hemoptysis, and/or neurologic complications. Most (81%) patients with diffuse pulmonary AVMs have HHT. Patients can have unilateral or bilateral diffuse pulmonary AVMs, the latter occurring in the majority of patients (72%), mostly affecting women. Usually, patients present at a young age, mean 24 years old, with cyanosis. The majority of patients (70%) have had neurologic complications by the time of diagnosis [11].

The mean PaO2 at presentation is 47 mmHg and 75% of patients have polycythemia due to chronic hypoxemia. Diffuse pulmonary AVMs are associated with increased mortality of 25% during a mean follow-up of 8.3 years, only reported in patients with bilateral involvement [10]. Death was due to pulmonary hemorrhage, cerebral abscess, or complications from other organ involvement from HHT. Treatment for diffuse pulmonary AVMs is similar to patients with focal pulmonary AVMs, with preventative embolization of AVMs with a feeding artery diameter of ≥3 mm. Post-embolization, the PaO2 improves in patients with unilateral involvement, but not signi cantly in most patients with diffuse involvement.

Patients with HHT can be affected by other vascular malformations (VMs) besides pulmonary AVMs. The most common locations for other VMs are the brain and liver. Though there is no international consensus on asymptomatic screening for brain VMs in adults, it is the current standard of care in HHT Centres of Excellence across North America, using MRI [38]. Routine screening for brain AVMs is recommended in children with HHT [19]. Diagnostic testing for liver VMs can be offered to patients with HHT who are asymptomatic from liver involvement. Imaging for liver VM is typically recommended in symptomatic patients since preventative treatment for liver VM is not available, or in cases where the documentation of liver VMs might help complete the diagnosis of HHT based on the clinical criteria [21].

Clinical Vignette 26.2

A 70-year-old woman presents with progressive exertional dyspnea and ankle edema. On physical examination her jugular venous pressure is elevated, she has mucocutaneous telangiectasia and she has ascites. An electrocardiogram reveals atrial brillation. Transthoracic echocardiography reveals an elevated estimated right ventricular systolic pressure of 43 mmHg, suggestive of pulmonary hypertension. Doppler ultrasound of the liver reveals a dilated hepatic artery at 7.5 mm with an increased hepatic artery peak fow velocity (120 cm/s) and decreased resistive index (0.55). Multi-detector triphasic helical CT reveals diffuse liver vascular malformations with an arterioportal shunt.

Pulmonary Hypertension

Pulmonary hypertension (PH) refers to an increased pulmonary arterial pressure, which can subsequently lead to right heart failure. Patients with HHT can present with PH, most commonly secondary to the presence of liver VMs (class 2 pulmonary hypertension), or patients can develop pulmonary arterial hypertension (PAH) (class 1 pulmonary hypertension) [39]. Patients PH secondary to liver VMs mostly present with increased cardiac output and are found to have an increased pulmonary artery wedge pressure with an increased cardiac index on right heart catheterization, while patients with class 1 PAH have an increased pulmonary vascular resistance [37, 40].

Pulmonary Hypertension Secondary to Liver Vascular Malformations

Liver VMs are highly prevalent in HHT, associated with all genotypes, though more frequent in patients with ACVRL1 mutation (84%) versus patients with an Endoglin mutation (60%) [8]. Only 5–8% of patients with liver VMs are symptomatic, based on cross-sectional studies [41, 42]. Liver VMs are more prevalent in HHT patients over 40 years of age and women appear to be more frequently affected than men [43, 44]. Liver VMs with severe shunting can eventually lead to high-output cardiac failure, typically in the sixth or seventh decades of life. Rarely women can also present with high-­ output heart failure from liver VMs during pregnancy [45, 46].

High-output heart failure develops secondary to arteriovenous (hepatic artery to hepatic vein) shunt and /or portosystemic (portal vein to hepatic vein) shunt. Arterioportal (hepatic artery to portal vein) shunts more typically lead to portal hypertension, ascites, and esophageal varices. There is often evidence of mixed shunt in symptomatic patients. Arteriovenous shunting leads to a hyperdynamic circulatory state. Subsequently, increased left atrial pressures and impaired pulmonary vasodilatation cause PH. PH and volume overload will lead to right ventricle strain and eventually dilatation, which subsequently lead to right ventricle enlargement and contractile dysfunction, leading to tricuspid regurgitation and eventually right heart failure [47].

Patients with PH secondary to live VMs typically present with symptoms of high-output heart failure: fatigue, palpitations, exertional dyspnea, orthopnea, and peripheral edema. On physical examination, a triad can be found of wide arterial pulse pressure, systolic ejection murmur at the left sternal border due to tricuspid regurgitation and a hepatic bruit.

Liver VMs can be detected by Doppler ultrasound of the liver. Major ndings on Doppler ultrasound in these patients are hepatic artery dilatation (>0.7 cm) and intrahepatic arterial hypervascularization. Minor criteria are the presence of

increased hepatic peak velocity >110 cm/s, decreased hepatic artery resistance index <0.6, an increased portal vein peak velocity >25 cm/s, and the tortuous course of the extrahepatic artery [48]. Multiphasic hepatic CT, MRI, or mesenteric angiography are the options for diagnostic con rmation of liver VMs and also provide more detailed information regarding the type(s) of the shunting present as well as other complications (biliary cystic dilatation, focal nodular hyperplasia, etc.) [21].

The suspicion of PH and high-output heart failure is generally con rmed on TTE, but right heart catheterization is helpful in cases where the association with liver VMs, or the cause of PH, is uncertain. Patients with PH secondary to liver VMs will have elevated mean pulmonary artery pressure, increased cardiac output, normal pulmonary vascular resistance, normal transpulmonary gradient, and elevated pulmonary capillary wedge pressure [49].

Routine management of high-output heart failure due to liver VMs includes salt restriction, diuretics, beta-blockade, and treatment of anemia and atrial brillation [19, 50]. In refractory cases, treatment with bevacizumab can be considered and/or liver transplantation [21]. Bevacizumab is an antibody against vascular endothelial growth factor (VEGF). Treatment with bevacizumab has been shown to improve NYHA class [51] and to improve the cardiac output in a patient with liver VM and high-cardiac output, with a complete response in 22% of patients and a partial response in 65% of patients at a 6-month follow-up. A complete response is considered a normalization of the cardiac index, which should be 2.5–3.9 L/min/m2 in men and 2.5–3.6 L/min/m2 in women. Bevacizumab treatment also reduced the mean duration of epistaxis and improved quality of life. Treatment had no effect on hepatic artery diameter or peak fow velocity [52].

Liver transplantation is considered in refractory liver VM patients, for high-output heart failure, portal hypertension, or biliary necrosis [21]. Perioperative mortality of liver transplantation in patients with HHT is reported at 10–17%, due to hemorrhage (intraoperative, cerebral, pulmonary, gastric), heart failure, or rejection of the liver or primary non-­ functional liver. After liver transplantation, the cardiac function improved in 75% of patients and stabilized in 21% of patients. The 10-year survival rate after liver transplantation in patients with HHT is 83% [53]. Patients with increased cardiac output and normal peripheral vascular resistance and normal right ventricle function are eligible for liver transplantation. Patients with severe pulmonary hypertension (mean pulmonary artery pressure ≥35 mmHg), elevated pulmonary vascular resistance (≥250 dyn s cm−5), and right ventricle dysfunction unfortunately are considered at higher risk as liver transplantation in these patients is associated with increased mortality [54].

Surgical hepatic ligation and percutaneous hepatic artery embolization have been performed to treat the intrahepatic

shunt. These procedures carry a signi cant risk of developing biliary ischemia and/or hepatic necrosis. In view of these serious complications, these procedures are generally not recommended, though are occasionally considered for patients with the refractory disease who are not considered candidates for liver transplantation [21, 53, 55].

Pulmonary Arterial Hypertension

Familial PAH is a rare disorder, with an estimated prevalence of 15 per million and is rarely caused by HHT [56]. PAH also occurs in HHT patients, though rarely (approximately 1% of HHT patients). Most affected patients to date have an ACVRL1 mutation [57–59]. PAH can be suspected based on symptoms: dyspnea, syncope, fatigue, and edema. HHT patients with PAH present with similar symptoms as patients with idiopathic PAH. Pathologic characteristics of arteriopathy in patients with HHT PAH consist of intimal proliferation, medial hypertrophy, plexiform lesions, and in situ thrombosis. The diagnosis is suspected based on symptoms or if an elevated peak tricuspid regurgitation velocity ≥ 2.9 m/s is found on transthoracic echocardiography or the presence of other echocardiographic signs characteristic of PH. PAH should be con rmed by right heart catheterization, as in patients with idiopathic PAH. Hemodynamic criteria for the diagnosis of PAH are the presence of an elevated mean pulmonary arterial pressure of ≥25 mmHg in rest, with a normal left atrial or wedge pressure (≤15 mmHg) and increased pulmonary vascular resistance >3 Wood units [39].

Complications from PAH in patients with HHT can be precipitated by anemia, leading to right heart failure. Patients with HHT are at increased risk for anemia due to hemorrhage, most commonly from epistaxis or from telangiectases in the gastrointestinal tract. Severe hemorrhage can lead to hypovolemia or anemia. Hypovolemia leads to reduced cardiac output and anemia will lead to decreased oxygen delivery which both can contribute to worsening right ventricular failure. Right heart failure can also be precipitated by embolization of pulmonary AVMs in patients with pulmonary arterial hypertension. Closing the shunt in the pulmonary AVM can lead to increased mean pulmonary artery pressures, with a subsequent increase in the right ventricle afterload. However, the risk of massive hemorrhage from untreated AVMs is likely greater in patients with PAH, and therefore decisions about embolization of pulmonary AVMs in the patients must be made on a case-by-case basis.

Management of PAH in patients with HHT is similar to management of patients with idiopathic PAH: besides lifestyle recommendations, medical management according to the guidelines for pulmonary hypertension is recommended [39]. Pulmonary vasodilators, i.e. bosentan, an endothelin receptor antagonist, have been reported to have a bene cial