Cardiac myxoma the great imitators: comprehensive histopathological and molecular approach

Cardiac myxomas are rare benign and slowly proliferating neoplasms of uncertain histogenesis with heterogeneous histomorphology and variable and sometimes clinically quite malignant pathological manifestations. Majority of cardiac myxoma occur sporadically while a relatively small proportion of diagnosed cases develop as a part of Carney complex syndrome with established familial pattern of inheritance. Although histologically indistinguishable these two forms of cardiac myxoma exhibit distinct cytogenetic make-up and apparent pathological differences important for their clinical presentation and prognosis. Additional problem is presented with secondary lesions with more aggressive histology and significantly faster cell proliferation suggesting their successive malignant alteration. Surgical resection of cardiac myxoma is currently the only treatment of choice. However, to avoid potentially hazardous operating procedures and possible postoperative complications and to prevent recurrence of the neoplastic lesions it is necessary to develop alternative approaches and identify a possible drug targets for their successful pharmacological treatment. Due to the rarity of the disease, a small number of cases in one institution and lack of comprehensive experimental data particularly concerning the cases of metastatic dissemination and secondary lesions with malignant nature, a comprehensive multi-institutional approach is required for better understanding of their molecular pathology and illumination of key molecular, genetic as well as epigenetic markers and regulatory pathways responsible for their development. In this article we provide comprehensive pathohistological, molecular and cytogenetic overview of sporadic cardiac myxoma cases restating the major hypothesis concerning their histogenesis and emphasizing potential approaches for their further reexamination

MINIMUM INVASIVE APPROACH TO AORT AORTAL CURRICULUM REOPERATIONS

Pozadina: Trenutna studija uspoređuje: (a) kratkotrajni i dugoročni morbiditet i mortalitet bolesnika podvrgnutih minimalno invazivnom postupku zamjene aortnog zalistka (mini-AVR) putem gornje hemisternotomije; (b) bolničke parametre i dugoročno preživljavanje nakon reoperativne zamjene aortnog zalistka (re-AVR) pacijenata koji su prethodno bili podvrgnuti mini-AVR ili postupku pune sternotomije (sAVR) te (c) ishode minimalno invazivnog reoperativnog AVR (Mre- AVR) zahvata u usporedbi s standardnim re-AVR pristupom putem pune sternotomije (Fre-AVR) kod visokorizičnih bolesnika sa ≥ 80 godina života. Metode: U studiju je uključeno: (a) 1639 bolesnika koji su podvrgnuti mini-AVR postupku, (b) 101 reoperativni AVR pacijent prethodno podvrgnut mini-AVR ili sAVR postupku, te (c) 105 bolesnika sa ≥80 godina života koji su podvrgnuti Mre- AVR ili Fre-AVR postupku. Sve tri skupine pacijenata regrutirane su u razdoblju od 1996. do 2013. godine, nakon odobrenja institucionalnog odbora Brigham i Women's Hospital, Boston, SAD. Podaci o pacijentima (postoperativna učestalost komplikacija i perioperativna smrtnost) prikupljeni su u trenutku prezentacije i ekstrahirani iz elektronskih medicinskih zapisa kliničke ustanove dok su podaci o dugoročnom preživljenju prikupljeni pretraživanjem Social Security Death Index baze podataka državnog odjela za javno zdravstvo (State Department of Public Health) ili direktnim praćenjem pacijenata. Rezultati: (a) Srednja dob pacijenata iznosila je 67 godina (SD, 14 godina, raspon, 22-95 godina). Od ukupne skupine pacijenata njih211 (13%) podvrgnuto je reoperativnom AVR. Postoperativno 2,3% (37/1639) pacijenata imalo je reoperaciju uslijed krvarenja, 2,7% (44/1639) pretopilo je moždani udar, 20,4% (334/1639) novonastalu atrijsku fibrilaciju, a 1,5% (24/1639) zahtijevalo je ugradnju trajnog elektrostimulatora srca. Samo 34% (571/1639) pacijenata zahtijevalo je pRBC transfuziju. Medijan pražnjenja bio je 6 dana (5-8), a 72,2% bolesnika (1184/1639) otpušteno je na kućnu njegu. Operativna smrtnost iznosila je 2,9% (48/1639), a dugoročno preživljenje nakon 1, 5, 10 i 15 godina iznosilo je 96%, 93%, 92% i 92%. Operativna smrtnost za reoperativne bolesnike iznosila je 5,7% (12/211). (b) Od 101 bolesnika iz ove skupine, 34 je podvrgnuto prethodnom mini-AVR postupku dok je njih 67 inicijalno operirano sAVR pristupom. Vremenski period od prethodnog AVR postupka bio je sličan u obje skupine (medijan ukupno 7,6 godina) pacijenata. S obzirom na prethodno ugrađene aortalne zalistke 57 pacijenata je imalo ugrađene biološke proteze a 44 pacijenta su dobila mehaničke aortalne zalistke; strukturna degeneracija zalistaka predstavljala je najčešću indikaciju za reoperaciju (43/101). Mini-AVR i sAVR bolesnici nisu se bitno razlikovali s obzirom na demografske podatke i preoperativne čimbenike rizika. Izrazit trend ka kraćem vremenskom tijeku operacije (skin-to-skin time) zapažen je kod mini-AVR (330 min vs. 353 min, P = 0,056) pristupa. Postoperativno, mini-AVR pacijenti imali su kraće vrijeme ventilacije (5,7 sati vs. 8,4 sati, P = 0,005), boravka u jedinici intenzivnog liječenja (37 sati vs 63 sata, P <0,0000) te ukupnog boravka u bolnici (6,5 dana prema 8 dana, P= 0,030). Zabilježena je samo jedna operativna smrtnost tijekom sAVR-u te niti jedna u mini-AVR grupi. Srednje vrijeme preživljenja [nakon 1 i 5 godina za mini- AVR 100% (95% CI 100-100) u oba slučaja], a za sAVR pacijente 93,9% (95% CI 88,2 - 99,7) odnosno 85,0 % (95% CI 75.1 - 94.9) (P = 0.041). (c) Od 105 pacijenata u ovoj skupini ispitanika, 51 pacijent podvrgnut je Mre-AVR postupku putem gornje hemisternotomije dok su preostala 54 pacijenta podvrgnuta standardnom Fre-AVR reoperativnom postupku. Postoperativno, 6 bolesnika (5,7%) podvrgnuto je reoperaciji uslijed krvarenja, 4 (3,8%) pacijenta doživjela su trajni moždani udar, 4 (3,8%) pacijenta su pretrpjeli novonastalo zatajenje bubrega, a 22 (21,0%) pacijenata novonastalu fibrilaciju atrija. Ukupna operativna smrtnost iznosila je 6,7%, a 1-godišnje i 5- godišnje preživljavanje 87% odnosno 53%. Operativna smrtnost u Fre-AVR skupini pacijenata iznosila je 9.2% a u Mre-AVR skupini 3.9% (P= 0.438).Kaplan-Meier analiza ukazala je na dulje vrijeme preživljenja Mre-AVR pacijenata i nakon (79% ±11.7% vs 92%±7.8%) i nakon 5 godina (38% ± 17.6% vs 65%±15.7%, P=0.028)dok su Cox-ovom regresijskom analizom kao prediktori smrtnosti utvrđeni heparinom-inducirana trombocitopenija, reoperacija uslijed krvarenja, starija dob pacijenata, puna sternotomija t infektivne komplikacije. Zaključak: Mini-AVR postupak putem gornje hemisternotomije predstavlja siguran i pouzdan postupak zamjene aortnih zalistaka srca, osobito kod pacijenata koji su podvrgnuti reoperativnom AVR zahvatu te kod pacijenata starijih od 80 godina života. Pored toga prednosti inicijalnog mini-AVR pristupa u vidu kraćeg bolničkog 71 boravka i poboljšanja dugoročnog preživljenja pacijenata pružaju se i na naknadni reoperativni AVR zahvat. Nadalje, minimalno invazivni pristup reoperativnoj zamjeni aortnih zalistaka srca povezan je s većim dugoročnim preživljenjem osoba starijih od 80 godina života.Background: The current study compares: (a) short- and long-term morbidity and mortality in patients with aortic valve disease who had minimally invasive aortic valve replacement (mini-AVR) through upper hemisternotomy; (b) in-hospital outcomes and long-term survival following reoperative aortic valve replacement (re- AVR) between patients who had previous mini-AVR or full sternotomy AVR (sAVR) and (c) the outcomes of minimaly invasive reoperative AVR (Mre-AVR) versus standard full sternotomy (Fre-AVR) approach in high-risk patients ≥ 80 years Methods: We identified: (a) 1639 patients who underwent mini-AVR, (b) 101 reoperative AVR patients who had previous mini-AVR or sAVR, and (c) 105 patients, aged ≥80 years, who underwent Mre-AVR or Fre-AVR (full sternotomy re- AVR). All thre grooups of patients were recruted in the period from 1996 to 2013 after institutional review board approval at Brigham and Women’s Hospital, Boston, USA. Patient data (postoperative compli-cation rates, and perioperative mortality) were collected at the time of presentaion and extracted from hospital electronic medical records according to The Society of Thoracic Surgeons National Adult Cardiac Database definitions, version 2.52 whereas the long-term survival data were collected via query of the Social Security Death Index, via the state Department of Public Health, and by routine follow-up. Results: (a) The mean age was 67 years (SD, 14 years; range, 22-95 years). Of the total cohort, 211 (13%) underwent reoperative AVR. Postoperatively, 2.3% (37/1639) had reoperations to correct bleeding, 2.7% (44/1639) had strokes, 20.4% (334/1639) had new-onset atrial fibrillation, and 1.5% (24/1639) required permanent pacemakers. Only 34% (571/1639) of the patients received packed red blood cells. The median discharge was on day 6 (5-8), and 72.2% of the patients (1184/1639) were discharged home. Operative mortality was 2.9% (48/1639), and long-term survival at 1, 5, 10, and 15 years was 96%, 93%, 92%, and 92%, respectively. Operative mortality was 5.7% (12/211) for the reoperative patients. (b) Of the 101 patients, 34 underwent previous mini-AVR and 67 underwent previous sAVR. Time from the previous AVR was similar in both groups (median 7.6 years overall). Of previous valve implants, 57 were bioprostheses, and 44 were mechanical; structural valve degeneration was the most common indication for surgery (43/101). Mini- AVR and sAVR patients did not differ significantly with regard to patient demographics and preoperative risk factors. Strong trend towards shorter skin-toskin operative times was observed for mini-AVR (330 min vs. 353 min, P= 0.056). Postoperatively, mini-AVR patients had shorter ventilation times (5.7hrs vs. 8.4hrs, P= 0.005), ICU stays (37hrs vs. 63hrs, P ≤0.001) and LOS (6.5d vs. 8d, P= 0.030). There was one operative mortality in sAVR and none in the mini-AVR group. Midterm survival (at 1 and 5 years for mini-AVR was 100% (95% CI 100-100) and 100% (95% CI 100- 100) and for sAVR was 93.9% (95% CI 88.2 - 99.7) and 85.0% (95% CI 75.1 - 94.9) respectively (P= 0.041). (c) Of the 105 patients, 51 underwent Mre-AVR through upper hemisternotomy and 54 standard Fre-AVR approach. The mean patient age was 82.8±3.8 years. No significant differences were found in the patient risk factors. Postoperatively, 6 patients (5.7%) underwent reoperation for bleeding, 4 (3.8%) experienced permanent stroke, 4 (3.8%) developed new renal failure, and 22 (21.0%) had new-onset atrial fibrillation. Overall, the operative mortality was 6.7%, and the 1- and 5-year survival was 87% and 53%, respectively. When Mre-AVR and Fre-AVR were compared, the operative mortality was 9.2% in the Fre-AVR group and 3.9% in the Mre-AVR group (P= 0.438). Kaplan-Meier analysis showed a survival benefit at both 1 year (79% ±11.7% vs 92%±7.8%) and 5 years (38% ± 17.6% vs 65%±15.7%, P=0.028) favoring Mre- AVR. Cox regression analysis identified heparin-induced thrombocytopenia, reoperation for bleeding, older age, full sternotomy, and an infectious complication as predictors of mortality. Conclusion: The mini-AVR through upper hemisternotomy represents safe and reliable AVR procedure, especially for patients undergoing reoperations and those older than 80 years. Futhermore, with shorter hospital stays and improved long-term survival mini-AVR confers benefits during subsequent re-AVR. Also, Mre-AVR approach in octogenarians was associated with better survival compared with Fre- AVR and might benefit this population

Epigenome alterations in aortic valve stenosis and its related left ventricular hypertrophy

Abstract Aortic valve stenosis is the most common cardiac valve disease, and with current trends in the population demographics, its prevalence is likely to rise, thus posing a major health and economic burden facing the worldwide societies. Over the past decade, it has become more than clear that our traditional genetic views do not sufficiently explain the well-known link between AS, proatherogenic risk factors, flow-induced mechanical forces, and disease-prone environmental influences. Recent breakthroughs in the field of epigenetics offer us a new perspective on gene regulation, which has broadened our perspective on etiology of aortic stenosis and other aortic valve diseases. Since all known epigenetic marks are potentially reversible this perspective is especially exciting given the potential for development of successful and non-invasive therapeutic intervention and reprogramming of cells at the epigenetic level even in the early stages of disease progression. This review will examine the known relationships between four major epigenetic mechanisms: DNA methylation, posttranslational histone modification, ATP-dependent chromatin remodeling, and non-coding regulatory RNAs, and initiation and progression of AS. Numerous profiling and functional studies indicate that they could contribute to endothelial dysfunctions, disease-prone activation of monocyte-macrophage and circulatory osteoprogenitor cells and activation and osteogenic transdifferentiation of aortic valve interstitial cells, thus leading to valvular inflammation, fibrosis, and calcification, and to pressure overload-induced maladaptive myocardial remodeling and left ventricular hypertrophy. This is especcialy the case for small non-coding microRNAs but was also, although in a smaller scale, convincingly demonstrated for other members of cellular epigenome landscape. Equally important, and clinically most relevant, the reported data indicate that epigenetic marks, particularly certain microRNA signatures, could represent useful non-invasive biomarkers that reflect the disease progression and patients prognosis for recovery after the valve replacement surgery