Chapter 24. Pulmonary Vascular Disease

Background

Idiopathic pulmonary arterial hypertension (IPAH) represents pulmonary arterial hypertension in its purest form. By definition, IPAH exists when an underlying cause of the pulmonary arterial hypertension (PAH) cannot be identified. It is a rare disease with a poor prognosis and is characterized by luminal obliteration of small pulmonary arteries. The overall result is increased resistance to pulmonary blood flow, increasing pulmonary artery pressure (PAP), and ultimately, right ventricular failure and death.

Women are affected more commonly than men, with a female-to-male ratio of approximately 1.7:1. Cruelly, there is a predilection for IPAH to affect otherwise normal young women of childbearing age. The mean age for developing the condition is approximately 40 years, but it can occur at any age. Elderly patients often have other coexisting cardiac and respiratory disease, making the diagnosis of pure IPAH more challenging.

Clinical Presentation

Most patients with IPAH present with exertional dyspnea, developing over months or years. This classical, although nonspecific, symptom is thought to be due to the inability of the right heart to raise output on exertion. Chest pain, syncope, and peripheral edema are more common in advanced IPAH and indicate right ventricular failure.1,2

The clinical signs of IPAH include right ventricular heave, loud pulmonary component of the second heart sound, a pansystolic murmur of tricuspid regurgitation, and a right ventricular third sound. Jugular venous distension, hepatomegaly, peripheral edema, ascites, and cold extremities indicate patients in a more advanced state with right ventricular failure at rest. Central cyanosis may also be present in advanced cases.

Unfortunately, the absence of findings on clinical examination and nonspecific symptoms frequently lead to a delay in referral to the appropriate specialist center and, subsequently, a delay in diagnosis and treatment. Symptoms are often initially attributed to poor physical fitness, especially in overweight patients, and the diagnosis only becomes apparent with the development of chest pain, syncope, or edema.

Imaging

Chest Radiograph

The chest radiograph may give the first clue to the presence of IPAH, providing invaluable information on the heart size, the lung parenchyma, and the pulmonary vasculature.

The main chest radiograph features of IPAH consist of enlargement of the main pulmonary arteries and rapid tapering of the vessels as they extend to the periphery of the lungs, giving rise to peripheral oligemia. The heart, particularly the right-sided chamber, is usually enlarged but may be of normal size (Fig. 24–1).

Ventilation/Perfusion Scan

In IPAH, the ventilation/perfusion scan is usually normal or shows heterogeneous perfusion.3 Occasionally, larger mismatch perfusion defects may be seen in IPAH, thought to be as a result of thrombosis in situ.

Computed Tomography

The key features of IPAH on computed tomography (CT) are as follows:

1. Enlargement of the main pulmonary artery (Fig. 24–2). In one study, a main pulmonary artery diameter of ≥29 mm had a positive predictive value of >95% for PAH.4

2. Right ventricular dilatation and hypertrophy and enlargement of the right atrium (Fig. 24–3). Flattening or "bowing" of the interventricular septum can also be observed.

3. Reflux of contrast from the right atrium into the inferior vena cava when CT pulmonary angiogram is performed. This occurs as a result of tricuspid regurgitation, and the extent of reflux correlates with mean PAP; however, it can be observed in normal patients.5

4. The presence of pericardial effusions.

5. Small centrilobular ground-glass nodules.

Electrocardiogram

The electrocardiogram (ECG) may demonstrate right ventricular hypertrophy and strain and right atrial dilatation in IPAH.

Pulmonary Function Tests

Pulmonary function tests in IPAH often reveal normal spirometry but reduced diffusion capacity for carbon monoxide.

Echocardiography

The use of echocardiography in the assessment of IPAH focuses on detection of elevated PAP, evaluation of the right ventricle, and exclusion of other possible differential diagnoses.

In IPAH, chronic progressive pressure loading results in right ventricular (RV) remodeling, particularly RV hypertrophy and later RV dilatation. RV dilatation can result in tricuspid annular dilatation, often causing significant tricuspid regurgitation. As IPAH progresses, there is impaired RV diastolic function and increased RV end-diastolic pressure, with displacement or "bowing" of the interventricular septum toward the left ventricle.

PAH can be suggested by abnormalities on a number of echocardiographic views:

1. Parasternal long axis view: The RV will appear dilated (Fig. 24–4), and in severe cases, there is compression of the left ventricular cavity with "bowing" of the interventricular septum.

2. Short axis view: The RV is again dilated, with the characteristic D-shaped left ventricle visible (Fig. 24–5).

3. Apical four-chamber view: There is dilatation and hypertrophy of the RV and often hypertrophy of the moderator band (Fig. 24–6). Tricuspid regurgitation jets will be visible in the majority of patients with pulmonary hypertension, and application of continuous wave Doppler mapping on this jet allows calculation of the tricuspid regurgitation velocity (Fig. 24–7). This velocity represents the RV to right atrial pressure difference and can be used to estimate pulmonary artery systolic pressure (PASP) through the Bernoulli equation: PASP = RV systolic pressure = 4 (VTR)2 + RAP, where VTR is tricuspid regurgitant velocity and RAP is right atrial pressure.

4. Tricuspid annular plane systolic excursion (TAPSE): TAPSE represents the basal to apical shortening of the RV during systole. TAPSE will be reduced when there is impaired RV systolic function, and a TAPSE of less than 1.5 cm is associated with poor prognosis in PAH.6

5. A pericardial effusion may be visible on a number of views, and the size of the effusion has prognostic importance in IPAH.

Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance (CMR) imaging is ideally suited for examining the complex geometry of the RV. Improvements in CMR technology have reduced the length of breath-holds required to obtain high-quality images, particularly important in patients with IPAH who are often dyspneic on minimal exertion.7

A diagnosis of IPAH is supported the following CMR abnormalities:

• Increased RV end-diastolic volume (RVEDV)
• Reduced RV ejection fraction, stroke volume, and cardiac output
• Poor left ventricular filling, observed as a low left ventricular end-diastolic volume (LVEDV)
• Bowing of the interventricular septum toward the left ventricle (Fig. 24–8)
• RV hypertrophy, occurring as a result of the increased pulmonary afterload (Fig. 24–9)

RV hypertrophy can be assessed using ventricular mass index (VMI), which is the ratio of RV mass to LV mass. VMI has been shown to correlate closely with mean PAP obtained at right heart catheterization.8 Studies have also shown that an increased RVEDV, poor left ventricular filling, and low stroke volume are associated with poor prognosis in IPAH.9

Velocity-encoded CMR imaging is another approach for assessing the patient with suspected IPAH. This technique allows us to quantify blood flow within the main pulmonary artery and calculate peak and average pulmonary artery flow velocities and provides an alternative method for estimating stroke volume and cardiac output. Pulmonary artery distensibility can also be measured by CMR and has been found to be significantly lower in PAH patients compared with normal subjects.10

Right Heart Catheterization

Right heart catheterization remains the gold standard for the diagnosis of IPAH. Patients typically have a markedly elevated mean PAP, usually ≥50 mm Hg (normal, <25 mm Hg). A low cardiac output and high pulmonary vascular resistance (PVR) indicate severe disease and poorer prognosis. If PAP is high, then vasoreactivity testing in an expert center should be done because a successful response mandates different therapy.

Management

There is as yet no cure for IPAH, so management is usually divided into general measures, disease-targeted therapy, and surgical intervention.11,12

General Measures

• Oxygen: Acute oxygen therapy can improve pulmonary hemodynamics in hypoxic and normoxic patients. Patients with resting partial pressure of oxygen in arterial blood (PaO2) of <8 kPa may be prescribed oxygen for at least 15 h/d.
• Anticoagulation: IPAH is associated with abnormalities in coagulation and fibrinolytic pathways and impaired platelet function. Anticoagulation may prevent vascular thrombotic lesions and pulmonary embolism.13,14
• Diuretics: In IPAH, there is excessive afterload, resulting in RV dilatation and right heart failure. Diuretic therapy, often at high doses, may benefit patients with significant fluid overload.
• Arrhythmia management: Tachyarrhythmias are poorly tolerated and often manifest with worsening dyspnea, syncope, or right heart failure.15,16 The use of β-blockers is contraindicated in IPAH because it limits the ability to raise cardiac output by tachycardia.

Disease-Targeted Therapy

In the last 10 to 15 years, a number of new disease-targeted therapies for PAH have been developed. These treatments are expensive and have significant adverse effects; however, they have been shown to improve symptoms and exercise capacity in IPAH, and some have been shown to improve survival.

The main classes of disease-targeted therapy for IPAH are as follows:

• Prostanoids: Prostanoids are analogs of prostacyclin and are available in intravenous (epoprostenol), nebulized (iloprost), and subcutaneous (treprostinil) forms. They are the treatment of choice for patients with severe (class IV) disease, and epoprostenol has been shown to improve survival in IPAH.17,18
• Phosphodiesterase-5 (PDE-5) inhibitors: PDE-5 inhibitors are oral agents that act by inhibiting the breakdown of cyclic guanosine monophosphate, thereby increasing the effect of locally produced nitric oxide. This results in inhibition of smooth muscle growth and pulmonary vasodilation. Sildenafil is the most widely used PDE-5 inhibitor at present.19
• Endothelin antagonists: Increased circulating levels of endothelin-1, a potent vasoconstrictor are observed in IPAH. Several oral agents are now available that can modify the endothelin system.20,21 Bosentan is a nonspecific endothelin antagonist, whereas ambrisentan and sitaxsentan are specific endothelin-A receptor blockers. Approximately 10% of patients on bosentan will have an elevation in hepatic transaminases, although the incidence is lower with the other endothelin antagonists.

It is now common practice to use combination therapy for patients with IPAH who have deteriorated despite targeted monotherapy. The rationale is that using multiple agents will be more effective in targeting the different pathophysiologic pathways that have been identified in IPAH. Approximately 30% of patients with IPAH are receiving combination therapy at present.

Surgical Intervention

Atrial septostomy is thought to be of benefit in patients with IPAH who are in World Health Organization (WHO) functional class IV with right heart failure refractory to medical therapy.22 Atrial septostomy can decompress the RV, increase left ventricular preload, and increase cardiac output, particularly during exercise. This improves systemic oxygen transport despite the arterial oxygen desaturation.

Despite the development of disease-targeted therapy, there are still a significant number of patients who deteriorate on medical treatment, and these patients should be referred for transplantation.23 In the United Kingdom, current practice is for patients with IPAH requiring transplantation to receive bilateral lung transplantations. Recent changes in surgical technique, perioperative care, and immunosuppression have significantly improved outcome following transplantation, with survival rates of 86% at 1 year, 75% at 5 years, and 66% at 10 years now described in patients who undergo transplantation for IPAH.24

Follow-Up

Imaging modalities, particularly echocardiography and cardiac magnetic resonance imaging (MRI), are becoming increasingly important in the follow-up of patients with IPAH, both in the setting of clinical trials and everyday clinical practice. Physicians have previously been reliant on WHO functional class, 6-minute walk test, biologic markers (such as N-terminal prohormone brain natriuretic peptide), and right heart catheterization to monitor response to treatment, all of which have acknowledged limitations.

Echocardiography is an attractive follow-up modality given that it is widely available, inexpensive, and safe. However, it is relatively operator dependent, and images may be suboptimal in patients with tachycardia, obesity, or poor acoustic windows. Cardiac MRI is now gaining widespread acceptance as the ideal marker in IPAH, providing abundant information regarding RV morphology and function in a safe, reproducible manner (Fig. 24–10). Extensive investigations are now under way to determine whether changes in CMR-derived RV functional parameters correspond to patient outcome.

Case Study

A 33-year-old woman presented with an 18-month history of progressively worsening exertional dyspnea.

Clinical examination revealed a loud second heart sound and a tricuspid regurgitation murmur. ECG demonstrated right axis deviation and RV hypertrophy. Chest radiograph revealed cardiomegaly, prominent pulmonary arteries, and peripheral oligemia (Fig. 24–11).

Her echocardiogram showed marked dilatation of the right-sided cardiac chambers and tricuspid regurgitation (Fig. 24–12). Her estimated PASP was 85 mm Hg. CT pulmonary angiogram revealed no evidence of pulmonary thromboembolic disease, but there was an enlarged main pulmonary artery and a dilated right heart (Fig. 24–13). Cardiac MRI demonstrated interventricular septal bowing and RV dilation, and planimetric evaluation revealed a markedly increased RVEDV, low LVEDV, and low stroke volume (Fig. 24–14).

She proceeded to right heart catheterization, where her mean PAP was elevated at 50 mm Hg, PVR was elevated at 12 Wood units, and cardiac output was low at 3.0 L/min. No other cause of PAH could be identified, so she was diagnosed as having IPAH. The patient was commenced on anticoagulation and the endothelin antagonist bosentan.

After 12 months of disease-targeted therapy, she had noticed a reduction in dyspnea, her 6-minute walk test had improved, and repeat cardiac MRI demonstrated an improvement in stroke volume and cardiac output, with a reduction in RV dilatation (Fig. 24–15).

Background

Chronic thromboembolic pulmonary hypertension (CTEPH) results from an obstruction of the pulmonary vessels with organized blood clots. It is estimated that 3.8% of patients suffering an acute pulmonary embolus will develop CTEPH.25 However, a significant proportion of CTEPH cases may originate from asymptomatic venous thromboembolism.26.

Patients at greatest risk include those with previous episodes of venous thromboembolism, massive and submassive pulmonary embolism, an elevated PASP on admission, or elevated pressure 2 months after initial presentation. Additional risk factors for CTEPH include the presence of ventriculoatrial shunts for the treatment of hydrocephalus, low-grade malignancy, splenectomy, chronic osteomyelitis, inflammatory bowel disease, and thyroid replacement therapy.27,28

The pathophysiology of CTEPH is related to increased resistance to flow through the pulmonary arteries, initially from obstruction of pulmonary arteries (usually main to subsegmental levels) by organized thromboembolic material and subsequently from vascular remodeling in smaller unobstructed vessels.29 The vascular remodeling arises in response to increased flow and consequent shear stress in the distal unobstructed pulmonary arterial vascular bed.

Clinical Presentation

The most common symptoms of CTEPH are exertional dyspnea and fatigue, although chest pain, syncope, hemoptysis, and vertigo are also observed. The clinical course is initially episodic, with long "honeymoon periods" of only mild or no symptoms. If CTEPH is left untreated, there is a progressive increase in PVR, RV dysfunction, and death.

The diagnosis of CTEPH is made based on radiologic investigations performed during the assessment of pulmonary hypertension.

Imaging

Chest Radiograph

The characteristic findings on chest radiograph in CTEPH are enlargement of the RV and prominence of the central pulmonary arteries. If thrombosis or embolism occurs in the central pulmonary arteries, then asymmetrical and/or bulging vessels may be present. Another feature of CTEPH is decreased vascularity termed mosaic oligemia.30 These areas of decreased vascularity on plain radiographs can be confirmed on pulmonary angiography to be associated with chronic emboli (Fig. 24–16). "Peripheral pruning" or discordance in caliber between central and peripheral pulmonary arteries is a distinct feature of PAH regardless of the underlying etiology and thus will often be visible in CTEPH.

Ventilation/Perfusion Scan

The role of ventilation/perfusion scintigraphy is to distinguish IPAH from CTEPH. With CTEPH, the ventilation/perfusion scan is usually high probability, showing multiple mismatch segmental or larger perfusion defects (Fig. 24–17). A normal or low probability scan effectively excludes CTEPH.31,32 In patients who have intermediate- or high-probability scans, the diagnosis of CTEPH can usually be confirmed by CT pulmonary angiography (CTPA).

Although ventilation/perfusion scintigraphy is a safe and highly sensitive test for suspected CTEPH, large mismatch perfusion defects may arise in other processes that result in obliteration of the central arteries and veins. These "CTEPH mimics" include large-vessel vasculitis, pulmonary artery sarcoma, extrinsic compression due to cancer, lymphadenopathy, fibrosing mediastinitis, and pulmonary veno-occlusive disease.33

Computed Tomography

The hallmark of CTEPH on CTPA is the absence or sudden loss of contrast-filled vessels. Abnormalities in the main pulmonary artery may be highly suggestive of CTEPH, with the most common finding being the eccentric location of thrombus, resulting in a crescentic filling defect adjacent to the vessel wall34 (Fig. 24–18). Other vascular signs of CTEPH that are visible on CT are recanalization within intraluminal fillings and arterial webs (Fig. 24–19) and stenoses.

Bronchial artery hypertrophy occurs in approximately half of patients with CTEPH and only rarely in IPAH.35 It occurs most commonly in chronic inflammatory diseases of the airways and when there is chronic pulmonary hypoperfusion, when the bronchial arteries act as a collateral blood supply to the pulmonary parenchyma. Bronchial artery hypertrophy is defined as curvilinear mediastinal vessels >1.5 mm in diameter, seen along the course of the proximal bronchial tree and is best identified on coronal reformatted projections (Fig. 24–20). In CTEPH, the distal circulation may be morphologically normal and therefore able to accommodate this increased collateral supply, whereas in IPAH, the plexogenic arteriopathy is centered at arteriolar level.

In CTEPH, there is mosaic oligemia visible on high-resolution scanning, caused by obliteration of parts of the vascular bed (Fig. 24–21). This results in hypoperfusion with arteries of diminished size in some areas and with normal or increased perfusion and enlarged arteries in other areas.

Peripheral lung parenchymal opacities are another common finding in CTEPH36,37 (Fig. 24–22). They represent pulmonary infarcts due to occlusion of segmental and smaller pulmonary arteries and therefore occur more commonly in "peripheral-type" CTEPH than "central-type."

Pulmonary Angiography

At present, pulmonary angiography remains the definitive investigation for the diagnosis and assessment of surgically correctable CTEPH. The typical findings include vascular cut-offs representing complete occlusion of the vessel (Fig. 24–23) and vascular webs that result from organization of thromboembolic material in the vessel lumen with subsequent scar formation. Smaller pulmonary arteries can appear tortuous and taper rapidly, particularly in patients with distal inoperable CTEPH (Fig. 24–24).

Other Investigations

The ECG and echocardiographic abnormalities observed in CTEPH are similar to those seen in IPAH, which have been discussed earlier in this chapter.

Magnetic resonance angiography (MRA) does not require exposure to radiation or nephrotoxic contrast agents and is becoming increasingly important in the diagnosis, assessment, and long-term follow-up of patients with CTEPH. In experienced centers, images produced with MRA are comparable to those acquired using conventional pulmonary angiography.

All patients with suspected CTEPH should undergo right heart catheterization to confirm the presence of pulmonary hypertension (mean PAP >25 mm Hg), to measure cardiac output (usually by thermodilution technique), and to calculate PVR. Right heart catheterization and pulmonary angiography are often performed as a single procedure.

Management

Surgical Intervention

It is widely recognized that the definitive treatment for CTEPH is pulmonary endarterectomy (PEA). It is the only proven treatment to give prognostic and symptomatic benefit. PEA is performed on cardiopulmonary bypass via a median sternotomy and involves the removal of organized and incorporated fibrous obstructive tissues from the pulmonary arteries. Completion of the endarterectomy procedure is usually possible within a 20-minute period of circulatory arrest for each lung.

PEA is a major undertaking, often performed in patients with significant RV dysfunction, and should only be carried out at a specialized center by a PEA-experienced surgeon. The decision as to whether PEA is feasible will depend on the abnormalities seen on CT and conventional angiography, on the hemodynamics observed at right heart catheterization, and on whether the patient has other significant comorbidities. Patients with proximal disease have a much better risk-to-benefit ratio from surgery than patients with more distal disease. Patients with a PVR >1200 dyne/s/cm have a higher risk of mortality with attempted PEA.38,39 In patients with a PVR disproportionately higher than the segmental obstruction visible by imaging, there is less benefit from PEA and a much higher risk of mortality. There are very few absolute contraindications to surgery, and good results have even been achieved in patients over age 80 years.

Despite the complexity of the procedure, PEA is associated with mortality rates of only 5% to 10%.37 Severe preoperative RV dysfunction and residual postoperative pulmonary hypertension are both associated with poor outcome after PEA. In many cases, RV and pulmonary hemodynamics will return to normal within hours of the procedure. Following a successful PEA, the occurrence of reperfusion lung injury is common, with up to a third of patients requiring prolonged ventilatory support, and is a key factor in determining perioperative morbidity and mortality.40 Shorter cardiac arrest periods, the use of cooling jackets to the head, and antegrade cerebral perfusion techniques have reduced the occurrence of cerebral injury associated with PEA.

Medical Therapies

All patients with CTEPH should receive lifelong anticoagulation with warfarin in the therapeutic international normalized ratio range between 2 and 3. It is common practice to insert an inferior vena cava filter in patients with CTEPH undergoing PEA surgery to reduce the risk of thromboembolism in the early postoperative period until full anticoagulation is reestablished.

The natural history of untreated CTEPH is dismal; <20% of patients survive for 2 years if the mean PAP is >50 mm Hg at the time of presentation.41 Although PEA is a realistic option for cure, unfortunately, up to 50% of patients are judged inoperable.42

In recent years, there has been increasing use of PAH-specific medical therapies in CTEPH. They have been used in a number of settings, including to provide hemodynamic stability prior to surgery, in patients with persisting or recurrent pulmonary hypertension despite PEA, and in patients who have distal inoperable disease.43-45 Use of the endothelin receptor antagonist bosentan in patients with inoperable CTEPH was associated with improvements in pulmonary hemodynamics, although not all studies report improvements in exercise capacity.46,47 There are currently ongoing studies examining the potential use of endothelin receptor antagonists, PDE-5 inhibitors, prostanoids, and other novel agents in CTEPH.

Case Study

An overweight 38-year-old woman, with a background of inhaler-controlled asthma, was referred with 18 months of worsening breathlessness. She had no past history of deep vein thrombosis or pulmonary embolism and no significant family history. On examination, she was cyanosed, with resting oxygen saturation of 90%, and had bilateral pitting ankle edema.

Her ECG showed right axis deviation and RV hypertrophy. Chest radiograph demonstrated prominent pulmonary arteries and some peripheral pruning (Fig. 24–25). On echocardiogram, she had a severely dilated RV with poor systolic function, dyskinetic septal motion, and elevated estimated PASP. The bubble contrast study was negative.

The patient had a high-probability ventilation/perfusion scan, with bilateral mismatched perfusion defects (Fig. 24–26). CTPA demonstrated a dilated main pulmonary artery (Fig. 24–27), dilated right-sided cardiac chambers (Fig. 24–28), multiple filling defects, cut-off of the right interlobar artery, and a paucity of vessels in the right lower lobe. There was also evidence of a left interlobar artery web (Fig. 24–29). CT also showed multiple peripheral lung parenchymal opacities (Fig. 24–30) and mosaic oligemia (Fig. 24–31).

She proceeded to right heart catheterization, which confirmed severe pulmonary hypertension (mean PAP, 58 mm Hg; cardiac index, 1.9 L/min/m2; PVR, 8.7 Wood units). Conventional pulmonary angiography was performed and confirmed the abnormalities identified at CTPA, namely the right-sided cut-off and a paucity of vessels in the lower lobes, particularly on the right (Fig. 24–32). The diagnosis of CTEPH was confirmed.

The patient was then anticoagulated, commenced on the PDE-5 inhibitor sildenafil as disease-targeted therapy to improve pulmonary hemodynamics, and referred to the national PEA center for consideration of PEA.

Background

Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between pulmonary arteries and pulmonary veins, resulting in right-to-left shunting and subsequent hypoxemia. The vast majority of PAVMs (at least 80%) occur in the context of hereditary hemorrhagic telangiectasia (HHT), although these are radiologically and histologically indistinguishable from idiopathic PAVMs. When PAVMs occur in the setting of HHT, they are more likely to be multiple and bilateral.48-50

Clinical Presentation

The most frequent presenting symptom of PAVM is exertional dyspnea,51 often related to the severity of right-to-left shunting. However, many patients have very little dyspnea and good exercise tolerance due to low PVR, facilitating increased cardiac output on exertion.52 Other symptoms include hemoptysis and chest pain, whereas clinical examination may reveal cyanosis, finger clubbing, and telangiectasia. Classical orthodeoxia (a reduction in oxygen saturation when rising from the supine position), present in a minority of patients with large PAVM, has limited diagnostic value.

The diagnosis of PAVM may be precipitated by one of the potentially severe infectious or embolic complications of the condition. Right-to-left shunting that bypasses the pulmonary capillary bed allows bacteria and thrombotic emboli into the systemic and often cerebral circulation. Cerebral abscesses occur in approximately 10% of patients with HHT and PAVM53 and are often due to multiple anaerobic organisms. Extracerebral infection can result in abscesses within soft tissue, knee, liver, kidney, and spinal cord, as well as causing endocarditis, meningitis, and septicaemia.54 These extracerebral infections are usually due to Staphylococcus aureus. As a result of passage of thrombotic emboli into the cerebral circulation, PAVMs are associated with an increased risk of ischemic stroke and transient ischemic attack.49 Severe hemorrhagic complications can also occur, including intrabronchial or intrapleural rupture of PAVM, but thankfully, these are rare.

Imaging

Chest Radiograph

Chest radiograph can detect large PAVM, often visible as a rounded 1- to 5-cm opacity with sharply defined borders and feeding vessels55 (Fig. 24–33); however, small PAVMs or those located at the costodiaphragmatic angles are not easily identifiable.

Contrast Echocardiography

Transthoracic contrast echocardiography is the screening test of choice, with a sensitivity of greater than 90% for the detection of PAVM in HHT patients.56 It is performed by injecting 4 to 5 mL of agitated saline solution with 0.5 mL room air into a peripheral vein while simultaneously imaging the right and left atria with two-dimensional echocardiography. This technique allows the right-to-left shunt to be directly visualized and helps distinguish intracardiac shunting (contrast enhancement of left atrium within one to three cardiac cycles) from the intrapulmonary shunting observed in PAVM (delay of four to eight cardiac cycles, or 2 to 5 seconds).

However, it has been noted that contrast echocardiography may be positive in patients with no PAVM visible on chest CT and that contrast echocardiography remains positive after endovascular treatment of PAVM in up to 90% of patients.57 This may be due to microscopic and diffuse PAVM causing genuine right-to-left shunting or is simply a false-positive test result.

Computed Tomography

Helical multidetector CT of the thorax is the accepted gold standard for the diagnosis of PAVM, identifying a nodular or rounded opacity of variable size, with both afferent and efferent vessels58 (Fig. 24–34). Additional intravenous injection of contrast shows enhancement of the PAVM, allowing differentiation from other nodules. CT of the thorax even allows for identification of thrombosed or very small PAVMs that may be missed using conventional pulmonary angiography and is overall a highly sensitive modality for the diagnosis of PAVM (>95%).59

Magnetic Resonance Imaging

A variety of MRI techniques have been studied in the evaluation of PAVM; however, it remains an expensive modality with limited availability and, at present, is not as efficient as CT.

Radionuclide Perfusion Lung Scanning

Radionuclide perfusion lung scanning has been found to be useful in the diagnosis of PAVM. In normal patients without PAVM, intravenous injection of radionuclide-labeled albumin particles results in filtering of these particles by the capillaries of the lung. However, in patients with PAVM, the intrapulmonary shunts allow passage of these large particles through the lungs, with eventual filtering by capillary beds in the other organs such as the brain or kidneys.

Shunt Fraction Measurement

Most patients with clinically significant PAVM have an elevation in the fraction of cardiac output that bypasses the pulmonary capillaries, the shunt fraction. This can be assessed using the 100% oxygen method, which involves measurement of PaO2 and arterial oxygen saturation after breathing 100% oxygen through a mouthpiece or airtight mask for 15 to 20 minutes (with a deep inspiration every minute). A shunt fraction of more than 5% is considered abnormal.

Despite its high specificity (98%), shunt fraction assessment has inadequate sensitivity (60% to 65%) for diagnosis of PAVM,56 and it is now mostly used for the quantification of right-to-left shunting rather than as a screening modality.

Screening for Pulmonary Hypertension

Pulmonary hypertension can complicate PAVM in two very distinct forms. The more common form occurs when there is high-output cardiac failure as a result of coexisting systemic AVM, mostly in the liver. In this context, right heart catheterization will show moderately elevated mean PAP and high cardiac output but normal PVR. The rarer form is when PAH occurs with PAVM in HHT. The hemodynamic profile at right heart catheterization shows markedly elevated mean PAP, reduced cardiac output, normal pulmonary artery occlusion pressure, and elevated PVR.

Doppler echocardiography is a useful screening tool when assessing patients with PAVM for pulmonary hypertension. Patients with elevated Doppler-derived estimates of PASP should proceed to right heart catheterization.

Pulmonary Angiography

Standard pulmonary angiography is no longer performed as an initial diagnostic procedure, but it is sensitive for the detection of PAVM amenable to embolization and is used to accurately define the architecture of individual lesions (Fig. 24–35). Pulmonary angiography is usually performed on all portions of the lungs at the time of embolotherapy to look for other PAVM, and all lesions are examined for intra- and extrathoracic vascular communications.

Management

Untreated PAVMs are associated with significant morbidity and mortality. Most deaths are related to stroke, cerebral abscess, hemoptysis, or hemothorax. The risk of neurologic complications increases with age and with the number of PAVMs. Untreated PAVMs gradually enlarge, usually at approximately 0.3 to 2 mm/y.60

Transcatheter embolotherapy is now the current standard treatment for PAVM61 and is recommended for PAVM when the feeding vessel(s) is (are) ≥3 mm in diameter, even in asymptomatic patients. This procedure involves direct catheter placement of embolic material (usually steel coils) into the feeding artery of the PAVM until blood flow ceases (Fig. 24–36). PAVMs with very large feeding vessels may require specific devices such as Amplatzer occluders or detachable balloons in order to prevent paradoxical embolization of material. Multiple PAVM can be embolized in a single session, although additional sessions may be required if additional PAVMs remain perfused.

The most common complication of embolotherapy is benign self-limited pleuritic chest pain, affecting 5% to 10% of patients.62 More serious but rare complications include stroke, transient ischemic attack, pulmonary infarction, and systemic migration of the closure device. Infections related to the procedure are prevented by the use of prophylactic antibiotics. Caution is warranted when performing embolotherapy in patients with PAVM and PAH. PAVM effectively unloads the RV, so embolization could theoretically lead to an increase in RV afterload and precipitate right heart failure.63

Several long-term series have demonstrated excellent procedural success and long-term efficacy (80%) for occlusion of PAVM.62,64 Decrease in right-to-left shunting can occur immediately, resulting in improved arterial blood gases and reduced dyspnea. The reperfusion rate for occluded PAVM is reported to be in the range 10% to 17%,65 so early and long-term follow-up is necessary to identify PAVMs that require repeat embolization. Similarly, many patients will have small detectable residual PAVMs that should be monitored and embolized when significant. Most centers now recommend CT of the thorax as the modality of choice for follow-up of PAVM.

Surgical intervention for PAVM is usually only necessary with lesions that are not technically amenable to embolotherapy or for patients with untreatable allergy to contrast material.

Case Study

A 31-year-old man, with a background of recurrent epistaxis and a family history of hereditary hemorrhagic telangiectasia, had a routine preoperative chest radiograph performed. It demonstrated a right mid-zone abnormality (Fig. 24–37). Clinical examination revealed oral telangiectasia. He underwent a CT scan of the chest, which showed a 28 × 20 mm PAVM in the apical segment of the right lower lobe. There was a clearly defined feeding artery and draining vein visible (Fig. 24–38). This was an isolated PAVM, and there was no evidence of hepatic malformations. A subsequent contrast echocardiogram was positive, with late entry of saline contrast into the left heart (Fig. 24–39).

Right heart catheterization was performed to exclude any coexisting pulmonary hypertension, and conventional pulmonary angiography helped confirm the location and anatomy of the abnormality (Fig. 24–40). The PAVM was then successfully embolized using multiple coils and an Amplatzer plug (Fig. 24–41). The patient will be followed up at his local pulmonary vascular unit and was also referred for genetic counseling.