Arrhythmia and cardiomyopathy in Heritable Thoracic Aortic Disease: an international retrospective cohort study

Abstract Background Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS) and related heritable thoracic aortic diseases (HTAD) are well-known for their aortic complications. Myocardial dysfunction and arrhythmia are less known in this setting but have been increasingly reported as additional causes of morbidity and mortality. Related to the rarity of the disorders, data on the prevalence of these features and clinical characteristics of the patients are difficult to obtain, calling for a multicentre initiative. Purpose To study the prevalence of myocardial dysfunction and arrhythmia in patients with HTAD and describe their clinical and genetic profile. Methods Nine centres from seven countries participated in this multicentre retrospective study. Medical records of patients 12 years or older carrying a (likely) pathogenic variant in the FBN1 gene, LDS genes (TGFBR1, TGFBR2, TGFB2, TGFB3 and SMAD3) or ACTA2 gene were screened. Patients presenting myocardial dysfunction and/or arrhythmia were identified, and clinical and genetic data were collected. Myocardial dysfunction included (a)symptomatic reduced ejection fraction (EF <50% – HFrEF) or symptomatic preserved EF (HFpEF), as documented in the patient charts. Arrhythmias included atrial fibrillation or flutter (AF/AFL), ventricular tachycardia (VT), ventricular fibrillation (VF) and (aborted) sudden cardiac death (SCD) (presumed arrhythmogenic). Results In total, 3219 patients with HTAD were screened: 2761 with a variant in FBN1, 385 with a variant in one of the LDS genes (TGFBR1, TGFBR2, TGFB2, TGFB3 and SMAD3) and 73 carrying a variant in ACTA2. Myocardial dysfunction and arrhythmia were not reported in patients carrying an ACTA2 variant. Myocardial dysfunction was observed in patients with a variant in FBN1 and the LDS genes, without significant differences in prevalence (2.3% vs. 1.8%, p=0.563). Patients with a variant in the LDS genes presenting myocardial dysfunction were younger than patients carrying a variant in FBN1 (25±11 years vs. 39±17 years, p=0.034). The prevalence of VT/VF/SCD was similar in patients with a variant in one of the LDS genes compared to those with a variant in FBN1 (1.6% vs. 0.8%, p=0.132) and there was no difference in age at time of event (26±13 years vs. 33±14 years, p=0.289). Among patients with a variant in the LDS genes, the prevalence of VT/VF/SCD was highest in patients carrying a variant in the TGFBR2 gene and was significantly higher compared to patients with a variant in FBN1 (3.4% vs. 0.8%, p=0.017). In contrast, AF/AFL was significantly more often reported in patients with a variant in FBN1 compared to those with a variant in one of the LDS genes (1.7% vs. 0.3%, p=0.033). Conclusions Myocardial dysfunction and arrhythmia are rare features in patients with HTAD. They occur predominantly in patients with a variant in FBN1 and LDS genes, but were not reported in patients carrying a variant in the ACTA2 gene. Further analysis to identify other contributing factors is necessary. FUNDunding Acknowledgement Type of funding sources: None. Figure 1

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Cardiomyopathy in Genetic Aortic Diseases

Frontiers in Pediatrics ◽

10.3389/fped.2021.682390 ◽

2021 ◽

Vol 9 ◽

Author(s):

Laura Muiño-Mosquera ◽

Julie De Backer

Keyword(s):

Marfan Syndrome ◽

Myocardial Dysfunction ◽

Genetic Defect ◽

Positive Family History ◽

Aortic Disease ◽

Aortic Aneurysms ◽

Aortic Diseases ◽

Pathogenic Variants ◽

Fibrillin 1

Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the Fibrillin-1 gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.

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Effect of Aortic Stent Implantation in the Treatment of Thoracic Aortic Disease

Journal of Clinical and Nursing Research ◽

10.26689/jcnr.v5i3.2240 ◽

2021 ◽

Vol 5 (3) ◽

Author(s):

Cheng Chen

Keyword(s):

Stent Implantation ◽

Operation Time ◽

Aortic Disease ◽

Observation Time ◽

Inflammatory Factors ◽

Clinical Effects ◽

Aortic Diseases ◽

Thoracic Aortic Disease ◽

Number Of Patients ◽

Significant Difference

Objective: To explore the effect of aortic stent implantation on patients in the treatment of thoracic aortic diseases. Methods: Selected patients from Yunnan Fuwai Cardiovascular (YFC) Hospital as a sample group to carry out the study, the main participants were thoracic aortic aneurysm patients admitted from June 2020 to June 2021. The number of patients involved were 80. The patients are divided into two groups and different treatment methods were adopted. A comparative analysis of the effects of aortic stent placement on patients was conducted. Results: Before treatment, there was no significant difference in the levels of various inflammatory factors between the two groups of patients, P>0.05. After treatment, the data indicators of the two groups were significantly different, as there were significant differences in the surgical indicators among the two groups of patients, P<0.05. As a result, the experimental group had shorter operation time, less intraoperative blood loss, shorter ICU observation time, lower levels of inflammatory factors, and better results. Conclusion: In the treatment of patients with thoracic aortic disease, the application of aortic stent implantation has significant clinical effects and are more conducive to the recovery of patients. It can be promoted and used in clinical trials.

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Sex Differences in Proximal Thoracic Aortic Disease Pathology: A Call to Action

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.056 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S29-S29

Author(s):

H Sadaf ◽

B Zhao ◽

L Lelenwa ◽

L Buja ◽

A Segura ◽

...

Keyword(s):

Sex Differences ◽

Care Center ◽

Elastic Fiber ◽

Aortic Disease ◽

Aortic Diseases ◽

Thoracic Aortic Disease ◽

Chi Square ◽

Aortic Aneurysm And Dissection ◽

Chi Square Test ◽

Fiber Fragmentation

Abstract Introduction/Objective Sex disparity is reported across all forms of cardiovascular diseases. Only few studies have focused on sex differences in thoracic aortic disease pathology. We aim to identify and understand sex differences in this patient group to bridge the knowledge gap and improve clinicopathologic outcomes. Methods/Case Report This is a retrospective analysis of 83 proximal thoracic aortic aneurysm and dissection (TAAD) cases treated at a single quaternary care center in 2019. Chart review was done for demographics. Consensus criteria (Stone JR et al. Cardiovasc Pathol 2015; 24:267-78; Halushka MK et al. Cardiovasc Pathol 2016; 25:247-57) and a scoring system (Waters KM et al. Cardiovasc Pathol 2017; 30:6-11) were used for pathology reporting. Clinical correlation was also made. Pearson’s chi-square test was used for statistical analysis. Results (if a Case Study enter NA) 83 patients (61 male and 22 female) were retrieved. Overall thoracic aortopathy was higher among males, accounting for 73.4% of individuals with TAAD. In a subgroup analysis, there was no sex difference in dissection, aortic root involvement, and bicuspid aortic valve (p>0.05). Genetic aortopathy was more prevalent in females than males (27.2% vs 9.8%, p=0.04) alongside early age at first aortic event (median age: 31y vs 52y). Histopathologically, females had frequent translamellar mucoid extracellular matrix accumulation (45.4% vs 22.9%, p=0.04), extensive (54.5% vs 27.8%, p=0.02) and severe (59% vs 34.4%, p=0.04) elastic fiber fragmentation, higher band like (9% vs 6.5%, p>0.05) plus extensive (13.6% vs 4.9%, p>0.05) smooth muscle nuclei loss, and extensive (13.6% vs 1.6%, p=0.01) plus dense (4.5% vs 1.6%, p>0.05) laminar medial collapse than males. Conclusion In our patient population, females have a lower prevalence of thoracic aortic disease treated with open repair. However, those who develop TAAD harbor a greater burden of wall pathology and probable worse outcomes. We recommend sex-based analysis of all research on thoracic aortic diseases.

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A review of endovascular treatment of thoracic aorta disease

Annals of The Royal College of Surgeons of England ◽

10.1308/rcsann.2018.0143 ◽

2018 ◽

Vol 100 (8) ◽

pp. 662-668 ◽

Cited By ~ 1

Author(s):

GJS Tan ◽

PLZ Khoo ◽

KMJ Chan

Keyword(s):

Thoracic Aorta ◽

Open Repair ◽

Aortic Disease ◽

Thoracic Endovascular Aortic Repair ◽

Aortic Aneurysms ◽

Endovascular Aortic Repair ◽

Aortic Diseases ◽

Thoracic Aortic Disease ◽

Thoracic Aortic Aneurysms ◽

Aortic Repair

Introduction The development of thoracic endovascular aortic repair has altered the approach and reduced the risk of treating the majority of descending thoracic aortic conditions. Primarily developed for the exclusion of thoracic aortic aneurysms, it is now used in place of open repair surgery for most descending thoracic aortic diseases, and has also been used to treat aortic arch diseases in selected cases. Methods A literature search was conducted of Medline and Embase databases from January 2007 to February 2017, using the key words ‘aortic disease’, ‘thoracic aorta’ and ‘endovascular repair’; 205 articles were identified, of which 25 studies were selected for review based on their relevance. Findings The key findings of the indications, techniques, outcomes, complications and comparisons with open surgical repair were extracted from the published studies and are summarised in this review. Thoracic endovascular aortic repair is the preferred choice of intervention for patients with descending thoracic aortic disease. With time, it has improved to be safer and has the potential to expand aortic treatment choices in future.

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Statins in Aortic Disease

Current Pharmaceutical Design ◽

10.2174/1381612823666171115100829 ◽

2018 ◽

Vol 23 (46) ◽

pp. 7109-7120

Author(s):

Vasiliki Tsigkou ◽

Gerasimos Siasos ◽

Evanthia Bletsa ◽

Maria-Paraskevi Panoilia ◽

Angeliki Papastavrou ◽

...

Keyword(s):

Aortic Valve ◽

Genetic Disorders ◽

Aortic Disease ◽

Current Data ◽

Valve Regurgitation ◽

Aortic Diseases ◽

Cochrane Database ◽

Effect Of Treatment ◽

Pleiotropic Actions ◽

Optimal Type

Background: Numerous studies indicate that statins have multiple beneficial actions (known as ‘pleiotropic actions') on cardiovascular system through the improvement of endothelial dysfunction, inflammation, oxidative stress, excessive arterial thrombosis, and stabilization of the atherosclerotic plaque. Aortic disease primarily consists of aortic valve stenosis, aortic valve regurgitation, aneurysm disease, and genetic disorders such as Marfan syndrome, bicuspid aortic valve and aortic coarctation. Many studies have revealed the cardioprotective actions of statins in aortic disease. Objective: Our aim was to present current data concerning the value of treatment with statins in aortic diseases. Methods: A thorough search of PubMed and the Cochrane Database was conducted to identify the studies and novel articles related to the use of statins in aortic disease. Results: Numerous studies in animals and humans indicate a beneficial effect of treatment with statins in the previous conditions apart from a few conflicting data. Conclusion: There is a need of further investigation in this field, especially for the estimation of the optimal type and dose of statins required in each clinical condition of aortic disease.

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Does age at aortic coarctation repair have an impact on left ventricle size and function?

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeaa356.108 ◽

2021 ◽

Vol 22 (Supplement_1) ◽

Author(s):

S Cardoso Torres ◽

CX Resende ◽

PG Diogo ◽

P Araujo ◽

RA Pinto ◽

...

Keyword(s):

Aortic Coarctation ◽

Surgical Repair ◽

Myocardial Dysfunction ◽

Global Longitudinal Strain ◽

Negative Relationship ◽

Late Complications ◽

Left Ventricular ◽

Funding Sources ◽

The Mean ◽

Clinical Records

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Adults with repaired aortic coarctation (CoA) require lifelong follow-up due to late complications, including left ventricular (LV) myocardial dysfunction. Age at the time of CoA repair is an important prognostic factor in these patients (pts). Purpose To evaluate LV size, ejection fraction (EF) and global longitudinal strain (GLS) values using 2D speckle tracking echocardiography (STE) in a population of adult pts with repaired CoA and to assess the relationship between these echocardiographic parameters and age at the time of CoA repair. Methods Retrospective analysis of adult pts with repaired CoA, followed in a Grown Up Congenital Heart Disease Centre. Pts with hemodynamically significant concomitant cardiac lesions were ruled out. Epidemiologic and clinical data were obtained from clinical records. Transthoracic echocardiograms were reviewed in order to assess GLS using 2DSTE (Echopac Software, GE). Results The study population consisted of 63 pts (61.9% male), with a mean age of 35.3 years at the time of the echocardiographic evaluation. The mean age at the time of the CoA repair was 117 months (95% CI 89.8-144.1 months). Surgical repair was performed in 46 pts (73%): resection with subclavian artery flap aortoplasty (n = 21); patch aortoplasty (n = 15) and head-to-head anastomosis (n = 10). In 10 pts there was no data regarding the type of surgical repair. Seven pts (11.1%) were submitted to percutaneous intervention (6 with aortic stent implantation and 1 with balloon aortic angioplasty). Mean LVEF was 63.4% (CI 95% 55.6 – 71.2%) and mean LV end-diastolic diameter (LVEDD) was 50mm (CI 95% 43-57mm). Mean GLS was - 17.3 (CI 95% 14.8- 19.8), which is inferior to the mean normal values reported for the software used. Age at the time of CoA repair had a statistically significant positive linear relationship with LVEDD (r= 0.282; p= 0.026) and a linear negative relationship with both GLS (r= -0,29; p= 0.022) and LVEF (r= -0.33; p= 0.05). Conclusion Older age at the time of CoA repair was associated with increased LVEDD and decreased GLS and LVEF. Also, GLS may be an important tool for the identification of subclinical LV dysfunction in adult pts with repaired CoA.

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Distinct remodeling pattern between pediatric and adult heart failure: a focus on Ca2+ signaling pathway at proteomic level

European Heart Journal ◽

10.1093/ehjci/ehaa946.3201 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Zhang ◽

U Kuzmanov ◽

S Urschel ◽

F Wang ◽

S Wang ◽

...

Keyword(s):

Heart Failure ◽

Signaling Pathways ◽

Myocardial Dysfunction ◽

Heart Defects ◽

Systolic Dysfunction ◽

Cellular Growth ◽

Reverse Remodeling ◽

Funding Source ◽

Course Of Illness ◽

Reduced Ejection Fraction

Abstract Background Dilated cardiomyopathy (DCM) is among the most common causes leading to end-stage heart failure with reduced ejection fraction (HF-rEF) in adult and pediatric patients. Despite similar phenotypes characterized as systolic dysfunction and eccentric ventricular dilation, pediatric DCM are biologically distinct entities with age- and development-specific features in the heart. Though underlying mechanisms may vary between the two populations, it's largely unexplored with few studies conducted to date. Purpose HF-rEF typically results from impaired myocardial contractility, triggered by defective cellular Ca2+ handling and cytoskeletal remodeling. Hence, we aim to integrate clinical profile and experimental data from human explanted hearts: 1) to unravel the age-dependent disparate Ca2+ signaling pathways; and 2) to identify pediatric-specific HF signatures or potential cures for precision managements. Methods Non-ischemic failing hearts (n=6 adult and n=6 pediatric) were procured immediately after excision via Human Explanted Heart Program. Age-matched adult non-failing control hearts (NFC, n=6) were obtained from deceased donors without cardiovascular history, while pediatric NFC (n=6) were collected from children with congenital heart defects but no primary myocardial dysfunction constituting relatively reasonable controls. Myocardial metabolic and oxidative profile were evaluated spectrophotometrically, and tissue remodeling was assessed immunohistochemically. Global proteomics and phosphoproteomics were performed on a Q-Exactive mass spectrometer, followed by network biology pathway analyses. Expression of screened proteins and kinases was validated by gel electrophoresis. Apoptosis and cellular growth signaling pathways were also incorporated into analysis. Results Both HF groups had remarkably lower LVEF (26.6±10.7% in pediatric vs. 26.5±9.1% in adult DCM) while compared to the NFC (both ≥60%) respectively. Histologically, adult-DCM demonstrated significantly worse fibrosis than pediatric-DCM (p<0.01). It was consistent with excessive reactive oxygen species (ROS) production and perturbed anti-ROS defense noted in adult-DCM, indicative of possible reverse remodeling in the pediatric failing hearts with shorter course of illness till transplant. Mechanistically, NCX1 was elevated with SERCA2 decreased in adult-DCM versus adult-NFC (p<0.05), while both pediatric groups exhibited comparable levels. Reduced p-/t-phospholamban and p-/t-CaMK in adult-DCM, unlike in pediatric-DCM, also illustrated altered phosphorylation patterns. Moreover, GSK-3β and AMPK pathways were inhibited while AKT-473 was activated in adult-DCM. Conclusions Pediatric DCM exhibited less adverse remodeling partially mediated by divergent Ca2+ handling and downstream signaling pathways, illustrating the fundamental differences between adult and pediatric DCM. Our findings may provide a scientific basis for the development of specific therapies for pediatric DCM. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Canadian Institutes for Health Research (CIHR); Heart & Stroke Foundation (HSF)

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Prevalence and prognostic impact of somatic mutations in patients with heart failure and reduced ejection fraction

European Heart Journal ◽

10.1093/ehjci/ehaa946.0966 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

D.J Vazquez Andres ◽

A Hernandez Vicente ◽

M Diez Diez ◽

M Gomez Molina ◽

A Quintas ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Somatic Mutations ◽

Myocardial Dysfunction ◽

Study Endpoint ◽

Prognostic Impact ◽

Reduced Ejection Fraction ◽

Increased Risk ◽

Patients With Heart Failure

Abstract Introduction Somatic mutations in hematopoietic cells are associated with age and have been associated with higher mortality in apparently healthy adults, especially due to atherosclerotic disease. In animal models, somatic mutations are associated with atherosclerosis progression and myocardial dysfunction, especially when gene TET2 is affected. Preliminary clinical data, referred to ischemic heart failure (HF), have associate the presence of these acquired mutations with impaired prognosis. Purpose To study the prevalence of somatic mutations in patients with heart failure with reduced ejection fraction (HFrEF) and their impact on long-term prognosis. Methods We studied a cohort of elderly patients (more than 60 years old) hospitalized with HFrEF (LVEF<45%). The presence of somatic mutations was assessed using next generation sequencing (Illumina HiSeq 2500), with a mutated allelic fraction of at least 2% and a panel of 55 genes related with clonal hematopoiesis. Patients were followed-up for a median of three years. The study endpoint was a composite of death or readmission for worsening HF. Kaplan-Meier analysis (log-rank test) and Cox proportional hazards regression models were performed adjusting for age, sex and LVEF. Results A total of 62 patients (46 males (74.2%), age 74±7.5 years) with HFrEF (LVEF 29.7±7.8%) were enrolled in the study. The ischemic etiology was present in 54% of patients. Somatic mutations in Dnmt3a or Tet2 were present in 11 patients (17.7%). No differences existed in baseline characteristics except for a higher prevalence of atrial fibrillation in patients with somatic mutations (70% vs. 40%, p=0.007). During the follow-up period, 40 patients (64.5%) died and 38 (61.3%) had HF re-admission. The KM survival analysis for the combined event is shown in Figure 1. Compared with patients without somatic mutations and after adjusting for covariates, there was an increased risk of adverse outcomes when the somatic mutations were present (HR 3.6, 95% CI [1.6, 7.8], p=0.0014). This results remains considering death as a competing risk (Gray's test p=0.0097) and adjusting for covariates (HR = 2.21 95% CI [0.98, 5], p=0.0556). Conclusions Somatic mutation are present in patients with HFrEF and determine a higher risk of adverse events in the follow-up. Further studies are needed to assess the clinical implications of these findings. Figure 1 Funding Acknowledgement Type of funding source: None

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