Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-ß) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT.

Follow-up of pulmonary right-to-left shunt in hereditary haemorrhagic telangiectasia.

Pulmonary arteriovenous malformations (PAVMs) are associated with severe neurological complications in hereditary haemorrhagic telangiectasia (HHT). Transthoracic contrast echocardiography (TTCE) is recommended for screening of pulmonary right-to-left shunts (RLS). Although growth of PAVMs is shown in two small studies, no studies on follow-up with TTCE exist.All HHT patients underwent a second TTCE 5 years after initial screening. Patients with a history of PAVM embolisation were excluded. Pulmonary RLS grade on TTCE after 5 years was compared to the grade at screening.200 patients (53.5% female, mean±sd age at screening 44.7±14.1 years) were included. Increase in RLS grade occurred in 36 (18%) patients, of whom six (17%) underwent embolisation. The change in grade between screening and follow-up was not more than one grade. Of patients with nontreatable pulmonary RLS at screening (n=113), 14 (12.4%) underwent embolisation. In patients without pulmonary RLS at initial screening (n=87), no treatable PAVMs developed during follow-up.Within 5 years, no treatable PAVMs developed in HHT patients without pulmonary RLS at initial screening. Increase in pulmonary RLS grade occurred in 18% of patients, and never increased by more than one grade. Of patients with nontreatable pulmonary RLS at initial screening, 12% underwent embolisation.

Pulmonary shunt fraction measurement compared to contrast echocardiography in hereditary haemorrhagic telangiectasia patients: time to abandon the 100% oxygen method?

BACKGROUND: The presence of pulmonary right-to-left shunting (RLS) is associated with severe neurological complications from paradoxical embolisation in patients with hereditary haemorrhagic telangiectasia (HHT) and screening is warranted. Pulmonary shunt fraction measurement with the 100% oxygen method can be used for the detection and quantification of functional pulmonary RLS, although transthoracic contrast echocardiography (TTCE) has emerged as the gold standard over the last few years. OBJECTIVE: The aim of this study was to determine the true diagnostic accuracy of the established 100% oxygen method in detecting pulmonary RLS, as compared to TTCE. METHODS: We analysed 628 persons screened for HHT between 2004 and 2010, all of whom underwent TTCE. A quantitative 3-point grading scale was used to differentiate between minimal, moderate or extensive pulmonary RLS on TTCE (grade 1-3, respectively). Additional shunt fraction measurement with the 100% oxygen method was pursued in cases of pO2 <13 or <12 kPa in patients younger or older than 30 years, respectively. A shunt fraction >5% was considered pathological. RESULTS: Both TTCE and the 100% oxygen method were performed in 210 subjects. Although the presence of a pathological shunt fraction correlated with an increased pulmonary shunt grade on TTCE, the 100% oxygen method confirmed a >5% shunt fraction in only 51% of patients with pulmonary RLS on TTCE (14, 20 and 72% for grade 1, 2 and 3, respectively). CONCLUSION: Pulmonary shunt fraction measurement with the 100% oxygen method is not a useful screening technique for the detection of pulmonary RLS in HHT as its sensitivity is too low and large pulmonary shunts on TTCE may remain undetected using this method.

Predicting the size of pulmonary arteriovenous malformations on chest computed tomography: a role for transthoracic contrast echocardiography.

This study aimed to investigate whether pulmonary shunt grade on transthoracic contrast echocardiography (TTCE) predicts the size of pulmonary arteriovenous malformations (PAVMs) on chest computed tomography (CT) and subsequent feasibility for transcatheter embolotherapy. We prospectively included 772 persons with possible or definite hereditary haemorrhagic telangiectasia, who underwent both TTCE and chest CT for screening of PAVMs. A quantitative three-point grading scale was used to classify the pulmonary shunt size on TTCE (grade 1-3). Transcatheter embolotherapy was performed for PAVMs deemed large enough for endovascular closure on chest CT. TTCE documented pulmonary shunting in 510 (66.1%) patients. The positive predictive value of a pulmonary shunt grade 1, 2 and 3 on TTCE for presence of PAVMs on chest CT was 13.4%, 45.3% and 92.5%, respectively (p<0.001). None of the 201 persons with a pulmonary shunt grade 1 on TTCE had PAVMs on chest CT large enough for transcatheter embolotherapy, while 38 (25.3%) and 123 (77.4%) individuals with a pulmonary shunt grade 2 and 3 on TTCE, respectively, underwent endovascular closure of PAVMs. Pulmonary shunt grade on TTCE predicts the size of PAVMs on chest CT and their feasibility for subsequent transcatheter embolotherapy. Chest CT can be safely withheld from all persons with a pulmonary shunt grade 1 on TTCE, as any PAVM found in these subjects will be too small for transcatheter embolotherapy.

Prognostic Value of Improved Kidney Function After Transcatheter Aortic Valve Implantation for Aortic Stenosis.

Transcatheter aortic valve implantation (TAVI) is associated with acute kidney injury (AKI), but can also improve the kidney function (IKF). We assessed the effects of kidney function changes in relation to baseline kidney function on 2-year clinical outcomes after TAVI. In total, 639 consecutive patients with aortic stenosis who underwent TAVI were stratified into 3 groups according to the ratio of serum creatinine post- to pre-TAVI: IKF (≤0.80; n = 95 [15%]), stable kidney function (0.80 to 1.5; n = 477 [75%]), and AKI (≥1.5; n = 67 [10%]). Different AKI risk scores were compared using receiving-operator characteristics. Median follow-up was 24 (8 to 44) months. At 3 months, the increase in estimated glomerular filtration rate in the IKF group remained, and the decreased estimated glomerular filtration rate in the AKI group recovered. Compared with a stable kidney function, AKI showed a higher 2-year mortality rate (adjusted hazard ratio [HR] 3.69, 95% confidence interval [CI] 2.43 to 5.62) and IKF a lower mortality rate (adjusted hazard ratio 0.53, 95% CI 0.30 to 0.93). AKI also predicted major and life-threatening bleeding (adjusted odds ratio 2.94, 95% CI 1.27 to 6.78). Independent predictors of AKI were chronic kidney disease and pulmonary hypertension. Independent predictors of IKF were female gender, a preserved kidney function, absence of atrial fibrillation, and hemoglobin level. Established AKI risk scores performed moderately and did not differentiate between AKI and IKF. In conclusion, AKI is transient and is independently associated with a higher mortality rate, whereas IKF is sustained and is associated with a lower mortality rate. These effects are independent of baseline kidney function. Further studies are warranted to investigate the role of IKF and generate a dedicated prediction model.

Percutaneous left atrial appendage closure-An alternative strategy for anticoagulation in atrial fibrillation and hereditary hemorrhagic telangiectasia?

Many patients with hereditary hemorrhagic telangiectasia (HHT) are unable to sustain oral anticoagulation (OAC) because of severe epistaxis, gastrointestinal (GI) bleeding and the risk of life-threatening bleeding from cerebral arteriovenous malformations (CAVMs) or pulmonary arteriovenous malformations (PAVMs). In patients with atrial fibrillation (AF), most thromboembolic complications arise from the left atrial appendage (LAA) and percutaneous transcatheter LAA closure proved to be non-inferior to OAC at mid-term follow-up. We report our experience with LAA closure in HHT with a follow-up of 12 months. Percutaneous LAA closure was performed in five patients with both HHT and high thromboembolic risk AF (CHA2DS2-VASc score ≥2) without peri-procedural complications. At 3 months no thromboembolic event occurred. After 12 months one patient had a transient ischemic attack while another patient had recurrence of stroke, this latter patient had a significant stenosis of the carotid artery and an incomplete closure of the LAA without any signs of thrombus on echocardiogram. Both patients had a non-treatable pulmonary right-to-left shunt (RLS). Percutaneous closure of the LAA may provide an alternative strategy to long-term OAC therapy in HHT patients with AF induced high stroke risk and intolerance for OAC.

Role of transthoracic contrast echocardiography in the clinical diagnosis of hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) can be diagnosed according to the four clinical Curaçao criteria, including the presence of pulmonary arteriovenous malformations (PAVMs). In the past few years, transthoracic contrast echocardiography (TTCE) replaced chest high-resolution CT (HRCT) imaging for the screening of PAVMs. The objective of this study was to determine whether the presence of any pulmonary shunt on TTCE can be accepted as a new clinical Curaçao criterion in diagnosing HHT. METHODS: Between 2004 and 2012, we included 487 first-degree relatives of known HHT-causing mutation carriers who underwent both TTCE and chest HRCT imaging to screen for PAVMs. A quantitative three-point grading scale was used to differentiate among minimal, moderate, or extensive pulmonary shunt on TTCE (grade 1-3). Genetic testing was performed in all people and considered the gold standard for the diagnosis of HHT. RESULTS: Chest HRCT imaging demonstrated PAVMs in 114 of 218 patients (52.3%) with a pulmonary shunt on TTCE. The addition of any pulmonary shunt on TTCE to the current clinical Curaçao criteria increased the number of positive criteria in 92 of 487 individuals (18.9%), which increased the sensitivity in diagnosing HHT from 88% to 94% at the expense of a decreased specificity from 74% to 70%. Accepting only pulmonary shunt grades ≥ 2 on TTCE as a diagnostic criterion for HHT enhanced the number of positive criteria in 30 (6.2%) individuals, which led to an increased sensitivity of 90% with no decrease in specificity (74%). CONCLUSIONS: The addition of only pulmonary shunt grades ≥ 2 on TTCE to the current clinical Curaçao criteria increases its sensitivity without affecting specificity in the diagnosis of HHT.

Methotrexate vs azathioprine in second-line therapy of sarcoidosis.

BACKGROUND: Steroids remain the first-choice therapeutic in sarcoidosis; however, long-term use is associated with toxicity. Evidence defining the best second-line therapeutic is currently lacking. The aim of this study was to compare the effect of methotrexate and azathioprine on prednisone tapering, pulmonary function, and side effects in the second-line treatment of sarcoidosis. METHODS: An international retrospective cohort study was performed, reviewing all patients with sarcoidosis who started methotrexate or azathioprine until 2 years after initiation or discontinuation. A linear mixed model with FEV1, vital capacity (VC), diffusing capacity of lung for carbon monoxide (DLCO), and prednisone dose changes over time as end points was used. Side effects were compared with χ2 tests. RESULTS: Two hundred patients were included, of whom 145 received methotrexate and 55 azathioprine. Prednisone daily dose decreased a mean of 6.32 mg/y (P < .0001) while on therapy, with a similar steroid-sparing capacity for methotrexate and azathioprine. Of all patients completing 1 year of therapy, 70% had a reduction in daily prednisone dose of at least 10 mg. FEV1 showed a mean increase of 52 mL/y (P = .006) and VC of 95 mL/y (P = .001) in both treatment groups. DLCO % predicted increased, with a mean of 1.23%/y (P = .018). There were more patients with infections in the azathioprine group (34.6% vs 18.1%, P = .01), but no differences regarding other side effects. CONCLUSIONS: This retrospective study comparing the effect of second-line therapy in sarcoidosis shows that both methotrexate and azathioprine have significant steroid-sparing potency, a similar positive effect on lung function, and comparable side effects, except for a higher infection rate in the azathioprine group.