HHT Patients Research Articles

Diagnostic and prognostic value of the left atrial myopathy evaluation in cardiac amyloidosis using echocardiography.

Cardiac amyloidosis (CA) is an under-recognized cause of heart failure. Left atrial (LA) myopathy contributes to a worse prognosis in heart failure and is a feature of transthyretin (ATTR) and light-chain (AL) CA. LA mechanical dispersion (LA-MD) is a novel marker of intra-atrial dyssynchrony implicated in LA myopathy and the future development of atrial fibrillation (AF). This study aimed to determine the characteristics and prognostic value of LA myopathy in ATTR and AL cardiomyopathy through a comprehensive LA echocardiographic evaluation. ATTR (n=86) and AL (n=86) CA patients were compared with hypertensive heart disease (HHT) patients (n=58). Transthoracic echocardiographic measurements including LA strain and LA-MD were obtained with patient follow-up for mortality. ATTR and AL patients had a median follow-up of 66months, with 26 mortality events. Left ventricular (LV) mass, diastolic function (average-e' and E/e'), LV global longitudinal strain, and LA volume and function (LA function index and strain) were more impaired in ATTR versus AL; these echocardiographic parameters were more impaired in both amyloid groups compared to HHT patients (P<0.05). LA-MD was increased in ATTR versus AL [median 72.2 (inter-quartile range 55-88.9) vs. 54 (43.5-64.2), respectively, P<0.001]. Multivariable logistic regression adjusted for age, presence of AF, LV mass, global and basal strain, and E/e' demonstrated that LA-MD was an independent determinant of ATTR CA (P=0.014). On multivariable analysis, LA reservoir strain was independently associated with the presence of heart failure in the CA group (P<0.001). LA minimum volume (cut-off ≥18mL/m2) was a determinant of mortality in AL CA [Cox proportional hazard ratio (HR) 1.042 (1.003-1.082), P=0.034 and Kaplan-Meier analysis, P=0.016]. Characterizing LA myopathy has significant diagnostic and prognostic utility in CA. ATTR patients have increased atrial dyssynchrony, which may have implications for AF development. LA reservoir strain was associated with heart failure in CA, whilst LA minimum volume was a predictor of mortality in AL CA.

Abstract 116: Increased Collagen I/Collagen III Ratio is Associated With Hemorrhage in Brain Arteriovenous Malformations in Human and Mouse

Background and purpose: Brain arteriovenous malformation (bAVM) is an important risk factor for hemorrhagic stroke in young adults, but the underlying mechanisms are unclear. Increase of Col I/Col III ratio enhances vessel wall stiffness and renders vessel less resistant to changes of blood flow and pressure. Hypothesis: Col I/Col III ratio is increased in bAVM vessels, which is associated with bAVM hemorrhage. Method: Human bAVMs were collected from HHT and sporadic bAVM patients. Temporal lobe specimens from epilepsy patients were used as controls. Three mouse models were used: 1) PdgfbicreER; Alk1 f/f ; 2) PdgfbicreER; Eng f/f ; 3) Alk 1 f/f . Mice in models 1 and 2 have Pdgfb promoter driving, tamoxifen (TM) inducible cre expression in endothelial cells (ECs). BAVMs were induced by intra-brain injection of AAV-VEGF to induce angiogenesis and i.p. injection of TM to delete Alk1 or Eng in ECs. In model 3, bAVMs were by intra-brain injection of AAV-VEGF and an adenoviral vector expressing Cre to delete Alk1 gene focally. Colony stimulating factor receptor inhibitor (PLX5622) was given to Alk1 f/f mice 8 week after model induction when bAVMs have fully developed to transiently deplete microglia. Vascular Col I and Col III levels were analyzed by immunostaining using anti- CD31 and anti-Col I or Col II antibodies. Brain AVM bleeding was detected by Prussian blue staining, and RNA-Sequencing used to study gene profiles. Results: Col I and Col III levels and the Col I/Col III ratio were higher in the vessels of human HHT and sporadic bAVM than controls. Col I/Col III ratio was higher in ruptured than unruptured sporadic bAVM. RNA-seq data shown that Col I and Co III mRNA levels were higher in Eng deficient bAVMs than normal brain angiogenic regions. Col I and Col III levels were higher on Alk1 and Eng deficient bAVMs compared to normal vessels. Col I/Col III ratio was also increased in the Alk1 deficient bAVMs. Depletion of microglia by PLX5622 reduced Col I and Col III levels and reduced microhemorrhage of Alk1 deficient bAVMs. Conclusion: Col I, Col III and Col I/Col III ratio are increased on human and mouse bAVM vessels, which is associated with bAVM hemorrhage. Depletion of microglia reduces Col I and Col III and hemorrhage in bAVMs in mice.

Cardiac "hypertrophy" phenotyping: differentiating aetiologies with increased left ventricular wall thickness on echocardiography.

Differentiating phenotypes of cardiac "hypertrophy" characterised by increased wall thickness on echocardiography is essential for management and prognostication. Transthoracic echocardiography is the most commonly used screening test for this purpose. We sought to identify echocardiographic markers that distinguish infiltrative and storage disorders that present with increased left ventricular (LV) wall thickness, namely, cardiac amyloidosis (CA) and Anderson-Fabry disease (AFD), from hypertensive heart disease (HHT). Patients were retrospectively recruited from Westmead Hospital, Sydney, and Princess Alexandra Hospital, Brisbane. LV structural, systolic, and diastolic function parameters, as well as global (LVGLS) and segmental longitudinal strains, were assessed. Previously reported echocardiographic parameters including relative apical sparing ratio (RAS), LV ejection fraction-to-strain ratio (EFSR), mass-to-strain ratio (MSR) and amyloidosis index (AMYLI) score (relative wall thickness × E/e') were evaluated. A total of 209 patients {120 CA [58 transthyretin amyloidosis (ATTR) and 62 light-chain (AL) amyloidosis], 31 AFD and 58 HHT patients; mean age 64.1 ± 13.7 years, 75% male} comprised the study cohort. Echocardiographic measurements differed across the three groups, The LV mass index was higher in both CA {median 126.6 [interquartile range (IQR) 106.4-157.9 g/m2]} and AFD [median 134 (IQR 108.8-152.2 g/m2)] vs. HHT [median 92.7 (IQR 79.6-102.3 g/m2), p < 0.05]. LVGLS was lowest in CA [median 12.29 (IQR 10.33-15.56%)] followed by AFD [median 16.92 (IQR 14.14-18.78%)] then HHT [median 18.56 (IQR 17.51-19.97%), p < 0.05]. Diastolic function measurements including average e' and E/e' were most impaired in CA and least impaired in AFD. Indexed left atrial volume was highest in CA. EFSR and MSR differentiated secondary (CA + AFD) from HHT [receiver operating curve-area under the curve (ROC-AUC) of 0.80 and 0.91, respectively]. RAS and AMYLI score differentiated CA from AFD (ROC-AUC of 0.79 and 0.80, respectively). A linear discriminant analysis with stepwise variable selection using linear combinations of LV mass index, average e', LVGLS and basal strain correctly classified 79% of all cases. Simple echocardiographic parameters differentiate between different "hypertrophic" cardiac phenotypes. These have potential utility as a screening tool to guide further confirmatory testing.

Twenty-Seven-Year Retrospective Review of Hemoptysis from Systemic Collaterals Following Pulmonary Arteriovenous Malformation Embolization

To determine the prevalence of hemoptysis secondary to post-embolization systemic collaterals and review the recurrence rate and treatment outcomes. The records of 930 patients with PAVM (801 with known or possible HHT), from a single HHT center between July 2, 1996 and July 22, 2021, were searched for a single lifetime episode of hemoptysis secondary to post-embolization systemic collaterals. Embolization was performed with permanent particles or gelatin slurry. Clinical features and treatment outcomes of identified patients were reviewed. Twenty-eight embolization procedures have been performed in 9 patients with post-PAVM embolization systemic artery collateral reperfusion. This included 8 patients with known HHT. Permanent particles were used in 5 cases and gelatine slurry was used in 19 cases. Due to the recurrence of hemoptysis, four patients required four embolizations each, two patients required three embolizations and two patients required two embolizations. Chronic unresolving hemoptysis was the presentation in 5 patients and massive hemoptysis requiring ICU admission in 4. The lifetime prevalence and incidence of hemoptysis secondary to systemic artery reperfusion in HHT patients was estimated to be 1.0% and 0.05%, respectively. Bronchial artery origin was most common (8 patients). In the first patient treated at this center, a major adverse event resulting in myocardial infarct and stroke occurred with the use of 300-500-micron permanent particles. This was presumed to be due to left-to-right shunting and subsequent systemic embolization. Subsequent patients were treated with gelatin sponge slurry without adverse events. This patient ultimately expired due to large volume hemoptysis, in the setting of bilateral diffuse PAVMs. A second patient, with history of childhood bronchial artery coil embolization, expired from large volume hemoptysis while awaiting lobectomy. In two cases, patients underwent surgery, including one lobectomy and one pneumonectomy, for recurrent hemoptysis (requiring at least five hospital admissions). The remaining five patients achieved prolonged resolution of hemoptysis with endovascular treatment alone. Lifetime prevalence of hemoptysis secondary to PAVM post-embolization systemic collaterals is rare, but recurrence is high. In this limited series, embolization with gelatin sponge slurry appeared safe, although surgical resection may ultimately be required in refractory and multifocal disease.

PH Roundtable: Genetics and Pulmonary Hypertension

PH Roundtable: Genetics and Pulmonary Hypertension

Incidence of Spontaneous Pulmonary AVM Rupture in HHT Patients.

The spontaneous rupture of pulmonary AVMs, resulting in pulmonary hemorrhage and hydrothorax, is a life-threatening complication. While this phenomenon has been previously reported, the true incidence is not yet known. This study retrospectively reviewed records of 801 HHT patients with pulmonary AVMs to identify a single lifetime episode of hemothorax or pulmonary hemorrhage secondary to pulmonary AVM rupture. The lifetime prevalence and incidence of pulmonary AVM rupture in HHT patients was 2.7% and 0.16% respectively. In these patients, AVM rupture represented the initial presentation of HHT in nine (40.9%) cases and was life-threatening in nine (40.9%) cases. All cases occurred in virgin lesions, and subsequent embolization was curative. While a feared complication, pulmonary AVM rupture is rare and is likely effectively prevented by existing embolization techniques and indications.

APPROACH TO ACUTE HYPOXIC RESPIRATORY FAILURE IN A PATIENT WITH COPD AND UNDERLYING HISTORY OF HEREDITARY HEMORRHAGIC TELENGIECTASIA WITH PULOMARY AV MALFORMATIONS

TOPIC: Lung Pathology TYPE: Medical Student/Resident Case Reports INTRODUCTION: Hereditary Hemorrhagic Telangiectasia is a multisystem disease which results in AV Malformations and telangiectasia. It has autosomal dominant inheritance and prevalence of 1 in 5000 to 1 in 10,000. 1 Patients with Pulmonary AVMs can present with hypoxia, more post exercise and in sedentary position with improvement on standing. Patients presenting with hypoxia with history of HHT should undergo thorough evaluation including radiological imaging and echocardiography to rule out recurrence of AVMs and sequelae such as pulmonary hypertension or pulmonary arterial hypertension, respectively. CASE PRESENTATION: We present a case of 66 y/o male with Past medical history of HHT with AVM s/p repair presented with complaints of dyspnea with cough and sputum production. In ER patient was hypoxic with SPO2 88% on room air. Patient had coarse rhonchi, scattered wheeze and telangiectasia on the nose and hands. Routine labs were normal. Legionella antigen, SARS antigen, COVID PCR were negative. Chest x-ray revealed peri hilar and basilar reticular opacities. CT of chest with contrast revealed prior right lower lobe AVM repair with almost complete resolution and signs of severe COPD with emphysema. Transthoracic echocardiogram ruled out pulmonary artery hypertension. Patient was treated for COPD exacerbation with albuterol/ ipratropium nebulization, steroids, oxygen support and azithromycin. DISCUSSION: HHT is a familial genetic disease with autosomal dominant mutations of endoglin gene on chromosome 9q33-q34 or ALK-1 gene on chromosome 12q13.2 50% of all HHT patients develop pulmonary AV malformations. Clinical finding includes hypoxic respiratory failure. Pulmonary AVMs lead to right to left shunt formation impairing effective gas exchange leading to hypoxia, interestingly these patients can participate in high intensity physical activity despite of being severely hypoxic, this has been attributed to hemodynamic compensatory responses. 3 This shunt can lead to paradoxical emboli causing strokes and brain abscess. Management of Pulmonary AVMs includes trans catheter coil vaso-occlusion of the artery. Recanalization of treated pulmonary AVMs and development or growth of untreated pulmonary AVMs has been known, warranting long term follow up. Pulmonary AVMs itself is a life threating condition, its course can be further complicated by chronic lung disease like COPD. These patients can present with dyspnea not explained by right to left shunting, it is attributed more to underlying lung conditions, in our patient's case, COPD. CONCLUSIONS: While HHT is not known to cause COPD, it can lead to worsening of COPD by causing Pulmonary hypertension due to high output cardiac failure or pulmonary artery hypertension. Therefore, in patients with history of HHT presenting with hypoxia, it is crucial to have detailed evaluation for recurrence of AV malformations or new onset pulmonary hypertension. REFERENCE #1: Mary E. Meek, M.D., James C. Meek, D.O., Michael V. Beheshti, M.D. Management of Pulmonary AV Malformations [Google Scholar, PubMed] REFERENCE #2: C. Sabba, M. Gallitelli, G. Pasculli, P. Supressa, F. Resta and E. Tafaro. HHT: A rare disease with a broad spectrum of clinical aspects [PubMed] REFERENCE #3: Dupius-Girod S., Cottin V, Shovlin C. The lung in hereditary hemorrhagic telangiectasia [Google Scholar] DISCLOSURES: No relevant relationships by Khushdeep Chahal, source=Web Response No relevant relationships by priyanka kapoor, source=Web Response

Abstract No. 218 Diagnostic accuracy of computed tomography angiogram chest in detecting pulmonary arteriovenous malformation: a comparison with invasive catheter pulmonary angiogram

To determine the diagnostic accuracy of computed tomography angiography (CTA) of the chest in the detection of pulmonary arteriovenous malformations (pAVM) compared to invasive pulmonary catheter angiogram of the chest both in HHT and non HHT patients. This retrospective study was approved by the institutional review board. A total of 341 pulmonary angiograms were performed for either embolization (treatment) of pAVM or for diagnosis of pAVM at our institution from January 2003 to June 2020. Two angiograms were excluded as they did not have prior CTA for pAVM. The remaining 339 pulmonary angiograms had an immediate prior CTA of the chest within a mean 7 ± 30 (SD) days prior to pulmonary angiogram. CTA was acquired after intravenous administration of contrast. The kV and mA were selected based on patient weight and ranges between 80 to 140. The mean fluoroscopy time was 33 ± 19 SD with range 2.4 to 120 minutes. Positive CTA of the chest was defined as the presence of pulmonary arteriovenous malformation with at least one well-defined feeding artery and a draining vein. A 2 × 2 contingency table was constructed and sensitivity, specificity, PPV, NPV, and accuracy were calculated. One hundred and eighty-five patients were included with mean age of 46 ± 19 SD, range 3 to 87 years with 68% of female. A total of 337 CTA of the chest were positive and 319 catheter pulmonary angiograms were positive for pulmonary AVM. There were 318 true positive, 19 false positives, 1 true negative, and 1 false negative. CTA angiogram chest demonstrated a sensitivity of 99.7%, a specificity of 5.0%, a positive predictive value of 94.4%, and a negative predictive value of 50.0%. Overall, the diagnostic accuracy of CTA angiogram chest was 94.10%. False positive CTA causes were catheter angiogram did not detect micro shunt (6/339), pulmonary vein to vein shunt (5/339), CTA wrong call for reperfusion (3/339), calcified granuloma (2/339), and tortuous or dilated pulmonary vessel (2/339). In the false negative CTA was not able to detect micro shunt (1/339). The limitation of our study is low specificity as those patients that have negative CTA angiogram chest do not proceed for catheter pulmonary angiogram unless they have other comorbidities and require CTA of the chest. Our result demonstrates that CTA of the chest is highly sensitive in detecting pulmonary arteriovenous malformation. This again highlights the importance of screening of pulmonary AVM in HHT patients.

Treatment of pulmonary hypertension in patients with Hereditary Hemorrhagic Telangiectasia – A case series and systematic review

RationalePulmonary Arterial Hypertension (PAH), a rare complication of HHT is associated with poor outcome. There are no trials to date that have investigated whether pulmonary vasodilator therapy improves hemodynamics or survival in this disease. ObjectiveTo determine whether pulmonary vasodilator therapy improves survival, exercise capacity, or hemodynamics in HHT patients with pre-capillary PH. MethodsWe performed a before-and-after observational study on a multicenter cohort of subjects with HHT-PAH who received intravenous prostanoid therapy. We then conducted a systematic review, searching Medline and EMBASE through December 2019. Studies that enrolled HHT-PAH subjects and reported treatment outcomes were selected. PROSPERO #158179. ResultsTwenty-one articles were selected. Studies were before-and-after observational studies, case reports, and case series. Among all subjects with HHT-PAH, both mPAP (65 ± 19 pre-treatment vs 51 ± 16 mmHg post-treatment p = 0.04) and PVR (12 ± 6 pre-treatment vs 8 ± 4 WU post-treatment p = 0.01) improved with treatment. The mPAP improved with either oral (57 ± 17 pre-treatment versus 44 ± 13 mmHg post-treatment, p = 0.03) or intravenous (80 ± 15 pre-treatment versus 64 ± 16 mmHg post-treatment, p = 0.017) therapy. PVR also improved with either oral (10 ± 4 pre-treatment versus 6 ± 3 WU post-treatment, p = 0.004) or intravenous (17 ± 5 pre-treatment versus 10 ± 4 WU post-treatment, p = 0.04) therapy. Survival among HHT-PAH patients who received oral or intravenous therapy was not different (p = 0.2). Unadjusted survival among HHT-PAH patients was longer than that of IPAH patients (p = 0.008). There was no difference in side effects among HHT-PAH patient who received oral or intravenous therapy (p = 0.1). ConclusionPulmonary vasodilator therapy is effective in improving hemodynamics of subjects with HHT-PAH and was not associated with increased risk of side effects.

Endoglin: An 'Accessory' Receptor Regulating Blood Cell Development and Inflammation.

Transforming growth factor-β1 (TGF-β1) is a pleiotropic factor sensed by most cells. It regulates a broad spectrum of cellular responses including hematopoiesis. In order to process TGF-β1-responses in time and space in an appropriate manner, there is a tight regulation of its signaling at diverse steps. The downstream signaling is mediated by type I and type II receptors and modulated by the ‘accessory’ receptor Endoglin also termed cluster of differentiation 105 (CD105). Endoglin was initially identified on pre-B leukemia cells but has received most attention due to its high expression on activated endothelial cells. In turn, Endoglin has been figured out as the causative factor for diseases associated with vascular dysfunction like hereditary hemorrhagic telangiectasia-1 (HHT-1), pre-eclampsia, and intrauterine growth restriction (IUPR). Because HHT patients often show signs of inflammation at vascular lesions, and loss of Endoglin in the myeloid lineage leads to spontaneous inflammation, it is speculated that Endoglin impacts inflammatory processes. In line, Endoglin is expressed on progenitor/precursor cells during hematopoiesis as well as on mature, differentiated cells of the innate and adaptive immune system. However, so far only pro-monocytes and macrophages have been in the focus of research, although Endoglin has been identified in many other immune system cell subsets. These findings imply a functional role of Endoglin in the maturation and function of immune cells. Aside the functional relevance of Endoglin in endothelial cells, CD105 is differentially expressed during hematopoiesis, arguing for a role of this receptor in the development of individual cell lineages. In addition, Endoglin expression is present on mature immune cells of the innate (i.e., macrophages and mast cells) and the adaptive (i.e., T-cells) immune system, further suggesting Endoglin as a factor that shapes immune responses. In this review, we summarize current knowledge on Endoglin expression and function in hematopoietic precursors and mature hematopoietic cells of different lineages.

An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study.

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder that causes chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHTassociated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, Epistaxis Severity Score (ESS), red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. Bevacizumab was given to 238 HHT patients for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% confidence interval: 2.9-3.5 g/dL); i.e., from a mean hemoglobin of 8.6 (8.5-8.8) g/dL to 11.8 (11.5-12.1) g/dL; P<0.0001) and decreased the ESS by 3.4 (3.2-3.7) points (mean ESS 6.8 [6.6-7.1] versus 3.4 [3.2-3.7]; P<0.0001) during the first year of treatment. Compared with 6 months before treatment, the number of red blood cell units transfused decreased by 82% (median of 6.0 [interquartile range, 0.0-13.0] units versus 0 [0.0-1.0] units; P<0.0001) and iron infusions decreased by 70% (median of 6.0 [1.0-18.0] infusions versus 1.0 [0.0-4.0] infusions, P<0.0001) during the first 6 months of bevacizumab treatment. Outcomes were similar regardless of the underlying pathogenic mutation. Following initial induction infusions, continuous/scheduled bevacizumab maintenance achieved higher hemoglobin and lower ESS than intermittent/as-needed maintenance but with more drug exposure. Bevacizumab was well tolerated: hypertension, fatigue, and proteinuria were the most common adverse events. Venous thromboembolism occurred in 2% of patients. In conclusion, systemic bevacizumab was safe and effective for managing chronic bleeding and anemia in HHT.

Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2)

PurposeDetermine the variant detection rate for ENG, ACVRL1, and SMAD4 in individuals who meet consensus (Curaçao) criteria for the clinical diagnosis of hereditary hemorrhagic telangiectasia. MethodsReview of HHT center database for individuals with three or more HHT diagnostic criteria, in whom molecular genetic analysis for ENG, ACVRL1, and SMAD4 had been performed. ResultsA variant known or suspected to be causal was detected in ENG in 67/152 (44.1%; 95% confidence interval [CI], 36.0–52.4%), ACVRL1 in 79/152 (52.0%; 95% CI, 43.7–60.1%), and SMAD4 in 2/152 (1.3%; 95% CI, 0.2–4.7%) family probands with definite HHT. Only 4/152 (2.6%; 95% CI, 0.7–6.6%) family probands did not have a variant in one of these genes. ConclusionPrevious reports of the variant detection rate for ENG and ACVRL1 in HHT patients have come from laboratories, which receive samples from clinicians with a wide range of expertise in recognizing clinical manifestations of HHT. These studies suggest a significantly lower detection rate (~75–85%) than we have found in patients who meet strictly applied consensus criteria (96.1%). Analysis of SMAD4 adds an additional detection rate of 1.3%. HHT as defined by the Curaçao criteria is highly predictive of a causative variant in either ENG or ACVRL1.

Higher prevalence of splenic artery aneurysms in hereditary hemorrhagic telangiectasia: Vascular implications and risk factors.

BackgroundSplenic artery aneurysm (SAA) is a rare but potentially fatal condition. Rupture results in 25% mortality up to 75% in pregnant women with 95% fetal mortality. Brief reports suggest an increased risk of developing SAA in patients with HHT.MethodsWe analyzed enhanced multidetector CT data in 186 HHT patients matched (gender and ± 5 year old) with 186 controls. We screened for SAA and recorded diameter of splenic and hepatic arteries and hepatic, pancreatic and splenic parenchymal involvements. We determined by univariate and multivariate analysis, the relationship with age, sex, genetic status, cardiovascular risk factors (CVRF) and visceral involvement.ResultsSAA concerned 24.7% of HHT patients and 5.4% of controls, p<0.001. Factors associated with increased risk of SAA in HHT were female gender (p = 0.04, OR = 2.12, IC 95% = 1.03–4.50), age (p = 0.0003, OR = 1.04, 95% CI = 1.02–1.06) and pancreatic parenchymal involvement (p = 0.04, OR = 2.13, 95% CI = 1.01–4.49), but not type of mutation, hepatic or splenic parenchymal involvements, splenic size or splenic artery diameter or CVRF.ConclusionsWe found a 4.57 higher rate of SAA in HHT patients without evidence of splenic high output related disease or increased CVRF. These results suggest the presence of a vascular intrinsic involvement. It should lead to screening all HHT patients for SAA. The vasculopathy hypothesis could require a change in management as screening of all systemic arteries and even the aorta and to further research in the field.

Hereditary hemorrhagic telangiectasia and health-related quality of life: a qualitative investigation.

The purpose of the study was to arrive at an accurate description of health-related quality of life of hereditary hemorrhagic telangiectasia patients. Thirteen semi-structured interviews were conducted in patients with hereditary hemorrhagic telangiectasia. Qualitative grounded theory analyses were performed using the participants' transcripts and revealed the following six categories: Impact of physical symptoms on daily life, Quality of family and social life, Emotional and psychological outcomes related to the disease, Knowledge having a severe disease and coping strategies to manage such disease, Recognition of the disease by professional colleagues and superiors, and Knowledge and understanding from health professionals in medical care. The definition of quality of life that emerged from the participants' transcripts was essentially related to health. Individuals with hereditary hemorrhagic telangiectasia mainly focused on the physical, psychological and emotional impacts of the symptoms and their consequences on professional life and social activities. Family relationships were also highlighted in the participants' transcripts. As such, HHT patients used coping strategies to manage their disease. Finally, a particularly salient issue referred to the lack of knowledge concerning the rare nature of this disease and the ensuing inherent sense of misunderstanding.

An International Multicenter Study of Intravenous Bevacizumab for the Treatment of Chronic Bleeding and Anemia in Hereditary Hemorrhagic Telangiectasia: The Inhibit-Bleed Study

An International Multicenter Study of Intravenous Bevacizumab for the Treatment of Chronic Bleeding and Anemia in Hereditary Hemorrhagic Telangiectasia: The Inhibit-Bleed Study

Efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. A double-blind, randomized, placebo-controlled trial

Hereditary hemorrhagic telangiectasia is a rare vascular genetic disease. Epistaxis is the most frequent and disabling manifestation, and timolol appears to be a new therapeutic option as non-selective beta-blockers have in vitro and in vivo anti-angiogenic properties. Our main objective was to evaluate the efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. This study is a single-center, randomized, phase 2, double-blind placebo-controlled study with an allocation ratio of 1:1. It was proposed to patients with hereditary hemorrhagic telangiectasia monitored at the French Reference Center, and we included patients aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis. The treatment was self-administered by the patient with a posology of one spray (50 µL) of timolol 0.5% or placebo in each nostril twice a day for 28 consecutive days. The primary efficacy endpoint was mean monthly epistaxis duration, assessed by monitoring epistaxis grids. A total of 58 patients were randomized and treated. The baseline characteristics were similar in the 2 groups. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 26 patients receiving the drug in comparison with the placebo group (p = 0.54). Toxicity was low and no severe adverse events were reported. One limitation is that we included all HHT patients with nosebleeds and did not take into account history of nasal surgery or nasal crusts. Timolol, administered by nasal spray at a dose of 0.25 mg in each nostril twice a day for 28 consecutive days, did not improve epistaxis in patients with hereditary hemorrhagic telangiectasia at 4 months after the beginning of the treatment.

Multiple ischemic stroke in Osler-Rendu-Weber disease

Hereditary hemorrhagic teleangiectasia (HHT, Osler-Rendu-Weber disease) is an autosomal dominantly inherited disorder caused by the mutation of several possible genes and characterized by malformations of the arteriovenous system in multiple organs. The clinical diagnosis is based on the Curacao criteria ((1) spontaneous, recurrent epistaxis; (2) teleangiectasias in characteristic sites (lips, oral cavity, nose, fingers); (3) visceral lesions (gastrointestinal, pulmonary, cerebral, spinal); (4) affected first degree relative). The aim of this study is to present the first genetically confirmed Hungarian case of hereditary hemorrhagic teleangiectasia with multiple ischemic strokes. Our 70-year-old woman has been suffering from severe epistaxis since her childhood and presented gastrointestinal bleeding during her adulthood as well. The characteristic skin lesions developed in the 5th decade of life. She was admitted to our department with loss of consciousness and fluctuating speech and swallowing problems. MRI of the brain supplemented with angiography revealed multiple arteriovenous malformations and multiple subacute ischemic lesions. The EEG demonstrated slowing of electric activity in the left frontal lobe. The neuropsychological assessment showed deficits in anterograde memory and executive functions. The diagnostic work-up for other characteristic alterations identified an arteriovenous malformation in the left lung. The genetic analysis demonstrated a heterozygous mutation in the 7th exon of the ENG gene at position 834 resulting in a thymine duplication and an early stop codon by a frame shift. The present case is largely similar to those already described in literature and draws the attention to the importance of multidisciplinary collaboration in the care of HHT patients.

Cross-sectional Study of the Occurrence of Epistaxis in HHT Patients

Cross-sectional Study of the Occurrence of Epistaxis in HHT Patients

Clinical and genetic findings in children with central nervous system arteriovenous fistulas.

To assess the spectrum of genetic anomalies in a cohort of children presenting at least one cerebral or spinal pial arteriovenous fistula (AVF), and to describe their clinical characteristics. From 1988 to 2016, all consecutive patients with at least one cerebral or spinal pial AVF were screened for genetic disease. All patients aged <18 years were included. Symptoms associated with AVF were recorded: heart failure, neurological deficit/seizure, and hemorrhage. The outcome was assessed using the modified Rankin Scale and school performance in children with cerebral AVF and the American Spinal Injury Association impairment scale in children with spinal AVF. Forty-three children were included. Twenty-five children were male and 18 were female. A germline mutation was identified in 23 probands (53.5 ± 14.9%): 8 in ENG (34.8 ± 14.2%), 1 in ACVRL1 (4.3 ± 6%) leading to a diagnosis of HHT, and 14 in RASA1 (60.9 ± 14.4%) leading to a diagnosis of capillary malformation/arteriovenous malformation type 1. No EphB4 gene mutation was identified. HHT patients presented a significantly lower rate of heart failure at diagnosis (p = 0.047). A trend toward an increased bleeding rate at presentation was observed in HHT (p = 0.069) and an increased rate of giant venous pouch in children in whom no mutation was identified (p = 0.097). Finally, an association with RASA1 mutation was observed in children with associated skin capillary hemangioma (p < 0001). These results highlight the importance of genetic testing in this setting in view of the high frequency of gene mutations in pediatric cerebrospinal AVFs, and show the predominance of RASA1 over HHT mutations. Ann Neurol 2017;82:972-980.

Follow-up of Thalidomide treatment in patients with Hereditary Haemorrhagic Telangiectasia

Patients with a hereditary vascular disorder called Rendu-Osler-Weber syndrome (Hereditary Haemorrhagic Telangiectasia, HHT) haemorrhage easily due to weak-walled vessels. Haemorrhage in lungs or brain can be fatal but patients suffer most from chronic and prolonged nosebleeds (epistaxis), the frequency and intensity of which increases with age. Several years ago, it was discovered serendipitously that the drug Thalidomide had beneficial effects on the disease symptoms in several of a small group of HHT patients: epistaxis and the incidence of anaemia were reduced and patients required fewer blood transfusions. In addition, they reported a better quality of life. However, Thalidomide has significant negative side effects, including neuropathy and fatigue. We followed up all HHT patients in the Netherlands who had been taking Thalidomide at the time the original study was completed to find out (i) how many had continued taking Thalidomide and for how long (ii) the nature and severity of any side-effects and (iii) whether side-effects had influenced their decision to continue taking Thalidomide. Only a minority of patients had continued taking the drug despite its beneficial effects on their symptoms and that the side effects were the primary reason to stop. Despite symptom reduction, alternative treatments are still necessary for epistaxis in HHT patients and a large-scale clinical trial is not justified although incidental use in the most severely affected patients can be considered.