PULMONARY HYPERTENSION Normal pulmonary arterial pressure in a person living at sea level has a mean value of 8–20 mm Hg

Five Classifications of PH

Diagnosis and Treatment SX: dyspnea on exertion, syncope, fatigue, chest pain, weakness Right sided heart dysfunction: orthopnea, peripheral edema, liver congestion, and abdominal bloating. CXR & ECG may suggest PH TEE- used for noninvasive screening of PH by providing estimations of PAPs and RV size and function. RIGHT HEART CATHETERIZATION- required for diagnosis, and pulmonary vasoreactivity testing during procedure. (Inhaled nitric oxide, iv epoprostenol, or iv adenosine) then repeat hemodynamic measurements Vasoreactivity defined as 10 mm Hg or more to an absolute of less than 40 mm Hg with no reduction in CO PULMONARY FUNCTION TEST- blood gas, CT, perfusion scans to evaluate pt for CTEPH (CTEPH= Chronic thromboembolic pulmonary HTN)

PAH or PVH

Idiopathic Pulmonary Hypertension (IPAH) The pulmonary arteries carry blood from the heart to the lungs, where the blood picks up oxygen. In people with PAH and IPAH, the small arteries become narrowed and constricted. One or more of these three things typically causes the narrowed arteries: •Tiny blood clots form in the smallest arteries in the lungs and block blood flow. •Increased cell growth in the blood vessels causes abnormally thick artery walls. •Artery walls squeeze and make blood flow more difficult. -Some people with IPAH have a genetic predisposition to the disease A noninvasive procedure called an echocardiogram may detect PAH. This imaging test can gauge the blood pressure inside your pulmonary arteries Treatment consist of : •calcium channel blockers •endothelin receptor antagonists •vasodilators

Pulmonary Arterial Hypertension (PAH) Pulmonary Arterial Hypertension (PAH).. High pressures in the pulmonary arteries cause the right side of heart to weaken Note the thickening of the right ventricle. Blood backs up and causes the ankles to swell. Treatment may Be an atrial septostomy, lung transplant, pulmonary thromboendarecectomy

Pts with high vasso response should be on calcium channel blockers

Classification WHO/ NYHA Scale Class I … No symptoms ( dyspnea, fatigue,syncope, CP ) with ordinary physical activity.– oral mono-therapy for class I (ambrisentan, bosentan, macitentan, riociguat, sildenafil, tadalafil) Class II … Symptoms with ordinary daily activities that slightly limit activity Level Oral mono-therapy for class I ( ambrisenan, bosentan, macitentan, riociguat, Sildenafil, tadalafil) Class III… Symptoms with less-than-ordinary daily activities that severely limit activity level– combination ambrisentan and tadalafil Class IV… Symptoms at rest; cannot conduct normal daily activities without symptoms. (tx with iv epoprostenol)

TREATMENT GUIDELINES Treatment of PH is determined by whether PH is arterial, venous, hypoxic, or misc Treatment is to optimize left ventricular function with diuretics, digoxin, blood Thinners, or repair/replace the mitral or aortic valve. -- Patients with left HF or hypoxemic lung diseases (groups II or III) should not routinely be treated with vasoactive agents including prostanoids, phosphodiesterase inhibitors, or endothelin antagonist… these are approved ONLY for pulmonary arterial hypertension. PAH- class III-IV… use iv epoprostenol, if can’t give iv, give inhaled agent plus an ERA

TREATMENT GUIDELINES High dose calcium channel blockers are useful in only 5% of IPAH patients who are vaso- Reactive by swans ganz cathers. VASO-reactive means the mean pulmonary artery pressure falls by more than 10 mm Hg to less than 40 mm Hg with an unchanged or increased cardiac output when challenged with : adenosine, epoprostenol, or nitric oxide are considered VASOACTIVE SUBSTANCES- include endothelin receptor antagonist, phosphodiesterase type Prostacyclin is commonly the most effective treatment for PAH. Epoprostenol is given continuous infusion, usually requiring central lines. Half-life is 3-5 minutes. Other prostanoids are treprostinil.. Can be given iv or subq. Iloprost is the only inhaled form of prostacyclin. PDE5 inhibitors came about in 2005. They increase pulmonary artery vasodilation, and inhibit vascular remodeling. 2009 Guanulate cyclase .. Eg: cinacigual and riociguat. (can’t be used w PDE5, but in place of

Surgical Intervention Atrial septostomy… hole placed atriums to relieve pressure at the cost of hypoxia Lung transplantation…. However the mean survival rate is just over 5 years Pulmonary thromboendartectomy (PTE) – Surgical remove of clot in lungs

Epidemiology In the 1980s.. Mean survival was 2.8 years, improving to 7 years in the late 2000s. More recently, the mean age at diagnosis has increased from 36 years to 50-65 years old. Distal pulmonary arteries have thickening, endotheliaial and smooth muscle cell dysfunction and proliferation, fibrosis, inflammation, and thrombosis. Includes production of vasodilatory and antiproliferative subgstances nitric acid and prostacyclin and increased vasoconstrictor & proliferative compounds thromboaxane A and endothelin-1. Pulmonary hypertension is defined as a mPAP of 25 mm Hg or greater at rest by right heart catheterization. Definition of PAH is Pulm capillary wedge pressure of 15 mm Hg or less and an elevated pulm vac resistance (PVR) of greater than 3 wood units /min

Classification of PAH symptoms Class I….. No symptoms (dyspnea, fatigue, syncope, chest pain) with ordinary physical activity. Class II... Symptoms with ordinary daily activities that slightly limit activity level Class III….. Symptoms with less-than-ordinary daily actives that severely limit activity level. Class IV…… Symptoms at rest, cannot conduct normal daily activities without symptoms.

Initial Non-pharmacologic treatment Treat corrective causes of hypoxemia; avoid dehydration, pain, fatigue, high altitude, smoking, iron deficiency, O2 to maintain O2 sats > 90% Supervised exercise activity (avoid strenuous) Warfarin (INR 1.5-2.5) if IPAH, heritable PAH , or PAH caused anorexigens, or assoc PAH Diuretics may be used for symptom management of fluid overload Digoxin may be used for atrial tachyarrhythmias Immunization (flu and PNA) Avoid pregnancy, discuss effective birth control w women of childbearing potential Positive response to acute vasoreactivity testing: initiate oral CCBfor WEHO functional classes I- III, and continue if sustained response; discontinue & consider PAH-specific therapies if no sustained response. CCB= Calcium channel blockers.

Calcium Channel Blockers 5% of PH will benefit from calcium channel blockers. They are first line drug for pts with WHO class 1-III who respond to vasoreactivity. During right-sided cath.. A vasoactive drug is given such as inhaled nitric oxide, IV epoprostenol, or iv adenosine are given. If a mPAP reduction of 10 mm Hg or more to an absolut e of less than 40 mm Hg with no reduction in cardiac output…. Positive for vasoreactivity and candidate for CCB. Calcium channel blockers improved survival at years compared to placebo was 94% vs 55% They improve mPAP, PVR, and WHO classification Amlodipine 40 mg q day Nifedipine extended release 240mg/ day Diltiazem immediate release 720mg/da7. (Verapamil should be avoided because of its negative inotropic effects)

Endothelin Receptor Antagonist (ERA) BOWENTAN (Traclear)…. REMS PROGRAM=Restricted due to severe hepatotoxicity and teratogenicity. edema, HA, hypotension, resp tract infection, arthralgia, sinusitis.. CYP2C9 interactions. Pregnancy test initially & q month. 62.5 mg bid, titrate to 125 mg bid after 4 weeks. AMBRISENTAN (Letairis) ….. Peripheral edema, HA, anemia, teratogenicity, flushing, nasal congestion Sinusitis, transaminitis 5 mg q day… titrate to 10mg q day MACITENTAN (Opsumit) … Anemia, teratogenicity, nasopharyngitis, pharyngitis, bronchitis, HA, transaminitis. Avoid CYP3A4… First to use mortality as it’s endpoint… placebo, macitentan 3mg, or 10 mg…... Mortality was 46.4%, 38%, 31.4% . 10 mg q day

ANTICOAGULATION PAH population has an increased thrombotic potential. Current guidelines support the use of anticoagulation in patients with idiopathic, heritable, and anorexigen-associated forms of PAH. COMPERA trial….. Mortality during 3 years was 14.2% for anticoagulation vs 21% for non=anticoagulation. REVEAL trail…. Found no difference in mortality between coagulation and anti-coagulation.

PDE-5 inhibitors and sGC stimulators PDE-5 INHIBITIORS (phosphodiesterase type 5 inhibitors)-prevent breakdown of cGMP in pulmonary smooth muscle through nitric oxide pathway. SILDENAFIL (Revatio, Viagra) = HA, dyspepsia, flushing epistaxis, dizziness, insomnia, hypotension, visual changes, tinnitus. TADALAFIL (Cialis)= ha, dyspepsia, flushing, nasopharyngitis, resp infection, hypotension, vision changes, tinnitus, nausea … interact w PYC3A4 inhib GUANYLATE CYLASE (Sgc) STIMULATORS-alternate to PDE-5s- reduces nitric oxide Improves exercise capacity & WHO functional class to delay worsning in PAH RIOCIGUAT (Adenpas) = HA, dyspepsia, gastritis, dizziness, N, D, Hypotension, vomiting, anemia, GI-reflux, constipation. Contrain with nitrates or PDE-5 inhib -smokers have 50% of the levels of non=smokers

PROSTACYCLINS Prostacylins (Epoprostenol FLOLAN) …..Prostacyclins are potent vasodilators that also have antiplatelet and and antiproliferative properties… they are given IV infusion for WHO CLASS III-IV patients. (Inhaled agents are for class III ) - IV epoprostenol for most severe cases (class III-IV) Treprostinil… IV, Inhalation, Oral … prolonged T1/2 = can dose qid. Iloprost.. Inhalation..(min of 2 hrs between doses). Use jet nebulizer over 4-10 min. Was the first inhaled prostacyclin. Assoc with flush and jaw pain and cough and bronchospasm.

TREATMENT GOALS - Attain a WHO functional class I or II - normal or near normal RV size and function - hemodynamic parameters showing normalization of RV - 6 minute walk distance (6MWD) > 380 meters - cardiopulmonary exercise testing that includes peak O2 consumption > 15 ml/min/kg and ventilator equivalent for CO2 less than 45 L minute/L/minute Normal brain natriuretic peptide( BNP) per age and sex. - recheck above in 3-6 months