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PURPOSE: Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. METHODS: We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. RESULTS: We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. CONCLUSION: Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.
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Aorta/fisiopatologia , Doenças do Tecido Conjuntivo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Marfan/genética , Adulto , Aorta/metabolismo , Biomarcadores/metabolismo , Estudos de Coortes , Tecido Conjuntivo/metabolismo , Tecido Conjuntivo/patologia , Doenças do Tecido Conjuntivo/fisiopatologia , Feminino , Testes Genéticos , Humanos , Masculino , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/fisiopatologiaRESUMO
PURPOSE: To assess whether ECG-gated non-contrast 2D steady-state free precession (SSFP) imaging allows for exact monitoring of aortic diameters in Marfan syndrome (MFS) patients using non-ECG-gated contrast-enhanced 3D magnetic resonance angiography (CE-MRA) and echocardiography for intraindividual comparison. METHODS: Non-ECG-gated CE-MRA and ECG-gated non-contrast SSFP at 1.5 T were prospectively performed in 50 patients. Two readers measured aortic diameters on para-sagittal images identically aligned with the aortic arch at the sinuses of Valsalva, sinotubular junction, ascending/descending aorta and aortic arch. Image quality was assessed on a three-point scale. Aortic root diameters acquired by echocardiography were used as reference. RESULTS: Intra- and interobserver variances were smaller for SSFP at the sinuses of Valsalva (p = 0.002; p = 0.002) and sinotubular junction (p = 0.014; p = 0.043). Image quality was better in SSFP than in CE-MRA at the sinuses of Valsalva (p < 0.0001), sinotubular junction (p < 0.0001) and ascending aorta (p = 0.02). CE-MRA yielded higher diameters than SSFP at the sinuses of Valsalva (mean bias, 2.5 mm; p < 0.0001), and comparison with echocardiography confirmed a higher bias for CE-MRA (7.2 ± 3.4 mm vs. SSFP, 4.7 ± 2.6 mm). CONCLUSION: ECG-gated non-contrast 2D SSFP imaging provides superior image quality with higher validity compared to non-ECG-gated contrast-enhanced 3D imaging. Since CE-MRA requires contrast agents with potential adverse effects, non-contrast SSFP imaging is an appropriate alternative for exact and riskless aortic monitoring of MFS patients.
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Aorta Torácica/patologia , Aneurisma da Aorta Torácica/patologia , Síndrome de Marfan/patologia , Adolescente , Adulto , Idoso , Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/diagnóstico por imagem , Ecocardiografia/métodos , Feminino , Humanos , Imageamento Tridimensional/métodos , Angiografia por Ressonância Magnética/métodos , Masculino , Síndrome de Marfan/diagnóstico por imagem , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores/métodos , Variações Dependentes do Observador , Adulto JovemRESUMO
OBJECTIVES: Mitral valve (MV) regurgitation is a common manifestation in patients with Marfan syndrome (MFS) and is age dependent. Valve pathology shares some features with myxomatous MV disease. Surgical treatment is still being debated and not well characterized in patients with MFS. PATIENTS AND METHODS: We retrospectively evaluated the results of mitral valve repair (MVR) of symptomatic patients with MFS who underwent surgery between January 2004 and April 2011. MFS was diagnosed following the Ghent criteria. MVR was performed in 12 patients. Three patients underwent minimally invasive MVR despite severe thorax deformities. Mean follow-up was 60.1 months (95% CI: 48-72) and was complete. RESULTS: Thirty-day mortality was 0%. One patient died because of arrhythmia 66 months after MVR. Transthoracic echocardiography at last visit showed mild mitral regurgitation in one patient (8.3%) and no mitral regurgitation in the remaining patients (91.7%). CONCLUSION: MVR was associated with excellent survival and a low rate of complications. Transthoracic echocardiography showed good results of the repaired valves even years later. Minimally invasive repairs are feasible even in deformed thoraces, lowering the risk for future aortic surgery. Because of excellent mid-term to long-term results, MVR may also be justified in asymptomatic Marfan patients.
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Implante de Prótese de Valva Cardíaca , Síndrome de Marfan/complicações , Insuficiência da Valva Mitral/cirurgia , Valva Mitral/cirurgia , Adolescente , Adulto , Idoso , Feminino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/instrumentação , Implante de Prótese de Valva Cardíaca/mortalidade , Humanos , Imageamento por Ressonância Magnética , Masculino , Síndrome de Marfan/mortalidade , Pessoa de Meia-Idade , Valva Mitral/fisiopatologia , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/mortalidade , Insuficiência da Valva Mitral/fisiopatologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Toracotomia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The aim of this retrospective cohort study was to investigate associations between depression and anxiety disorder and the risk of COVID-19 severity and mortality in patients treated in large hospitals in Germany. METHODS: This retrospective study was based on anonymized electronic medical data from 50 public healthcare service hospitals across Germany. Multivariable logistic regression models were used to study associations between depression, anxiety and mechanical ventilation and mortality due to COVID adjusted for age, sex, time of COVID-19 diagnosis, and pre-defined co-diagnoses. RESULTS: Of 28,311 patients diagnosed with COVID-19, 1970 (6.9%) had a diagnosis of depression and 369 (1.3%) had a diagnosis of anxiety disorder prior to contracting COVID-19. While multivariable logistic regression models did not indicate any association between depression diagnosis and the risk of mechanical ventilation, depression was associated with a decreased risk of mortality (OR: 0.71; 95% CI: 0.53-0.94). There was no association between anxiety disorders and risk of mortality, but there was a strong positive association between anxiety disorders and the risk of mechanical ventilation (OR: 2.04; 95% CI: 1.35-3.10). CONCLUSION: In the present study, depression and anxiety disorder diagnoses were not associated with increased COVID-19 mortality. Anxiety disorder was strongly associated with an increased risk of mechanical ventilation. Further studies are needed to clarify how depression and anxiety disorders may influence COVID-19 severity and mortality.
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COVID-19 , Humanos , COVID-19/epidemiologia , Estudos Retrospectivos , Depressão/epidemiologia , Depressão/etiologia , Teste para COVID-19 , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/etiologia , Ansiedade/epidemiologia , Ansiedade/etiologia , HospitaisRESUMO
BACKGROUND: Dementia has been identified as a major predictor of mortality associated with COVID-19. OBJECTIVE: The objective of this study was to investigate the association between dementia and mortality in COVID-19 inpatients in Germany across a longer interval during the pandemic. METHODS: This retrospective study was based on anonymized data from 50 hospitals in Germany and included patients with a confirmed COVID-19 diagnosis hospitalized between March 11, 2020 and July, 20, 2022. The main outcome of the study was the association of mortality during inpatient stays with dementia diagnosis, which was studied using multivariable logistic regression adjusted for age, sex, and comorbidities as well as univariate logistic regression for matched pairs. RESULTS: Of 28,311 patients diagnosed with COVID-19, 11.3% had a diagnosis of dementia. Prior to matching, 26.5% of dementia patients and 11.5% of non-dementia patients died; the difference decreased to 26.5% of dementia versus 21.7% of non-dementia patients within the matched pairs (nâ=â3,317). This corresponded to an increase in the risk of death associated with dementia (ORâ=â1.33; 95% CI: 1.16-1.46) in the univariate regression conducted for matched pairs. CONCLUSION: Although dementia was associated with COVID-19 mortality, the association was weaker than in previously published studies. Further studies are needed to better understand whether and how pre-existing neuropsychiatric conditions such as dementia may impact the course and outcome of COVID-19.
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COVID-19 , Demência , Humanos , Teste para COVID-19 , Alemanha/epidemiologia , Hospitalização , Hospitais , Estudos Retrospectivos , MortalidadeRESUMO
INTRODUCTION: SARS-CoV-2 infected patients with cancer have a worse outcome including a significant higher mortality, compared to non-cancer patients. However, limited data are available regarding in-hospital mortality during the Omicron phase of the pandemic. Therefore, the aim of the study was the comparison of mortality in patients with history of cancer and patients with active cancer disease during the different phases of the COVID-19 pandemic, focusing on the current Omicron variant of concern. METHODS: We conducted a multicenter, observational, epidemiological cohort study at 45 hospitals in Germany. Until July 20, 2022, all adult hospitalized SARS-CoV-2 positive patients were included. The primary endpoint was in-hospital mortality regarding cancer status (history of cancer and active cancer disease) and SARS-CoV-2 virus type. RESULTS: From March 11, 2020, to July 20, 2022, a total of 27,490 adult SARS-CoV-2 positive patients were included in the study. 2,578 patients (9.4%) had diagnosis of cancer, of whom 1,065 (41.3%) had history of cancer, whereas 1,513 (58.7%) had active cancer disease. Overall 3,749 out of the total of 27,490 patients (13.6%) died during the hospital stay. Patients with active cancer disease had a significantly higher mortality compared to patients without cancer diagnosis, in both phases of the pandemic (wild-type to Delta: OR 1.940 [1.646-2.285]); Omicron: 2.864 [2.354-3.486]). After adjustment to co-variables, SARS-CoV-2 infected patients with active cancer disease had the highest risk for in-hospital mortality compared to the other groups, in both phases of the pandemic. CONCLUSION: The CORONA Germany study indicates that hospitalized patients with active cancer disease are at high risk of death during a SARS-CoV-2 infection. Mortality of patients with history of cancer improved to nearly the level of non-cancer patients during Omicron phase.
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COVID-19 , Neoplasias , Adulto , Humanos , SARS-CoV-2 , Mortalidade Hospitalar , Pandemias , Estudos de Coortes , Alemanha/epidemiologiaRESUMO
BACKGROUND: With the emergence of new subvariants, the disease severity of Severe Acute Respiratory Syndrome Coronavirus-2 has attenuated. This study aimed to compare the disease severity in patients hospitalized with omicron variant infection to those with influenza infection. METHODS: We compared data from the multicenter observational, prospective, epidemiological "CORONA Germany" (Clinical Outcome and Risk in hospitalized COVID-19 patients) study on patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 to retrospective data on influenza infection cases from November 2016 to August 2022. Severe Acute Respiratory Syndrome Coronavirus-2 cases were classified as wild-type/delta variant before January 2022, or omicron variant from January 2022 onward. The primary outcome was in-hospital mortality, adjusted for age, gender, and comorbidities. RESULTS: The study included 35,806 patients from 53 hospitals in Germany, including 4,916 patients (13.7%) with influenza infection, 16,654 patients (46.5%) with wild-type/delta variant infection, and 14,236 patients (39.8%) with omicron variant infection. In-hospital mortality was highest in patients with wild-type/delta variant infection (16.8%), followed by patients with omicron variant infection (8.4%) and patients with influenza infection (4.7%). In the adjusted analysis, higher age was the strongest predictor for in-hospital mortality (age 80 years vs. age 50 years: OR 4.25, 95% CI 3.10-5.83). Both, patients with wild-type/delta variant infection (OR 3.54, 95% CI 3.02-4.15) and patients with omicron variant infection (OR 1.56, 95% CI 1.32-1.84) had a higher risk for in-hospital mortality than patients with influenza infection. CONCLUSION: After adjusting for age, gender and comorbidities, patients with wild-type/delta variant infection had the highest risk for in-hospital mortality compared to patients with influenza infection. Even for patients with omicron variant infection, the adjusted risk for in-hospital mortality was higher than for patients with influenza infection. The adjusted risk for in-hospital mortality showed a strong age dependency across all virus types and variants. TRIAL REGISTRATION NUMBER: NCT04659187.
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Background: Surgical replacement of the aortic root is the only intervention that can prevent aortic dissection and cardiovascular death in Marfan syndrome (MFS). However, in some individuals, MFS also causes sleep apnea. If sleep apnea predicts cardiovascular death, a new target for predictive, preventive, and personalized medicine (PPPM) may emerge for those individuals with MFS who have sleep apnea. Methods: This is an investigator-initiated study with long-term follow-up data of 105 individuals with MFS. All individuals were screened for sleep apnea regardless of symptoms. Cardiovascular death served as a primary endpoint, and aortic events as a secondary outcome. Results: Sleep apnea with an apnea-hypopnea index (AHI) > 5/h was observed in 21.0% (22/105) with mild sleep apnea in 13% (14/105) and moderate to severe sleep apnea in 7.6% (8/105). After a median follow-up of 7.76 years (interquartile range: 6.84, 8.41), 10% (10/105) had died, with cardiovascular cause of death in 80% (8/10). After adjusting for age and body mass index (BMI), the AHI score emerged as an independent risk factor for cardiovascular death (hazard ratio 1.712, 95% confidence interval [1.061-2.761], p = 0.0276). The secondary outcome of aortic events occurred in 33% (35/105). There was no effect of the AHI score on aortic events after adjusting for age and BMI (hazard ratio 0.965, 95% confidence interval [0.617-1.509]), possibly due to a high number of patients with prior aortic surgery. Interpretation: Sleep apnea is emerging as an independent predictor of cardiovascular death in MFS. It seems mandatory to screen all individuals with MFS for sleep apnea and to include these individuals, with both MFS and sleep apnea, in further studies to evaluate the impact of preventive measures with regard to cardiovascular death. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00291-4.
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OBJECTIVE: Marfan syndrome (MFS) is associated with a substantial risk for ventricular arrhythmia and sudden cardiac death (SCD). We used heart rate turbulence (HRT) and deceleration capacity (DC), to evaluate the risk stratification for these patients. METHODS: We enrolled 102 patients [45 male (44.1 %), age 40.5 ± 14.6 years] with MFS. Blood samples were obtained to determine N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Transthoracic echocardiography studies were conducted to evaluate heart function parameters and a 24-h holter ECG was performed. An analysis of two HRT parameters, turbulence onset (TO) and turbulence slope (TS), and DC was performed. Therefore, optimal cut-off values were calculated. Primary endpoint was the combination of SCD, ventricular arrhythmia and arrhythmogenic syncope. Secondary endpoint was total mortality. RESULTS: During a follow-up of 1145 ± 491 days, 12 (11.7 %) patients reached the primary and 8 (7.8 %) patients the secondary endpoint. Patients reaching the primary were significantly older, had a higher burden of premature ventricular complexes and NT-proBNP levels and lower values of LVEF, DC and HRT TS. Multivariate analysis identified NT-proBNP (HR 1.25, 95 % CI 1.01-1.56, p = .04) and the abnormal HRT (abnormal TS and/or TO (HR 7.04, 95 % CI 1.07-46.27, p = .04) as independent risk predictor of arrhythmogenic events. CONCLUSION: Patients with Marfan syndrome are at risk for severe ventricular arrhythmias and SCD. Abnormal HRT parameters and NT-proBNP values are independent risk factors for arrhythmogenic events and SCD. The assessment of these tools may help predicting SCD patients with MFS.
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Arritmias Cardíacas/epidemiologia , Morte Súbita Cardíaca/epidemiologia , Frequência Cardíaca/fisiologia , Síndrome de Marfan/complicações , Adulto , Fatores Etários , Arritmias Cardíacas/etiologia , Desaceleração , Ecocardiografia/métodos , Eletrocardiografia Ambulatorial/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Complexos Ventriculares Prematuros/epidemiologia , Complexos Ventriculares Prematuros/etiologiaRESUMO
Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent-1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%-53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential.
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A number of autosomal dominantly inherited disorders, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), are associated with predisposition to thoracic aortic aneurysms and dissections (TAADs). In the majority of cases, mutations in genes encoding components of the transforming growth factor-ß (TGF-ß) signaling pathway, such as FBN1, TGFBR1, TGFBR2 and SMAD3, underlie the disease. Recently, a familial syndromic form of TAAD with other clinical features that overlap the MFS-LDS spectrum has been described to be caused by heterozygous loss-of-function mutations in TGFB2, encoding the TGF-ß2 ligand of TGF-ß serine/threonine kinase receptors (TGFBRs). We analyzed the TGFB2 gene by sequencing in a cohort of 88 individuals with a Marfan-like phenotype and/or TAAD, who did not have mutations in known genes causing thoracic aortic disease. We identified the novel heterozygous c.1165dupA mutation in exon 7 of TGFB2 in three members of a family, a 51-year-old male, his brother and nephew with aortic aneurysms, cervical arterial tortuosity and/or skeletal abnormalities as well as craniofacial dysmorphisms. The 1-bp duplication causes a frameshift leading to a stable transcript with a premature stop codon after seven TGF-ß2-unrelated amino acids (p.Ser389Lysfs*8). As the resulting protein is unlikely functional and by considering data from the literature, we support the notion that functional haploinsufficiency for TGF-ß2 predisposes to thoracic aortic disease. Taken together, TGFB2 is a rarely mutated gene in patients with syndromic TAAD, and the clinical features of our TGFB2 mutation-positive individuals fit in the scheme of LDS, rather than MFS-related disorders.
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Aneurisma da Aorta Torácica/genética , Família , Haploinsuficiência , Fator de Crescimento Transformador beta2/genética , Adolescente , Adulto , Aneurisma da Aorta Torácica/patologia , Feminino , Humanos , Masculino , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUNDS: The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder caused by mutations in the transforming growth factor ß (TGF-ß) receptors TGFBR1 or TGFBR2. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. In order to gain further insight into the pathophysiology of the disorder, we investigated circulating outgrowth endothelial cells (OEC) from the peripheral blood of LDS patients from a cohort of 23 patients including 6 patients with novel TGF-ß receptor mutations. METHODS AND RESULTS: We performed gene expression profiling of OECs using microarray analysis followed by quantitative PCR for verification of gene expression. Compared to OECs of age- and sex-matched healthy controls, OECs isolated from three LDS patients displayed altered expression of several genes belonging to the TGF-ß pathway, especially those affecting bone morphogenic protein (BMP) signalling including BMP2, BMP4 and BMPR1A. Gene expression of BMP antagonist Gremlin-1 (GREM1) showed the most prominent up-regulation. This increase was confirmed at the protein level by immunoblotting of LDS-OECs. In immunohistochemistry, abundant Gremlin-1 protein expression could be verified in endothelial cells as well as smooth muscle cells within the arterial media. Furthermore, Gremlin-1 plasma levels of LDS patients were significantly elevated compared to healthy control subjects. CONCLUSIONS: These findings open new avenues in the understanding of the pathogenesis of Loeys-Dietz syndrome and the development of new diagnostic serological methods for early disease detection.
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Células Endoteliais/patologia , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Síndrome de Loeys-Dietz/fisiopatologia , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adulto , Aorta/metabolismo , Aorta/patologia , Proteína Morfogenética Óssea 2/biossíntese , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 4/biossíntese , Proteína Morfogenética Óssea 4/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/biossíntese , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Proliferação de Células/genética , Diagnóstico Precoce , Feminino , Perfilação da Expressão Gênica , Humanos , Proteínas de Ligação a TGF-beta Latente/biossíntese , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/genética , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , RNA Mensageiro/biossíntese , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Adulto JovemRESUMO
BACKGROUND: Total serum transforming growth factor-beta 1 (tsTGF-ß1) is increased in patients with Marfan syndrome (MFS), but it has not been assessed in thoracic aortic aneurysm and dissection (TAAD), Loeys-Dietz syndrome (LDS), and bicuspid aortic valve disease (BAVD). HYPOTHESIS: tsTGF-ß1 is increased in genetic aortic syndromes including TAAD, LDS, MFS, and BAVD. METHODS: We measured tsTGF-ß1 and performed sequencing of the genes FBN1, TGFBR1, and TGFBR2 in 317 consecutive patients with suspected or known genetic aortic syndrome (167 men, 150 women; mean age 43 ± 14 years). TAAD was diagnosed in 20, LDS in 20, MFS in 128, and BAVD in 30 patients, and genetic aortic syndrome was excluded in 119 patients. RESULTS: Elevated tsTGF-ß1 levels were associated with causative gene mutations (P = 0.008), genetic aortic syndrome (P = 0.009), and sporadic occurrence of genetic aortic syndrome (P = 0.048), whereas only genetic aortic syndrome qualified as an independent predictor of tsTGF-ß1 (P = 0.001). The tsTGF-ß1 levels were elevated in FBN1 and NOTCH1 mutations vs patients without mutations (both P = 0.004), and in NOTCH1 mutations vs ACTA2/MYH11 mutations (P = 0.015). Similarly, tsTGF-ß1 levels were elevated in MFS (P = 0.003) and in BAVD (P = 0.006) vs patients without genetic aortic syndrome. In contrast to specific clinical features of MFS, FBN1 in-frame mutations (P = 0.019) were associated with increased tsTGF-ß1 levels. CONCLUSIONS: tsTGF-ß1 is elevated in the entire spectrum of genetic aortic syndromes. However, gradual differences in the increases of tsTGF-ß1 levels may mirror different degrees of alteration of tsTGF-ß1 signaling in different genetic aortic syndromes.
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Aneurisma da Aorta Torácica/sangue , Valva Aórtica/anormalidades , Doenças das Valvas Cardíacas/sangue , Síndrome de Loeys-Dietz/sangue , Síndrome de Marfan/sangue , Fator de Crescimento Transformador beta1/sangue , Adolescente , Adulto , Idoso , Aneurisma da Aorta Torácica/genética , Doença da Válvula Aórtica Bicúspide , Feminino , Fibrilina-1 , Fibrilinas , Doenças das Valvas Cardíacas/genética , Humanos , Síndrome de Loeys-Dietz/genética , Masculino , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Mutação , Receptor Notch1/genética , Adulto JovemRESUMO
BACKGROUND: Echocardiographic upper normal limits of both main pulmonary artery (MPA) diameters (MPA-d) and ratio of MPA to aortic root diameter (MPA-r) are not defined in healthy adults. Accordingly, frequency of MPA dilatation based on echocardiography remains to be assessed in adults with Marfan syndrome (MFS). METHODS: We enrolled 123 normal adults (72 men, 52 women aged 42 ± 14 years) and 98 patients with MFS (42 men, 56 women aged 39 ± 14 years) in a retrospective cross-sectional observational controlled study in four tertiary care centers. We defined outcome measures including upper normal limits of MPA-d and MPA-r as 95 quantile of normal persons, MPA dilatation as diameters > upper normal limits, MPA aneurysm as diameters >4 cm, and indication for surgery as MPA diameters >6 cm. RESULTS: MPA diameters revealed normal distribution without correlation to age, sex, body weight, body height, body mass index and body surface area. The upper normal limit was 2.6 cm (95% confidence interval (CI) =2.44-2.76 cm) for MPA-d, and 1.05 (95% CI = .86-1.24) for MPA-r. MPA dilatation presented in 6 normal persons (4.9%) and in 68 MFS patients (69.4%; P < .001), MPA aneurysm presented only in MFS (15 patients; 15.3%; P < .001), and no patient required surgery. Mean MPA-r were increased in MFS (P < .001), but ratios >1.05 were equally frequent in 7 normal persons (5%) and in 8 MFS patients (10.5%; P = .161). MPA-r related to aortic root diameters (P = .042), reduced left ventricular ejection fraction (P = .006), and increased pulmonary artery systolic pressures (P = .040). No clinical manifestations of MFS and no FBN1 mutation characteristics related to MPA diameters. CONCLUSIONS: We established 2.6 cm for MPA-d and 1.05 for MPA-r as upper normal limits. MFS exhibits a high prevalence of MPA dilatation and aneurysm. However, patients may require MPA surgery only in scarce circumstances, most likely because formation of marked MPA aneurysm may require LV dysfunction and increased PASP.
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Aneurisma Aórtico/diagnóstico por imagem , Síndrome de Marfan/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Vasodilatação , Adolescente , Adulto , Idoso , Aneurisma Aórtico/fisiopatologia , Estudos Transversais , Ecocardiografia/normas , Feminino , Humanos , Masculino , Síndrome de Marfan/fisiopatologia , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Valores de Referência , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: Our purpose was to evaluate intraindividually the performance of contrast-enhanced magnetic resonance angiography (MRA) and non-contrast MRA for aortic root diameter measurements and to compare the results with routinely performed echocardiography in patients with suspected Marfan syndrome. METHODS AND MATERIALS: Aortic roots were examined prospectively in 51 consecutive patients with suspected Marfan syndrome by using contrast-enhanced MRA and non-contrast MRA at 1.5 T. Two readers independently measured aortic root diameters at the annulus, sinuses of Valsalva and sinutubular junction in both data sets and compared results with echocardiographic data. Intraclass correlation coefficient, Pearson correlation coefficient, Bland-Altman, and two-sided t-test were used to assess agreement between observers and methods. RESULTS: 38 (74.5%) of the 51 patients (25 female, 26 male; mean age 37.1 ± 13.7 years) had Marfan syndrome. Both, contrast-enhanced MRA and non-contrast MRA measurements of the sinuses of Valsalva revealed a strong correlation with echocardiography (r=0.850 and r=0.893, respectively). Intraclass correlation was markedly better for non-enhanced MRA (r=0.904) when compared to contrast-enhanced MRA (r=0.690). Image quality (p<0.001) as well as interobserver agreement (p<0.0042) of measurements of the sinuses of Valsalva was significantly better for non-enhanced MRA than for contrast-enhanced MRA. CONCLUSION: Non-contrast MRA was more reliable and more valid than contrast-enhanced MRA for assessment of aortic root dimensions in patients with suspected Marfan syndrome. Therefore contrast agents can be omitted for establishing the diagnosis of aortic involvement in Marfan syndrome.
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Aortografia/normas , Meios de Contraste , Ecocardiografia/normas , Angiografia por Ressonância Magnética/normas , Síndrome de Marfan/diagnóstico por imagem , Adulto , Feminino , Humanos , Masculino , Síndrome de Marfan/epidemiologia , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Marfan syndrome (MFS) is a variable, autosomal-dominant disorder of the connective tissue. In MFS serious ventricular arrhythmias and sudden cardiac death (SCD) can occur. The aim of this prospective study was to reveal underlying risk factors and to prospectively investigate the association between MFS and SCD in a long-term follow-up. METHODS: 77 patients with MFS were included. At baseline serum N-terminal pro-brain natriuretic peptide (NT-proBNP), transthoracic echocardiogram, 12-lead resting ECG, signal-averaged ECG (SAECG) and a 24-h Holter ECG with time- and frequency domain analyses were performed. The primary composite endpoint was defined as SCD, ventricular tachycardia (VT), ventricular fibrillation (VF) or arrhythmogenic syncope. RESULTS: The median follow-up (FU) time was 868 days. Among all risk stratification parameters, NT-proBNP remained the exclusive predictor (hazard ratio [HR]: 2.34, 95% confidence interval [CI]: 1.1 to 4.62, p=0.01) for the composite endpoint. With an optimal cut-off point at 214.3 pg/ml NT-proBNP predicted the composite primary endpoint accurately (AUC 0.936, p=0.00046, sensitivity 100%, specificity 79.0%). During FU, seven patients of Group 2 (NT-proBNP ≥ 214.3 pg/ml) reached the composite endpoint and 2 of these patients died due to SCD. In five patients, sustained VT was documented. All patients with a NT-proBNP<214.3 pg/ml (Group 1) experienced no events. Group 2 patients had a significantly higher risk of experiencing the composite endpoint (logrank-test, p<0.001). CONCLUSIONS: In contrast to non-invasive electrocardiographic parameter, NT-proBNP independently predicts adverse arrhythmogenic events in patients with MFS.
Assuntos
Morte Súbita Cardíaca/epidemiologia , Síndrome de Marfan/diagnóstico por imagem , Síndrome de Marfan/mortalidade , Adulto , Feminino , Seguimentos , Humanos , Masculino , Síndrome de Marfan/fisiopatologia , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Ultrassonografia , Adulto JovemRESUMO
BACKGROUND: Until today, FBN1 gene mutation characteristics were not compared with clinical features for the prediction of mitral valve disease progression. METHODS: Therefore, we conducted a study of 116 patients (53 men, 63 women aged 33 ± 15 years) with a causative FBN1 gene mutation and ≤ moderate mitral valve regurgitation at baseline. RESULTS: During 7.4 ± 6.8 years 30 patients developed progression of mitral valve regurgitation ≥ 1 grade (primary endpoint), and 26 patients required mitral valve surgery (secondary endpoint). Cox regression analysis identified an association of atrial fibrillation (hazard ratio (HR)=2.703; 95% confidence interval (CI) 1.013-7.211; P=.047), left ventricular ejection fraction (HR=.970; 95%CI .944-.997; P=.032), indexed end-diastolic left ventricular diameter (HR=15.165; 95%CI 4.498-51.128; P<.001), indexed left atrial diameter (HR=1.107; 95%CI 1.045-1.173; P=.001), tricuspid valve prolapse (HR=2.599; 95%CI 1.243-5.437; P=.011), posterior leaflet prolapse (HR=1.075; 95%CI 1.023-1.130; P=.009), and posterior leaflet thickening (HR=3.368; 95%CI 1.265-8.968; P=.015) with progression of mitral valve disease, whereas none of the FBN1 gene mutation characteristics were associated with progression of mitral valve disease. However, Cox regression analysis identified a marginal relationship of FBN1 gene mutations located both in a transforming-growth-factor beta-binding protein-like (TGFb-BP) domain (HR=3.453; 95%CI .982-12.143; P=.053), and in the calcium-binding epidermal growth factor-like (cbEGF) domain (HR=2.909; 95%CI .957-8.848; P=.060) with mitral valve surgery, a finding that was corroborated by Kaplan-Meier analysis (P=.014; and P=.041, respectively). CONCLUSION: Clinical features were better predictors of mitral valve disease progression than FBN1 gene mutation characteristics.
Assuntos
Progressão da Doença , Proteínas dos Microfilamentos/genética , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/genética , Mutação/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/patologia , Adulto JovemRESUMO
BACKGROUND: Marfan syndrome is associated with ventricular arrhythmia but risk factors including FBN1 mutation characteristics require elucidation. METHODS AND RESULTS: We performed an observational cohort study of 80 consecutive adults (30 men, 50 women aged 42±15 years) with Marfan syndrome caused by FBN1 mutations. We assessed ventricular arrhythmia on baseline ambulatory electrocardiography as >10 premature ventricular complexes per hour (>10 PVC/h), as ventricular couplets (Couplet), or as non-sustained ventricular tachycardia (nsVT), and during 31±18 months of follow-up as ventricular tachycardia (VT) events (VTE) such as sudden cardiac death (SCD), and sustained ventricular tachycardia (sVT). We identified >10 PVC/h in 28 (35%), Couplet/nsVT in 32 (40%), and VTE in 6 patients (8%), including 3 with SCD (4%). PVC>10/h, Couplet/nsVT, and VTE exhibited increased N-terminal pro-brain natriuretic peptide serum levels(P<.001). All arrhythmias related to increased NT-proBNP (P<.001), where PVC>10/h and Couplet/nsVT also related to increased indexed end-systolic LV diameters (Pâ=â.024 and Pâ=â.020), to moderate mitral valve regurgitation (Pâ=â.018 and Pâ=â.003), and to prolonged QTc intervals (Pâ=â.001 and Pâ=â.006), respectively. Moreover, VTE related to mutations in exons 24-32 (Pâ=â.021). Kaplan-Meier analysis corroborated an association of VTE with increased NT-proBNP (P<.001) and with mutations in exons 24-32 (P<.001). CONCLUSIONS: Marfan syndrome with causative FBN1 mutations is associated with an increased risk for arrhythmia, and affected persons may require life-long monitoring. Ventricular arrhythmia on electrocardiography, signs of myocardial dysfunction and mutations in exons 24-32 may be risk factors of VTE.
Assuntos
Arritmias Cardíacas/genética , Síndrome de Marfan/metabolismo , Síndrome de Marfan/patologia , Proteínas dos Microfilamentos/genética , Adulto , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Morte Súbita Cardíaca/patologia , Eletrocardiografia Ambulatorial , Éxons/genética , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Estimativa de Kaplan-Meier , Masculino , Síndrome de Marfan/genética , Pessoa de Meia-Idade , Mutação , Peptídeo Natriurético Encefálico/genética , Fragmentos de Peptídeos/genética , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/patologiaRESUMO
BACKGROUND: The relationship of aortic valve dysfunction and ascending aortic aneurysm is unclear in adults with bicuspid aortic valve disease. METHODS: We retrospectively studied 134 consecutive out-patients (98 men, 36 women aged 43 ± 18 years) with bicuspid aortic valve disease. To investigate the relationship of ascending aortic aneurysm and aortic valve dysfunction we exclusively considered severe pathologies that required treatment by surgical or percutaneous intervention. RESULTS: Of 134 patients, 39 had aortic valve dysfunction without concomitant ascending aortic aneurysm which had been treated previously with isolated valve surgery or percutaneous valvuloplasty comprising 25 patients with aortic stenosis (19%) and 14 patients with aortic regurgitation (10%). Conversely, 26 patients had ascending aortic aneurysm which had been treated previously with aortic surgery (19%). Of these, ascending aortic aneurysm was associated with severe aortic stenosis in 13 patients and with severe aortic regurgitation in 7 patients, whereas aneurysm was unrelated to severe aortic valve dysfunction in the remaining 6 patients including 2 without any degree of aortic valve dysfunction. The maximal aortic diameters were similar at the time of aortic surgery irrespective of presence of severe aortic valve dysfunction (P=.527). Other characteristics of patients with ascending aortic aneurysm were also similar irrespective of presence or type of aortic valve dysfunction. CONCLUSION: The majority of patients with bicuspid aortic valve disease exhibit ascending aortic aneurysm in conjunction with severe aortic valve dysfunction. However, in our study 6 of 134 (5%) of persons with bicuspid aortic valve disease developed ascending aortic aneurysm without aortic valve dysfunction.