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Cardiac Disease
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Preethi Pirlamarla, Gregary D. Marhefka
There are a handful of autosomal dominant cardiac conditions, for which the mother would ideally have sought prenatal screening to discuss potential transmission to children. These syndromes include hypertrophic cardiomyopathy, inherited arrhythmias like long QT, Marfan, Noonan, William, Holt-Oram, and DiGeorge (22q11 deletion) [6]. Certain genetic aortopathies are at higher risk for progressive aneurysm formation, dissection and extra-cardiac manifestations, which vary based on etiology. Genetic causes of aortopathy can contribute to intracellular pathology (ACTA2, FLNA, MYLK, PRKG1, MYH11, SKI, SMAD3,4 and TGFβR1,2) or those that affect the extracellular matrix (BGN, COL1A1, COL3A1, 5A1, FBN1, 2, LOX, MFAP5, PLOD1, PRKG1, and TGFβ1,2,3). Other genetic conditions to consider with well-known associated aortopathies are bicuspid aortic valve and Turner's syndrome (XO) [7]. As an ad-hoc member of the cardio-obstetrics team, a geneticist can assist in determining risk profiles.
Cardiac and cardiovascular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
The genes implicated in causing aneurysms of the thoracic aorta fall into four broad categories (after Pyeritz, 2014; see Appendix 1). The principal recognised genes include the following: Structural components of the extracellular matrix (e.g. FBN1, COL3A1, COL4A5, EFEMP2)Components of the TGF or BMP signalling pathways (TGFBR1, TGFBR2, TGFB2, SMAD3)Contractile elements of vascular smooth muscle (ACTA2, MYH11, MYLK, PRKG1, PKG1, FLNA, TSC2)Components of other signalling pathways (JAG1, NOTCH1, SLCA10)
Diseases of the Aorta
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
These are a heterogeneous group of nonsyndromic Thoracic Aortic Aneurysms (TAA) disorders which are heritable with autosomal dominance, variable expression and incomplete penetrance. Isolated TAAs are discovered in 11–19% of first-degree relatives of patients with TAAs, although the true rate may be higher due to undiscovered aneurysms. Nonsyndromic familial thoracic aortic aneurysms and dissections (FTAAD) are inherited in families as an autosomal dominant disorder and a variable age of onset of the aortic disease. Causative mutations in the following genes have been associated with FTAAD: smooth muscle-specific α-actin (ACTA2), vascular smooth muscle contractile protein β-MHC (MYH11), TGFBR2, myosin light chain kinase (MYLK), and a type 1 cyclic guanosine monophosphate-dependent protein kinase that controls smooth muscle relaxation (PRKG1). The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC α-actin (encoded by ACTA2) and the β-myosin heavy chain (encoded by MYH11). ACTA2 mutations interfere with actin filament assembly and decrease SMC contraction. Aortic tissues from affected individuals show aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These changes indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta. The primary mode of inheritance is autosomal dominant, but X-linked dominant and recessive modes are also evident. Mutations in ACTA2 are the most commonly identified, accounting for 10–14% of FTAAD. Mutations in MYLK are associated with acute aortic dissection with little or no aortic enlargement. A gain of function mutation of PRKG1 is associated with dissections occurring at a young age, as early as 17 years. The mean age at presentation for patients with FTAAD is therefore significantly younger than the mean age of presentation in sporadic cases. Patients with a family history of aortic aneurysms had faster growth rates compared with patients with sporadic TAAD and patients with Marfan syndrome. The clustering of mutations involving matrix components, TGF-β signalling, and smooth muscle contractile elements among the genetic TAA entities is beginning to clarify the pathogenetic underpinnings of thoracic aneurysmal disease, opening up avenues for newer medical therapies.
Sericin-mediated improvement of dysmorphic cardiac mitochondria from hypercholesterolaemia is associated with maintaining mitochondrial dynamics, energy production, and mitochondrial structure
Published in Pharmaceutical Biology, 2022
Kitiya Rujimongkon, Sumate Ampawong, Duangnate Isarangkul, Onrapak Reamtong, Pornanong Aramwit
The effect of sericin on the mitochondrial structure was observed by performing a quantitative proteomic study of the expression of ACTA2. Additionally, the mitochondrial structure count showed an increasing number of normal-stage mitochondria in sericin-treated cardiac mitochondria compared with nontreated mitochondria. This information indicated that the effect of sericin improved mitochondrial structure by inducing ACTA2 expression. ACTA2 is transcribed by the nuclear isoform of mitochondrial RNA polymerase and is localised in the cytosol (Lee et al. 2011). A related study reported that actin-mitochondrial interactions are necessary for mitochondrial dynamics, movement, and distribution in the cell (Boldogh and Pon 2006). Deletion of ACTA2 has an effect on apoptosis (Cheng et al. 2018). From these data, upregulation of ACTA2 is related to improved mitochondrial structure and is implicated in the recovery of energy production and protection from apoptosis.
Assessment of the Retinal Toxicity and Sealing Strength of Tissue Adhesives
Published in Current Eye Research, 2022
Anna Sharabura, John Chancellor, M. Zia Siddiqui, David Henry, Ahmed B. Sallam
We found that Tisseel VH fibrin sealant to be the best option because of its moderate strength (0.078 N) and low toxicity. Balagholi et al found that fibrin glue at a concentration of 84 mg/dl preserves the morphometric, genotypic, and phenotypic features of the cells in RPE cell transplantation.26 The limitations of using fibrin include its relatively high cost of $207 and the extremely low but potential risk of blood-borne infections.21 Fibrin is FDA approved for hemostasis in various abdominal surgeries, and the Vitagel kit (Orthovita, Inc., PA, USA) is FDA approved for surgical procedures, excluding neurosurgery and ophthalmic surgery.22 Fibrin adhesives have a long duration of action of 2 weeks and their application is easy and controlled. Further investigation needs to be done to determine whether application of fibrin adhesive decreases the incidence of PVR after retinal detachment repair. In a gene profile study by Balagholi et al, the expression of ACTA2 gene (encoding smooth muscle actin protein) was lower in the fibrin glue-encapsulated human RPE cells as compared to their control group.26 Additionally, we postulate that immediate closure of retinal tears using tissue glue may decrease the likelihood of RPE dispersion in the vitreous and thus decreases the development of PVR.
Risk reduction and pharmacological strategies to prevent progression of aortic aneurysms
Published in Expert Review of Cardiovascular Therapy, 2021
Gabe Weininger, Shin Mei Chan, Mohammad Zafar, Bulat a Ziganshin, John A. Elefteriades
Risk factors for aortic aneurysms also differ for AAAs and TAAs. Roughly 20% of TAAs are thought to be caused by genetic diseases [9,10]. Some of the more common genetic diseases known to be associated with both TAAs and AAAs include Marfan Syndrome (MFS), Type IV Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. More recent studies have also discovered mutations in smooth muscle cell components encoded by genes ACTA2 and MYH11, which appear to confer genetic predisposition to TAAs through altered TGF-β signaling [11,12]. Congenital bicuspid aortic valve (BAV), which is estimated to be present in 1–2% of the population [13], is another common cause of TAA [14,15]. For AAAs, the commonly cited risk factors are atherosclerosis (both peripheral and coronary artery disease are associated), age greater than 65, male sex, and a family history of AAA [16,17]. Additionally, hypertension and smoking are both strong risk factors for both AAAs and TAAs and will be discussed further below.