Induced Endothelial Cell Cycle Arrest Prevents Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Distinct endothelial cell cycle states (early G1 versus late G1) provide different "windows of opportunity" to enable the differential expression of genes that regulate venous versus arterial specification, respectively. Endothelial cell cycle control and arteriovenous identities are disrupted in vascular malformations including arteriovenous shunts, the hallmark of hereditary hemorrhagic telangiectasia (HHT). To date, the mechanistic link between endothelial cell cycle regulation and the development of arteriovenous malformations (AVMs) in HHT is not known. METHODS: We used BMP (bone morphogenetic protein) 9/10 blocking antibodies and endothelial-specific deletion of activin A receptor like type 1 (Alk1) to induce HHT in Fucci (fluorescent ubiquitination-based cell cycle indicator) 2 mice to assess endothelial cell cycle states in AVMs. We also assessed the therapeutic potential of inducing endothelial cell cycle G1 state in HHT to prevent AVMs by repurposing the Food and Drug Administration-approved CDK (cyclin-dependent kinase) 4/6 inhibitor (CDK4/6i) palbociclib. RESULTS: We found that endothelial cell cycle state and associated gene expressions are dysregulated during the pathogenesis of vascular malformations in HHT. We also showed that palbociclib treatment prevented AVM development induced by BMP9/10 inhibition and Alk1 genetic deletion. Mechanistically, endothelial cell late G1 state induced by palbociclib modulates the expression of genes regulating arteriovenous identity, endothelial cell migration, metabolism, and VEGF-A (vascular endothelial growth factor A) and BMP9 signaling that collectively contribute to the prevention of vascular malformations. CONCLUSIONS: This study provides new insights into molecular mechanisms leading to HHT by defining how endothelial cell cycle is dysregulated in AVMs because of BMP9/10 and Alk1 signaling deficiencies, and how restoration of endothelial cell cycle control may be used to treat AVMs in patients with HHT.

Symptom-related screening programme for early detection of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: the SYSPPE study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is the most severe long-term complication of acute pulmonary embolism (PE). We aimed to evaluate the impact of a symptom screening programme to detect CTEPH in PE survivors. METHODS: This was a multicentre cohort study of patients diagnosed with acute symptomatic PE between January 2017 and December 2018 in 16 centres in Spain. Patients were contacted by phone 2 years after the index PE diagnosis. Those with dyspnoea corresponding to a New York Heart Association (NYHA)/WHO scale≥II, visited the outpatient clinic for echocardiography and further diagnostic tests including right heart catheterisation (RHC). The primary outcome was the new diagnosis of CTEPH confirmed by RHC. RESULTS: Out of 1077 patients with acute PE, 646 were included in the symptom screening. At 2 years, 21.8% (n=141) reported dyspnoea NYHA/WHO scale≥II. Before symptom screening protocol, five patients were diagnosed with CTEPH following routine care. In patients with NYHA/WHO scale≥II, after symptom screening protocol, the echocardiographic probability of pulmonary hypertension (PH) was low, intermediate and high in 76.6% (n=95), 21.8% (n=27) and 1.6% (n=2), respectively. After performing additional diagnostic test in the latter 2 groups, 12 additional CTEPH cases were confirmed. CONCLUSIONS: The implementation of this simple strategy based on symptom evaluation by phone diagnosed more than doubled the number of CTEPH cases. Dedicated follow-up algorithms for PE survivors help diagnosing CTEPH earlier. TRIAL REGISTRATION NUMBER: NCT03953560.

Optimizing Venous Stenting: Consensus Recommendations for Enhanced Management of Lower Extremity Deep Vein Thrombosis.

INTRODUCTION: Deep vein thrombosis (DVT) poses a complex challenge and often leads to postthrombotic syndrome (PTS), a debilitating complication. The emergence of venous stents offers a potential preventive avenue against this complication. This study aimed to provide consensus recommendations on the use of venous stent for DVT. MATERIALS AND METHODS: From June to July 2023, 20 internal medicine, angiology and vascular surgery, and vascular and interventional radiology experts were involved in the Delphi process. Thirty-one recommendations, categorized into three thematic areas, were rigorously evaluated: indications for stent use, stent selection and placement, and monitoring and prevention of complications. Agreement was evaluated using a Likert scale, with consensus defined as agreement by two-thirds of the participants. RESULTS: Consensus was reached for 23 (74.2%) of 31 recommendations. The agreement was centered on considerations, such as stent placement in specific acute DVT scenarios, emphasizing pivotal stent characteristics. However, there were divergences in the recommended stent length to prevent migration and stent characteristics based on iliocaval bifurcation morphology. Notably, there was no consensus on whether patients with DVT caused by a major transient risk factor need more than 3 months of anticoagulation therapy or whether aspirin should be added to anticoagulant treatment after venous stenting. CONCLUSIONS: These consensus recommendations offer practical insights into optimizing venous stent use to prevent PTS in DVT patients. Addressing the critical aspects of stent selection, placement, and postprocedural care, these recommendations contribute to clinical decision-making. The identified divergences underscore the importance of consensus and thus indicate the need for further investigation.

The Impact of the Mediterranean Diet and Lifestyle Intervention on Lipoprotein Subclass Profiles among Metabolic Syndrome Patients: Findings of a Randomized Controlled Trial.

Metabolic syndrome (MetS) is associated with alterations of lipoprotein structure and function that can be characterized with advanced lipoprotein testing (ADLT). The effect of the Mediterranean diet (MedDiet) and weight loss on the lipoprotein subclass profile has been scarcely studied. Within the PREDIMED-Plus randomized controlled trial, a sub-study conducted at Bellvitge Hospital recruiting center evaluated the effects of a weight loss program based on an energy-reduced MedDiet (er-MedDiet) and physical activity (PA) promotion (intervention group) compared with energy-unrestricted MedDiet recommendations (control group) on ADLT-assessed lipoprotein subclasses. 202 patients with MetS (n = 107, intervention; n = 95, control) were included. Lipid profiles were determined, and ADLT was performed at baseline, 6, and 12 months. Linear mixed models were used to assess the effects of intervention on lipoprotein profiles. Compared to the control diet, at 12 months, the er-MedDiet+PA resulted in a significant additional 4.2 kg of body weight loss, a decrease in body mass index by 1.4 kg/m2, reduction in waist circumference by 2.2 cm, decreased triglycerides, LDL-cholesterol and non-HDL-cholesterol, and increased HDL-cholesterol. In er-MedDiet+PA participants, ADLT revealed a decrease in small dense-LDL-cholesterol (sd-LDL-C), intermediate-density lipoproteins, VLDL-triglyceride, and HDL-Triglyceride, and an increase in large LDL and large VLDL particles. In conclusion, compared to an ad libitum MedDiet (control group), er-MedDiet+PA decreased plasma triglycerides and the triglyceride content in HDL and VLDL particles, decreased sd-LDL-C, and increased large LDL particles, indicating beneficial changes against cardiovascular disease.

Aflibercept for Gastrointestinal Bleeding in Hereditary Hemorrhagic Telangiectasia: A Case Report.

Herein, we present the first described hereditary hemorrhagic telangiectasia (HHT) patient treated with aflibercept for severe GI involvement after tachyphylaxis to bevacizumab, with promising results. HHT is a rare genetic disease characterized by systemic vascular malformations. Gastrointestinal telangiectasia is one of the major involvements that can produce chronic severe iron-deficiency anemia. Nowadays, support treatment with iron replacement therapy, red blood cell transfusions, and antiangiogenic drugs-mainly bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF)-are the main therapeutic options for this complication. The evidence of alternative drugs in patients with failure to this approach, such as tachyphylaxis to bevacizumab, is scarce. Aflibercept is a VEGF inhibitor with antiangiogenic properties approved for the treatment of different types of cancer and ocular neovascularization diseases.

Angiogenesis, hereditary hemorrhagic telangiectasia and COVID-19.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominant disease characterized by pathologic angiogenesis that provokes vascular overgrowth. The evidence about the influence of Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in patients with rare diseases is scarce. We aimed to know the prevalence of coronavirus disease 2019 (COVID-19) in HHT patients. The HHT pathogenic angiogenesis and endothelial injury in COVID-19 are discussed using data from RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry. RiHHTa is an open, multicenter, prospective, observational registry including adult patients with HHT. A 27-item survey that captured clinical data of admitted HHT patients for COVID-19 was distributed to all RiHHTa investigators from June 8th to June 24th 2020. Only one out of 1177 HHT patients was admitted for COVID-19 pneumonia. She is a 74 years-old woman with a pathogenic variant in ACVRL1 gene. Her clinical course did not involve mechanical ventilation or worsening epistaxis, and she was successfully discharged after two weeks. The endothelial damage and the consequent angiogenic process in COVID-19 patients deserve further investigation.

Pre-existing Autoantibodies Neutralizing High Concentrations of Type I Interferons in Almost 10% of COVID-19 Patients Admitted to Intensive Care in Barcelona.

BACKGROUND: It is important to predict which patients infected by SARS-CoV-2 are at higher risk of life-threatening COVID-19. Several studies suggest that neutralizing auto-antibodies (auto-Abs) against type I interferons (IFNs) are predictive of critical COVID-19 pneumonia. OBJECTIVES: We aimed to test for auto-Abs to type I IFN and describe the main characteristics of COVID-19 patients admitted to intensive care depending on whether or not these auto-Abs are present. METHODS: Retrospective analysis of all COVID-19 patients admitted to an intensive care unit (ICU) in whom samples were available, from March 2020 to March 2021, in Barcelona, Spain. RESULTS: A total of 275 (70.5%) out of 390 patients admitted to ICU were tested for type I IFNs auto-antibodies (α2 and/or ω) by ELISA, being positive in 49 (17.8%) of them. Blocking activity of plasma diluted 1/10 for high concentrations (10 ng/mL) of IFNs was proven in 26 (9.5%) patients. Almost all the patients with neutralizing auto-Abs were men (92.3%). ICU patients with positive results for neutralizing IFNs auto-Abs did not show relevant differences in demographic, comorbidities, clinical features, and mortality, when compared with those with negative results. Nevertheless, some laboratory tests (leukocytosis, neutrophilia, thrombocytosis) related with COVID-19 severity, as well as acute kidney injury (17 [65.4%] vs. 100 [40.2%]; p = 0.013) were significantly higher in patients with auto-Abs. CONCLUSION: Auto-Abs neutralizing high concentrations of type I IFNs were found in 9.5% of patients admitted to the ICU for COVID-19 pneumonia in a hospital in Barcelona. These auto-Abs should be tested early upon diagnosis of SARS-CoV-2 infection, as they account for a significant proportion of life-threatening cases.

Satisfactory treatment of mucocutaneous lesions in hereditary hemorrhagic telangiectasia patients with dual pulsed dye laser and neodymium: yttrium-aluminum-garnet.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by telangiectasia and larger arteriovenous malformations (AVM) in different organs. Mucocutaneous telangiectasia can bleed and cause stigmatization, but the best treatment approach has not been defined yet. The aim of the study was to evaluate the efficacy and safety of dual pulsed dye laser and neodymium: yttrium-aluminum-garnet (PDL-Nd:YAG) laser treatment for mucocutaneous telangiectasia in HHT patients. It is a retrospective case series, where clinical files of all HHT patients treated with PDL-Nd:YAG laser at our Department between December 2010 and July 2019 were reviewed. Demographic, clinical, and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners scoring pretreatment and posttreatment pictures on a 5-point scale. Patient satisfaction and procedure pain were assessed using an ordinal scale (0-10). Forty-three treatment areas from 26 patients were analyzed. Lesions were predominantly located on the lower lip and cheeks. The median number of laser sessions per patient was 3 (interquartile range [IQR] 2-4). The median global severity score at baseline was 2 and became 0 at endpoint (p < 0.0001), with a median improvement rate of 4 (IQR 3-4). All patients reported a high degree of satisfaction (median 9) and tolerable pain (median 5). In conclusion, dual PDL-Nd: YAG laser is a convenient, safe, and effective treatment option for mucocutaneous telangiectasia in HHT patients.

Derivation and validation of a clinical prediction rule for thrombolysis-associated major bleeding in patients with acute pulmonary embolism: the BACS score.

BACKGROUND: Improved prediction of the risk of major bleeding in patients with acute pulmonary embolism (PE) receiving systemic thrombolysis is crucial to guide the choice of therapy. METHODS: The study included consecutive patients with acute PE who received systemic thrombolysis in the RIETE registry. We used multivariable logistic regression analysis to create a risk score to predict 30-day major bleeding episodes. We externally validated the risk score in patients from the COMMAND VTE registry. We also compared the newly created risk score against the Kuijer and RIETE scores. RESULTS: Multivariable logistic regression identified four predictors for major bleeding: recent major Bleeding (3 points), Age >75 years (1 point), active Cancer (1 point), and Syncope (1 point) (BACS). Among 1172 patients receiving thrombolytic therapy in RIETE, 446 (38%) were classified as having low-risk (none of the variables present, 0 points) of major bleeding according to the BACS score, and the overall 30-day major bleeding rate of this group was 2.9% (95% CI, 1.6-4.9%), compared with 44% (95% CI, 14-79%) in the high-risk group (>3 points). In the validation cohort, 51% (149/290) of patients were classified as having low-risk, and the overall 30-day major bleeding rate of this group was 1.3%. In RIETE, the 30-day major bleeding event rates in the Kuijer and RIETE low-risk stratum were 5.3% and 4.4%, respectively. CONCLUSIONS: The BACS score is an easily applicable aid for prediction of the risk of major bleeding in the population of PE patients who receive systemic thrombolysis.

Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A Randomized Noninferiority Trial.

Background: The potential role of new oral anticoagulants in antiphospholipid antibody syndrome (APS) remains uncertain. Objective: To determine whether rivaroxaban is noninferior to dose-adjusted vitamin K antagonists (VKAs) for thrombotic APS. Design: 3-year, open-label, randomized noninferiority trial. (EU Clinical Trials Register: EUDRA [European Union Drug Regulatory Authorities] code 2010-019764-36). Setting: 6 university hospitals in Spain. Participants: 190 adults (aged 18 to 75 years) with thrombotic APS. Intervention: Rivaroxaban (20 mg/d or 15 mg/d, according to renal function) versus dose-adjusted VKAs (target international normalized ratio, 2.0 to 3.0, or 3.1 to 4.0 in patients with a history of recurrent thrombosis). Measurements: The primary efficacy outcome was the proportion of patients with new thrombotic events; the primary safety outcome was major bleeding. The prespecified noninferiority margin for risk ratio (RR) was 1.40. Secondary outcomes included time to thrombosis, type of thrombosis, changes in biomarker levels, cardiovascular death, and nonmajor bleeding. Results: After 3 years of follow-up, recurrent thrombosis occurred in 11 patients (11.6%) in the rivaroxaban group and 6 (6.3%) in the VKA group (RR in the rivaroxaban group, 1.83 [95% CI, 0.71 to 4.76]). Stroke occurred more commonly in patients receiving rivaroxaban (9 events) than in those receiving VKAs (0 events) (corrected RR, 19.00 [CI, 1.12 to 321.9]). Major bleeding occurred in 6 patients (6.3%) in the rivaroxaban group and 7 (7.4%) in the VKA group (RR, 0.86 [CI, 0.30 to 2.46]). Post hoc analysis suggested an increased risk for recurrent thrombosis in rivaroxaban-treated patients with previous arterial thrombosis, livedo racemosa, or APS-related cardiac valvular disease. Limitation: Anticoagulation intensity was not measured in the rivaroxaban group. Conclusion: Rivaroxaban did not show noninferiority to dose-adjusted VKAs for thrombotic APS and, in fact, showed a non-statistically significant near doubling of the risk for recurrent thrombosis. Primary Funding Source: Bayer Hispania.

ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation.

OBJECTIVE: ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-ß (transforming growth factor-ß) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia-a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia. APPROACH AND RESULTS: In this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1+/- mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1+/- retinas and in turn normalize the vasculature. CONCLUSIONS: Overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia.

Impact of Thrombus Sidedness on Presentation and Outcomes of Patients with Proximal Lower Extremity Deep Vein Thrombosis.

Small studies have suggested differences in demographics and outcomes between left- and right-sided deep vein thrombosis (DVT), and also unilateral versus bilateral DVT. We investigated the clinical presentation and outcomes of patients with DVT based on thrombus sidedness. The authors used the data from the Registro Informatizado Enfermedad TromboEmbólica (RIETE) database (2001-2016) to identify patients with symptomatic proximal lower-extremity DVT. Main outcomes included cumulative 90-day symptomatic pulmonary embolism (PE) and 1-year mortality. Overall, 30,445 patients were included. The majority of DVTs occurred in the left leg (16,421 left-sided, 12,643 right-sided, and 1,390 bilateral; p < 0.001 for chi-squared test comparing all three groups). Comorbidities were relatively similar in those with left-sided and right-sided DVT. Compared with those with left-sided DVT, patients with right-sided DVT had higher relative frequency of PE (26% versus 23%, p < 0.001) and 1-year mortality (odds ratio [OR]: 1.08; 95% confidence interval [CI]: 1.00-1.18). This difference in mortality did not persist after multivariable adjustment (OR: 1.01; 95% CI: 0.93-1.1). Patients with bilateral DVT had a greater burden of comorbidities such as heart failure, and recent surgery compared with those with unilateral DVT (p < 0.001), and higher relative frequency of PE (48%), and 1-year mortality (24.1%). Worse outcomes in patients with bilateral DVT were attenuated but persisted after multivariable adjustment for demographics and risk factors (OR: 1.64; 95% CI: 1.43-1.87). Patients with bilateral DVT had worse outcomes during and after discontinuation of anticoagulation. There is a left-sided preponderance for proximal lower-extremity DVT. Compared with those with left-sided DVT, patients with right-sided DVT have slightly higher rates of PE. Bilateral DVT is associated with markedly worse short-term and 1-year outcomes.

[Update in the management of chronic thrombo-embolic pulmonary hypertension]. / Actualización del abordaje de la hipertensión pulmonar tromboembólica crónica.

Chronic thrombo-embolic pulmonary hypertension (CTEPH) is a potentially curable form of pulmonary hypertension (PH) that develops in up to 3% of patients after pulmonary embolism (PE). In these patients, PE does not resolve, leading to organized fibrotic clots, with the development of precapillary PH as a result of the proximal obstruction of the pulmonary arteries. In addition, a distal microvasculopathy may also develop, contributing to the increase of pulmonary vascular resistance. Transthoracic echocardiography is the diagnostic tool that allows to establish the suspicion of PH. Ventilation-perfusion lung scintigraphy is the fundamental tool in the study of patients with suspected CTEPH; if it is normal, virtually rules out the diagnosis. Right heart catheterization is mandatory for the diagnosis of these patients. CTEPH is defined as the existence of symptoms, residual perfusion defects and precapillary PH after a minimum period of three months of anticoagulation. Pulmonary angiography helps determine the extent and surgical accessibility of thromboembolic lesions. CTEPH patients are candidates for long-term anticoagulation. Pulmonary endarterectomy is the treatment of choice, resulting in significant clinical and hemodynamic improvement. About 25% of patients have residual PH post-endarterectomy. Balloon pulmonary angioplasty is an endovascular technique that targets more distal lesions, being potentially useful for patients with inoperable CTEPH or persistent/recurrent PH post-endarterectomy. Both types of patients may also benefit from pharmacological treatment for PH. These three therapies are the cornerstone of CTEPH treatment, which has evolved towards a multimodal approach.

New genetic drivers in hemorrhagic hereditary telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in around 90% of the patients; also 2% of patients harbor pathogenic variants at SMAD4 and GDF2. Importantly, the genetic cause of 8% of patients with clinical HHT remains unknown. Here, we present new putative genetic drivers of HHT. METHODS: To identify new HHT genetic drivers, we performed exome sequencing of 19 HHT patients and relatives with unknown HHT genetic etiology. We applied a multistep filtration strategy to catalog deleterious variants and prioritize gene candidates based on their known relevance in endothelial cell biology. Additionally, we performed in vitro validation of one of the identified variants. RESULTS: We identified variants in the INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, FOXO1 and SMAD6 genes as putative drivers in HHT. We have identified the SMAD6 p.(Glu407Lys) variant in one of the families; this is a loss-of-function variant leading to the activation of the BMP/TGFß signaling in endothelial cells. CONCLUSIONS: Variants in these genes should be considered for genetic testing in patients with HHT phenotype and negative for ACVRL1/ENG mutations.

Enoxaparin for Long-Term Therapy of Venous Thromboembolism in Patients with Cancer and Renal Insufficiency.

BACKGROUND: The optimal therapy of venous thromboembolism (VTE) in cancer patients with renal insufficiency (RI) is unknown. Current guidelines recommend to use low-molecular-weight heparin over direct oral anticoagulants to treat VTE in cancer patients at high risk of bleeding. METHODS: We used the Registro Informatizado Enfermedad Tromboemb00F3lica (RIETE) registry to compare the 6-month incidence rates of (1) VTE recurrences versus major bleeding and (2) fatal pulmonary embolism (PE) versus fatal bleeding in three subgroups (those with mild, moderate, or severe RI) of cancer patients receiving enoxaparin monotherapy. RESULTS: From January 2009 through June 2022, 2,844 patients with RI received enoxaparin for ≥6 months: 1,432 (50%) had mild RI, 1,168 (41%) moderate RI, and 244 (8.6%) had severe RI. Overall, 68, 62, and 12%, respectively, received the recommended doses. Among patients with mild RI, the rates of VTE recurrences versus major bleeding (4.6 vs. 5.4%) and fatal PE versus fatal bleeding (1.3 vs. 1.2%) were similar. Among patients with moderate RI, VTE recurrences were half as common as major bleeding (3.1 vs. 6.3%), but fatal PE and fatal bleeding were close (1.8 vs. 1.2%). Among patients with severe RI, VTE recurrences were threefold less common than major bleeding (4.1 vs. 13%), but fatal PE was threefold more frequent than fatal bleeding (2.5 vs. 0.8%). During the first 10 days, fatal PE was fivefold more common than fatal bleeding (2.1 vs. 0.4%). CONCLUSION: Among cancer patients with severe RI, fatal PE was fivefold more common than fatal bleeding. The recommended doses of enoxaparin in these patients should be revisited.

Long-term association between water intake and kidney function in a population at high cardiovascular risk.

OBJECTIVES: The evidence on water intake in the prevention of kidney function decline is scarce at population level in well-being individuals at high cardiovascular risk. Therefore, we aimed to longitudinally evaluate the associations between total water intake and subtypes and kidney function, through estimated-Glomerular Filtration Rate (eGFR). METHODS: Three-year prospective analysis conducted in 1986 older adults (aged 55-75 year) with overweight/obesity and metabolic syndrome from the PREDIMED-Plus study. Water intake was assessed using validated beverage and food frequency questionnaires. Serum creatinine-based eGFR (SCr-based eGFR; ml/min/1.73 m2) was estimated using the CKD-EPI equation at baseline, one-year and 3-years of follow-up. Mixed-effects linear regression models were fitted to evaluate the associations between baseline total water intake and subtypes, and SCr-based eGFR over 3-years of follow-up. RESULTS: Participants in the highest baseline tertile of total water intake, plain water and water from all fluids showed a lower decrease in SCr-based eGFR after 3-years of follow-up, compared to those in the lowest tertile. Participants with the highest tap water consumption showed a lower SCr-based eGFR decline after 1-year and 3-years of follow-up, in comparerd to participants in the lowest intake category (T3 vs. T1: ß: 1.4 ml/min/1.73 m2; 95%CI: 0.5-2.3, ß: 1.0; 95%CI: 0.1-2.0, respectively). CONCLUSIONS: Plain water rather than other water sources, and especially tap water, was associated with lower kidney function decline assessed through eGFR over 3-years of follow-up, in older individuals at high cardiovascular risk. TRIAL REGISTRATION: ISRCTN89898870. Retrospectively registered on 24 July 2014.

Identification of Low-risk Patients With Acute Symptomatic Pulmonary Embolism.

BACKGROUND: Identification of patients with acute symptomatic pulmonary embolism (PE) who are at low-risk for short-term complications to warrant outpatient care lacks clarity. METHOD: In order to identify patients at low-risk for 30-day all-cause and PE-related mortality, we used a cohort of haemodynamically stable patients from the RIETE registry to compare the false-negative rate of four strategies: the simplified Pulmonary Embolism Severity Index (sPESI); a modified (i.e., heart rate cutoff of 100beats/min) sPESI; and a combination of the original and the modified sPESI with computed tomography (CT)-assessed right ventricle (RV)/left ventricle (LV) ratio. RESULTS: Overall, 137 of 3117 patients with acute PE (4.4%) died during the first month. Of these, 41 (1.3%) died from PE, and 96 (3.1%) died from other causes. The proportion of patients categorized as having low-risk was highest with the sPESI and lowest with the combination of a modified sPESI and CT-assessed RV/LV ratio (32.5% versus 16.5%; P<0.001). However, among patients identified as low-risk, the 30-day mortality rate was lowest with the combination of a modified sPESI and CT-assessed RV/LV ratio and highest with the sPESI (0.4% versus 1.0%; P=0.03). The 30-day PE-related mortality rates for patients designated as low-risk by the sPESI, the modified sPESI, and the combination of the original and modified sPESI with CT-assessed RV/LV ratio were 0.7%, 0.4%, 0.7%, and 0.2%, respectively. CONCLUSIONS: The combination of a negative modified sPESI with CT-assessed RV/LV ratio ≤1 identifies patients with acute PE who are at very low-risk for short-term mortality.

Improving Hereditary Hemorrhagic Telangiectasia Molecular Diagnosis: A Referral Center Experience.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of the patients undergoing molecular testing. The identification of variants of unknown significance is often seen as a challenge in clinical practice that makes family screening and genetic counseling difficult. Here, we show that the implementation of cDNA analysis to assess the effect of splice site variants on mRNA splicing is a powerful tool. METHODS: Gene panel sequencing of genes associated with HHT and other arteriovenous malformation-related syndromes was performed. To evaluate the effect of the splice site variants, cDNA analysis of ENG and ACVRL1 genes was carried out. RESULTS: three novel splice site variants were identified in ENG (c.68-2A > T and c.1311+4_1311+8del) and ACVLR1 (c.526-6C > G) genes correspondingly in three individuals with HHT that met ≥ 3 Curaçao criteria. All three variants led to an aberrant splicing inducing exon skipping (ENG:c.68-2A > T and ACVRL1:c.526-6C > G) or intron retention (ENG:c.1311+4_1311+8del) allowing the confirmation of the predicted effect on splicing and the reclassification from unknown significance to pathogenic/likely pathogenic of two of them. CONCLUSIONS: RNA analysis should be performed to assess and/or confirm the impact of variants on splicing. The molecular diagnosis of HHT patients is crucial to allow family screening and accurate genetic counseling. A multidisciplinary approach including clinicians and geneticists is crucial when dealing with patients with rare diseases.