Towards computer aided diagnosis of infective endocarditis in whole-slide images of heart valve tissue using FISH

Infective endocarditis (IE) is an infection of the endocardium, and the heart valves associated with high morbidity and mortality. Fluorescence in situ Hybridization (FISH) is a molecular imaging technique used for diagnosis of IE based on histological heart valve tissue sections. FISH allows detection and identification of microorganisms and gives information about their quantity and spatial distribution. This information is important to guide appropriate antibiotic treatment. However, as manual FISH image analysis is time- and costexpensive, an automated image analysis pipeline (consisting of tissue segmentation, bacteria detection, and spot detection modules) is proposed to assist locating potential regions with microorganisms. The proposed approach was evaluated in a study, where five observers manually assessed a set of 171 fields-of-view (FoVs) captured in 400-fold magnification from 10 randomly chosen WSI for the presence of microorganisms, morphologically detected by the nucleic acid stain DAPI. The task of the observers was to mark the presented image using a 2-class score (‘positive/questionable’ or ‘negative’). The human assessment was compared to the results suggested by the algorithm. The proposed algorithm locates and ranks potential regions with microorganisms in heart valve sections so that experts can validate them in higher power FoVs for the presence of bacteria and identify their species. The automated system for preselecting and recommending adequate FoVs is thus a starting point to support experts and save human resources. It is now ready to be further developed for the detection of bacteria by FISH.

Randomised controlled trial into the role of ramipril in fibrosis reduction in rheumatic heart disease: the RamiRHeD trial protocol

IntroductionRheumatic heart disease (RHD) is a major burden in developing countries and accounts for 80% of all people living with the disease, where it causes most cardiovascular morbidity and mortality in children and young adults. Chronic inflammation and fibrosis of heart valve tissue due to chronic inflammation in RHD will cause calcification and thickening of the impacted heart valves, especially the mitral valve. This fibrogenesis is enhanced by the production of angiotensin II by increased transforming growth factor β expression and later by the binding of interleukin-33, which is known to have antihypertrophic and antifibrotic effects, to soluble sST2. sST2 binding to this non-natural ligand worsens fibrosis. Therefore, we hypothesise that ACE inhibitors (ACEIs) would improve rheumatic mitral valve stenosis.Methods and analysisThis is a single-centre, double-blind, placebo-controlled, randomised clinical trial with a pre–post test design. Patients with rheumatic mitral stenosis and valve dysfunction will be planned for cardiac valve replacement operation and will be given ramipril 5 mg or placebo for a minimum of 12 weeks before the surgery. The expression of ST2 in the mitral valve is considered to be representative of cardiac fibrosis. Mitral valve tissue will be stained by immunohistochemistry to ST2. Plasma ST2 will be measured by ELISA. This study is conducted in the Department of Cardiology and Vascular Medicine, Universitas Indonesia, National Cardiac Center Harapan Kita Hospital, Jakarta, Indonesia, starting on 27 June 2019.Ethics and disseminationThe performance and dissemination of this study were approved by the ethics committee of National Cardiovascular Center Harapan Kita with ethical code LB.02.01/VII/286/KEP.009/2018.Trial registration numberNCT03991910.

Congenital Gerbode Defects Complicated by Infective Endocarditis: 2 Case Reports

Gerbode defect is a rare shunt between the left ventricule and right atrium. The etiology is typically congenital. The infravalvular type is the most common. The congenital defects are believed to close by forming an aneurysmal pouch through incorporating adjacent tricuspid valve tissue. Endocarditis is responsible for this shunt by re-opening the defect. Diagnosis is based on the transesophageal echocardiography. Surgical closure demonstrated an excellent outcome. We present 2 cases with this uncommon congenital shunt complicated by infective endocarditis and septic embolism.

Early Aberrant Angiogenesis Due to Elastic Fiber Fragmentation in Aortic Valve Disease

Elastic fiber fragmentation (EFF) is a hallmark of aortic valve disease (AVD), and neovascularization has been identified as a late finding related to inflammation. We sought to characterize the relationship between early EFF and aberrant angiogenesis. To examine disease progression, regional anatomy and pathology of aortic valve tissue were assessed using histochemistry, immunohistochemistry, and electron microscopy from early-onset (<40 yo) and late-onset (≥40 yo) non-syndromic AVD specimens. To assess the effects of EFF on early AVD processes, valve tissue from Williams and Marfan syndrome patients was also analyzed. Bicuspid aortic valve was more common in early-onset AVD, and cardiovascular comorbidities were more common in late-onset AVD. Early-onset AVD specimens demonstrated angiogenesis without inflammation or atherosclerosis. A distinct pattern of elastic fiber components surrounded early-onset AVD neovessels, including increased emilin-1 and decreased fibulin-5. Different types of EFF were present in Williams syndrome (WS) and Marfan syndrome (MFS) aortic valves; WS but not MFS aortic valves demonstrated angiogenesis. Aberrant angiogenesis occurs in early-onset AVD in the absence of inflammation, implicating EFF. Elucidation of underlying mechanisms may inform the development of new pharmacologic treatments.

Effects of Altering Mitochondrial Antioxidant Capacity on Molecular and Phenotypic Drivers of Fibrocalcific Aortic Valve Stenosis

Background: While a small number of studies suggest that oxidative stress has an influential role in fibrocalcific aortic valve disease (FCAVD), the roles of specific antioxidant enzymes in progression of this disease remain poorly understood. Here, we focused on selectively altering mitochondrial-derived oxidative stress—which has been shown to alter progression of a myriad of age-associated diseases—on the progression of molecular and phenotypic drivers of FCAVD.Methods: We generated low-density lipoprotein receptor-deficient, Apolipoprotein B100-only mice (LA) that were either haploinsufficient for MnSOD (LA-MnSOD+/−) or genetically overexpressing MnSOD (LA-MnSODTg/0). After 6 months of Western diet feeding, mice underwent echocardiography to assess valvular and cardiac function and tissues were harvested. Quantitative-RT PCR, immunohistochemistry, and histopathology were used to measure changes in molecular pathways related to oxidative stress, calcification, and fibrosis.Results: While reductions in MnSOD increased oxidative stress, there was not an overt phenotypic effect of MnSOD deficiency on valvular and cardiac function in LA-MnSOD+/− mice. While markers of canonical bone morphogenetic protein signaling tended to increase in valve tissue from LA-MnSOD+/− (e.g., p-SMAD1/5/8 and osterix), we did not observe statistically significant increases in osteogenic signaling. We did, however, observe highly significant reductions in expression of osteopontin, which were associated with significant increases in calcium burden in LA-MnSOD+/− mice. Reciprocally, genetically increasing MnSOD did not preserve valve function in LA-MnSODTg/0, but we did observe slight reductions in p-SMAD1/5/8 levels compared to their non-transgenic littermates. Interestingly, overexpression of MnSOD dramatically increased expression of osteopontin in valve tissue from LA-MnSODTg/0 mice, but was not sufficient to attenuate calcium burden when compared to their LA-MnSOD0/0 littermates.Conclusions: Collectively, this study demonstrates that maintenance of mitochondrial antioxidant capacity is important in preventing accelerated disease progression in a mouse model of FCAVD, but that effectively altering mitochondrial antioxidant capacity as a monotherapeutic approach to slow key histopathological and molecular drivers of FCAVD remains biologically and therapeutically challenging.

Concordant Ventriculoarterial Connections With Abnormally Related Arterial Trunks (Anatomically Corrected Malposition) Associated With Right Ventricular Outflow Tract Obstruction by Accessory Valvar Tissue

Anatomically corrected malposition of the great arteries is a rare conotruncal anomaly that is often confused with congenitally corrected transposition of the great arteries. This case report describes the successful surgical management of an adolescent with severe right ventricular outflow obstruction caused by accessory tricuspid valve tissue in the presence of situs inversus with atrioventricular and ventriculoarterial concordance with malposed great arteries (anatomically corrected malposition) {I,L,D}.