RESUMO
Genome wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with the risk of common disorders. However, since the large majority of these risk SNPs reside outside gene-coding regions, GWAS generally provide no information about causal mechanisms regarding the specific gene(s) that are affected or the tissue(s) in which these candidate gene(s) exert their effect. The 'gold standard' method for understanding causal genes and their mechanisms of action are laborious basic science studies often involving sophisticated knockin or knockout mouse lines, however, these types of studies are impractical as a high-throughput means to understand the many risk variants that cause complex diseases like coronary artery disease (CAD). As a solution, we developed a streamlined, data-driven informatics pipeline to gain mechanistic insights on complex genetic loci. The pipeline begins by understanding the SNPs in a given locus in terms of their relative location and linkage disequilibrium relationships, and then identifies nearby expression quantitative trait loci (eQTLs) to determine their relative independence and the likely tissues that mediate their disease-causal effects. The pipeline then seeks to understand associations with other disease-relevant genes, disease sub-phenotypes, potential causality (Mendelian randomization), and the regulatory and functional involvement of these genes in gene regulatory co-expression networks (GRNs). Here, we applied this pipeline to understand a cluster of SNPs associated with CAD within and immediately adjacent to the gene encoding HDAC9. Our pipeline demonstrated, and validated, that this locus is causal for CAD by modulation of TWIST1 expression levels in the arterial wall, and by also governing a GRN related to metabolic function in skeletal muscle. Our results reconciled numerous prior studies, and also provided clear evidence that this locus does not govern HDAC9 expression, structure or function. This pipeline should be considered as a powerful and efficient way to understand GWAS risk loci in a manner that better reflects the highly complex nature of genetic risk associated with common disorders.
Assuntos
Doença da Artéria Coronariana , Estudo de Associação Genômica Ampla , Proteína 1 Relacionada a Twist/metabolismo , Animais , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Histona Desacetilases/metabolismo , Desequilíbrio de Ligação , Camundongos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Proteínas Repressoras/metabolismoRESUMO
INTRODUCTION: Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of myocardial infarction. Migraine headache has been reported to be common among patients with SCAD, but the degree of migraine-related disability has not been quantified. METHODS: Clinical data and headache variables were obtained from the baseline assessment of the prospective, multicenter iSCAD Registry. Migraine-related disability was quantified using the self-reported Migraine Disability Assessment (MIDAS). Demographic, clinical, psychosocial, and medical characteristics from data entry forms were compared between patients with and without migraine. RESULTS: Of the 773 patients with available data, 46% reported previous or current migraines. Those with migraines were more likely to be women (96.9% vs 90.3%, p = 0.0003). The presence of underlying carotid fibromuscular dysplasia was associated with migraine (35% vs 27%, p = 0.0175). There was not a significant association with carotid artery dissection and migraine. Current migraine frequency was less than monthly (58%), monthly (24%), weekly (16%), and daily (3%). Triptan use was reported in 32.5% of patients, and 17.5% used daily migraine prophylactic medications. Using the MIDAS to quantify disability related to migraine, 60.2% reported little or no disability, 14.4% mild, 12.7% moderate, and 12.7% severe. The mean MIDAS score was 9.9 (mild to moderate disability). Patients with SCAD had higher rates of depression and anxiety (28.2% vs 17.7% [p = 0.0004] and 35.3% vs 26.7% [p = 0.0099], respectively). CONCLUSIONS: Migraines are common, frequent, and a source of disability in patients with SCAD. The association between female sex, anxiety, and depression may provide some insight for potential treatment modalities.
Assuntos
Anomalias dos Vasos Coronários , Transtornos de Enxaqueca , Sistema de Registros , Doenças Vasculares , Humanos , Feminino , Masculino , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/diagnóstico , Pessoa de Meia-Idade , Doenças Vasculares/epidemiologia , Doenças Vasculares/congênito , Doenças Vasculares/diagnóstico , Anomalias dos Vasos Coronários/epidemiologia , Anomalias dos Vasos Coronários/complicações , Anomalias dos Vasos Coronários/diagnóstico , Adulto , Estudos Prospectivos , Fatores de Risco , Avaliação da Deficiência , Idoso , Displasia Fibromuscular/epidemiologia , Displasia Fibromuscular/complicações , Displasia Fibromuscular/diagnóstico , Displasia Fibromuscular/diagnóstico por imagem , Depressão/epidemiologia , Depressão/diagnósticoRESUMO
Multifocal fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection are both sex-biased diseases disproportionately affecting women over men in a 9:1 ratio. Traditionally known in the context of renovascular hypertension, recent advances in knowledge about FMD have demonstrated that FMD is a systemic arteriopathy presenting as arterial stenosis, aneurysm, and dissection in virtually any arterial bed. FMD is also characterized by major cardiovascular presentations including hypertension, stroke, and myocardial infarction. Similar to FMD, spontaneous coronary artery dissection is associated with a high prevalence of extracoronary vascular abnormalities, including FMD, aneurysm, and extracoronary dissection, and recent studies have also found genetic associations between the two diseases. This review will summarize the relationship between FMD and spontaneous coronary artery dissection with a focus on common clinical associations, histopathologic mechanisms, genetic susceptibilities, and the biology of these diseases. The current status of disease models and critical future research directions will also be addressed.
Assuntos
Anomalias dos Vasos Coronários , Displasia Fibromuscular , Fatores Sexuais , Doenças Vasculares/congênito , Aneurisma/etiologia , Dissecção Aórtica/etiologia , Angiografia , Constrição Patológica/etiologia , Anomalias dos Vasos Coronários/diagnóstico por imagem , Anomalias dos Vasos Coronários/epidemiologia , Anomalias dos Vasos Coronários/genética , Anomalias dos Vasos Coronários/patologia , Feminino , Displasia Fibromuscular/diagnóstico por imagem , Displasia Fibromuscular/epidemiologia , Displasia Fibromuscular/genética , Displasia Fibromuscular/patologia , Predisposição Genética para Doença , Variação Genética , Humanos , Hipertensão/etiologia , Masculino , Infarto do Miocárdio/etiologia , Acidente Vascular Cerebral/etiologia , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/epidemiologia , Doenças Vasculares/genética , Doenças Vasculares/patologiaRESUMO
Introduction: Mitral valve prolapse and aortic root dilatation are reported in association with hypermobile Ehlers-Danlos syndrome (hEDS), but the full phenotypic spectrum of cardiovascular complications in this condition has not been studied in the aftermath of updated nosology and diagnostic criteria. Methods: We performed a retrospective review of 258 patients (> 94% adults) referred to a multidisciplinary clinic for evaluation of joint hypermobility between January 2017 and December 2020 and diagnosed with hEDS or a hypermobility spectrum disorder (HSD) to determine the incidence and spectrum of cardiovascular involvement. Results: Mitral valve prolapse was present in 7.5% and thoracic aortic dilatation in 15.2%. Aortic dilatation was more frequent in individuals with hEDS (20.7%) than with HSD (7.7%) and similarly prevalent between males and females, although was mild in > 90% of females and moderate-to-severe in 50% of males. Five individuals (1.9%) with hEDS/HSD had extra-aortic arterial involvement, including cervical artery dissection (CeAD, n = 2), spontaneous coronary artery dissection (SCAD, n = 2), and SCAD plus celiac artery pseudoaneurysm (n = 1). This is the first series to report the prevalence of CeAD and SCAD in hEDS/HSD. Conclusions: Cardiovascular manifestations in adults with hEDS/HSD, especially females, are typically mild and readily assessed by echocardiography. Since the risk of progression has not yet been defined, adults with hEDS/HSD who are found to have aortic dilatation at baseline should continue ongoing surveillance to monitor for progressive dilatation. Cardiovascular medicine specialists, neurologists, and neurosurgeons should consider hEDS/HSD on the differential for patients with CeAD or SCAD who also have joint hypermobility.
Assuntos
Síndrome de Ehlers-Danlos , Instabilidade Articular , Prolapso da Valva Mitral , Adulto , Ecocardiografia , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/epidemiologia , Feminino , Humanos , Instabilidade Articular/diagnóstico por imagem , Instabilidade Articular/epidemiologia , Masculino , Prolapso da Valva Mitral/diagnóstico por imagem , Prolapso da Valva Mitral/epidemiologiaRESUMO
This article is a comprehensive document on the diagnosis and management of fibromuscular dysplasia (FMD), which was commissioned by the working group 'Hypertension and the Kidney' of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM). This document updates previous consensus documents/scientific statements on FMD published in 2014 with full harmonization of the position of European and US experts. In addition to practical consensus-based clinical recommendations, including a consensus protocol for catheter-based angiography and percutaneous angioplasty for renal FMD, the document also includes the first analysis of the European/International FMD Registry and provides updated data from the US Registry for FMD. Finally, it provides insights on ongoing research programs and proposes future research directions for understanding this multifaceted arterial disease.
Assuntos
Angiografia/normas , Angioplastia/normas , Fármacos Cardiovasculares/uso terapêutico , Displasia Fibromuscular/diagnóstico por imagem , Displasia Fibromuscular/terapia , Angioplastia/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Tomada de Decisão Clínica , Consenso , Displasia Fibromuscular/epidemiologia , Predisposição Genética para Doença , Humanos , Valor Preditivo dos Testes , Fatores de Risco , Resultado do TratamentoRESUMO
Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10-10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10-4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.
Assuntos
Displasia Fibromuscular/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas dos Microfilamentos/genética , Animais , Artérias/metabolismo , Artérias/patologia , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Espessura Intima-Media Carotídea , Modelos Animais de Doenças , Exoma/genética , Feminino , Displasia Fibromuscular/patologia , Regulação da Expressão Gênica , Genótipo , Humanos , Hipertensão/genética , Hipertensão/patologia , Masculino , Proteínas dos Microfilamentos/biossíntese , Miócitos de Músculo Liso , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Peixe-Zebra/genéticaRESUMO
BACKGROUND AND PURPOSE: Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy most often affecting the carotid and renal arteries. In the United States Registry for FMD, 41.7% of patients experienced an aneurysm and/or dissection by the time of entry into the Registry. We sought to determine the occurrence of neurovascular events after FMD diagnosis and any changes on cervical artery imaging that may be attributable to FMD. METHODS: Patients followed at the Mount Sinai Medical Center (US Registry for FMD enrollment center) with confirmed FMD and > 1 cervical artery imaging study (at least ± 6 months from the baseline carotid duplex ultrasound [CDU]) between the years 2003 and 2015 were included. Medical records and cervical artery imaging ([CDU], magnetic resonance angiogram [MRA], and computed tomography angiogram [CTA]) were reviewed. New arterial dissection, aneurysm, transient ischemic attack, stroke, or new FMD findings were recorded. RESULTS: Among 146 FMD patients with complete information, 52 (35.6%) had an aneurysm and 52 (35.6%) had a dissection. Mean clinical follow-up was 35.3 ± 25.3 months (range 5-153 months); patients underwent 4 ± 2.7 CDU (range 1-17); 86.3% had ≥1 neck MRA or CTA. After FMD diagnosis, 3 patients (2%) experienced a new carotid artery dissection; 1 patient experienced a stroke due to concomitant atherosclerosis. No new aneurysms occurred. In patients with cervical artery FMD, imaging findings remained stable throughout follow-up. No patient developed new cervical artery FMD findings on follow-up imaging. CONCLUSIONS: No new cervical artery FMD or aneurysm was observed on subsequent imaging. New carotid dissection was uncommon over a mean follow-up period of 35.3 ± 25.3 months and was the only non-atherosclerotic vascular event observed after FMD diagnosis.
Assuntos
Artérias , Dissecação da Artéria Carótida Interna/epidemiologia , Displasia Fibromuscular/epidemiologia , Ataque Isquêmico Transitório/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Dissecação da Artéria Vertebral/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artérias/diagnóstico por imagem , Dissecação da Artéria Carótida Interna/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Progressão da Doença , Feminino , Displasia Fibromuscular/diagnóstico por imagem , Humanos , Ataque Isquêmico Transitório/diagnóstico por imagem , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Acidente Vascular Cerebral/diagnóstico por imagem , Fatores de Tempo , Ultrassonografia Doppler Dupla , Estados Unidos/epidemiologia , Dissecação da Artéria Vertebral/diagnóstico por imagem , Adulto JovemAssuntos
Cardiologia , Paclitaxel , Cardiologia/educação , Humanos , Sociedades Médicas , Máquina de Vetores de Suporte , RedaçãoAssuntos
Máquina de Vetores de Suporte , Veias , Artérias/diagnóstico por imagem , Consenso , Humanos , RedaçãoRESUMO
Background: Advanced therapies are increasingly utilized to treat pulmonary embolism (PE). A unique data platform allows access to electronic health record data for comparison of the safety of PE therapies. Methods: All data from Truveta (Truveta, Inc) were analyzed (16 systems, 83,612,413 patients, 535,567 with PE). All patients treated with ultrasound-assisted catheter-directed thrombolysis (USCDT) (Boston Scientific) or mechanical thrombectomy (MT) (Inari Medical) for PE were identified. The primary analysis was based on index procedures performed from January 2009 to May 2023, and contemporary analysis on those performed from January 2018 to May 2023. Bleeding was assessed via direct laboratory analysis and transfusion administration documentation. International Society for Thrombosis and Hemostasis (ISTH) and Bleeding Academic Research Consortium (BARC) 3b definitions were recreated. Multiple logistic regression analysis of major bleeding was performed. In-hospital death and median length of stay were measured. Results: For the primary analysis, 2259 patients (N = 1577 USCDT, N = 682 MT) and for the contemporary analysis 1798 patients (N = 1137 USCDT, N = 661 MT) met the criteria. Incidence of hemoglobin reduction (>2 and >5 g/dL) and transfusions received were significantly higher among MT-treated patients in both analyses, as was ISTH and BARC 3b major bleeding (primary: ISTH MT 17.3% vs USCDT 12.4% P = .002; BARC 3b MT 15.4% vs USCDT 11.8% P = .019) (contemporary: ISTH MT 17.2% vs USCDT 11.0% P = .0002; BARC 3b MT 15.4% vs USCDT 10.6% P = .002). Regression analysis demonstrated that MT is associated with major bleeding. Median length of stay, all-cause 30-day readmission and in-hospital mortality were similar between groups. Intracranial hemorrhage was more common with MT. Conclusions: Major bleeding derived from direct laboratory and transfusion data occurred more frequently with MT vs USCDT. Intracranial hemorrhage was more common among MT-treated patients. In the absence of randomized data, these results provide guidance regarding the bleeding risk and safety of strategies for advanced PE therapy.
RESUMO
BACKGROUND: Myocardial infarction secondary to spontaneous coronary artery dissection (SCAD) can be traumatic and potentially trigger posttraumatic stress disorder (PTSD). In a large, multicenter, registry-based cohort, we documented prevalence of lifetime and past-month SCAD-induced PTSD, as well as related treatment seeking, and examined a range of health-relevant correlates of SCAD-induced PTSD. METHODS AND RESULTS: Patients with SCAD were enrolled in the iSCAD (International SCAD) Registry. At baseline, site investigators completed medical report forms, and patients reported demographics, medical/SCAD history, psychosocial factors (including SCAD-induced PTSD symptoms), health behaviors, and health status via online questionnaires. Of 1156 registry patients, 859 patients (93.9% women; mean age, 52.3 years) completed questionnaires querying SCAD-induced PTSD. Nearly 35% (n=298) of patients met diagnostic criteria for probable SCAD-induced PTSD in their lifetime, and 6.4% (n=55) met criteria for probable past-month PTSD. Of 811 patients ever reporting any SCAD-induced PTSD symptoms, 34.8% indicated seeking treatment for this distress. However, 46.0% of the 298 patients with lifetime probable SCAD-induced PTSD diagnoses reported never receiving trauma-related treatment. Younger age at first SCAD, fewer years since SCAD, being single, unemployed status, more lifetime trauma, and history of anxiety were associated with greater past-month PTSD symptom severity in multivariable regression models. Greater past-month SCAD-induced PTSD symptoms were associated with greater past-week sleep disturbance and worse past-month disease-specific health status when adjusting for various risk factors. CONCLUSIONS: Given the high prevalence of SCAD-induced PTSD symptoms, efforts to support screening for these symptoms and connecting patients experiencing distress with empirically supported treatments are critical next steps. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04496687.
Assuntos
Anomalias dos Vasos Coronários , Transtornos de Estresse Pós-Traumáticos , Doenças Vasculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Angiografia Coronária , Vasos Coronários , Sistema de Registros , Fatores de Risco , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Doenças Vasculares/epidemiologia , Doenças Vasculares/congênitoRESUMO
The aim of this study was to determine how genetic variants contribute to warfarin dosing variability when non-genetic factors are controlled. Thirty healthy subjects were subjected to a warfarin dosing algorithm with daily international normalized ratio (INR) measurements to INR ≥ 2.0, then off warfarin to INR ≤ 1.2. The primary outcome was the cumulative dose required to achieve INR ≥ 2.0 for 2 consecutive days. CYP2C9 (p=0.004) and VKORC1 (p=0.02) variant carriers required lower cumulative doses, and CYP4F2 carriers required higher doses (p=0.04). Subjects with variants in both CYP2C9 and VKORC1 required fewer days to reach INR ≥ 2.0 than wild-type subjects or those with variants in CYP2C9 or VKORC1 (p=0.01). Genetic contribution to dose variability (~62%) was greater than previously reported, suggesting that uncontrolled clinical variables influence the effect of these variants. In conclusion, genotype-guided warfarin-dosing algorithms may rely more on genetic variables in healthier individuals than in patients with clinical confounders.
Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Sistema Enzimático do Citocromo P-450/genética , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Varfarina/farmacocinética , Adulto , Algoritmos , Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2C9 , Sistema Enzimático do Citocromo P-450/metabolismo , Família 4 do Citocromo P450 , Relação Dose-Resposta a Droga , Feminino , Variação Genética , Humanos , Coeficiente Internacional Normatizado , Masculino , Análise Multivariada , Vitamina K Epóxido Redutases/metabolismo , Adulto JovemRESUMO
Raynaud's phenomenon is an exaggerated response to cold stimuli that may be primary or secondary. The diagnosis relies on patient history and physical examination to distinguish RP from other vasomotor dysfunction (e.g. acrocyanosis, pernio, small fiber neuropathy with vasomotor symptoms, and complex regional pain syndrome). Achenbach syndrome, or spontaneous venous hemorrhage, may also be mistaken for RP but is a self-limiting phenomenon. Laboratory evaluation and vascular diagnostic testing may identify SRP causes. Regardless of etiology, treatment includes warming with trigger avoidance, and consideration of vasodilators (eg. calcium channel, alpha-1 blockers). SRP with digital ulceration may require PDE5i, endothelin-1 receptor blockers, and prostanoids. Refractory cases may require pneumatic arterial pumps, botulinum toxin administration, or surgical sympathectomy.
Assuntos
Doença de Raynaud , Humanos , Doença de Raynaud/diagnóstico , Doença de Raynaud/etiologia , Doença de Raynaud/terapiaRESUMO
Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.