2/3 of IPAH patients have homozygous form

role of nitric oxide synthase (NOS) polymorphism contributing to PAH

decreased NO production resulting in vasoconstriction

role of carbamyl-phosphate synthetase (CPS) polymorphism contributing to PAH

decreased NO production resulting in vasconstriction

role of decreased KV 1.5 potassium channel expression contributing to PAH

depolarization and opening of calcium channels resulting in vasoconstriction

role of bone morphogenic protein receptor mutation (BMPR2) contributing to PAH

-altered apoptosis that favors smooth muscle cell proliferation

-seen in 70% of patients with familial PAH and up to 40% in IPAH

role of activin receptor-like kinase mutation (ALK-1) contributing to PAH

promotes vascular remodeling

cor-pulmonale

right ventricular failure because of the high pressures against which the ventricle must pump blood

what are the PAH pathological pathways?

the nitric oxide (NO) pathway

the endothelin pathway

the prostacyclin pathway

the transforming growth factor-beta (TGF-B) pathway

the inflammation pathway

the nitric oxide (NO) pathway

NO is a strong vasodilator

produced by endothelial cells and acts to relax the pulmonary vasculature.

a decrease in NO production or bioavailability → vasoconstriction and increased pulmonary vascular resistance

the endothelin pathway

endothelin-1 (ET-1) is a potent vasoconstrictor

produced by endothelial cells and smooth muscle cells

upregulation of ET-1 production → pulmonary vasoconstriction and vascular remodeling

what is the severity of PAH correlated to?

endothelin levels

the prostacyclin pathway

prostacyclin (PGI2) is a vasodilator

produced by endothelial and inhibit platelet aggregation and smooth muscle cell proliferation

a decrease in PGI2 production or bioavailability → vasoconstriction and vascular remodeling

the transforming growth factor-beta (TGF-β) pathway

TGF-β is a cytokine that is involved in cell growth, differentiation, and matrix production.

an upregulation of TGF-β activity → vascular smooth muscle cell proliferation and extracellular matrix deposition

the inflammation pathway

infiltration of inflammatory cells into the pulmonary vasculature and the upregulation of inflammatory cytokines.

inflammatory cells and cytokines contribute to vasoconstriction and vascular remodeling

what is the primary vascular change that results in th elevared pressure in PAH?

narrow or obliteration of small pulmonary arteries

WHO functional class I

patients have no limitation on physical activity and do not demonstrate the noted manifestations

WHO functional class II

mild limitations on physical activity

WHO funcitonal class III

moderate limitations on physical activity

WHO functional class IV

unable to perform any physical activity, even at rest

what are the four conventional therapies used in the treatment of PAH?

oral anticoagulants (thrombosis)

diuretics (edema)

oxygen (maintaining oxygenation)

digoxin (right heart failure)

CCBs

Nifedipine, Amlodipine, Diltiazem

endothelial receptor antagonists

Bosentan, Ambrisentan, Macitentan

ET-1 is a potent vasoconstrictor that is elevated in patients with PAH

block the action of endothelin-1 (ET-1) on endothelin receptors A and B

nitric oxide

NO a potent vasodilator that is decreased in PAH

activates guanylate cyclase → increases the intracellular (cGMP) → smooth muscle relaxation and vasodilation

prostacyclins

Iloprost, epoprostenol, Treprostinil, Beraprost

synthetic analogs of prostacyclin

bind to the prostacyclin receptor → activating adenylate cyclase → increasing cyclic (cAMP)

which of the prostacyclins also suppresses neutrophil adhesion and elastase secretion?

Epoprostenol

which of the prostacyclins also has lusitropic (myocardium relaxation) and negative inotropic effects?

Treprostinil

IP prostacyclin receptor agonist

Selexipag

bind to the prostacyclin receptor → activating adenylate cyclase → increasing cyclic (cAMP)

phosphodiesterase-5 inhibitors

Sildenafil, Tadalafil

PDE-5: responsible for breaking down cGMP in smooth muscle cells → vasoconstriction

inhibition of PDE-5 → vasodilation

soluble guanylate cyclase (sGC) stimulators

Riociguat

sGC catalyzes the production cGMP from guanosine triphosphate (GTP)