Transcriptomal Insights of Heart Failure from Normality to Recovery.

Current management of heart failure (HF) is centred on modulating the progression of symptoms and severity of left ventricular dysfunction. However, specific understandings of genetic and molecular targets are needed for more precise treatments. To attain a clearer picture of this, we studied transcriptome changes in a chronic progressive HF model. Fifteen sheep (Ovis aries) underwent supracoronary aortic banding using an inflatable cuff. Controlled and progressive induction of pressure overload in the LV was monitored by echocardiography. Endomyocardial biopsies were collected throughout the development of LV failure (LVF) and during the stage of recovery. RNA-seq data were analysed using the PANTHER database, Metascape, and DisGeNET to annotate the gene expression for functional ontologies. Echocardiography revealed distinct clinical differences between the progressive stages of hypertrophy, dilatation, and failure. A unique set of transcript expressions in each stage was identified, despite an overlap of gene expression. The removal of pressure overload allowed the LV to recover functionally. Compared to the control stage, there were a total of 256 genes significantly changed in their expression in failure, 210 genes in hypertrophy, and 73 genes in dilatation. Gene expression in the recovery stage was comparable with the control stage with a well-noted improvement in LV function. RNA-seq revealed the expression of genes in each stage that are not reported in cardiovascular pathology. We identified genes that may be potentially involved in the aetiology of progressive stages of HF, and that may provide future targets for its management.

Evolution of a circulatory support system with full implantability: personal perspectives on a long journey.

Implantable mechanical circulatory support systems have evolved dramatically over the last 50 years. The objective has been to replace or support the failing left ventricle with a device that pumps six litres of blood each minute, a massive 8,640 litres per day. Noisy cumbersome pulsatile devices have been replaced by smaller silent rotary blood pumps that are much more patient friendly. Nonetheless, the tethering to external components, together with the risks of power line infection, pump thrombosis and stroke, must be addressed before widespread acceptance. Infection predisposes to thromboembolism, so elimination of the percutaneous electric cable has the capacity to transform outcomes, reduce costs and improve quality of life. Developed in the UK, the Calon miniVAD is powered by an innovative coplanar energy transfer system. As such, we consider it can achieve those ambitious objectives.

Mechanical assist devices for acute cardiogenic shock.

BACKGROUND: Cardiogenic shock (CS) is a state of critical end-organ hypoperfusion due to a primary cardiac disorder. For people with refractory CS despite maximal vasopressors, inotropic support and intra-aortic balloon pump, mortality approaches 100%. Mechanical assist devices provide mechanical circulatory support (MCS) which has the ability to maintain vital organ perfusion, to unload the failing ventricle thus reduce intracardiac filling pressures which reduces pulmonary congestion, myocardial wall stress and myocardial oxygen consumption. This has been hypothesised to allow time for myocardial recovery (bridge to recovery) or allow time to come to a decision as to whether the person is a candidate for a longer-term ventricular assist device (VAD) either as a bridge to heart transplantation or as a destination therapy with a long-term VAD. OBJECTIVES: To assess whether mechanical assist devices improve survival in people with acute cardiogenic shock. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid) and Web of Science Core Collection in November 2019. In addition, we searched three trials registers in August 2019. We scanned reference lists and contacted experts in the field to obtain further information. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials on people with acute CS comparing mechanical assist devices with best current intensive care management, including intra-aortic balloon pump and inotropic support. DATA COLLECTION AND ANALYSIS: We performed data collection and analysis according to the published protocol. Primary outcomes were survival to discharge, 30 days, 1 year and secondary outcomes included, quality of life, major adverse cardiovascular events (30 days/end of follow-up), dialysis-dependent (30 days/end of follow-up), length of hospital stay and length of intensive care unit stay and major adverse events. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta-analyses for the prespecified outcomes Summary statistics for the primary endpoints were risk ratios (RR), hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS: The search identified five studies from 4534 original citations reviewed. Two studies included acute CS of all causes randomised to treatment using TandemHeart percutaneous VAD and three studies included people with CS secondary to acute myocardial infarction who were randomised to Impella CP or best medical management. Meta-analysis was performed only to assess the 30-day survival as there were insufficient data to perform any further meta-analyses. The results from the five studies with 162 participants showed mechanical assist devices may have little or no effect on 30-day survival (RR of 1.01 95% CI 0.76 to 1.35) but the evidence is very uncertain. Complications such as sepsis, thromboembolic phenomena, bleeding and major adverse cardiovascular events were not infrequent in both the MAD and control group across the studies, but these could not be pooled due to inconsistencies in adverse event definitions and reporting. We identified four randomised control trials assessing mechanical assist devices in acute CS that are currently ongoing. AUTHORS' CONCLUSIONS: There is no evidence from this review of a benefit from MCS in improving survival for people with acute CS. Further use of the technology, risk stratification and optimising the use protocols have been highlighted as potential reasons for lack of benefit and are being addressed in the current ongoing clinical trials.

Can we remove scar and fibrosis from adult human myocardium?

The pathological processes leading to heart failure are characterized by the formation of fibrosis and scar, yet the dynamics of scar production and removal are incompletely understood. Spontaneous disappearance of myocardial collagen is reported in infancy but doubted in adulthood where scar volume constitutes a better prognostic indicator than the conventional parameters of ventricular function. Whilst certain drugs are known to attenuate myocardial fibrosis evidence is emerging that stem cell therapy also has the potential to reduce scar size and improve myocardial viability. Both animal studies and clinical trials support the concept that, as in infancy, cellular processes can be triggered to remove collagen and regenerate injured myocardium. The molecular mechanisms likely involve anti-fibrotic cytokines growth factors and matrix-metalloproteinases. Autologous cardiac, bone-marrow and adipose tissue derived stem cells have each shown efficacy. Specific immune privileged mesenchymal stem cells and genetically modified immunomodulatory progenitor cells may in turn provide an allogenic source for the paracrine effects. Thus autologous and allogenic cells both have the potential through paracrine action to reduce scar volume, boost angiogenesis and improve ventricular morphology. The potential benefit of myocardial cell therapy for routine treatment of heart failure is an area that requires further study.

Extra-corporeal membrane oxygenation for refractory cardiogenic shock after adult cardiac surgery: a systematic review and meta-analysis.

BACKGROUND: Postcardiotomy cardiogenic shock (PCCS) refractory to inotropic support and intra-aortic balloon pump (IABP) occurs rarely but is almost universally fatal without mechanical circulatory support. In this systematic review and meta-analysis we looked at the evidence behind the use of veno-arterial extra-corporeal membrane oxygenation (VA ECMO) in refractory PCCS from a patient survival rate and determinants of outcome viewpoint. METHODS: A systematic review was performed in January 2017 using PubMed (with no defined time period) using the keywords "postcardiotomy", "cardiogenic shock", "extracorporeal membrane oxygenation" and "cardiac surgery". We excluded papers pertaining to ECMO following paediatric cardiac surgery, medical causes of cardiogenic shock, as well as case reports, review articles, expert opinions, and letters to the editor. Once the studies were collated, a meta-analysis was performed on the proportion of survivors in those papers that met the inclusion criteria. Meta-regression was performed for the most commonly reported adverse prognostic indicators (API). RESULTS: We identified 24 studies and a cumulative pool of 1926 patients from 1992 to 2016. We tabulated the demographic data, including the strengths and weaknesses for each of the studies, outcomes of VA ECMO for refractory PCCS, complications, and APIs. All the studies were retrospective cohort studies. Meta-analysis of the moderately heterogeneous data (95% CI 0.29 to 0.34, p < 0.01, I 2  = 60%) revealed overall survival rate to hospital discharge of 30.8%. Some of the commonly reported APIs were advanced age (>70 years, 95% CI -0.057 to 0.001, P = 0.058), and long ECMO support (95% CI -0.068 to 0.166, P = 0.412). Postoperative renal failure, high EuroSCORE (>20%), diabetes mellitus, obesity, rising lactate whilst on ECMO, gastrointestinal complications had also been reported. CONCLUSION: Haemodynamic support with VA ECMO provides a survival benefit with reasonable intermediate and long-term outcomes. Many studies had reported advanced age, renal failure and prolonged VA ECMO support as the most likely APIs for VA ECMO in PCCS. EuroSCORE can be utilized to anticipate the need for prophylactic perioperative VA ECMO in the high-risk category. APIs can be used to aid decision-making regarding both the institution and weaning of ECMO for refractory PCCS.

National Survey of UK Consultant Surgeons' Opinions on Surgeon-Specific Mortality Data in Cardiothoracic Surgery.

BACKGROUND: In the United Kingdom, cardiothoracic surgeons have led the outcome reporting revolution seen over the last 20 years. The objective of this survey was to assess cardiothoracic surgeons' opinions on the topic, with the aim of guiding future debate and policy making for all subspecialties. METHODS AND RESULTS: A questionnaire was developed using interviews with experts in the field. In January 2015, the survey was sent out to all consultant cardiothoracic surgeons in the United Kingdom (n=361). Logistic regression, bivariate correlation, and the χ(2) test were used to assess whether there was a relationship between answers and demographic variables. Free-text responses were analyzed using the grounded theory approach. The response rate was 73% (n=264). The majority of respondents (58.1% oppose, 34.1% favor, and 7.8% neither) oppose the public release of surgeon-specific mortality data and associate it with several adverse consequences. These include risk-averse behavior, gaming of data, and misinterpretation of data by the public. Despite this, the majority overwhelmingly supports publication of team-based measures of outcome. The free-text responses suggest that this is because most believe that quality of care is multifactorial and not represented by an individual's mortality rate. CONCLUSIONS: There is evident opposition to surgeon-specific mortality data among UK cardiothoracic surgeons who associate this with several unintended consequences. Policy makers should refine their strategy behind publication of surgeon-specific mortality data and possibly consider shift toward team-based results for which there will be the required support. Stakeholder feedback and inclusive strategy should be completed before introducing major initiatives to avoid unforeseen consequences and disagreements.

The value of surgeon-specific outcome data: results of a questionnaire.

OBJECTIVES: The publication of surgeon-specific data has been controversial. To assess the profession's opinion, a forum was organized at the 2015 EACTS meeting followed by a questionnaire of the value of surgeon-specific outcome and its impact. METHODS: A series of presentations were made including assessments of quality and safety in one major European country, the relationship between volume and outcome, the role of guidelines, the effect of publication of results on training, and discussion for and against publication of surgeon-specific data. A questionnaire was given to all attendees at the forum on the value of surgeon-specific data and their impact on the specialty. RESULTS: The questionnaire was completed by 118 attendees. Of the total, 69% felt that mortality is a surrogate for quality and that it should be reported at the hospital and unit level as opposed to the individual surgeon level, but 81% wished there were different criteria for quality outcome. Of the total, 91% felt that the individual surgeons' data should be collected but not published in public portals, and that publication produces risk-averse behaviour; 65% felt that it hinders innovation; 86% felt that EuroSCORE II is not reliable in identifying high-risk patients and the same number felt that it has affected entry into the specialty. CONCLUSIONS: The information that is collectable will be published, but we can control the way in which it is published and presented.

Implantation of a Novel Allogeneic Mesenchymal Precursor Cell Type in Patients with Ischemic Cardiomyopathy Undergoing Coronary Artery Bypass Grafting: an Open Label Phase IIa Trial.

Heart failure is a life-limiting condition affecting over 40 million patients worldwide. Ischemic cardiomyopathy (ICM) is the most common cause. This study investigates in situ cardiac regeneration utilizing precision delivery of a novel mesenchymal precursor cell type (iMP) during coronary artery bypass surgery (CABG) in patients with ischemic cardiomyopathy (LVEF < 40 %). The phase IIa safety study was designed to enroll 11 patients. Preoperative scintigraphy imaging (SPECT) was used to identify hibernating myocardium not suitable for conventional myocardial revascularization for iMP implantation. iMP cells were implanted intramyocardially in predefined viable peri-infarct areas that showed poor perfusion, which could not be grafted due to poor target vessel quality. Postoperatively, SPECT was then used to identify changes in scar area. Intramyocardial implantation of iMP cells with CABG was safe with preliminary evidence of efficacy of improved myocardial contractility and perfusion of nonrevascularized territories resulting in a significant reduction in left ventricular scar area at 12 months after treatment. Clinical improvement was associated with a significant improvement in quality of life at 6 months posttreatment in all patients. The results suggest the potential for in situ myocardial regeneration in ischemic heart failure by delivery of iMP cells.

Progression of matrixin and cardiokine expression patterns in an ovine model of heart failure and recovery.

BACKGROUND: The molecular mechanisms underlying the geometrical changes of the left ventricle during the progression to heart failure and recovery are not well defined. OBJECTIVE: Here we investigate the involvement of matrixins and cardiokines in an ovine model of pressure-induced left ventricular failure (LVF). METHODS: Fifteen sheep underwent supracoronary aortic banding with an inflatable cuff. A controlled and progressive increase of LV pressure was monitored echocardiographically. Endomyocardial biopsies were collected throughout the development of LVF and subsequent recovery after pressure unloading. RESULTS: Thirteen sheep developed LVF with a subsequent recovery. Peak left ventricular hypertrophy (LVH) and dilatation (LVD) occurred at 31.5 ± 1.6 weeks and 102.7 ± 2.2 weeks post-banding respectively, with an increase in LV internal diameter in diastole (LVIDd 5.11 ± 0.12 compared to the control 3.37 ± 0.07 cm, p<0.001), with preserved LV ejection fraction (LVEF). Reduced LVEF became evident 116.5 ± 2.7 weeks post-banding. Clinical and echocardiographic improvements were observed following deflation of the aortic banding cuff. By 138.1 ± 3.1 weeks cardiac performance recovered with restoration of LVEF. Significant changes in the expression of matrix metalloproteinases (MMP)-1, -2, -3, vascular endothelial cell growth factor (VEGF), fibroblast growth factor (FGF)-2, interferon (INF)-α-2 and soluble CD40 ligand (sCD40L) were observed throughout the progression to failure and recovery. CONCLUSIONS: We used an ovine model to study reversible LV remodelling without interruption and found significant changes in matrixin and cardiokine expression during LV progression to failure and recovery.

Recruitment to UK cardiothoracic surgery in the era of public outcome reporting.

OBJECTIVES: Since 1999 important widely publicized issues have affected morale in UK cardiothoracic (CT) surgery. Because more surgeons are needed, we sought to investigate whether these events have affected recruitment and demographic change in the specialty between 1999 and 2014. METHODS: We collected information on UK consultant CT surgeons using the SCTS public portal, the GMC Specialist Register and the NHS Annual Workforce Census via the Health & Social Care Information Centre. We analysed the demographics of UK CT surgeons with regard to country of primary medical qualification and ethnicity between 1999 and 2014. We compared the changes with other surgical specialties, cardiology and respiratory medicine. RESULTS: There has been a worrying decline in UK medical graduates entering the specialty and a 4-fold increase (282%) in consultant appointments from Europe. Whilst consultant numbers expanded by 83% overall, 59% of congenital heart surgeons, 46% of thoracic surgeons and 36% of adult cardiac surgeons are overseas graduates. It is found that 5% are female. Currently, only 32% of trainee surgeons are UK graduates. Of those receiving UK Certificate of Completion of Training in 2013, only 18% were UK graduates compared with 68% in 2000. Comparison with other specialties shows fewer UK graduates in CT surgery with the exception of Obstetrics and Gynaecology (52%). In cardiology, 77% are UK graduates with only 8% from Europe. CONCLUSIONS: Repeated negative messages have had a detrimental influence on recruitment. Because 55% of UK medical graduates, but less than 5% of CT surgeons are female, recruitment problems may worsen. Action is needed to restore interest in the specialty.

Surgeon-specific mortality data disguise wider failings in delivery of safe surgical services.

OBJECTIVES: Feedback of clinical outcome data to clinicians can promote and enhance patient safety. Surgeon-specific mortality data (SSMD) have been released to the public for a number of specialties. This implies that one individual is culpable for all deaths. Debate continues about SSMD because of risk-averse behaviour. In the USA, improved outcome measures derived from phase of care mortality analysis (POCMA) and the failure to rescue (FTR) are replacing SSMD, but they have not been tested in Europe. METHODS: Using POCMA and FTR analysis, we studied hospital deaths in 1558 cardiac surgical patients between 2009 and 2013. Comorbidity and urgency status were used to calculate modified logistic EuroSCORE (MLE). The circumstances of death were critically reviewed by a panel of four experienced surgeons. Death certificate information and autopsy were taken into account. Deaths were then classified: Class 1 surgeon dependent, Class 2 FTR or Class 3 where multiple factors conspired to cause death. RESULTS: There were 51 deaths providing 3.3% mortality, as predicted by MLE. In the 86% who underwent autopsy, no surgical error was identified. Most deaths in each group were related to high-risk status, age, frailty, comorbidity and urgency. FTR was the predominant factor occurring in 45%. Though difficult operations were implicated in 37%, no deaths occurred in the operating theatre. Some FTR deaths occurred in low-risk patients. Scrutiny of FTR deaths provided important information that could be used for quality improvement. CONCLUSIONS: The study showed that most deaths cannot be prevented by the operating surgeon. They occurred through issues of patient comorbidity, lack of process or infrastructure. This casts doubt on SSMD publication alone as a tool for quality improvement. In contrast, POCMA and FTR highlight problems of process, and are more likely to promote advances in surgical care.

The CentriMag centrifugal blood pump as a benchmark for in vitro testing of hemocompatibility in implantable ventricular assist devices.

Implantable ventricular assist devices (VADs) have proven efficient in advanced heart failure patients as a bridge-to-transplant or destination therapy. However, VAD usage often leads to infection, bleeding, and thrombosis, side effects attributable to the damage to blood cells and plasma proteins. Measuring hemolysis alone does not provide sufficient information to understand total blood damage, and research exploring the impact of currently available pumps on a wider range of blood cell types and plasma proteins such as von Willebrand factor (vWF) is required to further our understanding of safer pump design. The extracorporeal CentriMag (Thoratec Corporation, Pleasanton, CA, USA) has a hemolysis profile within published standards of normalized index of hemolysis levels of less than 0.01 g/100 L at 100 mm Hg but the effect on leukocytes, vWF multimers, and platelets is unknown. Here, the CentriMag was tested using bovine blood (n = 15) under constant hemodynamic conditions in comparison with a static control for total blood cell counts, hemolysis, leukocyte death, vWF multimers, microparticles, platelet activation, and apoptosis. The CentriMag decreased the levels of healthy leukocytes (P < 0.006), induced leukocyte microparticles (P < 10(-5) ), and the level of high molecular weight of vWF multimers was significantly reduced in the CentriMag (P < 10(-5) ) all compared with the static treatment after 6 h in vitro testing. Despite the leukocyte damage, microparticle formation, and cleavage of vWF multimers, these results show that the CentriMag is a hemocompatible pump which could be used as a standard in blood damage assays to inform the design of new implantable blood pumps.