An spanish study of secondary findings in families affected with mendelian disorders: choices, prevalence and family history.

Clinical exome sequencing has the potential to identify pathogenic variants unrelated to the purpose of the study (secondary findings, SFs). Data describing actual choices of SFs in participants in a clinical setting and factors influencing their decision are virtually non-existant in Europe. In this work, we report the acceptance rate of SFs, calculate their prevalence and study factors associated with the decision in a cohort of patients affected with a rare genetic disorder in a Spanish Hospital. Finally, we re-examine the presence of previously non reported family history in positive cases. We retrospectively reviewed informed consent choices and SF results from 824 unrelated probands affected with rare genetic disorders who underwent whole-genome or exome sequencing. Ninety percent of families (740/824) affected with rare disorders wished to be informed of SFs. Declining SFs was associated with a prenatal setting (30% vs. 8.7%, p = 0.025), consanguinity (19% vs. 8.7%, p = 0.013), male gender (10.6% vs. 1.5%, p = 0.00865) and the proband being a minor (10.6% vs. 1.5%, p = 0.014). Overall, 27 pathogenic or likely pathogenic variants were identified in 27 individuals, with an SF prevalence of 3.6%. Disclosure of SFs increased the percentage of positive family histories and resulted in early diagnosis or changes in the management of 10 individuals from five families. We show that the acceptance of SFs in Spain is high and the disclosure of SFs leads to a clinically meaningful change in the medical management of individuals.

Aortic flow dynamics and stiffness in Loeys-Dietz syndrome patients: a comparison with healthy volunteers and Marfan syndrome patients.

AIMS: To assess aortic flow and stiffness in patients with Loeys-Dietz syndrome (LDS) by 4D flow and cine cardiovascular magnetic resonance (CMR) and compare the results with those of healthy volunteers (HV) and Marfan syndrome (MFS) patients. METHODS AND RESULTS: Twenty-one LDS and 44 MFS patients with no previous aortic dissection or surgery and 35 HV underwent non-contrast-enhanced 4D flow CMR. In-plane rotational flow (IRF), systolic flow reversal ratio (SFRR), and aortic diameters were obtained at 20 planes from the ascending (AAo) to the proximal descending aorta (DAo). IRF and SFRR were also quantified for aortic regions (proximal and distal AAo, arch and proximal DAo). Peak-systolic wall shear stress (WSS) maps were also estimated. Aortic stiffness was quantified using pulse wave velocity (PWV) and proximal AAo longitudinal strain. Compared to HV, LDS patients had lower rotational flow at the distal AAo (P = 0.002), arch (P = 0.002), and proximal DAo (P < 0.001) even after adjustment for age, stroke volume, and local diameter. LDS patients had higher SFRR in the proximal DAo compared to both HV (P = 0.024) and MFS patients (P = 0.015), even after adjustment for age and local diameter. Axial and circumferential WSS in LDS patients were lower than in HV. AAo circumferential WSS was lower in LDS compared to MFS patients. AAo and DAo PWV and proximal AAo longitudinal strain revealed stiffer aortas in LDS patients compared to HV (P = 0.007, 0.005, and 0.029, respectively) but no differences vs. MFS patients. CONCLUSION: Greater aortic stiffness as well as impaired IRF and WSS were present in LDS patients compared to HV. Conversely, similar aortic stiffness and overlapping aortic flow features were found in Loeys-Dietz and Marfan patients.

Vein of Galen aneurysm, dilated cardiomyopathy, and slender habitus in a patient with a recurrent pathogenic variant in PACS2.

The PACS2 gene encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation that has been shown to be highly expressed during human prenatal brain development. Pathogenic variants in PACS2 have been recently shown to be implicated in a phenotype with global developmental delay/intellectual disability, seizures, autistic traits, facial dysmorphic features, and cerebellar dysgenesis. Here, we report a 25-year-old male with intellectual disability, epileptic encephalopathy, cerebellar dysgenesis, facial dysmorphism, and a previously reported pathogenic variant in PACS2. To our knowledge, this is the oldest patient reported who, in addition to the known phenotype described in PACS2 patients, presented with a vein of Galen malformation and dilated cardiomyopathy as previously unreported findings.

Clinical Risk Prediction in Patients With Left Ventricular Myocardial Noncompaction.

BACKGROUND: Left ventricular noncompaction (LVNC) is a heterogeneous entity with uncertain prognosis. OBJECTIVES: This study sought to develop and validate a prediction model of major adverse cardiovascular events (MACE) and to identify LVNC cases without events during long-term follow-up. METHODS: This is a retrospective longitudinal multicenter cohort study of consecutive patients fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance. MACE were defined as heart failure (HF), ventricular arrhythmias (VAs), systemic embolisms, or all-cause mortality. RESULTS: A total of 585 patients were included (45 ± 20 years of age, 57% male). LV ejection fraction (LVEF) was 48% ± 17%, and 18% presented late gadolinium enhancement (LGE). After a median follow-up of 5.1 years, MACE occurred in 223 (38%) patients: HF in 110 (19%), VAs in 87 (15%), systemic embolisms in 18 (3%), and 34 (6%) died. LVEF was the main variable independently associated with MACE (P < 0.05). LGE was associated with HF and VAs in patients with LVEF >35% (P < 0.05). A prediction model of MACE was developed using Cox regression, composed by age, sex, electrocardiography, cardiovascular risk factors, LVEF, and family aggregation. C-index was 0.72 (95% confidence interval: 0.67-0.75) in the derivation cohort and 0.72 (95% confidence interval: 0.71-0.73) in an external validation cohort. Patients with no electrocardiogram abnormalities, LVEF ≥50%, no LGE, and negative family screening presented no MACE at follow-up. CONCLUSIONS: LVNC is associated with an increased risk of heart failure and ventricular arrhythmias. LVEF is the variable most strongly associated with MACE; however, LGE confers additional risk in patients without severe systolic dysfunction. A risk prediction model is developed and validated to guide management.

Aortic Branch Aneurysms and Vascular Risk in Patients With Marfan Syndrome.

BACKGROUND: Aortic branch aneurysms are not included in the diagnostic criteria for Marfan syndrome (MFS); however, their prevalence and eventual prognostic significance are unknown. OBJECTIVES: The goal of this study was to assess the prevalence of aortic branch aneurysms in MFS and their relationship with aortic prognosis. METHODS: MFS patients with a pathogenic FBN1 genetic variant and at least one magnetic resonance or computed tomography angiography study assessing aortic branches were included. Aortic events and those related to aneurysm complications were recorded during follow-up. RESULTS: A total of 104 aneurysms were detected in 50 (26.7%) of the 187 patients with MFS (mean age 37.9 ± 14.4 years; 54% male) included in this study, with the iliac artery being the most common location (45 aneurysms). Thirty-one patients (62%) had >1 peripheral aneurysm, and surgery was performed in 5 (4.8%). Patients with aneurysms were older (41.9 ± 12.7 years vs. 36.7 ± 14.8 years; p = 0.040) and had more dilated aortic root (42.2 ± 6.4 mm vs. 38.8 ± 8.0 mm; p = 0.044) and dyslipidemia (31.0% vs. 9.7%; p = 0.001). In a subgroup of 95 patients with no previous aortic surgery or dissection followed up for 3.3 ± 2.6 years, the presence of arterial aneurysms was associated with a greater need for aortic surgery (hazard ratio: 3.4; 95% confidence interval: 1.1 to 10.3; p = 0.028) in a multivariable Cox analysis adjusted for age and aortic diameter. CONCLUSIONS: Aortic branch aneurysms are present in one-quarter of patients with MFS and are related to age and aortic dilation, and they independently predict the need for aortic surgery. The systematic use of whole-body vascular assessment is recommended to identify other sites of vascular involvement at risk for complications and to define the subgroup of patients with more aggressive aortic disease.

Negative screening of Fabry disease in patients with conduction disorders requiring a pacemaker.

Identification of Fabry disease (FD) in cardiac patients has been restricted so far to patients with left ventricular hypertrophy. Conduction problems are frequent in FD and could precede other manifestations, offering a possible earlier diagnosis.We studied the prevalence of FD in 188 patients < 70 years with conduction problems requiring pacemaker implantation. Although classical manifestations of FD were not rare, no patient with FD was identified. Screening efforts should not be conducted in this population.

Safe and Efficacious Use of 1-Month Triple Therapy in Patients with Atrial Fibrillation and High Bleeding Risk Undergoing PCI.

BACKGROUND: The impact of short or prolonged use of triple therapy (TT) on outcomes in patients with atrial fibrillation (AF) and high risk of bleeding undergoing percutaneous coronary intervention (PCI) is unclear. We compared clinical outcomes according to the duration of TT in patients with AF and HAS-BLED ≥ 3 at 1 year of follow-up. METHODS: A prospective observational cohort enrolled 735 patients with AF between 2010 and 2015. Of these, 521 (70.9%) had HAS-BLED ≥ 3 and 380 (72.9%) were discharged on TT. TT was prescribed for 1 month in 233 patients (61.3%). The primary endpoint was the incidence of Bleeding Academic Research Consortium (BARC ≥ 3). The secondary endpoint was the occurrence of ischemic events (cardiac death, MI, stroke, or stent thrombosis). RESULTS: Patients on 1-month TT had a higher median HAS-BLED. Intracraneal hemorrhage was twofold more frequently in patients on > 1-month TT but without statistical significance (0.9% vs 2.1%, p = 0.20). Rates of the primary endpoint (bleeding BARC ≥ 3) were 8.2% vs 10.9% and did not differ between groups, while secondary endpoint did not occur more frequently in the 1-month TT group compared with the > 1-month TT group (26.6% vs 23.1%). In adjusted multivariate analyses, patients receiving 1-month TT had a similar risk of the primary endpoint compared to those with > 1-month TT (HR 1.47; 95% CI 0.48-4.47, p = 0.50). No difference was found in the secondary ischemic endpoint (HR 1.24; 95% CI 0.77-2.00, p = 0.38). CONCLUSIONS: In patients with AF undergoing PCI at lower ischemic risk and higher bleeding risk, 1 month of TT seems safe and efficacious. Further studies are warranted in patients at high ischemic risk.

Safety of drug-eluting stents compared to bare metal stents in patients with an indication for long-term oral anticoagulation: A propensity score matched analysis.

BACKGROUND: Drug-eluting stents (DES) reduce stent restenosis compared with bare-metal stents (BMS). However, their use in patients requiring long-term oral anticoagulation (OAC) is controversial owing to increased risk of bleeding associated with OAC plus antiplatelet treatment over time. OBJECTIVE: To assess the safety of DES vs BMS in patients requiring long-term OAC for any reason. METHODS: Prospective observational multicenter study conducted at 6 teaching centers of patients undergoing percutaneous coronary intervention who required OAC for any reason. Adverse outcomes were analyzed at 1 year of follow-up. RESULTS: We identified 1002 patients requiring OAC (mean age: 72 years, male 72%). Six- hundred and thirteen patients (61.2%) received BMS and 389 (38.8%) DES. Diabetes, previous PCI, myocardial infarction and acute coronary syndrome at admission (P < 0.0001) were more common in patients with DES. Antithrombotic prescribing was similar at discharge between groups (TT: 51.5% vs 50.9%, clopidogrel plus OAC: 7.0% vs 5.0% and DAPT: 41.4% vs 42.7%, p = 0.52). DES and BMS patients showed similar rates of total bleeding (15.2% vs 13.4%, adjusted HR 0.82 [0.58-1.17, p = 0.82 and major bleeding (6.2% vs 6.0%; adjusted HR 1.22 [0.71-2.09], p = 0.46) and MACE (15.2% vs 18.6%, adjusted HR: 0.82 [0.57-1.17], p = 0.28, while restenosis was lower in patients with DES (5.3% vs 8.5%, adjusted HR. (0.52 [0.29-0.92], p = 0.02. Cox analysis after propensity score selection of 368 matched pairs demonstrated that DES use was not associated with a higher incidence of total bleeding or major bleeding. CONCLUSION: DES use is safe in patients with an indication for long-term OAC.