Arrhythmia and impaired myocardial function in heritable thoracic aortic disease: An international retrospective cohort study.

BACKGROUND: Heritable thoracic aortic diseases (HTAD), typically entailing aortic complications, can be caused by pathogenic variants or likely pathogenic variants (PV/LPVs) in several genes, including fibrillin1 (FBN1), Actin Alpha2 (ACTA2) and genes encoding components of the transforming growth factor (TGF)-ß signaling pathway. In addition to aortic complications, non-aortic cardiac disease such as impaired myocardial function and/or arrhythmia have been increasingly reported, mainly in Marfan syndrome with underlying FBN1 PV/LPVs and are acknowledged as additional causes of morbidity and mortality. The prevalence of these manifestations in the various HTAD entities is largely unknown. METHODS: This international multicentre retrospective study collected data on patients with HTAD presenting non-aortic cardiac disease. A total of 9 centers from 7 different countries participated. Patients 12 years or older carrying a PV/LPV in one of the following genes: FBN1, TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3 and ACTA2 were screened. Non-aortic cardiac disease included impaired myocardial function and/or arrhythmia. Impaired myocardial function was defined as (a)symptomatic reduced ejection fraction (EF<50%). Arrhythmias included atrial fibrillation (AF), atrial flutter (AFL), ventricular tachycardia (VT), ventricular fibrillation (VF) and (aborted) sudden cardiac death (presumed arrhythmogenic) (SCD). RESULTS: Medical records of 3219 patients with HTAD were screened (2761, 385 and 73 carrying a PV/LPV in FBN1, in a TGF-ß signaling gene and in ACTA2 respectively). Non-aortic cardiac disease was reported 142 times in 101 patients (3.1%) (age 37 [range 12-77] years, 39% female): 88 patients carrying an FBN1 PV/LPV and 13 carrying a PV/LPV in one of the TGF-ß signaling genes. Neither impaired myocardial function nor arrhythmia was reported in screened patients carrying a PV/LPV in ACTA2. Among the 142 reported non-aortic cardiac diseases, 68 (48%) were impaired myocardial function, 47 (33%) were AF/AFL and 27 (19%) were VT/VF/SCD. Among the patients with non-aortic cardiac disease, prior cardiac surgery was noted in 80% and severe valvular disease (valvular surgery or severe valvular regurgitation) in 58%, while 18% of the patients developed non-aortic cardiac disease in the absence of any of the latter. CONCLUSIONS: In patients with HTAD, arrhythmia and impaired myocardial function was reported in patients with PV/LPVs in FBN1 and in the TGF-ß signaling genes and not in patients harboring PV/LPVs in ACTA2. Though infrequent, non-aortic cardiac disease should be acknowledged as potentially severe, also occurring in young patients with no underlying significant valvular or aortic disease.

Marfan Syndrome Versus Bicuspid Aortic Valve Disease: Comparative Analysis of Obstetric Outcome and Pregnancy-Associated Immediate and Long-Term Aortic Complications.

Pregnancy poses a threat to women with aortopathy. Conclusive data on the obstetric and aortic outcome in this risk collective, especially when it comes to aortic complications in the long term, are still missing. This study offers a comparative analysis of pregnancy-associated outcome in 113 consecutive women with Marfan syndrome or bicuspid aortic valve disease, including 46 ever-pregnant and 37 never-pregnant women with Marfan syndrome, and 23 ever-pregnant and 7 never-pregnant females with bicuspid aortic valve disease. The overall obstetric outcome was comparable between ever-pregnant women with Marfan syndrome and with bicuspid aortic valve disease (p = 0.112). Pregnancy-associated aortic dissection occurred in two women with Marfan syndrome (3%) during a total of 62 completed pregnancies, whereas no single case of aortic event occurred in women with bicuspid aortic valve disease during a total of 36 completed pregnancies (p = 0.530). In the long-term follow-up, aortic dissection occurred in 21% of ever-pregnant women with Marfan syndrome, but in none of the women with bicuspid aortic valve disease (p = 0.022). Proximal aortic surgery was performed with similar frequency in ever-pregnant women with Marfan syndrome and with bicuspid aortic valve disease in the long term (p = 0.252). However, ever-pregnant women with Marfan syndrome were younger when surgery was performed (44 ± 9 vs. 59 ± 7 years; p = 0.041). In Marfan syndrome, long-term growth of the aorta was comparable between ever-pregnant and never-pregnant women. Pregnancy thus exhibited an increased immediate aortic risk only in women with Marfan syndrome, but not in women with bicuspid aortic valve disease. Previous pregnancy did not relate to an increased long-term risk of adverse aortic events in women with Marfan syndrome or with bicuspid aortic valve disease.

Features of Marfan syndrome not listed in the Ghent nosology - the dark side of the disease.

Introduction: The revised Ghent nosology presents the classical features of Marfan syndrome. However, behind its familiar face, Marfan syndrome hides less well-known features.Areas covered: The German Marfan Organization listed unusual symptoms and clinical experts reviewed the literature on clinical features of Marfan syndrome not listed in the Ghent nosology. Thereby we identified the following features: (1) bicuspid aortic valve, mitral valve prolapse, pulmonary valve prolapse, tricuspid valve prolapse, (2) heart failure and cardiomyopathy, (3) supraventricular arrhythmia, ventricular arrhythmia, and abnormal repolarization, (4) spontaneous coronary artery dissection, anomalous coronary arteries, and atherosclerotic coronary artery disease, tortuosity-, aneurysm-, and dissection of large and medium-sized arteries, (5) restrictive lung disease, parenchymal lung disease, and airway disorders, (6) obstructive- and central sleep apnea, (7) liver and kidney cysts, biliary tract disease, diaphragmatic hernia, and adiposity, (8) premature labor, and urinary incontinence, (9) myopathy, reduced bone mineral density, and craniofacial manifestations, (10) atrophic scars, (11) caries, and craniomandibular dysfunction, (12) headache from migraine and spontaneous cerebrospinal fluid leakage, (13) cognitive dysfunction, schizophrenia, depression, fatigue, and pain, (14) and activated fibrinolysis, thrombin, platelets, acquired von Willebrand disease, and platelet dysfunction.Expert commentary: Future research, nosologies, and guidelines may consider less well-known features of Marfan syndrome.

Case-matched Comparison of Cardiovascular Outcome in Loeys-Dietz Syndrome versus Marfan Syndrome.

Background: Pathogenic variants in TGFBR1, TGFBR2 and SMAD3 genes cause Loeys-Dietz syndrome, and pathogenic variants in FBN1 cause Marfan syndrome. Despite their similar phenotypes, both syndromes may have different cardiovascular outcomes. Methods: Three expert centers performed a case-matched comparison of cardiovascular outcomes. The Loeys-Dietz group comprised 43 men and 40 women with a mean age of 34 ± 18 years. Twenty-six individuals had pathogenic variants in TGFBR1, 40 in TGFBR2, and 17 in SMAD3. For case-matched comparison we used 83 age and sex-frequency matched individuals with Marfan syndrome. Results: In Loeys-Dietz compared to Marfan syndrome, a patent ductus arteriosus (p = 0.014) was more prevalent, the craniofacial score was higher (p < 0.001), the systemic score lower (p < 0.001), and mitral valve prolapse less frequent (p = 0.003). Mean survival for Loeys-Dietz and Marfan syndrome was similar (75 ± 3 versus 73 ± 2 years; p = 0.811). Cardiovascular outcome was comparable between Loeys-Dietz and Marfan syndrome, including mean freedom from proximal aortic surgery (53 ± 4 versus 48 ± 3 years; p = 0.589), distal aortic repair (72 ± 3 versus 67 ± 2 years; p = 0.777), mitral valve surgery (75 ± 4 versus 65 ± 3 years; p = 0.108), and reintervention (20 ± 3 versus 14 ± 2 years; p = 0.112). In Loeys-Dietz syndrome, lower age at initial presentation predicted proximal aortic surgery (HR = 0.748; p < 0.001), where receiver operating characteristic analysis identified ≤33.5 years with increased risk. In addition, increased aortic sinus diameters (HR = 6.502; p = 0.001), and higher systemic score points at least marginally (HR = 1.175; p = 0.065) related to proximal aortic surgery in Loeys-Dietz syndrome. Conclusions: Cardiovascular outcome of Loeys-Dietz syndrome was comparable to Marfan syndrome, but the severity of systemic manifestations was a predictor of proximal aortic surgery.

[The value of routine second-look endoscopy in the management of acute gastroduodenal ulcer bleeding]. / A tervezett ellenôrzô endoszkópia értéke az akut gastroduodenalis fekélyvérzés ellátásában.

UNLABELLED: The role of routine second-look endoscopy in the management of patients with acute peptic ulcer bleeding is controversial. A more precise identification of higher risk patient group, based on both clinical and endoscopic criteria, is needed to determine whether there are high-risk patients who may benefit from this management strategy. AIM: Or aim was to find out whether scheduled second-look endoscopy has any beneficial effect in the clinical outcome. METHODS: Both endoscopic and clinical data were analyzed in 274 acute gastroduodenal ulcer bleeding patients. The need for repeated endoscopic haemostatic intervention was used as a measure to evaluate the potential beneficial effect of the second look endoscopy. Patients were categorized according to the Forrest classification detected during the emergency endoscopy. RESULTS: In the subgroup of actively bleeding patients (Forrest Ia, Ib) a second endoscopic haemostasis was performed in 23.8% of cases. In the patient subgroup with visible vessel ulcers (Forrest IIa) and in those with adherent clot covered ulcers (Forrest IIb) the needs for a repeated haemostasis were 13.0% and 13.3% respectively. Despite the not statistically significant differences, remarkable clinical impact was noted favoring scheduled second look endoscopy in patients with initially active ulcer bleeding. CONCLUSION: In the light of the retrospective study results it may be concluded that the scheduled second look endoscopy strategy offers a beneficial clinical outcome for selected patients estimated to be a very high risk of re-bleeding following the initial endoscopic therapy for active bleeding.

Characterization of regional and local deposition of inhaled aerosol drugs in the respiratory system by computational fluid and particle dynamics methods.

The present work describes the local deposition patterns of therapeutic aerosols in the oropharyngeal airways, healthy and diseased bronchi and alveoli using computational fluid and particle dynamics techniques. A user-enhanced computational fluid dynamics commercial finite- volume software package was used to compute airflow fields, deposition efficiencies, and deposition patterns of therapeutic aerosols along the airways. Adequate numerical meshes, generated in different airway sections, enabled us to more precisely define trajectories and local deposition patterns of inhaled particles than before. Deposition patterns show a high degree of heterogeneity of deposition along the airways, being more uniform for nanoparticles compared to micro-particles in the whole respiratory system at all inspiratory flow rates. Extrathoracic and tracheobronchial deposition fractions of nanoparticles decrease with increasing flow rates. However, vice versa happens to the micron-size particles, that is, the deposition fraction is higher at high flow rates. Both airway constrictions and the presence of tumors significantly increased the deposition efficiencies compared to the deposition efficiencies in healthy airways by a factor ranging from 1.2 to 4.4. In alveoli, the deposition patterns are strongly influenced by particle size and direction of gravity. This study demonstrated that numerical modeling can be a powerful tool in the aerosol drug delivery optimization. Present results may be integrated in future aerosol drug therapy protocols.

Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling.

Angiotensin II infusion causes endothelial dysfunction by increasing NAD(P)H oxidase-mediated vascular superoxide production. However, it remains to be elucidated how in vivo angiotensin II treatment may alter the expression of the gp91(phox) isoforms and the endothelial nitric oxide synthase (NOS III) and subsequent signaling events and whether, in addition to the NAD(P)H oxidase, NOS III contributes to vascular superoxide formation. We therefore studied the influence of in vivo angiotensin II treatment (7 days) in rats on endothelial function and on the expression of the NAD(P)H oxidase subunits p22(phox), nox1, nox4, and gp91(phox) and NOS III. Further analysis included the expression of NO-downstream targets, the soluble guanylyl cyclase (sGC), the cGMP-dependent protein kinase I (cGK-I), and the expression and phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser239 (P-VASP). Angiotensin II caused endothelial dysfunction and increased vascular superoxide. Likewise, we found an increase in vascular protein kinase C (PKC) activity, in the expression of nox1 (6- to 7-fold), gp91(phox) (3-fold), p22(phox) (3-fold), NOS III mRNA, and protein. NOS-inhibition with N(G)-nitro-L-arginine decreased superoxide in vessels from angiotensin II-treated animals, compatible with NOS-uncoupling. Vascular NO assessed with electron paramagnetic resonance was markedly reduced. Likewise, a decrease in sGC-expression and P-VASP levels was found. In vivo PKC-inhibition with chelerythrine reduced angiotensin II-induced superoxide production and markedly inhibited upregulation of NAD(P)H oxidase subunits. We therefore conclude that angiotensin II-induced increases in the activity and the expression of NAD(P)H oxidase are at least in part PKC-dependent. NADPH oxidase-induced superoxide production may trigger NOS III uncoupling, leading to impaired NO/cGMP signaling and to endothelial dysfunction in this animal model. The full text of this article is available at http://www.circresaha.org.

Superoxide production and expression of nox family proteins in human atherosclerosis.

BACKGROUND: NAD(P)H oxidases are important sources of superoxide in the vasculature, the activity of which is associated with risk factors for human atherosclerosis. This study was designed to investigate the localization of superoxide production and the expression of the Nox family of NAD(P)H oxidase proteins (gp91phox, Nox1, and Nox4) in nonatherosclerotic and atherosclerotic human coronary arteries. METHODS AND RESULTS: In coronary artery segments from explanted human hearts, we examined intracellular superoxide production with dihydroethidium. In nonatherosclerotic coronary arteries, superoxide was present homogenously throughout the intima, media, and adventitia. In atherosclerotic arteries, there was an additional intense area of superoxide in the plaque shoulder, which is rich in macrophages and alpha-actin-positive cells. p22phox colocalized with gp91phox mainly in macrophages, whereas Nox4 was found only in nonphagocytic vascular cells. Expression of gp91phox and p22phox mRNA was associated with the severity of atherosclerosis. gp91phox correlated with the plaque macrophage content, whereas Nox4 correlated with the content of alpha-actin-positive cells. Nox1 expression was low both in human coronary arteries and isolated vascular cells. CONCLUSIONS: Several Nox proteins, including gp91phox and Nox4, may contribute to increased intracellular oxidative stress in human coronary atherosclerosis in a cell-specific manner and thus may be involved in the genesis and progression of human coronary atherosclerotic disease.

Upregulation of Nox-based NAD(P)H oxidases in restenosis after carotid injury.

Restenosis, a frequent complication of coronary angioplasty, is associated with increased superoxide (O2*(-)) production. Although the molecular identity of the responsible oxidase is unclear, an NAD(P)H oxidase appears to be involved. In smooth muscle, p22phox and 2 homologues of gp91phox, nox1 and nox4, are expressed, whereas fibroblasts contain gp91phox. To begin investigating the possibility that these oxidase components might contribute to the increased O2*(-) that accompanies neointimal formation, we measured their expression after balloon injury of the rat carotid artery. The increase in O2*(-) production 3 to 15 days after surgery was not due to inflammatory cell infiltration but appeared to be derived from medial and neointimal smooth muscle cells and adventitial fibroblasts. Nox1 and p22phox mRNAs were increased 2.7- and 3.6-fold, respectively, at day 3 after injury and remained elevated for 15 days. gp91Phox was increased 7 to 15 days after injury, and nox4 expression was increased 2-fold, but only at day 15 after surgery. These results confirm and extend our previous in vitro data and suggest that in the vasculature, the nox-based NAD(P)H oxidases serve different functions. This dynamic regulation of oxidase components may be critical to smooth muscle phenotypic modulation in restenosis and atherosclerosis.