Pulmonary HTN

Cardiac Catheterization

• • Must be done for accurate measurement of pulmonary artery pressure, cardiac output, and LV filling pressure, as well as for exclusion of an underlying cardiac shunt.

  • Measure pressures only at end expiration.

  • Patients with pulmonary arterial hypertension undergo drug testing with a short-acting pulmonary vasodilator at the time of cardiac catheterization to determine the extent of pulmonary vasodilator reactivity.

    • IH nitric oxide, IV adenosine, IV epoprostenol have comparable effects in reducing PAP acutely.

    • NO given via IH in 10–20 ppm.

    • Adenosine given in doses of 50 g/kg per min and increased every 2 min until side effects develop.

    • Epoprostenol is given in doses of 2 ng/kg per min and increased every 30 min until side effects develop.

    • Patients who respond can often be treated with calcium channel blockers and have a more favorable prognosis.

  • A marked reduction in pulmonary artery pressure from acute vasodilator testing is defined as a fall in mean pulmonary artery pressure (MPAP) 10 mmHg and a final MPAP that is <40 mmHg.

    • Acute illness with reversible PH (pneumonia, pulmonary edema, etc.) should be treated and resolved before w/up for chronic causes of PH is started.

      • TTE: initial evaluation. PAP, TR?, signs of elevated R ventricular pressure (dilated or hypokinetic right ventricle, paradoxical septal motion, or a "D"-shaped right ventricle); left ventricular dysfx (reduction in the left ventricle size consistent with right ventricular pressure overload), VHD, check for R > L shunt (PFO, ASD) with an echo bubble (agitated saline); or contrast study (radionuclide lung perfusion scan that looks for abnormal accumulation of tracer in brain or kidneys).

      • Once PH is diagnosed, patients should undergo a through evaluation for causes:

        • CXR: dilated central pulmonary arteries, decreased vascular markings in the periphery or pruning (PAH), right ventricular enlargement with opacification of retrosternal space (best seen on lateral view). Very large pulmonary vasculature throughout lung fields (congenital systemic - pulmonary shunt), regional oligemia of pulmonary vasculature may suggest PE. Interstitial infiltrates, and hyperinflated lungs may suggest secondary causes of PH (ILD, COPD).

        • PFTs: COPD, ILD. Often shows a mild-moderate reduction in the DLCO.

        • ABG: hypoxemia, oxy-Hb desat. with exertion. A normal PO2 does not exclude the presence of PH. Hypercapnia is an important clue for a hypoventilation syndrome.

        • 6-min walk test: oxg-Hb desat with exertion. Distance covered during 6-min walk assists in quantifying functional limits within modified NYHA classification.

        • ECG: Demonstrates signs of right ventricular and right atrial hypertrophy, RBBB, and right ventricular strain pattern (S wave in lead I with Q wave and inverted T wave in lead III)

        • Stress test: Exercise test must be performed with caution, and only if necessary.

        • V/Q lung scanning.

        • CT chest with PE protocol (HRCT) and CTA.

        • Pulmonary arteriography

        • Lung Bx

        • Radionuclide ventriculography

        • Sleep study

        • Screening Lab tests

        • R. heart cath with vasoreactivity

Conditions Associated with Pulmonary Hypertension

• • Collagen Vascular Disease

  • All of the collagen vascular diseases may be associated with PAH.

  • CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal involvement, sclerodactyly, and telangiectasia) and in scleroderma, and less frequently in SLE, Sjögren's syndrome, dermatomyositis, polymyositis, and rheumatoid arthritis.

  • It is usual for these patients to have some element of coexistent interstitial pulmonary fibrosis even though it may not be apparent on chest x-ray, CT, or pulmonary function tests. Consequently, these patients tend to have hypoxemia as an important clinical feature, along with the other classic findings of pulmonary hypertension.

  • Treatment of these patients is identical to that of patients with IPAH but is less effective.

  • Natural history of the underlying collagen vascular disease is not affected.

Congenital Systemic to Pulmonary Shunts

• • Large post-tricuspid cardiac shunts (e.g., ventricular septal defect, patent ductus arteriosus) to produce severe PAH.

  • Although less common, it may also occur in pre-tricuspid shunts (e.g., atrial septal defect, anomalous pulmonary venous drainage).

  • In patients with uncorrected shunts, the clinical features include those associated with right-to-left shunting such as hypoxemia and peripheral cyanosis, which worsen dramatically with exertion. PAH may occur years or even decades after surgical correction of these lesions, in which case there will be no associated right-to-left shunting. These patients present similarly to patients with IPAH but tend to have better long-term survival. The treatments are similar to those for IPAH.

Portal Hypertension

• • Portal hypertension is associated with PAH, but the mechanism remains unknown.

  • Patients with advanced cirrhosis can have the combined features of a high-output cardiac state in association with the features of pulmonary hypertension and RV failure.

  • A normal cardiac output may actually reflect a marked impairment of RV function. The etiology of ascites and edema can be confusing in these patients since it can have both cardiac and hepatic causes. Patients with mild pulmonary hypertension who have a favorable response to epoprostenol have undergone successful liver transplantation with improvement of the pulmonary vascular disease.

Anorexigens

• • A causal relationship has been established between exposure to several anorexigens, including aminorex and the fenfluramines, and the development of PAH.

  • Often the pulmonary hypertension will not develop until years after the last exposure.

  • While the clinical features are identical to those of IPAH, the patients appear to be less responsive to medical treatments and have a poorer prognosis.

Pulmonary Venoocclusive Disease

• • Pulmonary venoocclusive disease is a rare and distinct pathologic entity found in <10% of patients who present with unexplained pulmonary hypertension.

  • Histologically it is manifest by intimal proliferation and fibrosis of the intrapulmonary veins and venules, occasionally extending to the arteriolar bed.

  • The pulmonary venous obstruction explains the increase in pulmonary capillary wedge pressure observed in patients with advanced disease. These patients may develop orthopnea that can mimic LV failure. The therapy of this condition is not established.

Pulmonary Capillary Hemangiomatosis

• • Pulmonary capillary hemangiomatosis is a very rare form of pulmonary hypertension. Histologically it is characterized by the presence of infiltrating thin-walled blood vessels throughout the pulmonary interstitium and walls of the pulmonary arteries and veins.

  • The presenting symptoms are usually those of IPAH but often with hemoptysis as a clinical feature. The diagnosis can be made with pulmonary angiography. The clinical course is usually one of progressive deterioration leading to death. There is no established therapy.

Pulmonary Venous Hypertension

• • Pulmonary hypertension occurs as a result of increased resistance to pulmonary venous drainage.

  • Often associated with diastolic dysfunction of the left ventricle; diseases affecting the pericardium or mitral or aortic valves; or rare entities such as cor triatriatum, left atrial myxoma, extrinsic compression of the central pulmonary veins from fibrosing mediastinitis, and pulmonary venoocclusive disease.

  • Pulmonary venous hypertension affects the pulmonary veins and venules, producing arterialization of the external elastic lamina, medial hypertrophy, and focal eccentric intimal fibrosis. Microcirculatory lesions include capillary congestion, focal alveolar edema, and dilatation of the interstitial lymphatics. Although these lesions are potentially reversible, regression may take years after the underlying cause is removed.

  • In some patients pulmonary venous hypertension triggers reactive vasoconstriction in the pulmonary arterial bed and results in proliferative changes of the intima and media that can produce severe elevations in pulmonary artery pressure.

  • Clinically it may be confusing and appear as if two separate disease processes are occurring simultaneously. The distinction is important, however, as treatments that are effective in PAH may make patients with pulmonary venous hypertension worse.

Left Ventricular Diastolic Dysfunction

• • Pulmonary hypertension as a result of LV diastolic failure is common but often unrecognized.

  • It can occur with or without LV systolic failure.

  • The most common causes are hypertensive heart disease; coronary artery disease; or impaired LV compliance related to age, diabetes, obesity, and hypoxemia.

  • Symptoms of orthopnea and paroxysmal nocturnal dyspnea are prominent. Many patients improve considerably if LV end-diastolic pressure is lowered.

Mitral Valve Disease

• • Mitral stenosis and mitral regurgitation represent important causes of pulmonary hypertension. These patients often have reactive pulmonary vasoconstriction resulting in marked elevations in pulmonary artery pressures. An echocardiogram usually shows abnormalities such as thickened mitral valve leaflets with reduced mobility or severe mitral regurgitation documented by Doppler echocardiography. At cardiac catheterization, a pressure gradient between the pulmonary capillary wedge pressure and LV end-diastolic pressure is diagnostic of mitral stenosis.

  • In patients with mitral stenosis, corrective surgery of the mitral valve or mitral balloon valvuloplasty predictably results in a reduction in pulmonary artery pressure and pulmonary vascular resistance. Patients with mitral regurgitation, however, may not have as dramatic a response from surgery due to persistent elevations in LV end-diastolic pressure

Pulmonary Hypertension Associated with Lung Disease and Hypoxemia

The mechanism of hypoxic pulmonary vasoconstriction involves the inhibition of potassium currents and membrane depolarization of pulmonary vascular smooth muscle as a result of the change in membrane sulfhydryl redox status. Increased calcium entry into the vascular smooth-muscle cells mediates hypoxic pulmonary vasoconstriction. Pulmonary vascular remodeling in response to chronic hypoxia is also mediated by a reduction in nitric oxide production; an increase in endothelin 1; and increased expression of platelet-derived growth factors, vascular endothelial growth factor, and angiotensin II. Chronic hypoxia results in muscularization of the arterioles with minimal effects on the intima. When it occurs as an isolated entity, the changes produced are potentially reversible.

Although chronic hypoxia is an established cause of pulmonary hypertension, it rarely leads to an increase in the systolic pulmonary artery pressure >50 mmHg. Polycythemia in response to the hypoxemia is a characteristic finding. Hypoxia may also occur in conjunction with other causes of pulmonary hypertension associated with more extensive vascular changes. Clinically, the hypoxia tends to have an added adverse effect. Patients with chronic hypoxia who have a marked elevation in pulmonary pressure should be evaluated for other causes of the pulmonary hypertension.

Chronic Obstructive Lung Disease

• • Chronic obstructive lung disease (COLD) is associated with mild pulmonary hypertension in the advanced stages).

  • Pulmonary hypertension has been attributed to multiple factors, including hypoxic pulmonary vasoconstriction, acidemia, hypercapnia, the mechanical effects of high lung volume on pulmonary vessels, the loss of small vessels in the vascular bed, and regions of emphysematous lung destruction.

  • The presence of pulmonary hypertension in patients with COLD confers a worse outcome.

  • The only effective therapy is supplemental oxygen. Several large clinical trials have documented that continuous oxygen therapy relieves some of the pulmonary vasoconstriction, relieves chronic ischemia throughout the systemic and pulmonary vascular beds, and improves survival. Long-term oxygen therapy is indicated if the resting arterial PO2, remains <55 mmHg.

Interstitial Lung Disease

• • Pulmonary hypertension from interstitial lung disease is often associated with obliteration of the pulmonary vascular bed by lung destruction and fibrosis.

  • In addition, hypoxemia and pulmonary vasculopathy can be contributory factors.

  • Interstitial lung disease is often associated with the collagen vascular diseases.

  • A large number of patients have pulmonary fibrosis of unknown etiology. Patients are commonly older than 50 years and report an insidious onset of progressive dyspnea and cough for months to years. It is uncommon for the mean pulmonary artery pressure to exceed 40 mmHg. While none of the medical treatments developed for PAH have been shown to be effective in these patients, their use may worsen the hypoxemia.

Sleep-Disordered Breathing

• • The incidence of pulmonary hypertension in the setting of obstructive sleep apnea, a common condition, appears to be <20% and is generally mild. Some patients, however, present with severe pulmonary hypertension in conjunction with sleep apnea, which may or may not be related. It is recommended that the sleep apnea and the PAH be treated as coexisting problems.

Alveolar Hypoventilation

• • Pulmonary hypertension can occur in patients with chronic hypoventilation and hypoxia secondary to thoracovertebral deformities.

  • Symptoms are slowly progressive and related to hypoxemia.

  • In patients with advanced disease, intermittent positive-pressure breathing and supplemental oxygen have been used successfully.

Pulmonary hypertension secondary to hypoxemia has been reported in patients with neuromuscular disease as a result of generalized weakness of the respiratory muscles and in patients with diaphragmatic paralysis, generally a result of trauma to the phrenic nerve. Patients with nontraumatic bilateral diaphragmatic paralysis may go unrecognized until they present with either respiratory failure or pulmonary hypertension.

Chronic Thromboembolic Pulmonary Hypertension

Patients appropriately treated for acute pulmonary thromboembolism with intravenous heparin and chronic oral warfarin therapy usually do not develop chronic pulmonary hypertension. However, some patients have impaired fibrinolytic resolution of the thromboembolism, which leads to organization and incomplete recanalization and chronic obstruction of the pulmonary vascular bed. The entity of chronic thromboembolic pulmonary hypertension has been well characterized and often mimics PAH. In many patients, the initial pulmonary thromboembolism was undetected or untreated. Many of these patients have underlying thrombophilic disorders, such as the lupus anticoagulant/anticardiolipin antibody syndrome, prothrombin gene mutation, or Factor V Leiden

• • The physical examination is typical of pulmonary hypertension but may include bruits heard over areas of the lung, representing blood flow through vessels with partial occlusion. A perfusion lung scan or contrast-enhanced spiral CT scan usually reveals multiple thromboemboli. However, pulmonary angiography is necessary to determine the precise location and proximal extent of the thromboemboli, and hence the potential for operability.

  • Treatment

    • Pulmonary thromboendarterectomy is an established surgical treatment in patients whose thrombi are accessible to surgical removal. The operative mortality is fairly high, at ~12% in experienced centers. Postoperative survivors who have a good result can expect to realize an improvement in functional class and exercise tolerance.

    • Lifelong anticoagulation using warfarin is mandatory. Thrombolytic therapy is rarely of help in patients with chronic thromboembolic pulmonary hypertension and may expose these patients to the increased risk of bleeding without potential benefit.

Sickle Cell Disease

• • Cardiovascular system abnormalities are prominent in the clinical spectrum of sickle cell disease, including pulmonary hypertension.

  • The etiology is multifactorial, including hemolysis, impaired nitric oxide bioavailability, hypoxemia, thromboembolism, chronic high cardiac output, and chronic liver disease.

  • Pulmonary hypertension in patients with sickle cell disease is associated with a higher morbidity and mortality. Intensification of sickle cell disease–specific therapy appears to reduce the morbidity. The use of drugs to treat pulmonary hypertension is under clinical trials, but their efficacy remains unknown.

Other Disorders Directly Affecting Pulmonary Vasculature

Sarcoidosis

• • Sarcoidosis can produce severe pulmonary hypertension as a result of chronic severe fibrocystic lung involvement, or direct cardiovascular involvement.

  • Patients with sarcoidosis who present with progressive dyspnea and clinical features of pulmonary hypertension need a thorough evaluation.

  • There is a subset of patients with sarcoidosis who present with severe pulmonary hypertension believed to be due to direct pulmonary vascular involvement.

  • Many of these patients exhibit a favorable response to intravenous epoprostenol therapy.

Schistosomiasis

• • Schistosomiasis is the most common cause of pulmonary hypertension worldwide.

  • The development of pulmonary hypertension often occurs in the setting of hepatosplenic disease and portal hypertension.

  • Schistosome ova can embolize from the liver to the lungs, where they result in an inflammatory pulmonary vascular reaction and chronic changes.

  • The diagnosis is confirmed by finding the parasite ova in the urine or stools of patients with symptoms, which can be difficult.

  • The efficacy of therapies directed toward pulmonary hypertension in these patients is unknown.

HIV Infection

• • The mechanism by which HIV infection produces pulmonary hypertension remains unknown.

  • The evaluation and treatments are identical to those for IPAH.

  • Treatment of the HIV infection does not appear to affect the severity or natural history of the underlying pulmonary hypertension.