​Kembara Xtra - Medicine - Pulmonary Arterial Hypertension

​Kembara Xtra - Medicine - Pulmonary Arterial Hypertension 
A kind of pulmonary hypertension known as pulmonary arterial hypertension (PAH) is characterized by anomalies in the small pulmonary arteries (precapillary PH), which raise the pulmonary arterial pressure (PAP) and vascular resistance and eventually lead to right-sided heart failure. PAH is a chronic condition linked to higher mortality.
- PH was previously divided between primary PH (now known as idiopathic IPAH, which has no known cause) and secondary PH (which has a cause or an associated ailment), but it is now evident that several kinds of secondary PH closely resemble primary PH (IPAH) in terms of their histology, natural history, and response to treatment. As a result, the WHO divides PH into five groups based on mechanism, with PAH being assigned to group 1.
- When other groups of PH are ruled out, right-heart catheterization is used to diagnose PAH, which is defined by a mean PAP 20 mm Hg at rest and a pulmonary vascular resistance (PVR) of 3 Wood units; pulmonary capillary wedge pressure 15 mm Hg (excludes PH due to left heart disease, i.e., group 2 PH).
- Mild or absent chronic lung disease or other sources of hypoxemia (group 3 PH does not include PH caused by lung disease or hypoxemia)
- No venous thromboembolic illness (group 4 PH; excludes chronic thromboembolic PH [CTEPH])
- No systemic disease, such as sarcoidosis, hematologic disease, such as myeloproliferative disease, or metabolic disease, such as glycogen storage disease (group 5 PH excluded)
The following major categories make up PAH:
- Idiopathic: Sporadic and devoid of risk factors or family history
- Heritable: family examples of IPAH with or without mutations, or IPAH with mutations
- Drug- or toxin-induced: most frequently linked to anorexics (such as fenfluramine), rapeseed oil, L-tryptophan, dasatinib (Bcr-Abl tyrosine kinase inhibitor), and illegal narcotics like methamphetamine and cocaine.
Connective tissue conditions (such as systemic lupus erythematosus, rheumatoid arthritis, and scleroderma), HIV infection, portal hypertension (HTN), congenital heart disease, and schistosomiasis (chronic hemolytic anemia coupled to group 5 PH—unclear/multifactorial causes) are all associated with this condition (1).
- Due to more differences than similarities with PAH, pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) and persistent PH of the newborn (PPHN) are categorized as different groups.
In contrast to PAH, which affects the tiny muscular pulmonary arterioles, PVOD and/or PCH are uncommon causes of PH that are characterized by broad diffuse blockage of the pulmonary veins.

Epidemiology 

 Sex (IPAH): female > male (female:male ratio ranges from 1.7 to 4.8:1.0) Age: can arise at any age; mean age 37 years Overall PAH: 5 to 52 cases per million
Low, between 2 and 6 per million for IPAH; 1/25,000 for drug-induced PAH with use of anorectics for more than three months; and 0.5/100 for HIV.
Associated Portal HTN: 1 to 6/100
Scleroderma-associated PAH: 15–50 cases per million; IPAH: 6 cases per million; Scleroderma-associated prevalence: 6–60%


Pathophysiology and Etiology 
Pulmonary: Remodeling of the pulmonary arteries caused by enhanced cell proliferation and decreased rates of apoptosis results in inflammation, vasoconstriction, endothelial dysfunction, and intimal proliferation.
Cardiovascular: RV remodeling associated with PAH is brought on by right ventricular hypertrophy (RVH), which finally results in right-sided heart failure and right ventricular (RV) ischemia because of decreased right coronary artery flow.
IPAH: Unknown by definition. True IPAH is mostly sporadic or occasionally familial in origin.
 Autoimmune (high frequency of antinuclear antibodies), occult thromboembolism, and pulmonary arteriolar hyperactivity and vasoconstriction
Genetics
25% of IPAH cases and 75% of heritable PAH (HPAH) cases both had BMPR2 autosomal dominant mutations.
 Autosomal dominant mutations in endoglin and ALK1 are also linked to PAH.

Female sex, past anorectic medication usage, a recent acute pulmonary embolism, and first-degree relatives of patients with familial PAH are risk factors.


PAH symptoms are generic, which increases the risk of missing or delaying a diagnosis of this dangerous illness.

History 

lower extremity edema, dyspnea, weakness, syncope, vertigo, chest pain, and palpitations


clinical assessment 
The following criteria must be met: Pulmonary component of S2 (at apex in >90% of patients); RV lift; Early systolic click of the pulmonary valve; Pansystolic murmur of tricuspid regurgitation; Diastolic murmur of pulmonic insufficiency (Graham Steell murmur); RV S3 or S4; Edema as jug

Multiple Diagnoses 

Other causes of dyspnea include: pulmonary parenchymal illness, such as restrictive lung disease, chronic obstructive pulmonary disease, or interstitial lung disease; and pulmonary vascular disease, such as pulmonary thromboembolism.
Cardiomyopathy and other respiratory diseases like sleep apnea are examples of cardiac illness.


Laboratory Results 

 RVH and right axis deviation on echocardiography (ECG), or RV strain (increased P wave amplitude, incomplete right bundle branch block pattern, and an R-to-S ratio greater than one in lead V1).
Arterial blood gas results: arterial hypoxemia and hypocapnia. Reduced diffusion capacity was found during pulmonary function testing.
A ventilation/perfusion (V/Q) scan should be performed to rule out group 4 PH and look for CTEPH and proximal pulmonary artery emboli.
Exercise-induced changes in maximum oxygen uptake, minute ventilation, anaerobic threshold, and PO2 alveolar-arterial gradient are correlated with disease severity, as measured by the 6-minute walk distance (6MWD) test.
 Up to 40% of patients test positive for antinuclear antibodies
LFTs: Check for portopulmonary HTN, a chronic liver disease consequence.
HIV testing, thyroid testing, and screening for sickle cell disease
In young, otherwise healthy patients with modest symptoms, elevated brain natriuretic peptide (BNP) and N-terminalproBNP may be helpful for the early diagnosis of PAH. It can also be used to evaluate the severity and prognosis of an illness.
Chest radiograph: RV enlargement is a late finding; prominent central pulmonary arteries; peripheral hypovascularity of pulmonary arterial branches.
The most popular screening method is echo doppler, which should be utilized if PAH is suspected. Echo does not diagnose PAH but implies it.
 Calculates the mean PAP, evaluates the anatomy and function of the heart, and rules out congenital abnormalities.
 Enlargement of the right atrium and ventricles; tricuspid regurgitation
 In patients at risk for HPAH, screen for BMPR2 gene mutations to rule out underlying cardiac illness such as atrial septal defect with secondary PH or mitral stenosis.
For suspected signs of obstructive sleep apnea, polysomnography is recommended.

Other/Diagnostic Procedures
Pulmonary angiography should be performed if a V/Q scan indicates CTEPH. Use caution as this procedure could result in hemodynamic collapse.
The gold standard for diagnosing PAH is right-sided cardiac catheterization.
It is crucial to measure PAPs and hemodynamics in order to confirm the diagnosis and assess severity and prognosis. Verify the absence of underlying cardiac disease (such as left-sided heart disease) and evaluate the effectiveness of vasodilator therapy.
Lung biopsy is not advised unless primary pulmonary parenchymal disease is present, and the 6MWD assesses PAH severity and predicts prognosis.

Treatment of underlying illnesses/conditions that may contribute to PAH can help manage symptoms, enhance quality of life, and increase survival rates.
 The following are some appropriate therapeutic objectives:
- Modified NYHA FC I or II - ECG/CMR with RV size and function that are normal or almost normal
- Hemodynamic measurements indicating that the RV function has returned to normal (RAP 8 mm Hg and cardiac index [CI] >2.5 to 3.0 L/min/m2).
- 6MWD between 380 and 440 m
- Normal BNP levels during cardiopulmonary exercise testing, which includes peak oxygen consumption of more than 15 mL/min/kg and EqCO2 below 45 L/min.



Avoid vigorous physical activity; receive psychosocial support; and receive supervised exercise instruction.
Don't become pregnant.
 Immunization against pneumococcal and influenza
 Maintain an arterial blood oxygen pressure of at least 60 mm Hg.

Medication - Screens for pulmonary vasoreactivity/responsiveness using inhaled nitrous oxide; epoprostenol (IV) or adenosine (IV): Positive response may be a prognostic indicator. Acute vasodilator test during heart catheterization for all patients who are potential candidates for long-term oral calcium channel blocker (CCB) therapy.
- Contraindicated in hemodynamic instability or right-sided heart failure
Chronic vasodilator therapy: Use CCBs if the patient has IPAH and the acute vasodilator test results in a favorable response (a fall in mean PAP of 10 mm Hg and to a value 40 mm Hg, with unchanged/increased cardiac output).
13% of patients will at first respond, with an adequate response confirmed after 3 to 4 months of treatment. The clinical response to CCB therapy over the long term is minimal (7%).
Nifedipine (long acting), diltiazem, and amlodipine are CCBs.
Verapamil should be avoided as it has a strong inotropic effect.
- CCBs are contraindicated in patients whose cardiac index is less than 2 L/min/m2 or whose right atrial pressure is greater than 15 mm Hg if PAH has a negative response to an acute vasodilator test or worsens with treatment; particular vasodilator selection is based on risk assessment.
Patients in WHO-FC II who don't respond to acute vasoreactivity should be given an oral medication (3)[B].
Nonresponders who continue or advance to WHO-FC III should be given consideration for treatment with any PAH medications that have been licensed.
Due to the survival advantage (NNT = 5), continuous IV epoprostenol is advised as the first-line therapy for WHO-FC IV PAH.
If the clinical response is insufficient, consecutive combination therapy should be taken into consideration. Treatment options include prostanoid plus ERA or prostanoid plus a phosphodiesterase type 5 (PDE5) inhibitor.
Ambrisentan, bosentan, macitentan, riociguat, sildenafil, and tadalafil are among the WHO-FC II PAH-approved medications (3)[B].
Ambrisentan, bosentan, epoprostenol (IV), macitentan, riociguat, sildenafil, tadalafil, and treprostinil (SC, inhaled) are among the medications approved by WHO-FC III PAH.epoprostenol (IV), a WHO-FC IV PAH-approved medication - Drug classes:
 Prostacyclins: epoprostenol (IV), treprostinil (IV, SC, or inhaled), iloprost, and beraprost improve cardiopulmonary hemodynamics and exercise capacity.
 Selexipag, a receptor agonist for prostatecyclin IP
Endothelin receptor antagonists, such as bosentan (PO), ambrisentan (PO), and macitentan, have been shown to increase exercise capacity while decreasing mortality.
Category X pregnancy; check LFTs every month.
PDE5 inhibitors such as sildenafil (PO), tadalafil (PO), and vardenafil may enhance symptoms, cardiopulmonary hemodynamics, and exercise capacity.
Riociguat (PO), a guanylate cyclase stimulant, increases exercise capacity. Anticoagulation - Improved survival was initially suggested in patients with IPAH alone. Recent research provides some support for the beneficial benefits of anticoagulation on survival in IPAH, HPAH, or PAH linked to anorexigens.
- In numerous observational studies, warfarin with an INR of 1.5 to 2.5 has been shown to improve patient survival.
Indications not to use: Avoid in patients who have experienced syncope or severe hemoptysis; take drug interactions into account.
 Patients with RV volume overload (such as peripheral edema or ascites) should take diuretics.
Digoxin is utilized in RV failure and/or atrial dysrhythmias, enhances cardiac output, and maintains RV contractility, however there are few long-term data in PAH.

Referral 

If PAH is suspected, consult a cardiologist and/or a pulmonologist for additional assessment and therapy.

Surgery 
Patients with confirmed large-vessel thromboembolic illness should be given pulmonary thrombectomy consideration.
 Heart-lung or lung transplantation for severe PAH with right-sided heart failure despite optimal medical therapy to improve symptoms before lung transplant or as a standalone treatment Balloon atrial septostomy.

Admission 

Hospitalization with invasive monitoring is required to screen for vasodilator responsiveness and begin vasodilator therapy. Medical therapy is mostly palliative. The National Heart, Lung, and Blood Institute has created a national registry.

Exercise: walking or low-intensity aerobic activity, as tolerated, once stable; respiratory training; follow-up; influenza and pneumococcal immunizations
patient observation
Analyze the effectiveness of treatments and illness progression often. The 6-minute walk test and the cardiopulmonary exercise test are tests used to gauge therapy effectiveness.

Salt and fluid limits in the diet, especially when the RV fails

Modification of Lifestyle 
Discuss the prognosis, dietary modifications, and all available treatment options, including transplant.

Prognosis – 5-year survival rate is 34% (NIH registry); current data suggest 5-year survival 70% with improved treatment. Median survival is 2 to 3 years from diagnosis.
 Right-sided heart failure, the most prevalent type, pneumonia, abrupt death, and cardiac death
 Negative prognostic indicators
Rapid worsening of symptoms and clinical signs of RV failure
- Peak VO2 during cardiopulmonary exercise testing 10.4 mL/kg/min - WHO functional PAH class IV (or NYHA functional class III or IV) - 6MWD 300 m - ECG with pericardial effusion, considerable RV enlargement/dysfunction, and right atrial enlargement
- raised mean PAP - Significantly raised BNP and NT-proBNP; other markers also show promise in predicting survival: RDW, GDF-15, interleukin-6, creatinine. - Mean right atrial pressure >20 mm Hg. - Cardiac index 2 L/min/m2.
- Diseases in the scleroderma spectrum
Due to high maternal mortality rates (30–50%) and fetal wasting, pregnancy should be avoided. Complications include thromboembolism, heart failure, pleural effusion, and abrupt death.

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