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.

Hereditary hemorrhagic telangiectasia: how accurate are the clinical criteria?

The clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria. Three out of four criteria are required for a definite clinical diagnosis HHT, two criteria are considered "possible" HHT, and 0 or 1 criterion makes the diagnosis unlikely. However, these consensus diagnostic criteria have not been validated. We report on the diagnostic accuracy of the clinical criteria. A total of 450 consecutive persons ≥16 years of age were screened for HHT between May 2004 and September 2009, including a chest CT to screen for pulmonary arteriovenous malformations (AVMs). We selected 263 first-degree relatives of disease-causing mutation carriers who underwent mutation analysis. Genetic test results were considered the gold standard. The family mutation was present in 186 patients (mean age 42.9 ± 14.6 yr; 54.8% female). A clinical diagnosis was definite, "possible", and unlikely in 168 (90.3%), 17 (9.1%), and 1 (0.5%) patient, respectively. In 77 persons the family mutation was absent (mean age 37.1 ± 12.3 yr, 59.7% female). In this group a clinical diagnosis was definite, possible, and unlikely in 0, 35 (45.5%), and 42 (54.5%) persons, respectively. The positive predictive value of a definite clinical diagnosis was 100% (95% CI 97.8-100), the negative predictive value of an unlikely diagnosis 97.7% (95% CI 87.9-99.6). Of 52 patients with "possible" HHT, 17 (32.7%) displayed an HHT-causing mutation. The Curaçao clinical criteria have a good diagnostic performance. Genetic testing is particularly helpful in patients with a "possible" clinical diagnosis HHT.

Grade of pulmonary right-to-left shunt on contrast echocardiography and cerebral complications: a striking association.

BACKGROUND: A pulmonary right-to-left shunt (RLS) carries the risk of cerebral paradoxical embolization and severe neurologic complications. Recognizing patients at risk is important to facilitate appropriate management strategies, but a direct relation between pulmonary shunt size and risk of complications remains controversial. This study evaluated the potential relation between pulmonary shunt grade on transthoracic contrast echocardiography (TTCE) and prevalence of cerebral manifestations in patients screened for hereditary hemorrhagic telangiectasia (HHT). METHODS: We conducted a two-center, cross-sectional study of all consecutive patients screened for HHT between 2004 and 2011. Pulmonary shunt grading on TTCE (grade 0, no microbubbles; grade 1, < 30 microbubbles; grade 2, 30-100 microbubbles; grade 3, > 100 microbubbles) was performed according to contrast opacification of the left ventricle. Cerebral complications were defined as ischemic stroke, transient ischemic attack, or brain abscess diagnosed by a neurologist and confirmed by appropriate imaging techniques. RESULTS: A pulmonary RLS was present in 530 out of 1,038 patients (51.1%; mean age, 44.3 ± 15.6 years; 58.6% women). The presence of a cerebral manifestation (n = 51) differed significantly among pulmonary shunt grades on TTCE: 1.4%, 0.4%, 6.5%, and 20.9% for grades 0, 1, 2 and 3, respectively. A pulmonary shunt grade 1 was not associated with an increased prevalence of cerebral manifestations (OR, 0.44; 95% CI, 0.05-4.13; P = .47), whereas pulmonary shunt grade 2 (OR, 4.78; 95% CI, 1.14-20.0; P = .03) and grade 3 (OR, 10.4; 95% CI, 2.4-45.3; P = .002) were both independent predictors for the prevalence of a cerebral ischemic event or brain abscess. CONCLUSIONS: The pulmonary RLS grade on TTCE is strongly associated with the prevalence of cerebral complications in patients screened for HHT.

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.

Polymorphisms in ACVRL1 and endoglin genes are not associated with sporadic and HHT-related brain AVMs in Dutch patients.

We aimed to replicate the association of the IVS3-35A>G polymorphism in the activin receptor-like kinase (ACVRL) 1 gene and the 207G>A polymorphism in the endoglin (ENG) gene with sporadic brain arteriovenous malformations (BAVM) in Dutch BAVM patients. In addition, we assessed whether these polymorphisms contribute to the risk of BAVM in patients with hereditary haemorrhagic telangiectasia type 1 (HHT1). We genotyped 143 Dutch sporadic BAVM patients and 360 healthy volunteers for four variants in the ACVRL1 gene including IVS3-35A>G and two variants in the ENG gene including 207G>A. Differences in allele and genotype frequencies between sporadic BAVM patients and controls and their combined effect were analysed with a likelihood ratio test. Furthermore, we compared the allele and genotype frequencies between 24 HHT1 patients with a BAVM with those of a relative with HHT1 without a BAVM in a matched pair analysis using Wilcoxon signed rank test. No significant differences in allele frequency were found between sporadic BAVM cases and controls or between HHT1 patients with and without BAVM for any of the polymorphisms or the combination of ACVRL1 and ENG polymorphisms. Meta-analysis of the current and the two previous studies for the ACVRL1 IVS3-35A polymorphism showed a persisting association between the ACVRL1 IVS3-35A polymorphism and risk of sporadic BAVM (odds ratio, 1.86; 95% CI: 1.32-2.61, p<0.001). We did not replicate the previously found association between a polymorphism in ACVRL1 IVS3-35A>G and BAVM in Dutch patients. However, meta-analysis did not rule out a possible effect.

Relation between migraine and size of echocardiographic intrapulmonary right-to-left shunt.

An increased prevalence of intrapulmonary right-to-left shunt (RLS) has been shown in patients with migraine. The aim of this study was to determine whether the size of intrapulmonary RLS was associated with migraine with aura (MA+) and migraine without aura (MA-) in subjects screened for hereditary hemorrhagic telangiectasia. A total of 462 consecutive subjects were screened for hereditary hemorrhagic telangiectasia and underwent transthoracic contrast echocardiography. A pulmonary shunt was established when contrast appeared in the left atrium after 4 cardiac cycles. Shunt size was assessed semiquantitatively as small (<30 microbubbles), moderate (30 to 100 microbubbles), or large (>100 microbubbles). A headache questionnaire was completed by 420 subjects (91%). Two independent neurologists diagnosed migraine according to the International Headache Society criteria. Of 420 screened subjects (mean age 43.4 ± 15.4 years, 61.4% women), 44 (10.5%) had MA+ and 45 (10.7%) had MA-. MA+ was an independent predictor for an intrapulmonary RLS (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.36 to 6.47, p=0.006) in multivariate analysis. MA- was not correlated with RLS (OR 1.21, 95% CI 0.56 to 2.64, p=0.60). When comparing patients with MA+ to those without migraine in a multivariate analysis, the presence of an intrapulmonary shunt predicted MA+ (OR 2.5, 95% CI 1.2 to 5.2, p=0.01), as did female gender (OR 3.15, 95% CI 1.29 to 7.65, p<0.01). The correlation of MA+ and RLS could be entirely attributed to large intrapulmonary shunts (OR 7.61, 95% CI 3.11 to 18.61, p<0.001), as small (OR 0.6, 95% CI 0.13 to 2.78, p=0.52) and moderate (OR 1.33, 95% CI 0.35 to 5.02, p=0.68) shunts did not appear to be risk factors for MA+. In conclusion, patients with large intrapulmonary RLS have an increased risk for MA+.

Real prevalence of pulmonary right-to-left shunt according to genotype in patients with hereditary hemorrhagic telangiectasia: a transthoracic contrast echocardiography study.

BACKGROUND: Transthoracic contrast echocardiography (TTCE) can detect pulmonary right-to-left shunting (RLS) and is used to screen for pulmonary arteriovenous malformations (PAVMs) in patients with hereditary hemorrhagic telangiectasia (HHT). We studied the prevalence and size of pulmonary RLS in HHT type 1, HHT type 2, and HHT-negative controls, and its positive predictive value (PPV) and negative predictive value (NPV) for PAVMs that can be treated by embolotherapy. METHODS: In 343 consecutive persons referred for possible HHT as first-degree family members of index patients a TTCE and chest CT scan were performed. All persons were offered genetic analysis. RESULTS: An HHT-causing mutation was confirmed in 92 (mean age 41 ± 15 y; 59% female) HHT1 relatives and in 97 (mean age 47 ± 14 y; 52% female) HHT2 relatives. TTCE showed a pulmonary RLS in 78 (85%) HHT1- and 34 (35%) HHT2-related mutation carriers, respectively (P < .0001). In HHT1 relatives, 29 of 53 (55%) PAVMs and in HHT2 relatives three of 17 (18%) PAVMS were treated, resulting in a PPV of TTCE for treatable PAVMs of 36.3% and 8.3%, respectively. The accompanying NPV was 100%. A minimal, moderate, or large shunt was present in 12 (13%), 24 (26%), and 42 (46%) HHT1-related, and in 20 (21%), 6 (6%), and 8 (8%) HHT2-related mutation carriers, respectively (P for trend < .0001). A large shunt predicted treatable PAVMs in 55.8% of HHT1 relatives and 37.5% of HHT2 relatives. TTCE was positive in four (6%) of 63 persons without HHT. CONCLUSIONS: A pulmonary shunt on TTCE is more prevalent and larger in HHT1- compared with HHT2-related mutation carriers. Shunt grading is helpful to predict treatable PAVMs, particularly in the HHT2 group. TTCE is also positive in a small fraction of persons without HHT.

Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their quality of life and are clinically difficult to treat. We report here that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in the majority of a small group of subjects with HHT tested. The blood hemoglobin levels of the treated individuals rose as a result of reduced hemorrhage and enhanced blood vessel stabilization. In mice heterozygous for a null mutation in the Eng gene (encoding endoglin), an experimental model of HHT, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects. Thalidomide treatment increased platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation. The effects of thalidomide treatment were partially reversed by pharmacological or genetic interference with PDGF signaling from endothelial cells to pericytes. Biopsies of nasal epithelium from individuals with HHT treated or not with thalidomide showed that similar mechanisms may explain the effects of thalidomide treatment in humans. Our findings demonstrate the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations.

Grading of pulmonary right-to-left shunt with transthoracic contrast echocardiography: does it predict the indication for embolotherapy?

RATIONALE: Pulmonary arteriovenous malformations (PAVMs) are associated with severe neurologic complications in patients with hereditary hemorrhagic telangiectasia (HHT). Therefore, screening is warranted. Transthoracic contrast echocardiography (TTCE) can effectively detect a pulmonary right-to-left shunt (RLS). OBJECTIVES: To determine prospectively the predictive value of TTCE grading to detect PAVMs on high-resolution CT (HRCT) scans of the chest and the indication for embolotherapy. METHODS: Three hundred seventeen patients, referred for possible HHT, were screened for PAVMs. Patients who underwent both chest HRCT scanning and TTCE were included in the study (n = 281). For the purposes of this study we used a 3-point grading scale, and shunt grades 3 and 4 according to the classification model of Barzilai et al were combined. Embolotherapy was performed of all PAVMs judged large enough for treatment. RESULTS: Echocardiographic criteria for a pulmonary RLS were present in 105 patients (41%) [mean (+/- SD) age, 43.7 +/- 15.7 years; female gender, 63%]. Chest HRCT scan findings were positive in 55 patients (52%) in this group. The positive predictive value of shunt grade for the presence of PAVMs on chest HRCT scans was 22.9% for grade 1 (n = 35), 34.8% for grade 2 (n = 23), and 83.0% for grade 3 (n = 47), respectively. None of the patients with PAVMs seen on chest HRCT scans and a TTCE grade 1 (n = 8) or 2 (n = 8) were candidates for embolotherapy. Of 39 patients with TTCE grade 3 and PAVMs seen on chest HRCT scans, 26 patients (67%) underwent embolotherapy. CONCLUSION: An increased echocardiographic shunt grade correlates with an increased probability of PAVMs seen on chest HRCT scans. Only patients with a TTCE grade 3 displayed PAVMs on chest HRCT scans that were large enough for embolotherapy.