PH Grand Rounds: Case Studies in Hereditary Hemorrhagic Telangiectasia: Heritable Pulmonary Arterial Hypertension and High-Output Heart Failure

CASE 1

Presentation and Evaluation: JW is a 64-year-old woman with HHT who presents with episodic dyspnea and abdominal fullness. She reports chronic daily epistaxis for several years, and her history is notable for iron deficiency anemia requiring both oral and intravenous (IV) iron therapy. She is a lifelong nonsmoker with no history of heavy alcohol use or illicit drug use. She has a family history of recurrent epistaxis in her mother, maternal aunt, maternal niece, and both her sons. Her physical examination is remarkable for several mucocutaneous telangiectasias on the lip and tongue, a hyperdynamic precordium with a II/VI systolic ejection murmur heard along the left sternal border, bruits in the right upper quadrant of the abdomen, and small punctate telangiectasias on the hand and chest.

JW's labs are noteworthy for hemoglobin of 9.9, hematocrit of 33.5, and platelets of 200,000. Recent esophagogastroduodenoscopy (EGD) found several gastrointestinal (GI) telangiectasias that were treated by argon plasma coagulation. Chest computed tomography (CT) reveals 2 pulmonary arteriovenous malformations (PAVMs), cardiomegaly with dilation of all 4 chambers, and a dilated pulmonary artery (PA) (Figure 1A). The PAVMs are small (feeding arteries <3 mm) and do not require embolization. In addition, an abdominal CT shows innumerable hepatic AVMs (HAVMs) with marked dilatation and tortuosity of celiac and hepatic arteries (Figure 1B). Abdominal magnetic resonance imaging (MRI) confirms the presence of multiple arteriovenous malformations (AVMs) and hepatomegaly with a total liver volume of 1882 mL (normal, 1200–1600 mL) (Figure 1C).1 On transthoracic echocardiogram (TTE), the left ventricle (LV) is enlarged but has normal function, while the right ventricle's (RV) size and function appear normal and pulmonary artery systolic pressure (PASP) is 35 mm Hg (Figures 2A, 2B and Table 1). She undergoes a right heart catheterization (RHC), which reveals elevated cardiac output (CO) and cardiac index (CI) with minimal increases in PA pressure (PAP) and pulmonary artery wedge pressure (PAWP) (Table 2).

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Table 1. Transthoracic Echocardiogram Results for Case 1, Before and After Bevacizumab

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Table 2. Right Heart Catheterization Results for Case 1, Before and After Bevacizumab

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Diagnosis: The patient is diagnosed with HOHF and mild PH secondary to liver AVMs and chronic anemia.

Treatment and Response: Over the next 2 years, JW is aggressively treated with multiple interventions. The epistaxis improves with nasal hygiene, cauterizations, and tranexamic acid (TxA). Her chronic iron deficiency anemia requires multiple iron infusions and several blood transfusions to maintain ferritin above 50 ng/mL and hemoglobin consistently above 10 g/dL. She is also treated with bevacizumab: 5 mg/kg doses every 2 weeks for 6 treatments, followed by monthly for 3 treatments, and then every other month. Her dyspnea and abdominal fullness improved and she required less frequent IV iron therapy and no further transfusions.

After 9 months of bevacizumab, RHC showed significant reduction in CI (Table 2) and 6-minute walk distance (6MWD) increased from 470 to 565 meters. Fifteen months after beginning bevacizumab, indices from echocardiography confirm improvement in her hyperdynamic state with decreased LV end-diastolic volume index (LVEDVI), left atrial volume index (LAVI), and LV outflow tract's time-velocity integral (VTI), signifying a decrease in her stroke volume (Figures 2C, 2D and Table 1). Six-minute walk distance remains excellent at 520 meters. Her long-term prognosis has improved considerably.

CASE 2

Presentation and Evaluation: JS is a 54-year-old woman who presents to the HHT center after chest imaging detected PAVMs. She also reports chronic daily epistaxis, fatigue, and intermittent palpitations. She denies any history of blood transfusions or iron therapy. She is a nonsmoker and denies alcohol or illicit drug use. Her family history is relevant for recurrent epistaxis in her father and paternal uncle. On examination, she has a lower lip telangiectasia and an abdominal bruit. Her labs are unremarkable. CT angiogram shows multiple PAVMs (Figures 3A, 3B) and innumerable HAVMs with dilated celiac and hepatic arteries. Additionally, she has a right paraspinous AVM (Figure 3C) and a right renal sinus AVM (Figure 3D). EGD shows no GI telangiectasias. TTE shows normal LV and RV size and function with normal ejection fraction, a PASP of 35 mm Hg (Figures 4A, 4B and Table 3). Due to her HAVMs, RHC is performed and reveals normal PA pressures and a borderline high-output state (Table 4).

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Table 3. Transthoracic Echocardiogram for Case 2

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Table 4. Right Heart Catheterization Results for Case 2, Initial Visit (2009) and During Hospitalization (2016)

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Initial Assessment and Management: JS meets all 4 Curacao clinical criteria for HHT (ie, family history, spontaneous/recurrent epistaxis, mucocutaneous telangiectasias, and visceral AVMs). Furthermore, genetic testing reveals a mutation in the gene for activin receptor-like kinase 1 (ACVRL1).

In addition to genetic counseling, she undergoes nasal cauterization. She has successful embolizations for both her pulmonary and renal AVMs. Her paraspinous AVM is monitored but not intervened upon due to its proximity to spinal artery. She receives IV iron therapy.

Seven Years Later: JS presents with dyspnea, exertional chest tightness, abdominal fullness, and decreased oral intake. Examination now reveals elevated jugular venous pressure, trace lower extremity edema, and parasternal lift. B-type natriuretic peptide (BNP) is 1171. TTE shows markedly dilated RV with severely depressed global RV systolic function, dilated right atrium (RA), severe tricuspid regurgitation (TR) and PASP of 85 mm Hg (Figures 4C, 4D and Table 3). Given her decompensated state, the patient undergoes RHC (Table 4).

Diagnosis: The patient is diagnosed with heritable PAH related to ACVRL1 mutation, modified World Health Organization functional class IIIB.

Treatment and Response: She is diuresed and started on an endothelin receptor antagonist, ambrisentan, during her hospitalization. Soon after discharge, she is also started on inhaled treprostinil, which is considered to carry fewer challenges and side effects than a parenteral prostacyclin analog (eg, hypotension, bleeding, and risk of bloodstream infection). Four months later, she reports significant improvement in her symptoms to (modified) functional class II and exertional capacity by an improved 6MWD. Patient was lost to follow-up as she sought care at an HHT center of excellence closer to her home.

Discussion: HHT is a hereditary multiorgan condition that is transmitted through an autosomal dominant inheritance pattern and affects between 1 in 5000 to 1 in 8000 of the population.2 Diagnosis is made by satisfying at least 3 of 4 Curacao clinical criteria: family history (ie, affected first-degree relative), spontaneous and recurrent epistaxis, mucocutaneous telangiectasias (customarily affecting the lips, tongue, palate, pinna of ears, and hands), visceral AVMs (including lungs, liver, brain, GI tract, and spinal cord), or by identification of a causative genetic mutation in one of the known HHT genes.3 Prior studies suggest nearly 90% of HHT patients have epistaxis and 50% to 80% present with mucocutaneous telangiectasias. Additionally, 5% to 15% of HHT patients have cerebral AVMs, 15% to 30% have macroscopic PAVMs, 13% to 45% have GI telangiectasias, and 8% to 31% have liver AVMs.45 Likelihood of manifestations varies by the age of any affected individual.

HHT is caused by genetic mutations primarily in 1 of 2 genes: endoglin (ENG) and ACVRL1. Both genes encode cell receptors involved in the TGF-beta signaling pathway and mutations disrupt angiogenesis homeostasis. 67 HHT is subdivided into type 1 and 2.8 HHT type 1 patients have ENG mutations and are more likely to have cerebral and pulmonary AVMs,2 while HHT type 2 patients have ACVRL1 mutations and are more likely to have HAVMs. Less commonly, SMAD4 mutations lead to an overlap syndrome that has features of HHT and juvenile polyposis.

Pulmonary hypertension is a relatively rare complication of HHT. Due to the lack of prospective screening studies and a heavy reliance on echocardiography, the true prevalence of PH in HHT is unknown. Similar to systemic sclerosis, sickle cell disease, end-stage renal disease, or cirrhosis, PH can develop in HHT by more than one mechanism and requires thorough evaluation when suspected (Table 5). Recently published experience highlights the impact that PH has on mortality in HHT.910

Table 5. Differences Between HPAH and HOHF

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Some ACVRL1 mutations, and possibly ENG mutations, are linked to the development of a proliferative arteriopathy in the pulmonary circulation, similar to idiopathic pulmonary arterial hypertension (IPAH) and pulmonary arterial hypertension (PAH) due to bone morphogenetic protein receptor 2 (BMPR2) mutations. This form of PH is classified as Group 1 PH, HPAH in patients with concomitant HHT diagnosis (Case 2).11 Patients with ACVRL1 mutations often manifest PAH before HHT is apparent and earlier in life than HPAH patients with BMPR2 mutations.12 Therefore, the diagnosis of IPAH or HPAH in young adults or children should at least make one consider an underlying HHT mutation, especially if epistaxis is a notable complaint or if a visceral AVM is detected in the lung, liver, or brain. Interestingly, Girard and colleagues also identified a relatively higher frequency of mutations in exon 10 of the ACVRL1 gene in HHT-PAH cases.

More commonly, PH develops in HHT as a late manifestation of left-sided dysfunction (Case 1), which results from extensive HAVMs. Similar to endstage renal disease patients who develop PH from an overgrown artificial arteriovenous fistula, HAVMs shunt blood “left to right,” thus chronically increasing cardiac preload. This abnormal physiology eventually overwhelms myocardial capacity and workload with ensuing HOHF and increased left-sided filling pressures. The combination of elevated left-sided filling pressures, increased cardiac output, and possible abnormal pulmonary vascular response (due to ACVRL1 or ENG mutations) leads to PH and eventually RHF. Because PH develops as a consequence of left-sided dysfunction, this more common form of PH in HHT best fits into Group 2 PH or PH owing to left heart dysfunction.

In a recent study, 45% of patients with HHT were diagnosed with PH. HHT patients with PH had a higher likelihood of having visceral AVMs and a higher mortality rate compared to HHT patients without PH.5 Furthermore, HHT patients who develop PH tend to present earlier than PH patients without HHT.12

In addition to the customary diagnostic studies performed in any individual with unexplained or severe PH (eg, ventilation-perfusion scanning, pulmonary function testing), additional noninvasive evaluations are warranted when PH is suspected in the context of HHT (Table 5). Laboratory evaluation should include the complete blood count (CBC), red blood cell indices (MCV and RDW), and comprehensive iron studies, due to the increased risk for iron deficiency from chronic epistaxis and/or GI bleeding. In addition, chest CT angiogram should be performed to look for PAVMs, if the bubble echocardiogram suggests transpulmonary communications. Importantly, careful imaging of the liver, either by ultrasound, abdominal CT, or MRI, must be performed to assess the burden of HAVMs. Ultimately, RHC is crucial for confirming a PH diagnosis, distinguishing between the types of PH, and providing prognostic information in either type of PH found in HHT. The most distinguishing hemodynamic feature is the pulmonary vascular resistance (PVR), which is significantly elevated in HPAH and emblematic of the proliferative arteriopathy. Meanwhile, the PVR in HOHF will either be normal or at most only mildly elevated (ie, <4 Wood units).

The treatment approach of Group 1 (PAH) and Group 2 (HOHF) PH in HHT should first include basic heart failure management. Diuretics help immensely by optimizing volume status and minimizing exertional symptoms. LV afterload reduction may be helpful only when LV systolic function is depressed in the late stages of HOHF, but caution must be exercised due to borderline systemic pressures from significant burden of left-to-right shunts. General treatment for HHT hinges on controlling epistaxis, treating underlying visceral AVMs (pulmonary or brain either to provide symptomatic relief or prevent complications), and addressing comorbidities such as anemia and arrhythmias. Atrial tachyarrhythmias should be aggressively abolished, as loss of atrioventricular synchrony can have profound impact with this already complex pathophysiology. Supplemental oxygen should be used judiciously to correct hypoxemia from mechanisms other than anatomic shunts (eg, PAVMs, patent foramen ovale), as continuous oxygen delivery can aggravate epistaxis. Lastly, oral and/or intravenous iron replacement and possibly transfusions should be administered to avoid significant anemia (ie, <10 g/dL), which further fuels the high-output state and/or compromises peripheral oxygen delivery.

Beyond these basic steps, management of HOHF and Group 2 PH in HHT has evolved separately over the last decade. The anti-angiogenic effect of bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF) signaling, has been exploited to reduce HHT-related epistaxis and GI bleeding as well as decrease burden of HAVMs and the degree of left-to-right shunting, which in turn improves HOHF (shown in Case 1).13 In one prospective study of 25 HHT patients with HOHF, bevacizumab dosed 5 mg/kg every 2 weeks for 6 treatments led to significant improvement in hemodynamics and epistaxis with an acceptable safety profile. In spite of this promising early experience, many questions over bevacizumab still abound, including when to initiate treatment and how long someone should be treated, as the effect of bevacizumab on AVMs and telangiectasias wanes over time. Other treatment options include HAVM embolization (if a small number of AVMs) and liver transplantation (if liver is occupied by multiple AVMs).14–16 However, HAVM embolization is controversial and rarely attempted due to concerns of hepatic or biliary necrosis. Liver transplantation is reserved for refractory cases and has excellent long-term results.

Treatment of HPAH in HHT diverges from HOHF and Group 2 PH by the use of pulmonary vasodilators. Bosentan, sildenafil, inhaled iloprost, and IV epoprostenol have all been used with varying degrees of success.1017–20 However, PH medications can be challenging in this population and have the potential to worsen HHT-related bleeding.10 Phosphodiesterase type-5 inhibitors and the prostacyclin analogs through inhibition of platelet aggregation can promote bleeding from existing sites. Furthermore, pulmonary vasodilators increase blood flow through the vascular lesions of HHT, thus increasing the risk of bleeding. One additional challenging aspect is the approach to PAVMs in the setting of severe HPAH. While embolization of PAVMs usually has negligible hemodynamic effects, this may not be assumed for the unique situation of HPAH with severely elevated PVR and sizable PAVMs.21 In this rare situation, embolization of a large PAVM or multiple smaller PAVMs may lead to further increase in the PVR and hemodynamic instability due to acute worsening of RV function. Timing and sequence of interventions (ie, initiation of pulmonary vasodilators and embolization) in these dicey situations is unclear but should warrant multidisciplinary input and the availability of advanced therapies, including IV prostacyclin analogs, inotropic support, and even extracorporeal life support. Overall prognosis of patients with HPAH in HHT is guarded, and mortality may be worse than other forms of HPAH and IPAH.12 Accordingly, these rare and tough cases of HPAH should be managed closely and jointly by centers with expertise in PAH and HHT.

Conclusion: PH may be encountered in HHT not infrequently and emerging evidence illustrates that PH portends a worse prognosis. Importantly, PH develops by 1 of 2 main mechanisms, with HOHF and Group 2 PH being much more common than HPAH (Group 1 PH). While basic heart failure management is similar for both entities, unique treatment options have emerged for both entities and should be considered after careful characterization of hemodynamics by RHC and with the input of an HHT expert.