KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets. METHODS: Utilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy. RESULTS: We identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epithelioid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the (normal) mesothelial line MeT-5A, and was also upregulated in patient tumor samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration. CONCLUSION: These functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and potentially druggable targets.

Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis.

BACKGROUND: Fibulin-3 (FBLN3) was recently presented as a promising novel biomarker for malignant pleural mesothelioma (MPM), warranting independent validation studies. METHODS: ELISA was used to measure cellular and secreted FBLN3 in cell lines, in plasma of xenograft tumour-bearing mice, in plasma from two independent series of MPM and non-MPM patients and in pleural fluid from a third series. Diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and Kaplan-Meier method, respectively. RESULTS: FBLN3 was expressed in all MPM and benign mesothelial cell lines tested, and a correlation was observed between cellular protein expression and secreted levels. Human FBLN3 was detectable in plasma of tumour-bearing mice, suggesting that MPM cells contribute to levels of circulating FBLN3. Plasma FBLN3 was significantly elevated in MPM patients from the Sydney cohort, but not the Vienna cohort, but the diagnostic accuracy was low (63%, (95% CI: 50.1-76.4) and 56% (95% CI: 41.5-71.0), respectively). Although FBLN3 levels in pleural effusions were not significantly different between cases and controls, FBLN3 levels in pleural effusion fluid were found to be independently associated with prognosis (hazard ratio of 9.92 (95% CI: 2.14-45.93)). CONCLUSIONS: These data confirm the potential prognostic value of pleural effusion FBLN3, but question the diagnostic value of this protein in MPM patients.

The freestyle aortic bioprosthesis: a systematic review.

BACKGROUND: The Medtronic Freestyle bioprosthesis (FSB) provides an alternative to other prostheses for both aortic valve and aortic root surgery. This paper is a systematic review of the post-operative outcomes in patients with aortic valve and/or aortic root disease following FSB implantation. METHODS: Electronic databases were searched for primary analysis, prospective randomised studies comparing the FSB with an alternative aortic prosthesis were included. Additionally, case series that included data for at least 100 individual operated patients were used for secondary analysis. RESULTS: Among three identified randomised studies, 199 FSB cases were compared with homografts, and stented and an alternative stentless bioprosthesis. The FSB showed comparable hospital mortality (4.5% vs. 5.3%) and eight-year actuarial survival (80±5.0% versus 77±6.0%) with the homograft (respectively) and comparable reduction in left ventricular mass index relative to other prosthesis types. Over 6000 individual patients were included in the selected 15 case series. Weighted mean operative mortality, neurological event rate and five-year actuarial survival was 5.2%, 5.5% and 77.8%, respectively. CONCLUSION: The FSB performed comparably against alternative prostheses regarding in-hospital mortality, long-term survival and reduction in left ventricular mass index. Included case series demonstrated robust post-operative outcomes in both the short and long term.

Geriatric cardiac surgery: chronology vs. biology.

Cardiac surgery is increasingly performed in elderly patients, and whilst the incidence of common risk factors associated with poorer outcome increases with age, recent studies suggest that outcomes in this population may be better than is widely appreciated. As such, in this review we have examined the current evidence for common cardiac surgical procedures in patients aged over 70 years. Coronary artery bypass grafting (CABG) in the elderly has similar early safety to percutaneous intervention, though repeat revascularisation is lower. Totally avoiding instrumentation of the ascending aorta with off-pump techniques may also reduce the incidence of neurological injury. Aortic valve replacement (AVR) significantly improves quality of life and provides excellent short- and long-term outcomes. Combined AVR and CABG carries higher risk but late survival is still excellent. Mini-sternotomy AVR in the elderly can provide comparable survival to full-sternotomy AVR. More accurate risk stratification systems are needed to appropriately select patients for transcatheter aortic valve implantation. Mitral valve repair is superior to replacement in the elderly, although choosing the most effective method is important for achieving maximal quality of life. Minimally-invasive mitral valve surgery in the elderly has similar postoperative outcomes to sternotomy-based surgery, but reduces hospital length of stay and return to activity. In operative candidates, surgical repair is superior to percutaneous repair. Current evidence indicates that advanced age alone is not a predictor of mortality or morbidity in cardiac surgery. Thus surgery should not be overlooked or denied to the elderly solely on the basis of their "chronological age", without considering the patient's true "biological age".

Minimally invasive mitral valve surgery using single dose antegrade Custodiol cardioplegia.

OBJECTIVE: Our unit began a minimally invasive mitral surgery (MIMS) program utilising antegrade Custodiol solution as the sole cardioplegia. The aim of this paper is to report our results of this program. PATIENTS/METHODS: Early clinical outcomes were identified and assessed for the first consecutive 100 MIMS patients with comparisons made to a historical group operated via a sternotomy (n=113). The efficacy of myocardial protection was assessed using surrogate outcomes of myocardial protection with serial sodium concentrations also analysed. RESULTS: Six hours postoperatively 12 patients required inotropic support. Peak troponin-I in the first 24 hours was 5.1 (0.8-40 µg/L [median(range)]. Sodium levels decreased following administration of Custodiol but by six hours postoperatively the sodium had returned to greater than 130 mmol/L in all but five patients. Blood transfusion was smaller in the MIMS versus historical group (RBC 17% vs. 65%). MIMS patients had a shorter duration of ventilation, hospital stay and one-year mortality rate (0%). CONCLUSIONS: In this series of patients undergoing MIMS, single dose antegrade Custodiol offers satisfactory and safe myocardial protection. Early clinical outcomes were also satisfactory. Whilst our findings are observational, they nevertheless support the use of this less invasive approach to mitral surgery using single dose Custodiol for myocardial protection.

Hybrid Transcatheter Approach to an Iatrogenic Left Ventricle-Coronary Sinus Fistula.

This clinical case describes a subacute presentation of decompensated heart failure secondary to an iatrogenic left ventricle-to-coronary sinus fistula after sequential mitral valve surgical procedures. Computed tomography was used to select an unconventional hybrid transapical access approach and facilitate successful closure using a vascular plug.

Anaortic off-pump coronary artery bypass grafting in the elderly and very elderly.

BACKGROUND: Elderly patients undergoing surgical revascularisation may disproportionately benefit from avoiding manipulation of the ascending aorta and cardiopulmonary bypass. In this multi-centre observational study, we sought to determine the 30-day outcomes of anaortic off-pump coronary artery bypass (OPCAB) in an elderly and very-elderly population. METHODS: Data were prospectively collected for all patients aged >70 years old (y) undergoing anaortic OPCAB at three hospitals between January 2002 and October 2011. Analysis was carried out on two age sub-groups (70-79 y vs. ≥80 y). Multiple logistic regression was used to identify predictors of post-operative 30-day mortality. RESULTS: In total, 1135 patients >70 years underwent anaortic OPCAB - 817 (72%) patients were aged 70-79 y while 318 (28%) were aged ≥80 y. The rate of mortality and morbidity for both groups was low: 30-day mortality (70-79 y: 1.8%; ≥80 y: 2.8%) or permanent stroke (70-79 y: 0.2%; ≥80 y: 0.9%). Chronic lung disease, a history of previous myocardial infarction and left main disease were independent predictors of 30-day mortality. CONCLUSIONS: OPCAB is associated with low rates of 30-day mortality and peri-operative stroke in this elderly and very elderly patient cohort. Anaortic OPCAB can provide excellent short-term post-operative outcomes and may give the elderly and very elderly population the opportunity to benefit from surgical coronary revascularisation.

Association of Volume and Outcomes in 234 556 Patients Undergoing Surgical Aortic Valve Replacement.

BACKGROUND: The relationship between institutional volume and operative mortality after surgical aortic valve replacement (SAVR) remains unclear. METHODS: From January 2013 to June 2018, 234 556 patients underwent isolated SAVR (n = 144 177) or SAVR with coronary artery bypass grafting (CABG) (n = 90 379) within the Society of Thoracic Surgeons Adult Cardiac Surgery Database. The association between annualized SAVR volume (group 1 [1-25 SAVRs], group 2 [26-50 SAVRs], group 3 [51-100 SAVRs], and group 4 [>100 SAVRs]) and operative mortality and composite major morbidity or mortality was assessed. Random effects models were used to evaluate whether historical (2013-2015) SAVR volume or risk-adjusted outcomes explained future (2016-2018) risk-adjusted outcomes. RESULTS: The annualized median number of SAVRs per site was 35 (interquartile range, 22-59; isolated aortic valve replacement [AVR], 20; AVR with CABG, 13). Among isolated SAVR cases, the mean operative mortality and composite morbidity or mortality were 1.5% and 9.7%, respectively, at the highest-volume sites (group 4), with significantly higher rates among progressively lower-volume groups (P trend < .001). After adjustment, lower-volume centers had increased odds of operative mortality (group 1 vs group 4 [reference]: adjusted odds ratio [AOR] for SAVR, 2.24 [95% CI, 1.91-2.64]; AOR for SAVR with CABG, 1.96 [95% CI, 1.67-2.30]) and major morbidity or mortality (AOR for SAVR, 1.53 [95% CI, 1.39-1.69]; AOR for SAVR with CABG, 1.46 [95% CI, 1.32-1.61]) compared with the highest-volume institutions. Substantial variation in outcomes was observed across hospitals within each volume category, and prior outcomes explained a greater proportion of hospital operative outcomes than did prior volume. CONCLUSIONS: Operative outcomes after SAVR with or without CABG is inversely associated with institutional procedure volumes; however, prior outcomes are more predictive of future outcomes than is prior volume. Given the excellent outcomes observed at many lower-volume hospitals, procedural outcomes may be preferable to procedural volumes as a quality metric.

Coronary artery bypass grafting with and without manipulation of the ascending aorta--a meta-analysis.

BACKGROUND: The main criticism of surgery in the SYNTAX trial was increased rate of stroke when compared to percutaneous coronary intervention. We aimed to determine whether avoiding aortic manipulation would decrease the rate of stroke. METHOD: We performed a meta-analysis of seven studies comparing coronary artery bypass grafting (CABG) with and without manipulation of the ascending aorta. RESULTS: When anaortic off-pump coronary artery bypass grafting (OPCAB) was compared with conventional CABG, the rate of stroke was 0.38% vs. 1.87% (p<0.0001). When anaortic OPCAB was compared with OPCAB using a side-clamp or proximal graft anastomosis device the rate of stroke was 0.31% vs. 1.35% (p=0.003). CONCLUSION: Avoiding aortic manipulation during CABG may decrease the rate of peri-operative stroke.

Off-pump coronary artery bypass grafting in elderly and high-risk patients--a review.

Elderly and high-risk patients are increasingly being considered for myocardial revascularisation. Most trials comparing the various options for revascularisation exclude elderly and 'high-risk' patients. We have reviewed the options for myocardial revascularisation for elderly patients, and for patients with a number of common 'high-risk' co-morbidities--diabetes mellitus, renal insufficiency, poor left ventricular ejection fraction, peripheral vascular disease, left main coronary artery disease and chronic obstructive pulmonary disease--with a focus on coronary artery bypass grafting without the use of cardiopulmonary bypass and aortic manipulation.

Contemporary Surgical and Transcatheter Management of Mitral Annular Calcification.

BACKGROUND: The presence of mitral annular calcification (MAC) in patients with mitral valve (MV) stenosis or regurgitation is a difficult scenario for surgeons and the heart team. Patients with MAC most often have a significant number of comorbidities that exclude them as surgical candidates. This review highlights the various contemporary techniques available to manage MAC during treatment of the MV. METHODS: This study is a focused review of the anatomy, pathology, and management of MAC. The review describes the surgical and transcatheter techniques with outcomes, where available. RESULTS: The incidence of MAC is between 5% and 42% in patients with severe MV disease. The pathophysiology underlying MAC is not yet clear, but it most likely is related to processes of inflammation and atherosclerosis. Surgical techniques can be grouped into those in which the MAC is completely resected en bloc and those in which the MAC is incompletely resected or left in situ. Transcatheter therapies are feasible in some patients, but they have been limited by the anatomic constraints of MAC; most importantly left ventricular outflow tract obstruction and paravalvular regurgitation. CONCLUSIONS: Surgeons as part of the heart team now have a range of techniques to manage MAC in those patients with severe MV disease. Transcatheter therapies may increase the options for patients whose surgical risk is too high.

The International Society for Minimally Invasive Cardiothoracic Surgery Expert Consensus Statement on Transcatheter and Surgical Aortic Valve Replacement in Low- and Intermediate-Risk Patients: A Meta-Analysis of Randomized and Propensity-Matched Studies.

OBJECTIVE: There is an increasing amount of evidence supporting use of transcatheter aortic valve replacement (TAVR) for treatment of aortic stenosis in patients at low or intermediate risk for surgical aortic valve replacement (SAVR). TAVR is now approved for use in all patient cohorts. Despite this, there remains debate about the relative efficacy of TAVR compared with SAVR in lower-risk cohorts and various subgroups of patients. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and propensity-matched trials to guide a consensus among expert cardiologists and surgeons. METHODS: Studies comparing TAVR and SAVR in low- and intermediate-risk patients were identified by a thorough search of the major databases. Mortality, stroke, and other perioperative outcomes were assessed at 30 days and 1 year. RESULTS: Early mortality was lower in TAVR compared to SAVR in RCTs, but not propensity-matched studies in low-risk cohorts (0.66% vs 1.5%; odds ratio [OR] = 0.44, 95% confidence interval [CI] 0.20 to 0.98, I2 = 0%). No difference in mortality between TAVR and SAVR was identified in intermediate-risk patients at early or later time points. Incidence of perioperative stroke in 3 low-risk RCTs was significantly lower in TAVR (0.4%) than SAVR (1.4%; OR = 0.33, 95% CI 0.13 to 0.81, I2 = 0%). There was no difference in stroke for intermediate-risk patients between TAVR and SAVR. The expert panel of cardiologists and cardiac surgeons provided recommendations for TAVR and SAVR in various clinical scenarios. CONCLUSIONS: In RCTs comparing TAVR and SAVR in low-risk patients, early mortality and stroke were lower in TAVR, but did not differ at 1 year. There was no difference in mortality and stroke in intermediate-risk patients. The Multidisciplinary Heart Team must consider individual patient characteristics and preferences when recommending TAVR or SAVR. The decision must consider the long-term management of each patient's aortic valve disease.

Anaortic, total-arterial, off-pump coronary artery bypass surgery: how to do it.

Several large series have demonstrated that performing off-pump coronary artery bypass surgery without manipulating the ascending aorta (anaortic) utilising all-arterial grafts provides superior protection against neurological injury. Recent series comparing percutaneous coronary intervention (PCI) with surgical revascularisation have demonstrated superior results for surgery over PCI. However, a significant criticism of coronary artery surgery remains the higher incidence of neurological injury when compared to PCI. We present a simple and reproducible technique for anaortic, total-arterial off-pump coronary artery revascularisation.

Valve-Sparing Root Replacement Versus Composite Valve Grafting in Aortic Root Dilation: A Meta-Analysis.

BACKGROUND: Aortic valve-sparing operations theoretically have fewer stroke and bleeding complications but may increase late reoperation risk versus composite valve grafts. METHODS: We meta-analyzed all studies comparing aortic valve-sparing (reimplantation and remodelling) and composite valve-grafting (bioprosthetic and mechanical) procedures. Early outcomes were all-cause mortality, reoperation for bleeding, myocardial infarction, and thromboembolism/stroke. Long-term outcomes included all-cause mortality, reintervention, bleeding, and thromboembolism/stroke. Studies exclusively investigating dissection or pediatric populations were excluded. RESULTS: A total of 3794 patients who underwent composite valve grafting and 2424 who underwent aortic valve-sparing procedures were included from 9 adjusted and 17 unadjusted observational studies. Mean follow-up was 5.8 ± 3.0 years. Aortic valve sparing was not associated with any difference in early mortality, bleeding, myocardial infarction, or thromboembolic complications. Late mortality was significantly lower after valve sparing (incident risk ratio, 0.68; 95% confidence interval [CI], 0.54-0.87; P < .01). Late thromboembolism/stroke (incident rate ratio, 0.36; 95% CI, 0.22-0.60; P < .01) and bleeding (incident rate ratio, 0.21; 95% CI, 0.11-0.42; P < .01) risks were lower after valve sparing. Procedure type did not affect late reintervention. CONCLUSIONS: Aortic valve sparing appears to be safe and associated with reduced late mortality, thromboembolism/stroke, and bleeding compared with composite valve grafting. Late durability is equivalent. Aortic valve sparing should be considered in patients with favorable aortic valve morphology.

Analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience Database for Patient- and Circuit-Related Adverse Events Involving Extracorporeal Membrane Oxygenation.

BACKGROUND/PURPOSE: We assessed commonly reported patient- and circuit-related adverse events involving extracorporeal membrane oxygenation (ECMO) devices by analyzing post-marketing surveillance data from the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. ECMO is a rescue therapy for critically ill patients requiring oxygenation and cardiopulmonary support. Key configurations include veno-venous (VV) ECMO for respiratory support and veno-arterial (VA) ECMO for cardio-respiratory support. Robust data on the most commonly reported complications associated with ECMO therapy are limited. METHODS/MATERIALS: The MAUDE database was queried from January 1, 2009, through March 31, 2019, yielding 93 reports. After excluding duplicate reports, 82 reports were included in the final analysis. RESULTS: Percentages represent the proportion of total submitted MAUDE reports on ECMO. Of the reported cases, 24 were VV-ECMO, 8 were VA-ECMO, and the remainder were unspecified. The most commonly reported patient-related adverse events included hemodynamic decompensation of patients (12.2%), death (12.2%), atrial perforation (7.3%), and bleeding (7.3%). The most commonly reported failure modes were in the following circuit components: mechanical pump (19.5%, mostly due to technical failure or clots), membrane oxygenator (19.5%, mostly due to tear in the membrane or temperature probe), and access cannulae (18.3%, mostly due to structural damage). CONCLUSIONS: Analysis of the MAUDE database demonstrates that in real-world practice, ECMO devices are associated with important complications. With broadened global utilization of ECMO devices, standard complication and failure reporting policies may improve patient selection, operator proficiency, and existing device technology. SUMMARY: An analysis of the Food and Drug Administration's Manufacturer and User Facility Device Experience database demonstrates that in real-world practice, extracorporeal membrane oxygenation devices are associated with serious complications. The most commonly reported patient-related adverse events were hemodynamic decompensation of patients and death, and the most commonly reported failure modes were in the device's mechanical pump and membrane oxygenator.

Smoking and TAVR.

See Article Qintar et al.

Valve-in-Valve TAVR: State-of-the-Art Review.

An increasing number of surgically implanted bioprostheses will require re-intervention for structural valve deterioration. Valve-in-valve transcatheter aortic valve replacement (ViV TAVR) has become an alternative to reoperative surgery, currently approved for high-risk and inoperable patients. Challenges to the technique include higher rates of prosthesis-patient mismatch and coronary obstruction, compared to native valve TAVR. Herein, we review results of ViV TAVR and novel techniques to overcome the aforementioned challenges.