Primary pulmonary hypertension

Involves the small pulmonary arteries which have vascular proliferation and remodeling.

Characterized by pulmonary vascular remodeling, cellular proliferation, and poor outcomes.
It is associated with progressive rise in pulmonary vascular load, leading to hypertrophy and remodeling of the right ventricle.

PPH is associated with both hereditary and idiopathic subtypes.

PPH is categorized into five clinical groups.

Risk factors: 

Family history, pulmonary embolism, HIV/AIDS, sickle cell disease, cocaine use, COPD, sleep apnea, living at high altitudes, and mitral valve problems.

Frequency 1,000 new cases a year.

The epidemiology of PAH is about 125–150 deaths per year in the U.S., and worldwide the incidence is similar at 4 cases per million. 

Females have a higher incidence rate than males (2–9:1).

Death results from right ventricular failure if pulmonary hypertension is left untreated.

Mutations associated with this conditions these include bone morphogenetic protein receptor type 2 (BMPR2) and eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4).

Defined by a systolic pulmonary artery pressure greater than 25 mmHg and increased vascular resistance without evidence of thromboembolic or other cardiorespiratory disease.

Diagnosed when there is both an increased need and pulmonary artery pressure of 25 mmHgor higher at rest or 30 mm of mercury with exercise and a pulmonary capillary wage pressure of less than 15 mmHg.

Defined hemodynamically by a mean pulmonary arterial pressure of higher than 20 mmHg at rest, as measured by right heart catheterization.

Diagnosis requires that secondary primary hypertension related to lung disease, hypoxia, thromboembolism, left ventricular muscle or valve disease, must be ruled out.

Most commonly associated with connective tissue diseases, congenital heart disease, porto- pulmonary disease, HIV infection, or the use of anorexigens.

Rarely can occur in idiopathic form, in which 10% of cases are familial.

Increased vascular resistance caused by vasoconstriction, pulmonary vessel remodeling and thrombosis.

Pulmonary endothelial dysfunction which leads to impaired production of vasodilators nitric oxide and prostacyclin and overexpression of vasoconstrictors such as endothelin-1.

Incidence in France and Scotland are 2.4 cases and 7.1-7.6 cases per million persons per year and a prevalence of 15 cases and 26 -52 cases per million , respectively.

Pulmonary vasodilation effects of nitric oxide are mediated via cyclic guanosine monophosphate (cGMP) which is rapidly degraded by phosphodiesterases.

Phosphodiesterase 5 is the major type of phosphodiesterase in the lung and it metabolizes cGMP and it is upregulated in pulmonary hypertension.

Sildenafil citrate inhibits phosphodiesterase type 5 promoting the accumulation of intracellular cGMP and thereby increases nitric oxide mediated vasodilation in the lung.

Treatment for pulmonary arterial hypertension includes anticoagulants, diuretics, digoxin, calcium channel blockers, oxygen supplementation, vasodilators, prostanoids and endothelin-receptor antagonists.

When present in pregnancy mortality rates of 35-50 percent.

Median survival of 2.8 years.

Continuous intravenous administration of epoprostenol improves survival.

Four agents presently approved for treatment: intravenous epoprostenol, inhaled prostacyclin analogue iloprost, subcutaneous and intravenously administered prostacyclin analogue treprostinil, and oral endothelin-receptor agonist bosentan.

Endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors and prostacyclin and its analogues approved for treatment.

Above agents shown to improve 6 minute distances walked in 12-16 weeks.

Macitentan, a dual endothelin-receptor antagonist, significantly reduces morbidity and mortality (Pulido T et al),

Parenteral prostanoids are the most potent and effective therapies for pulmonary arterial hypertension and improve long-term outcomes and quality of life.

IV treprostinil and IV epoprostenol are administered by continuous infusion.

Adverse side effects seen with all useful agents.

Lung transplantation considered for patients who fail medical treatment.

Sotatercept treatment results in reduction in pulmonary vascular resistance  in patients  on therapy for pulmonary arterial hypertension.

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