Surgical Heritage: You Had to Be There, Ross: The Comeback Kid.

Half a century after the first pulmonary autograft operation (Ross operation), performed in 1967 by Donald Ross in central London, there is a very strong conviction that the Ross operation is the best available valve substitute today, not only for children, but also for younger and older adults. The Ross operation has stimulated a lot of science to do with tissue-engineering and biology of heart valves, which is a promising avenue for the future. For one of us (M.Y.), it has certainly been a privilege to be associated with the comeback of the Ross operation.

Long-Term Clinical and Echocardiographic Outcomes Following the Ross Procedure: A Post Hoc Analysis of a Randomized Clinical Trial.

Importance: The Ross procedure as treatment for adults with aortic valve disease (AVD) has been the subject of renewed interest. Objective: To evaluate the long-term clinical and echocardiographic outcomes following the Ross procedure for the treatment of adults with AVD. Design, Setting, and Participants: This post hoc analysis of a randomized clinical trial included adult patients (age <69 years) who underwent a Ross procedure for the treatment of AVD, including those with active endocarditis, rheumatic AVD, decreased ejection fraction, and previous cardiac surgery. The trial, conducted from September 1, 1994, to May 31, 2001, compared homograft root replacement with the Ross procedure at a single center. Data after 2010 were collected retrospectively in November and December 2022. Exposure: Ross procedure. Main Outcomes and Measures: The primary end point was long-term survival among patients who underwent the Ross procedure compared with that in the age-, country of origin- and sex-matched general population. Secondary end points were freedom from any reintervention, autograft reintervention, or homograft reintervention and time-related valve function, autograft diameter, and functional status. Results: This study included 108 adults (92 [85%] male) with a median age of 38 years (range, 19-66 years). Median duration of clinical follow-up was 24.1 years (IQR, 22.6-26.1 years; 2488 patient-years), with 98% follow-up completeness. Of these patients, 9 (8%) had active endocarditis and 45 (42%) underwent reoperations. The main hemodynamic lesion was stenosis in 30 (28%) and regurgitation in 49 (45%). There was 1 perioperative death (0.9%). Twenty-five year survival was 83.0% (95% CI, 75.5%-91.2%), representing a relative survival of 99.1% (95% CI, 91.8%-100%) compared with the general population (83.7%). At 25 years, freedom from any reintervention was 71.1% (95% CI, 61.6%-82.0%); from autograft reintervention, 80.3% (95% CI, 71.9%-89.6%); and from homograft reintervention, 86.3% (95% CI, 79.0%-94.3%). Thirty-day mortality after the first Ross-related reintervention was 0% and after all Ross-related reinterventions was 3.8% (n = 1); 10-year survival after reoperation was 96.2% (95% CI, 89.0%-100%). Conclusions and Relevance: This study found that the Ross procedure provided excellent survival into the third decade postoperatively that was comparable to that in the general population. Long-term freedom from reintervention demonstrated that the Ross procedure may be a durable substitute into late adulthood, showing a delayed but progressive functional decline. Trial Registration: isrctn.org Identifier: ISRCTN03530985.

Nine days extended release of adenosine from biocompatible MOFs under biologically relevant conditions.

Adenosine is a small molecule directly involved in maintaining homeostasis under pathological and stressful conditions. Due to its rapid metabolism, delivery vehicles capable of exhibiting extended release of adenosine are of paramount interest. Herein, we demonstrate a superior long-term (9 days) release profile of adenosine from biocompatible MOFs in a physiologically relevant environment. The key to the biocompatibility of MOFs is their stability under biologically relevant conditions. This study additionally highlights the interplay between the chemical stability of prototypal MOFs, assessed under physiological conditions, and their cytotoxicity profiles. Cytotoxicity of the prototypal Zn-based MOF (ZIF-8) and three Zr-based MOFs (UiO-66, UiO-66-NH2, and MOF-801) on six cell types was assessed. The cell types selected were valve interstitial cells (VICs), valve endothelial cells (VECs), adipose tissue-derived stem cells (ADSCs), and cell lines U937, THP1, and HeLa. Zr-based MOFs demonstrated a wide tolerance range in the cell culture cytotoxicity assays, demonstrating cell viability up to a very high dose of ∼1000 µg mL-1, as compared to ZIF-8 which showed notable cytotoxicity in as little as ∼100 µg mL-1 dose. This study demonstrates, for the first time, the utilization of biocompatible MOFs for adenosine delivery as well as establishes a direct link between structural instability in the cell culture medium and the observed cytotoxicity of the studied MOFs.

Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its modulation via phosphorylation.

AIMS: Dilated cardiomyopathy (DCM) is associated with mutations in many genes encoding sarcomere proteins. Truncating mutations in the titin gene TTN are the most frequent. Proteomic and functional characterizations are required to elucidate the origin of the disease and the pathogenic mechanisms of TTN-truncating variants. METHODS AND RESULTS: We isolated myofibrils from DCM hearts carrying truncating TTN mutations and measured the Ca2+ sensitivity of force and its length dependence. Simultaneous measurement of force and adenosine triphosphate (ATP) consumption in skinned cardiomyocytes was also performed. Phosphorylation levels of troponin I (TnI) and myosin binding protein-C (MyBP-C) were manipulated using protein kinase A and λ phosphatase. mRNA sequencing was employed to overview gene expression profiles. We found that Ca2+ sensitivity of myofibrils carrying TTN mutations was significantly higher than in myofibrils from donor hearts. The length dependence of the Ca2+ sensitivity was absent in DCM myofibrils with TTN-truncating variants. No significant difference was found in the expression level of TTN mRNA between the DCM and donor groups. TTN exon usage and splicing were also similar. However, we identified down-regulation of genes encoding Z-disk proteins, while the atrial-specific regulatory myosin light chain gene, MYL7, was up-regulated in DCM patients with TTN-truncating variants. CONCLUSION: Titin-truncating mutations lead to decreased length-dependent activation and increased elasticity of myofibrils. Phosphorylation levels of TnI and MyBP-C seen in the left ventricles are essential for the length-dependent changes in Ca2+ sensitivity in healthy donors, but they are reduced in DCM patients with TTN-truncating variants. A decrease in expression of Z-disk proteins may explain the observed decrease in myofibril passive stiffness and length-dependent activation.

Novel concepts and early results of repairing common arterial trunk.

OBJECTIVES: Common Arterial Trunk (CAT) continues to have a very poor prognosis globally. To address that, we have developed a novel technique targeting key concepts for the correction of all components of the anomaly, using autologous arterial tissue. This aims to enhance results, availability worldwide, and importantly to avoid the need for repeated reoperations. METHODS: From January 2019 to 4 January 2021, all patients with isolated CAT had repair of the defect using autologous arterial trunk tissue with direct right ventricle (RV) to pulmonary artery (PA) connection. Clinical outcomes, follow-up which included multi-slice computed tomography 3D segmentation and 4D cardiovascular magnetic resonance flow, are presented. RESULTS: Twenty patients were included in the study (median age 4.5 months). There were 2 hospital deaths due to systemic infection and pulmonary hypertensive crisis, respectively. Following discharge all patients remained asymptomatic with no signs of heart failure and improved pattern of growth (median follow-up: 8 months). Early postoperative 3D segmentation showed a conical shaped neo-right ventricular outflow chamber connecting the body of the RV to the main PA through a valveless ostium, and normal crossing of PA and neo-aorta. 4D cardiovascular magnetic resonance pattern of flow showed normal rapid laminar flow through the atrioventricular valves followed by a vortex towards the outflow tracts. There was laminar flow through the neo-aorta and neo-PA with velocity not exceeding 2.5 m/s. The PA regurgitant fraction was 25 ± 5% and was limited to early diastole. CONCLUSIONS: The initial results of utilizing the key concepts, using autologous arterial tissue for the repair of CAT, are encouraging, both clinically and by multimodality imaging.

Organ Culture Model of Aortic Valve Calcification.

A significant amount of knowledge has been gained with the use of cell-based assays to elucidate the mechanisms that mediate heart valve calcification. However, cells used in these studies lack their association with the extra-cellular matrix or the influence of other cellular components of valve leaflets. We have developed a model of calcification using intact porcine valve leaflets, that relies upon a biological stimulus to drive the formation of calcified nodules within the valve leaflets. Alizarin Red positive regions were formed in response to lipopolysaccharide and inorganic phosphate, which could be quantified when viewed under polarized light. Point analysis and elemental mapping analysis of electron microscope images confirmed the presence of nodules containing calcium and phosphorus. Immunohistochemical staining showed that the development of these calcified regions corresponded with the expression of RUNX2, osteocalcin, NF-kB and the apoptosis marker caspase 3. The formation of calcified nodules and the expression of bone markers were both inhibited by adenosine in a concentration-dependent manner, illustrating that the model is amenable to pharmacological manipulation. This organ culture model offers an increased level of tissue complexity in which to study the mechanisms that are involved in heart valve calcification.

Leucine-Rich α-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-α Receptor.

Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role of LRG1 in endothelial activation. LRG1 in endothelial cells (ECs) of arteries and serum of patients with critical limb ischemia (CLI) was assessed by immunohistochemistry and ELISA, respectively. LRG1 expression in sheared and tumor necrosis factor-α (TNF-α)-treated ECs was analyzed. The mechanistic role of LRG1 in endothelial activation was studied in vitro. Plasma of 37-week-old Lrg1 -/- mice was used to investigate causality between LRG1 and tumor necrosis factor receptor 1 (TNFR1) shedding. LRG1 was highly expressed in ECs of stenotic but not normal arteries. LRG1 concentrations in serum of patients with CLI were elevated compared to healthy controls. LRG1 expression was shear dependent. It could be induced by TNF-α, and the induction of its expression was mediated by NF-κB activation. LRG1 inhibited TNF-α-induced activation of NF-κB signaling, expression of VCAM-1 and ICAM-1, and monocyte capture, firm adhesion, and transendothelial migration. Mechanistically, LRG1 exerted its function by causing the shedding of TNFR1 via the ALK5-SMAD2 pathway and the subsequent activation of ADAM10. Consistent with this mechanism, LRG1 and sTNFR1 concentrations were correlated in the serum of CLI patients. Causality between LRG1 and TNFR1 shedding was established by showing that Lrg1 -/- mice had lower plasma sTNFR1 concentrations than wild type mice. Our results demonstrate a novel role for LRG1 in endothelial activation and its potential therapeutic role in inflammatory diseases should be investigated further.

Clinical, cellular, and molecular characterisation of cardiac rhabdomyoma in tuberous sclerosis.

BACKGROUND: Rhabdomyoma is the most common cardiac tumour in children. It is usually associated with tuberous sclerosis complex caused by mutations in TSC-1 or TSC-2 genes. This tumour typically regresses by unknown mechanisms; however, it may cause inflow or outflow obstruction that necessitates urgent surgery. Here we investigate the clinical features and the genetic analysis of patients with tuberous sclerosis complex presenting with large rhabdomyoma tumours. We also investigate the potential role of autophagy and apoptosis in the pathogenesis of this tumour. METHODS: All the patients with cardiac rhabdomyoma referred to Aswan Heart Centre from 2010 to 2018 were included in this study. Sanger sequencing was performed for coding exons and the flanking intronic regions of TSC1 and TSC2 genes. Histopathological evaluation, immunohistochemistry, and western blotting were performed with P62, LC3b, caspase3, and caspase7, to evaluate autophagic and apoptotic signaling. RESULTS: Five patients were included and had the clinical features of tuberous sclerosis complex. Three patients, who were having obstructive tumours, were found to have pathogenic mutations in TSC-2. The expression of two autophagic markers, P62 and LC3b, and two apoptotic markers, caspase3 and caspase7, were increased in the tumour cells compared to normal surrounding myocardial tissue. CONCLUSION: All the patients with rhabdomyoma were diagnosed to have tuberous sclerosis complex. The patients who had pathogenic mutations in the TSC-2 gene had a severe disease form necessitating urgent intervention. We also demonstrate the potential role of autophagy and apoptosis as a possible mechanism for tumourigenesis and regression. Future studies will help in designing personalised treatment for cardiac rhabdomyoma.

Long-term survival after xenograft versus homograft aortic root replacement: Results from a prospective randomized trial.

OBJECTIVE: The study objective was to investigate the long-term survival of patients undergoing xenograft versus homograft full root aortic valve replacement. METHODS: A total of 166 patients requiring aortic valve surgery were randomized to undergo the Freestyle (Medtronic Inc, Minneapolis, Minn) bioprosthesis (N = 90) or a homograft (N = 76) full root aortic valve replacement between 1997 and 2005 in a single institution. Six patients randomly assigned to the homograft crossed over to the Freestyle bioprosthesis because of the unavailability of suitably sized homografts. All surgeons were required to adhere to the standard surgical technique for homograft root implantation previously described. Follow-up was 98.5% complete. RESULTS: The mean age of the study population was 65 ± 8 years. Coronary artery bypass grafting was associated with root aortic valve replacement in 76 of 166 patients (46%, P = not significant between groups), and overall hospital mortality was 4.8% (8/166, P = not significant between groups). Median follow-up was 13.8 years (range, 0-21.8 years; 2033 patient-years). The Kaplan-Meier survival analysis showed that there was no significant difference in overall survival between the 2 arms at 5, 10, and 15 years. Twenty-year survival was 28.3% ± 5% for the Freestyle group versus 25.1% ± 5.7% for the homograft group (P = .90), which was comparable to the age- and sex-matched UK general population. The freedom from aortic valve reoperation at 20 years was comparable for the Freestyle group versus the homograft group (67.9% ± 8.8% vs 67.2% ± 10.3%, respectively; P = .74). CONCLUSIONS: This is the first study to investigate the long-term survival of xenograft versus homograft full root aortic valve replacement from a prospective randomized trial. The observed 20-year overall survival and freedom from aortic valve reoperation serve as a benchmark for future studies on interventions for aortic valve disease in the elderly.

A New Technique for Shaping the Aortic Sinuses and Conserving Dynamism in the Remodeling Operation.

BACKGROUND: Preserving dynamism and recreating the sinuses in the Dacron graft are thought to be important for optimizing results of aortic valve-conserving operations. METHODS: We describe a novel technique that preserves dynamism and recreates the sinotubular junction. In addition, it tailors 3 sinuses of defined longitudinal and transverse curvatures in a straight Dacron tube during the operation. The technique has been used in 6 patients with varied aortic root pathology. We performed preoperative and postoperative multimodality imaging using computerized image analysis as well as 3-dimensional models. RESULTS: There was no early or midterm death. Upon discharge, patients were clinically well, with echocardiographic evidence of minimal (3 patients) or mild (3 patients) aortic regurgitation. Computed tomography and cardiac magnetic resonance imaging with extensive image analysis of the aortic root size, shape, and function showed partial or complete normalization of these parameters. This included the shape and dynamism of the aortic annulus and the size and shape of the geometric (effective) orifice. The 4-dimensional magnetic resonance imaging pattern of flow in the sinuses and ascending aorta showed favorable vortices in the sinuses, right-handed helical flow, and marked diminution of energy loss in the ascending aorta. CONCLUSIONS: The novel technique described here is simple, practical, and cost-effective because it uses a widely available straight Dacron tube. The technique does not use rigid internal or external support. The early results are encouraging. Larger series with longer follow-up are required.

Expression and function of mechanosensitive ion channels in human valve interstitial cells.

BACKGROUND: The ability of heart valve cells to respond to their mechanical environment represents a key mechanism by which the integrity and function of valve cusps is maintained. A number of different mechanotransduction pathways have been implicated in the response of valve cells to mechanical stimulation. In this study, we explore the expression pattern of several mechanosensitive ion channels (MSC) and their potential to mediate mechanosensitive responses of human valve interstitial cells (VIC). METHODS: MSC presence and function were probed using the patch clamp technique. Protein abundance of key MSC was evaluated by Western blotting in isolated fibroblastic VIC (VICFB) and in VIC differentiated towards myofibroblastic (VICMB) or osteoblastic (VICOB) phenotypes. Expression was compared in non-calcified and calcified human aortic valves. MSC contributions to stretch-induced collagen gene expression and to VIC migration were assessed by pharmacological inhibition of specific channels. RESULTS: Two MSC types were recorded in VICFB: potassium selective and cation non-selective channels. In keeping with functional data, the presence of both TREK-1 and Kir6.1 (potassium selective), as well as TRPM4, TRPV4 and TRPC6 (cationic non-selective) channels was confirmed in VIC at the protein level. Differentiation of VICFB into VICMB or VICOB phenotypes was associated with a lower expression of TREK-1 and Kir6.1, and a higher expression of TRPV4 and TRPC6. Differences in MSC expression were also seen in non-calcified vs calcified aortic valves where TREK-1, TRPM4 and TRPV4 expression were higher in calcified compared to control tissues. Cyclic stretch-induced expression of COL I mRNA in cultured VICFB was blocked by RN-9893, a selective inhibitor of TRPV4 channels while having no effect on the stretch-induced expression of COL III. VICFB migration was blocked with the non-specific MSC blocker streptomycin and by GSK417651A an inhibitor of TRPC6/3. CONCLUSION: Aortic VIC express a range of MSC that play a role in functional responses of these cells to mechanical stimulation. MSC expression levels differ in calcified and non-calcified valves in ways that are in part compatible with the change in expression seen between VIC phenotypes. These changes in MSC expression, and associated alterations in the ability of VIC to respond to their mechanical environment, may form novel targets for intervention during aortic valvulopathies.

Tissue Engineered Materials in Cardiovascular Surgery: The Surgeon's Perspective.

In cardiovascular surgery, reconstruction and replacement of cardiac and vascular structures are routinely performed. Prosthetic or biological materials traditionally used for this purpose cannot be considered ideal substitutes as they have limited durability and no growth or regeneration potential. Tissue engineering aims to create materials having normal tissue function including capacity for growth and self-repair. These advanced materials can potentially overcome the shortcomings of conventionally used materials, and, if successfully passing all phases of product development, they might provide a better option for both the pediatric and adult patient population requiring cardiovascular interventions. This short review article overviews the most important cardiovascular pathologies where tissue engineered materials could be used, briefly summarizes the main directions of development of these materials, and discusses the hurdles in their clinical translation. At its beginnings in the 1980s, tissue engineering (TE) was defined as "an interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function" (1). Currently, the utility of TE products and materials are being investigated in several fields of human medicine, ranging from orthopedics to cardiovascular surgery (2-5). In cardiovascular surgery, reconstruction and replacement of cardiac and vascular structures are routinely performed. Considering the shortcomings of traditionally used materials, the need for advanced materials that can "restore, maintain or improve tissue function" are evident. Tissue engineered substitutes, having growth and regenerative capacity, could fundamentally change the specialty (6). This article overviews the most important cardiovascular pathologies where TE materials could be used, briefly summarizes the main directions of development of TE materials along with their advantages and shortcomings, and discusses the hurdles in their clinical translation.

Long-term adaptive versus maladaptive remodelling of the pulmonary autograft after the Ross operation.

OBJECTIVES: Following the Ross operation, the pulmonary autograft undergoes structural changes (remodelling). We sought to determine the extent, nature and possible determinants of long-term remodelling in the different components of the pulmonary autograft. METHODS: Ten pulmonary autografts and 12 normal control valves (6 pulmonary and 6 aortic) were examined by conventional histology, immunocytochemistry and electron microscopy. The structural changes were quantified by morphometry. RESULTS: The leaflets from free-standing root replacement valves demonstrated thickening to levels comparable to the normal aortic leaflets, largely due to the addition of a thin layer of 'neointima' formed of radial elastic fibres, collagen bundles and glycoaminoglycans, on the ventricular aspect of the leaflets. The leaflets of valves from sub-coronary implantation demonstrated a significantly thicker fibroelastic layer on the ventricularis and calcium deposition in the fibrosa. The media of the explanted valves showed increased number of lamellar units to levels comparable to normal aortic roots. Electron microscopy of valves inserted as free-standing roots showed increased organization into continuous layers. However, intralamellar components showed varying degrees of 'disorganization' in comparison to those in the normal aortic media. In addition, there was a marked increase in the number of vasa vasorum with thickened arteriolar wall in the outer media and adventitia. CONCLUSIONS: Following the Ross operation, in the very long term, all components of the autograft showed varying degrees of remodelling, which was judged to be largely adaptive. Defining the type, determinants and possible functional effects of remodelling could help in understanding and optimizing the results of the Ross operation.

Cor Triatriatum Sinister (Divided Left Atrium): Histopathologic Features and Clinical Management.

BACKGROUND: Cor triatriatum sinister (CTS), or divided left atrium, is a rare congenital cardiac disease in which the left atrium is divided into 2 chambers by a fibromuscular diaphragm that will cause blood flow obstruction to the left ventricle. Recent animal studies suggested the role of hyaluronidase-2 (HYAL-2) deficiency as a risk factor for developing CTS. The histopathologic features of this diaphragm and our surgical experience with the management of this disease are reviewed. METHODS: Ten patients underwent surgical correction of CTS between 2010 and 2018. All patients had complete clinical and imaging evaluation. The fibromuscular diaphragms were histologically evaluated with myosin, troponin, vimentin, smooth muscle actin, and HYAL-2 to characterize the structure of the CTS diaphragm. RESULTS: All patients underwent excision of CTS diaphragm using cardiopulmonary bypass with no early mortality. Most patients had the classic form of CTS in which the diaphragm separates the pulmonary and the vestibular chambers with no atrial septal defect. The histologic studies demonstrated the presence of fibrous, mesenchymal cells, along with cardiac muscle cells, at the site of membrane attachments. HYAL-2 enzyme was expressed in the CTS diaphragm. CONCLUSIONS: Surgical repair of CTS provides satisfactory results with low risk of death. Our histologic studies revealed the cellular composition of the CTS diaphragm. HYAL-2 deficiency may not explain the pathogenesis of CTS, and further studies are needed to evaluate the complex mechanisms involved in the development of this disease.

Multidisciplinary evaluation and management of obstructive hypertrophic cardiomyopathy in 2020: Towards the HCM Heart Team.

Patients with hypertrophic cardiomyopathy (HCM) exhibit a variable phenotype with ventricular hypertrophy as the cardinal manifestation and left ventricular (LV) outflow tract obstruction (LVOTO) as a key pathophysiologic determinant. Patients with severe LVOTO usually present with exertional dyspnea, exertional syncope, and heart failure symptoms, while successful relief of LVOTO by pharmacological or invasive interventions leads to a dramatic improvement in clinical status. Proper management of obstructive HCM remains challenging and poses numerous clinical dilemmas. Since the development of surgical myectomy over half a century ago, progress in the management of LVOTO in HCM has paralleled technological advances in genetic testing, cardiac imaging, arrhythmic prophylaxis, cardiac surgery and interventional cardiology. These changes have been incorporated in dedicated scientific guidelines on both sides of the Atlantic. However, either the 2011 American guidelines or the 2014 European guidelines remain largely based on expert consensus for lack of recommendations with level of evidence A regarding any of the treatment options commonly employed in HCM. Consequently, management of obstructive HCM patients remains largely subjective and dependent on clinical judgment, local expertise, and patient preference. Following the trend that has emerged for other cardiac diseases amenable to invasive interventions, adequate evaluation and management of obstruction in HCM today requires a multidisciplinary team capable of optimizing referral, choosing the best available options, minimizing complications and ensuring state-of-the-art results. The concept of an HCM Heart Team is coming of age. This review aims to provide an update of available pharmacologic and invasive options for the management of LVOTO in HCM, either in adulthood or in childhood, highlighting areas for multidisciplinary integration and future development.

Raising awareness for rheumatic mitral valve disease.

Rheumatic heart disease (RHD) is a major burden in low- to mid-income countries, where each year it accounts for over a million premature deaths associated with severe valve disease. Life-saving valve replacement procedures are not available to the majority of affected RHD patients, contributing to an increased risk of death in young adults and creating a devastating impact. In December 2017, a group of representatives of major cardiothoracic societies and industry, discussed the plight of the millions of patients who suffer from RHD. A comprehensive solution based on this global partnership was outlined in "The Cape Town Declaration on Access to Cardiac Surgery in the Developing World". The key challenge in controlling RHD is related to identification and removal of barriers to the translation of existing knowledge into policy, programs, and practice to provide high-quality care for patients with RHD. This review provides an overview on RHD by emphasizing the disease medical and economic burdens worldwide, risk factors, recent advance for early disease detection, and overall preventive strategies.

Nucleotide ecto-enzyme metabolic pattern and spatial distribution in calcific aortic valve disease; its relation to pathological changes and clinical presentation.

BACKGROUND: Extracellular nucleotide metabolism contributes to chronic inflammation, cell differentiation, and tissue mineralization by controlling nucleotide and adenosine concentrations and hence its purinergic effects. This study investigated location-specific changes of extracellular nucleotide metabolism in aortic valves of patients with calcific aortic valve disease (CAVD). Individual ecto-enzymes and adenosine receptors involved were analyzed together with correlation with CAVD severity and risk factors. RESULTS: Nucleotide and adenosine degradation rates were adversely modified on the aortic surface of stenotic valve as compared to ventricular side, including decreased ATP removal (1.25 ± 0.35 vs. 2.24 ± 0.61 nmol/min/cm2) and adenosine production (1.32 ± 0.12 vs. 2.49 ± 0.28 nmol/min/cm2) as well as increased adenosine deamination (1.28 ± 0.31 vs. 0.67 ± 0.11 nmol/min/cm2). The rates of nucleotide to adenosine conversions were lower, while adenosine deamination was higher on the aortic sides of stenotic vs. non-stenotic valve. There were no differences in extracellular nucleotide metabolism between aortic and ventricular sides of non-stenotic valves. Furthermore, nucleotide degradation rates, measured on aortic side in CAVD (n = 62), negatively correlated with echocardiographic and biochemical parameters of disease severity (aortic jet velocity vs. ATP hydrolysis: r = - 0.30, p < 0.05; vs. AMP hydrolysis: r = - 0.44, p < 0.001; valvular phosphate concentration vs. ATP hydrolysis: r = - 0.26, p < 0.05; vs. AMP hydrolysis: r = - 0.25, p = 0.05) while adenosine deamination showed positive correlation trend with valvular phosphate deposits (r = 0.23, p = 0.07). Nucleotide and adenosine conversion rates also correlated with CAVD risk factors, including hyperlipidemia (AMP hydrolysis vs. serum LDL cholesterol: r = - 0.28, p = 0.05; adenosine deamination vs. total cholesterol: r = 0.25, p = 0.05; LDL cholesterol: r = 0.28, p < 0.05; triglycerides: r = 0.32, p < 0.05), hypertension (adenosine deamination vs. systolic blood pressure: r = 0.28, p < 0.05) and thrombosis (ATP hydrolysis vs. prothrombin time: r = - 0.35, p < 0.01). Functional assays as well as histological and immunofluorescence, flow cytometry and RT-PCR studies identified all major ecto-enzymes engaged in nucleotide metabolism in aortic valves that included ecto-nucleotidases, alkaline phosphatase, and ecto-adenosine deaminase. We have shown that changes in nucleotide-converting ecto-enzymes were derived from their altered activities on valve cells and immune cell infiltrate. We have also demonstrated a presence of A1, A2a and A2b adenosine receptors with diminished expression of A2a and A2b in stenotic vs. non-stenotic valves. Finally, we revealed that augmenting adenosine effects by blocking adenosine deamination with deoxycoformycin decreased aortic valve thickness and reduced markers of calcification via adenosine-dependent pathways in a mouse model of CAVD. CONCLUSIONS: This work highlights profound changes in extracellular nucleotide and adenosine metabolism in CAVD. Altered extracellular nucleotide hydrolysis and degradation of adenosine in stenotic valves may affect purinergic responses to support a pro-stenotic milieu and valve calcification. This emphasizes a potential mechanism and target for prevention and therapy. .

Transection and Relocation of Anomalous Left Coronary Artery After Aborted Sudden Cardiac Death.

Anomalous origin of the left main coronary artery from the right coronary sinus is associated with sudden cardiac death. We present a young adult who was diagnosed with this anomaly after an aborted sudden cardiac death. He underwent a complete anatomical repair by translocating the left coronary artery to the left coronary sinus of Valsalva, with excellent 10 years outcome.

Rheumatic Heart Disease Worldwide: JACC Scientific Expert Panel.

Rheumatic heart disease (RHD) is a preventable heart condition that remains endemic among vulnerable groups in many countries. After a period of relative neglect, there has been a resurging interest in RHD worldwide over the past decade. In this Scientific Expert Panel, the authors summarize recent advances in the science of RHD and sketch out priorities for current action and future research. Key questions for laboratory research into disease pathogenesis and epidemiological research on the burden of disease are identified. The authors present a variety of pressing clinical research questions on optimal RHD prevention and advanced care. In addition, they propose a policy and implementation research agenda that can help translate current evidence into tangible action. The authors maintain that, despite knowledge gaps, there is sufficient evidence for national and global action on RHD, and they argue that RHD is a model for strengthening health systems to address other cardiovascular diseases in limited-resource countries.