Pulmonary Hypertension definition pathophysiology clinical features treatment

Pulmonary Hypertension Definition Pathophysiology Clinical features Treatment Definition :  an abnormal elevation in pulmonary artery pressure, may be the result of left heart failure, pulmonary parenchymal or vascular disease, thromboembolism, or a combination of these factors. It is  generally is a feature of advanced disease. Pathophysiology Right ventricle

• Responds to an increase in pulmonary vascular resistance by increasing right ventricular (RV) systolic pressure to preserve cardiac output.
• Ability of the RV to adapt to increased vascular resistance is influenced by several factors, including age and the rapidity of the development of pulmonary hypertension.
• Large acute pulmonary thromboembolism can result in RV failure and shock, whereas chronic thromboembolic disease of equal severity may result in only mild exercise intolerance.
• Chronic changes occur in the pulmonary circulation, resulting in progressive remodeling of the vasculature, which can sustain or promote pulmonary hypertension even if the initiating factor is removed.
• Coexisting hypoxemia can impair the ability of the ventricle to compensate.
• Studies support the concept that RV failure occurs in pulmonary hypertension when the RV myocardium becomes ischemic as a result of excessive demands and inadequate RV coronary blood flow.
• The onset of RV failure, often manifest by peripheral edema, is associated with a poor outcome.

Symptoms

• Most common symptom – exertional dyspnea.
• Other common symptoms are fatigue, angina pectoris, syncope, near syncope, and peripheral edema.

Physical examination

• Increased jugular venous pressure
• Reduced carotid pulse
• Palpable RV impulse
• Increased pulmonic component of the second heart sound,
• Right-sided fourth heart sound
• Tricuspid regurgitation.
• Peripheral cyanosis and/or edema tend to occur in later stages of the disease.

Laboratory Findings

1. Chest x-ray

• shows enlarged central pulmonary arteries.
• lung fields may reveal other pathology.

 

2. Electrocardiogram(ECG)–  shows right axis deviation and RV hypertrophy

3. Echocardiogram commonly

• demonstrates RV and right atrial enlargement,
• reduction in left ventricular (LV) cavity size, and a
• tricuspid regurgitant jet that can be used to estimate RV systolic pressure by Doppler.

4. Pulmonary function tests(PFT)– helpful in documenting underlying obstructive airways disease

5. High-resolution chest computed tomography (HRCT) -preferred to diagnose restrictive lung disease.

6. Perfusion lung scan

• always abnormal in patients with thromboembolic pulmonary hypertension.
• Hypoxemia and an abnormal diffusing capacity for carbon monoxide occur with pulmonary hypertension of many causes.
• diffuse defects of a nonsegmental nature often can be seen in long-standing pulmonary hypertension in the absence of thromboemboli.

7. Laboratory tests

• Antinuclear antibody(ANA) and HIV testing.
• Thyroid-stimulating hormone level – because of the high frequency of thyroid abnormalities in patients with idiopathic pulmonary hypertension.

  8. Cardiac Catheterization

• mandatory for accurate measurement of pulmonary artery pressure, cardiac output, and LV filling pressure as well as documentation of an underlying cardiac shunt.
• pressures to be recorded only at end expiration.
• It is recommended that patients with PAH to undergo drug testing with a short-acting pulmonary vasodilator to determine the extent of pulmonary vasodilator reactivity.
• Inhaled nitric oxide, intravenous adenosine, and intravenous epoprostenol have comparable effects in reducing pulmonary artery pressure acutely.
• Patients who respond usually can be treated with calcium channel blockers and have a more favorable prognosis

 Pulmonary Arterial Hypertension

• Pulmonary arterial hypertension (PAH) refers to a variety of diseases that include idiopathic PAH.

Histopathology

• characterized by medial hypertrophy, eccentric and concentric intimal fibrosis, recanalized thrombi appearing as fibrous webs, and plexiform lesions.

Pathobiology

• Vasoconstriction, vascular proliferation, thrombosis, and inflammation appear to underlie the development of PAH.
• Abnormalities in multiple molecular pathways and genes that regulate the pulmonary vascular endothelial and smooth muscle cells have been identified.

These abnormalities include

• decreased expression of the Voltage-regulated potassium channel
• Mutations in the bone morphogenetic protein-2 receptor
• Increased tissue factor expression
• Overactivation of the serotonin transporter
• Transcription factor activation of hypoxia-inducible factor-1 alpha
• Activation of nuclear factor of activated T cells.

loss of apoptosis of the smooth muscle cells that allows their proliferation and the emergence of apoptosis-resistant endothelial cells that can obliterate the vascular lumen. In addition, thrombin deposition in the pulmonary vasculature from a procoagulant state that develops as an independent abnormality or as a result of endothelial dysfunction may amplify the vascular proliferation Multiple biologic pathways that can lead to pulmonary arterial hypertension: BMPR-2, bone morphogenetic protein receptor-2; HIF, hypoxia inducible factor; KV 1.5, voltage-regulated potassium channel 1.5; NFAT, nuclear factor of activated T cells. Idiopathic Pulmonary Arterial Hypertension

• formerly referred to as primary pulmonary hypertension, is uncommon, with an estimated incidence of two cases per million.
• There is a female predominance, with most patients presenting in the fourth and fifth decades, although the age range is from infancy to >60 years.
• Familial IPAH accounts for up to 20% of cases of IPAH and is
• characterized by autosomal dominant inheritance and incomplete penetrance.
• The clinical and pathologic features of familial and sporadic IPAH are identical.
• Heterozygous germ-line mutations involving the gene that code the type II bone morphogenetic protein receptor (BMPR II), a member of the transforming growth factor (TGF) superfamily, appear to account for most cases of familial IPAH.

Natural History

• The natural history of IPAH is uncertain, but the disease typically is diagnosed late in its course.
• Before current therapies, a mean survival of 2–3 years from the time of diagnosis was reported.
• Functional class remains a strong predictor of survival, with patients who are in New York Heart Association (NYHA) functional class IV having a mean survival of <6 months.
• The cause of death is usually RV failure, which is manifest by progressive hypoxemia, tachycardia, hypotension, and edema.

Treatment: Pulmonary Arterial Hypertension

• patients should be cautioned against participating in activities that impose physical stress.
• Diuretic therapy relieves peripheral edema and may be useful in reducing RV volume overload.
• Pulse oximetry should be monitored, as O2 supplementation helps alleviate dyspnea and RV ischemia in patients whose arterial O2 saturation is reduced.
• Anticoagulant therapy is advocated for all patients with. The dose of warfarin generally is titrated to achieve an international normalized ratio (INR) of 2–3 times control

Several treatments are approved for PAH Calcium Channel Blockers

• Patients who respond to short-acting vasodilators at the time of cardiac catheterization (a fall in mean pulmonary arterial pressure 10 mmHg and a final mean pressure <40 mmHg) should be treated with calcium channel blockers.
• Typically, these patients require high doses (e.g., nifedipine, 240 mg/d, or amlodipine, 20 mg/d)
• Dramatic reductions in pulmonary artery pressure and pulmonary vascular resistance associated with improved symptoms.
• Regression of RV hypertrophy and Improved
• Not effective in patients who are not vasoreactive.

Endothelin Receptor Antagonists

• The endothelin receptor antagonists bosentan and ambrisentan
• bosentan is initiated at 62.5 mg bid for the first month and increased to 125 mg bid thereafter. Ambrisentan is initiated as 5 mg once daily and can be increased to 10 mg daily.
• high frequency of abnormal hepatic function tests associated with these drugs, primarily an increase in transaminases, it is recommended that liver function be monitored
• Bosentan is contraindicated in patients who are on cyclosporine or glyburide concurrently.

Phosphodiesterase-5 Inhibitors

• Sildenafil and tadalafil, phosphodiesterase-5 inhibitors, are approved for the treatment of PAH.
• Phosphodiesterase-5 is responsible for the hydrolysis of cyclic GMP in pulmonary vascular smooth muscle, the mediator through which nitric oxide lowers pulmonary artery pressure and inhibits pulmonary vascular growth.
• The effective dose for sildenafil is 20–80 mg tid. And tadalafil is 40 mg once daily.
• The most common side effect is headache. Should not be given to patients who are taking nitrovasodilators.

 Prostacyclins

1. Iloprost

• a prostacyclin analogue, via inhalation for PAH.
• Therapy can be given at either 2.5 or 5 g per inhalation treatment via a dedicated nebulizer.
• The most common side effects are flushing and cough.
• Because of the very short half-life (<30 min) it is recommended that treatments be administered as often as every 2 h.

2.Epoprostenol

• Approved as a chronic IV treatment of PAH. .
• Drug administration requires placement of a permanent central venous catheter and infusion through an ambulatory infusion pump system.
• Side effects include flushing, jaw pain, and diarrhea, which are tolerated by most patients.
• epoprostenol range from 25 to 40 ng/kg per min

3.Treprostinil

• an analogue of epoprostenol, given intravenously, subcutaneously, or via inhalation.
• Side effects are similar to those seen with epoprostenol. treprostinil from 75 to 150 ng/kg per min
• The intravenous prostacyclins have the greatest efficacy as treatments for PAH and are often effective in patients who have failed all other treatments.
• The major problem with intravenous therapy is infection related to the indwelling venous catheter, which requires close monitoring and diligence on the part of the patient.
• In addition, abrupt discontinuation of intravenous prostacyclins can lead to a rebound increase in pulmonary pressure.

• It is recommended that every patient diagnosed with PAH be treated.
• Although no drug has been demonstrated to be superior as first-line therapy, many prefer to initiate treatment with an oral or inhaled form of therapy.
• Patients who fail to improve adequately within the first 2 months should be switched to a different therapy
• The use of these drugs in combination has become popular, but the only randomized clinical trial demonstrating beneficial effects added sildenafil to patients treated with epoprostenol.

Lung Transplantation

• Lung transplantation is considered for patients who, while on an intravenous prostacyclin, continue to manifest right heart failure.
• Acceptable results have been achieved with heart-lung, bilateral lung, and single-lung transplantation.
• The availability of donor organs often influences the choice of procedure.