Calcific Aortic Valve Disease: Molecular Mechanisms And Therapeutic Approaches

Calcification occurs in atherosclerotic vascular lesions and in the aortic valve. Calcific aortic valve disease (CAVD) is a slow, progressive disorder that ranges from mild valve thickening without obstruction of blood flow, termed aortic sclerosis, to severe calcification with impaired leaflet motion, termed aortic stenosis. In the past, this process was thought to be ‘degenerative’ because of time-dependent wear and tear of the leaflets, with passive calcium deposition. The presence of osteoblasts in atherosclerotic vascular lesions and in CAVD implies that calcification is an active, regulated process akin to atherosclerosis, with lipoprotein deposition and chronic inflammation. If calcification is active, via pro-osteogenic pathways, one might expect that development and progression of calcification could be inhibited. The overlap in the clinical factors associated with calcific valve disease and atherosclerosis provides further support for a shared disease mechanism. In our recent research we used an in vitro porcine valve interstitial cell model to study spontaneous calcification and potential promoters and inhibitors. Using this model, we found that denosumab, a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand may, at a working concentration of 50 μg/mL, inhibit induced calcium deposition to basal levels

A leukocita és trombocita funkció változások prediktív értékének vizsgálata intenzív betegellátást igénylő kórképekben = Investigation of predictive values of leukocyte and platelet function changes in critically ill patients

Intenzív terápiás kezelést igénylő számos kórképben közös tényező a szervezet szisztémás gyulladásos reakciója, melynek elsődleges kiváltó oka különböző lehet, de az előidézett válaszreakciók nagymértékben hasonlóak. A gyulladásos reakciót a szabadgyökök, citokinek felszaporodása, a fehérvérsejtek, trombociták és endotél sejtek aktiválódása kíséri. Munkánk során betegekből vett vérmintákban vizsgáltuk az oxidatív stressz és a gyulladásos folyamatok markereinek változását: 1. szívműtéten átesett betegekben; 2. pulmonális embóliás betegek trombolítikus terápiája során; 3. alsó végtagi revaszkularizációs műtéten átesett betegekben; 4. égési traumát szenvedett betegekben; 5. szeptikus betegekben. A kutatás eredményei újabb ismeretekkel szolgáltak a szervezet szisztémás gyulladásos válaszreakciójában meghatározó mechanizmusokról, melyek kórjelző értékkel bírhatnak, alkalmasak lehetnek a terápiás beavatkozások hatásosságának megítélésére, és hozzájárulhatnak újabb terápiás lehetőségek kimunkálásához. Az újabb biomarkerek vizsgálata javíthatja az intenzív betegellátást igénylő betegek korai diagnózisát, és ennek következtében hatással lehet e betegek mortalitására és morbiditására. Eredményeinkről a pályázati periódus alatt 44 kongresszusi előadásban és 14 megjelent (IF: 15,805) közleményben számoltunk be. A pályázatban résztvevő kutatók közül ketten PhD fokozatot szereztek. | Surgical trauma, thrombosis, embolism, polytrauma, burn injury may induce systemic inflammatory response syndrome (SIRS). The primary cause of SIRS could be different, but the pathomechanism of the inflammatory response is rather similar, involving oxidative stress, platelet, leukocyte, endothelial cell activation and release of different inflammatory mediators. In this project we investigated the changes of oxidative stress markers and inflammatory mediators in blood samples taken from: 1. patients underwent to open heart surgery with or without extracorporeal circulation; 2. patients with pulmonary embolism underwent to thrombolytic therapy; 3. patients with lower limb revascularization surgery; 4. patients with severe burn injury; 5. patients suffering from sepsis following surgical trauma. By monitoring the oxidative stress parameters, platelet and leukocyte function, adhesion molecule and inflammatory antigen expression, ratio of pro- and antiinflammatory cytokines we searched for markers having predictive value to follow up of patient recovery and leading to set up new therapeutic strategies. The use of biomarkers may improve early diagnosis and therapy in critically ill patients, and may consecutively influence the morbidity and mortality of these patients, and may provide promising decision support for the intensive therapeutics to guide the allocation of hospital resources

A poststernotomiás sebfertőzések kezelési sikertelenségének prediktív faktorai = Predictive factors for treatment failure of post-sternotomy wound infections

Absztrakt: Bevezetés és célkitűzés: A szívműtétek során a sternotomia utáni sebfertőzések komoly aggodalomra adnak okot, ugyanis befolyásolják a morbiditást, a mortalitást és a kórházi költségeket is. A rekonstrukció sikertelensége tovább növeli ezeket a kockázatokat, mert a sebfertőzések súlyos szövődményekkel járhatnak. Azoknak a tényezőknek a feltárása, amelyek jelentősen befolyásolhatják a sebészi kezelés sikerességét. Módszer: Egycentrumos retrospektív vizsgálat történt egymást követő 3177, medián sternotomián átesett beteg adataiból. A poststernotomiás sebfertőzések diagnózisa 60 betegnél (1,9%) volt megállapítható. Az adatok alapos elemzésével olyan tényezőket kerestünk, amelyek jelentősen hozzájárulhatnak a sebészi rekonstrukció sikertelenségéhez. Eredmények: A diagnózis késői felállítása mellett a pozitív sebváladék mikrobiológiai vizsgálata, a radikális sebészi rekonstrukció és a perifériás érbetegség jelentősen befolyásolja a sebészi kezelés eredményességét. A radikális sebészi rekonstrukció szignifikánsan magasabb arányban járt sikerrel, mint a hagyományos kezelés (81,8 vs. 11,1%), p<0,001. Következtetés: Szükséges azonosítani azokat a tényezőket, amelyek prediktív jelentőséggel bírnak a sebészi kezelés szempontjából, ezek segíthetnek a kezelési algoritmusok fejlesztésében és a sebészi rekonstrukciók sikerességében. Orv Hetil. 2018; 159(14): 566–570. | Abstract: Introduction and aim: Post-sternotomy wound infection is still a major concern and it affects morbidity, mortality, and hospital costs. Reconstruction failure may further increase these risks with significant financial implications. Method: Here, we attempted to verify some factors that may significantly influence the success of the surgical treatment. We performed a single-center retrospective analysis of data from 3177 consecutive patients who underwent midline sternotomy. The diagnostic signs of post-sternotomy wound infections were observed in 60 patients (1.9%). These data were thoroughly analyzed. Results: Beside late diagnosis, the positive microbiological culture of the wounds, radical surgical intervention and peripheral vascular disease were found to significantly contribute to the development of surgical reconstruction failure. Radical surgical reconstruction was associated with a higher success rate (81.8 vs. 11.1%), p<0.001. Conclusion: Identification of the predictive factors that may lead to treatment failure can assist in developing treatment algorithms and improving the success rates of surgical reconstructions. Orv Hetil. 2018; 159(14): 566–570

Cardiac Repair and Regeneration: The Value of Cell Therapies

Ischaemic heart disease is the predominant contributor to cardiovascular morbidity and mortality; one million myocardial infarctions occur per year in the USA, while more than five million patients suffer from chronic heart failure. Recently, heart failure has been singled out as an epidemic and is a staggering clinical and public health problem associated with significant mortality, morbidity and healthcare expenditures, particularly among those aged ≥65 years. Death rates have improved dramatically over the last four decades, but new approaches are nevertheless urgently needed for those patients who go on to develop ventricular dysfunction and chronic heart failure. Over the past decade, stem cell transplantation has emerged as a promising therapeutic strategy for acute or chronic ischaemic cardiomyopathy. Multiple candidate cell types have been used in preclinical animal models and in humans to repair or regenerate the injured heart, either directly or indirectly (through paracrine effects), including: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), neonatal cardiomyocytes, skeletal myoblasts (SKMs), endothelial progenitor cells, bone marrow mononuclear cells (BMMNCs), mesenchymal stem cells (MSCs) and, most recently, cardiac stem cells (CSCs). Although no consensus has emerged yet, the ideal cell type for the treatment of heart disease should: (a) improve heart function; (b) create healthy and functional cardiac muscle and vasculature, integrated into the host tissue; (c) be amenable to delivery by minimally invasive clinical methods; (d) be available ‘off the shelf’ as a standardised reagent; (e) be tolerated by the immune system; (f) be safe oncologically, i.e. not create tumours; and (g) circumvent societal ethical concerns. At present, it is not clear whether such a ‘perfect’ stem cell exists; what is apparent, however, is that some cell types are more promising than others. In this brief review, we provide ongoing data on agreement and controversy arising from clinical trials and touch upon the future directions of cell therapy for heart disease

Early Results of a Novel Mitral Valve Repair Procedure: The Interpapillary Polytetrafluoroethylene Bridge Formation

BACKGROUND: Surgical repair of ischemic mitral regurgitation (IMR) associated with chordal rupture in patients with ischemic cardiomyopathy is challenging as it aims to correct several structural pathologies at once. There are ongoing studies evaluating multiple approaches, however long term results are still scarce. METHODS AND RESULTS: 19 patients with IMR underwent mitral valve repair with interpapillary polytetrafluoroethylene (PTFE) bridge and neochordae formation at the Zala County Teaching Hospital. Concomitant coronary artery bypass grafting was performed in all patients. Post-procedural Transesophageal Echocardiogram (TEE) showed no mitral regurgitation (MR) in eighteen (94.7%) patients, with a leaflet coaptation mean height of 8 ± 3 mm. No operative mortality was observed. At the follow up (mean 17.7 ± 4.6 months; range 9 to 24 months), 17 (89%) patients showed no leakage and 2 had regurgitation grade ≤1, with documented NYHA functional class I or II in all patients. CONCLUSION: This retrospective study presents the first results of a novel surgical approach to treating ischemic mitral regurgitation. The interpapillary PTFE bridge formation is a safe and feasible surgical procedure that is reproducible, time sparing and effectively eliminates mitral valve regurgitation with promising long-term results

Influence of dextran-70 on systemic inflammatory response and myocardial ischaemia-reperfusion following cardiac operations

INTRODUCTION: Experimental studies have demonstrated that dextran-70 reduces the leukocyte–endothelium interaction, but clinical evidence is still lacking. Our objective was to justify the anti-inflammatory effect of dextran-70 following cardiac operations. METHODS: Forty patients undergoing coronary bypass surgery (n = 32) or aortic valve replacement (n = 8) were enrolled in this prospective, randomized, double-blind study. Two groups were formed. In group A (n = 20), dextran-70 infusion was administered at a dose of 7.5 ml/kg before the initiation of cardiopulmonary bypass and at a dose of 12.5 ml/kg after the cessation of cardiopulmonary bypass. Group B served as a control with identical amounts of gelatin infusion (n = 20). The plasma concentration of procalcitonin, C-reactive protein, IL 6, IL 6r, IL 8, IL 10, soluble endothelial leukocyte adhesion molecule-1, soluble intercellular adhesion molecule-1, cardiac troponin-I and various haemodynamic parameters were measured in the perioperative period. Multivariate methods were used for statistical analysis. RESULTS: In group A, lower peak (median) plasma levels of procalcitonin (0.2 versus 1.4, p < 0.001), IL 8 (5.6 versus 94.8, p < 0.001), IL 10 (47.2 versus 209.7, p = 0.001), endothelial leukocyte adhesion molecule-1 (88.5 versus 130.6, p = 0.033), intercellular adhesion molecule-1 (806.7 versus 1,375.7, P = 0.001) and troponin-I (0.22 versus 0.66, p = 0.018) were found. There was no significant difference in IL 6, IL-6r and C-reactive protein values between groups. Higher figures of the cardiac index (p = 0.010) along with reduced systemic vascular resistance (p = 0.005) were noted in group A. CONCLUSION: Our investigation demonstrated that the use of dextran-70 reduces the systemic inflammatory response and cardiac troponin-I release following cardiac operation. TRIAL REGISTRATION NUMBER: ISRCTN38289094

Coronary-artery bypass surgery in patients with left ventricular dysfunction

The role of coronary-artery bypass grafting (CABG) in the treatment of patients with coronary artery disease and heart failure has not been clearly established.Between July 2002 and May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). The primary outcome was the rate of death from any cause. Major secondary outcomes included the rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes.The primary outcome occurred in 244 patients (41%) in the medical-therapy group and 218 (36%) in the CABG group (hazard ratio with CABG, 0.86; 95% confidence interval [CI], 0.72 to 1.04; P=0.12). A total of 201 patients (33%) in the medical-therapy group and 168 (28%) in the CABG group died from an adjudicated cardiovascular cause (hazard ratio with CABG, 0.81; 95% CI, 0.66 to 1.00; P=0.05). Death from any cause or hospitalization for cardiovascular causes occurred in 411 patients (68%) in the medical-therapy group and 351 (58%) in the CABG group (hazard ratio with CABG, 0.74; 95% CI, 0.64 to 0.85; P<0.001). By the end of the follow-up period (median, 56 months), 100 patients in the medical-therapy group (17%) underwent CABG, and 555 patients in the CABG group (91%) underwent CABG.In this randomized trial, there was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary end point of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; STICH ClinicalTrials.gov number, NCT00023595.)

Myocardial viability and survival in ischemic left ventricular dysfunction

The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain.In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds.Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53).The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.)