Two-year outcome after implantation of a full magnetically levitated left ventricular assist device: results from the ELEVATE Registry.

AIMS: The ELEVATE Registry was designed to study long-term outcomes with the Heartmate 3 (HM3), a fully magnetically levitated centrifugal ventricular assist device, in a real-world population following CE-mark approval. METHODS AND RESULTS: A total of 540 patients, implanted in Europe and the Middle East were followed in ELEVATE. The registry included 463 patients receiving the HM3 as primary implant (Primary Implant Cohort), 19 patients underwent a pump upgrade from another device (Pump Exchange Cohort) and 58 patients who had experienced an outcome before having the possibility to sign the Informed Consent, for which only outcome data were collected (Anonymized Cohort). Data collection included demographics, survival, adverse events, EQ-5D Visual Analog Score quality of life (EQ-5D VAS QOL) questionnaire, and 6-min walk distance (6MWD). Mean age was 55.6 ± 11.7 years (89% male, 48% ischaemic cardiomyopathy). Seventy per cent of patients were in INTERMACS Profile 1-3 and 12.7% were on temporary mechanical circulatory support. Primary Implant Cohort survival was 83% after 2 years. In the Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Primary Implant Cohort, strokes were observed in 10.2%, gastrointestinal bleedings in 9.7%, pump thrombosis in 1.5%, and outflow graft twists in 3.5%. Heartmate 3 implantation resulted in a significant and sustained improvement of functional capacity and QOL. CONCLUSION: In a real-world population, cohort implanted with the HM3 left ventricular assist device we demonstrate good long-term survival, sustained improvement of functional capacity, and low rates of adverse events (including pump thrombosis). CLINICALTRIALS.GOV IDENTIFIER: NCT02497950.

Comparative analysis of regional outcomes and adverse events after continuous-flow left ventricular assist device implantation: An IMACS analysis.

INTRODUCTION: Regional outcomes after implantation of continuous-flow left ventricular assist devices (LVADs) have not been described. We examined differences in patient selection, survival, and adverse events across 3 geographic regions of the world: the Americas, Asia-Pacific, and Europe. METHODS: Using data from The International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support registry, all adult patients implanted with a continuous-flow LVADs were included in this International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support analysis (n = 15,560), of whom, 9,988 (64%) received axial-flow devices and 5,572 (36%) received centrifugal-flow devices. RESULTS: There were significant interregional differences in the rate of implantation of patients aged >70 years (Americas: 14%, Asia-Pacific: 1%, Europe: 5%; p < 0.0001), morbidly obese (Americas: 5%, Asia-Pacific: 1%, Europe: 1%; p < 0.0001), male (Americas: 79%, Asia-Pacific: 77%, Europe: 85%; p < 0.0001), and implanted as destination therapy (Americas: 48%, Asia-Pacific: 4%, Europe: 22%; p < 0.0001). The rates of centrifugal pump usage varied by region (Americas: 30%, Asia-Pacific: 34%, Eu: 74%; p < 0.0001). Survival rates varied by region and the type of pump flow, with survival at 12 and 48 months (axial flow vs centrifugal flow) being 82% vs 82% and 52% vs 53 in Americas; 92% vs 86% and 83% vs 74% in Asia-Pacific; and 80% vs 75% and 69% vs 53% in Europe, respectively (regional survival p < 0.0001). CONCLUSION: There are marked global differences in LVAD recipient characteristics, device utilization, and post-operative care. These heterogeneities along with differences in patient management and transplantation rates may impact long-term survival. Regional differences in adverse event incidence warrant further investigation.

Durable left ventricular assist device support as a bridge to heart transplant candidacy†.

OBJECTIVES: Left ventricular assist devices are funded in the UK exclusively as a bridge to transplant (BTT). However, patients who potentially could receive a transplant may develop reversible contraindications to transplant. Bridge to candidacy (BTC) has sometimes been controversial, given the uncertain clinical efficacy of BTC and the risk that reimbursement could be denied. We analysed the UK ventricular assist device database to understand how common BTC was and to assess patient survival rates and incidences of transplants. METHODS: We identified BTC implants in patients with pulmonary hypertension, chronic kidney disease and obesity using the UK guidelines for heart transplants. RESULTS: A total of 306 of 540 patients had complete data and 157 were identified as BTC (51%). Overall, there was no difference in survival rates between patients designated as BTC and those designated at BTT (71.9 vs 72.9% at 1 year, respectively; P = 0.82). However, the survival rate was lower at all time points in those with an estimated glomerular filtration rate (eGFR) <40 and in patients with a body mass index (BMI) >32 up to 1-year postimplant. There were no significant differences in the incidence of transplant between patients who were BTC and BTT or for any subgroup up to 5 years. However, we noted a diverging trend towards a lower cumulative incidence of transplant for patients with a BMI >32. CONCLUSIONS: BTC is common in the UK and appears clinically effective, given that the survival rates and the incidence of transplants were comparable with those for BTT. Patients with a high BMI have a worse survival rate through to 1 year and a trend for a lower incidence of a transplant. Patients with a low eGFR also have a worse survival rate, but a similar proportion received transplants.

Clinical characteristics and survival in cardiogenic shock admissions to a UK heart transplant unit.

AIM: We describe the characteristics and outcomes of cardiogenic shock (CS) admissions to a UK transplant unit, which is previously unreported. PATIENTS & METHODS: Fifty-nine unselected, consecutive patients over a 38-month period in CS (INTERMACS ≤2) and potentially eligible for transplant were retrospectively reviewed. RESULTS: Patients were predominantly male (76.3%), young (mean age 42.2 years) and with severe end-organ dysfunction (acute liver/kidney injury 83%, mean lactate 3.5 mmol/l). 57.6% required mechanical support and 28.8% cardiac transplant. 30 days, discharge and 1-year survival were 78, 68 and 63%, respectively. Predictors of death included no transplant, increasing age and increasing creatinine. CONCLUSION: Patients with CS and potential for transplant require significant resource input but demonstrate favorable outcomes in our experience.

The renin-angiotensin-aldosterone system in heart failure for the non-specialist: the past, the present and the future.

Heart failure is one of the major public health challenges facing the Western world. Its prevalence is increasing as the population ages and modern techniques are implemented to manage cardiac disease. In response, there has been a sustained effort to develop novel strategies to address the high levels of associated morbidity and mortality. Indeed, agents that target the renin-angiotensin-aldosterone system (RAAS) have transformed the way in which we manage heart failure. Despite this, mortality in heart failure is poorer than in many malignancies and a large burden of morbidity and recurrent hospitalisation remains. Here, we review the role of RAAS modulation within the field of systolic heart failure. In particular, we provide practical guidance on using current RAAS blockade agents and focus on the recent emergence of new agents that promise additional substantial benefit to those living with left ventricular systolic dysfunction.

Prolonged asystole in a patient with an isolated left ventricular assist device.

Left ventricular assist devices (LVADs) are well established in the management of end-stage heart failure as either destination therapy, a bridge prior to cardiac transplantation or during myocardial recovery. Despite LVADs requiring adequate left ventricular preload to effectively augment systemic circulation, there have been rare cases of patients with LVADs surviving sustained, normally fatal arrhythmias, such as ventricular fibrillation and asystole. Whilst current reports describe an LVAD patient surviving 15 days with such an arrhythmia, we describe the case of a patient with an LVAD surviving 104 days of asystole via a Fontan mechanism of circulation, which we believe is the longest known survival of a sustained fatal arrhythmia. This case highlights the physiology of circulations supported by LVADs and the unique challenges that may arise in managing ambulant LVAD patients, such as predicting prognosis. Given the increasing use of LVADs to treat end-stage heart failure, these issues are likely to become more frequently encountered in the future.

Myocardial recovery with mechanical circulatory support.

Mechanical circulatory support (MCS) is instituted in patients with advanced heart failure, some of who may experience sufficient recovery in cardiac function to allow withdrawal of mechanical support. The incidence of left ventricular recovery with MCS is unclear as reported series in the literature demonstrate widely divergent rates. A number of clinical parameters (including echocardiographic, haemodynamic and physiological) are used to indicate likely left ventricular recovery during pump speed reduction but no internationally agreed definition exists. Withdrawal of MCS is not without risk and so robust clinical and biochemical definitions are important to minimize patient morbidity and mortality. Here we review our current understanding of left ventricular recovery with MCS.

Is foxglove effective in heart failure?

BACKGROUND: Digoxin is the oldest known treatment for heart failure (HF) and has been demonstrated to reduce admissions for worsening heart failure in a large randomized trial recruiting patients in sinus rhythm with heart failure and ejection fraction <45%. This study forms the basis for current international guidelines recommending that digoxin should be considered in patients with symptomatic HF despite optimal doses of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, ß-blockers, and mineralocorticoid receptor antagonists in addition to device therapy, if indicated. However, digoxin predates mortality reducing HF therapies, and this article reviews the historical and recent data. METHODS: Multiple PubMed searches were performed including, but not limited to, the search terms "digoxin," "heart failure," "efficacy," "treatment," "side-effects," "morbidity," "mortality," and "arrythmia." Articles were excluded if not relevant, not in English or without abstract. Reference lists of relevant articles were manually searched for further references. Due to the large number of articles retrieved, a selection was reviewed based on the authors' best judgement. RESULTS: Three randomized controlled trials and three large contemporary observational reports of digoxin therapy in heart failure and sinus rhythm were retrieved. Other studies were noted that included patients with heart failure and atrial fibrillation, which were also reviewed. CONCLUSION: Definitive randomized evidence of digoxin efficacy as add-on therapy in HF is lacking because most landmark trials of modern HF disease modifying agents postdate the randomized studies of digoxin. Furthermore, questions remain regarding the optimum dose of digoxin and there are signals that digoxin may be harmful in some patients with HF. All contemporary data for digoxin in HF are derived from observational studies and the findings are conflicting. Despite two centuries of experience using cardiac glycosides to treat HF, fundamental questions regarding the efficacy and safety of digoxin in HF remain unanswered.

Multiparametric cardiovascular magnetic resonance surveillance of acute cardiac allograft rejection and characterisation of transplantation-associated myocardial injury: a pilot study.

BACKGROUND: Serial surveillance endomyocardial biopsies are performed in patients who have recently undergone heart transplantation in order to detect acute cardiac allograft rejection (ACAR) before symptoms occur, however the biopsy process is associated with a number of limitations. This study aimed to prospectively and longitudinally evaluate the performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting and monitoring ACAR in the early phase post-transplant, and characterize graft recovery following transplantation. METHODS: All patients receiving a heart transplant at a single UK centre over a period of 25 months were approached within one month of transplantation. Multiparametric CMR was prospectively performed on the same day as biopsy on four separate occasions (6 weeks, 10 weeks, 15 weeks and 20 weeks post-transplant). CMR included assessment of global and regional ventricular function, myocardial tissue characterization (T1 mapping, T2 mapping, extracellular volume, LGE) and pixel-wise absolute myocardial blood flow quantification. CMR parameters were compared with biopsy findings. As is standard, grade 2R or higher ACAR was considered significant. RESULTS: 88 CMR-matched biopsies were performed in 22 patients. Eight (9%) biopsies in 5 patients demonstrated significant ACAR. Significant ACAR was associated with a reduction in circumferential strain (-12.7±2.5% vs. -13.7±3.6%, p=0.047) but there was considerable overlap between groups. Whilst trends were observed between ACAR and proposed CMR markers of oedema, particularly after adjusting for primary graft dysfunction, differences were not significant. Significant improvements were seen in markers of graft structure and contractility, oedema and microvascular function over the period studied, although few parameters normalised. CONCLUSIONS: This study provides novel insight into the myocardial injury associated with transplantation, and its recovery, however multiparametric CMR was not able to accurately detect ACAR during the early phase post-transplantation.

Multiparametric cardiovascular magnetic resonance assessment of cardiac allograft vasculopathy.

OBJECTIVES: This study sought to evaluate the diagnostic performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting cardiac allograft vasculopathy (CAV) using contemporary invasive epicardial artery and microvascular assessment techniques as reference standards, and to compare the performance of CMR with that of angiography. BACKGROUND: CAV continues to limit the long-term survival of heart transplant recipients. Coronary angiography has a Class I recommendation for CAV surveillance and annual or biannual surveillance angiography is performed routinely in most centers. METHODS: All transplant recipients referred for surveillance angiography at a single UK center over a 2-year period were prospectively screened for study eligibility. Patients prospectively underwent coronary angiography followed by coronary intravascular ultrasound, fractional flow reserve, and index of microcirculatory resistance. Within 1 month, patients underwent multiparametric CMR, including assessment of regional and global ventricular function, absolute myocardial blood flow quantification, and myocardial tissue characterization. In addition, 10 healthy volunteers underwent CMR. RESULTS: Forty-eight patients were recruited, median 7.1 years (interquartile range: 4.6 to 10.3 years) since transplantation. The CMR myocardial perfusion reserve was the only independent predictor of both epicardial (ß = -0.57, p < 0.001) and microvascular disease (ß = -0.60, p < 0.001) on stepwise multivariable regression. The CMR myocardial perfusion reserve significantly outperformed angiography for detecting moderate CAV (area under the curve, 0.89 [95% confidence interval (CI): 0.79 to 1.00] vs. 0.59 [95% CI: 0.42 to 0.77], p = 0.01) and severe CAV (area under the curve, 0.88 [95% CI: 0.78 to 0.98] vs. 0.67 [95% CI: 0.52 to 0.82], p = 0.05). CONCLUSIONS: CAV, including epicardial and microvascular components, can be detected more accurately using noninvasive CMR-based absolute myocardial blood flow assessment than with invasive coronary angiography, the current clinical surveillance technique.

Should we consider patients with coexistent hepatitis B or C infection for orthotopic heart transplantation?

Heart transplantation (HTX) is the gold standard surgical treatment for patients with advanced heart failure. The prevalence of hepatitis B and hepatitis C infection in HTX recipients is over 10%. Despite its increased prevalence, the long-term outcome in this cohort is still not clear. There is a reluctance to place these patients on transplant waiting list given the increased incidence of viral reactivation and chronic liver disease after transplant. The emergence of new antiviral therapies to treat this cohort seems promising but their long-term outcome is yet to be established. The aim of this paper is to review the literature and explore whether it is justifiable to list advanced heart failure patients with coexistent hepatitis B/C infection for HTX.

Should we consider heart rate reduction in cardiac transplant recipients?

Increased resting heart rate is an independent modifiable risk factor for the development of cardiovascular disease. Numerous studies have demonstrated improved clinical outcomes with heart rate reduction in patients with coronary artery disease and heart failure, but its role in transplanted hearts is not yet established. Sinus tachycardia is more common in heart transplant recipients due to graft denervation. Although a large number of studies have recognized increased heart rate as a predictor of native coronary artery atherosclerosis and overall cardiac mortality, contradicting results have been observed in heart transplant recipients. There is no clear consensus about what the normal range of heart rate should be following heart transplantation. The aim of this article was to review the literature to evaluate whether heart rate reduction should be considered in heart transplant recipients.

Heart rate after cardiac transplantation-lessons from the tortoise and the shrew.

There is a striking consistency in the total number of heart beats accrued over a lifetime across a range of animal species despite vast differences in size. Moreover, an inverse relationship is observed between heart rate and lifespan, leading to speculation that elevated heart rate could significantly affect longevity. It is the aim of this review to analyze heart rate as a contributing factor in defining the functional lifespan of the transplanted human heart, which may unavoidably determine the longevity of the recipient. Sinus tachycardia occurs as a result of sympathetic/parasympathetic denervation, an unavoidable consequence of transplantation. The effect of elevated heart rate in this cohort has been scarcely reported. We highlight herein multitudinous mechanisms whereby elevated heart rate accelerates the deterioration in cardiac function and arterial elasticity due to injury and stress accumulation. Additionally, we propose a significant role for heart rate in confounding the alloimmune response. Tachycardia exacerbates injurious episodes of myocardial ischemia and significantly increases the production of reactive oxygen species via increased metabolism. These factors promote immune infiltration and activation, contributing to acute and chronic rejection. Further research is required to assess the potential therapeutic benefits of heart rate reduction.

Brain natriuretic peptide induces CD8+ T cell death via a caspase 3 associated pathway--implications following heart transplantation.

BACKGROUND: Brain natriuretic peptide (BNP) remains elevated after cardiac transplantation despite replacement of the failing ventricle. Serum peaks are also seen during acute rejection episodes independent of intracardiac hemodynamic disturbance. High BNP levels are also reported during bacterial sepsis, burns, stroke and myocardial infarction. Given all of these conditions are linked by immune activation processes, we hypothesised that BNP is an immunoactive agent. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of 40 cardiac transplant recipients. Cells were co-cultured for 72h in the presence or absence of BNP. Cells were then immunophenotyped using flow cytometry. Cell death pathways were determined using caspase 3 quantification and mitochondrial membrane assessment. Supernatants were analysed for cytokine, chemokine and growth factor production using luminex. RESULTS: Co-culture of CD8+ T cells with BNP reduced cell number, and increased intracellular caspase 3. Supernatant analysis revealed that BNP reduced the expression of inflammatory cytokines including TNF-α, IL-1α and IL-6. However it preserved the production of anti-inflammatory and regulatory cytokines such as IL-4, 5 and 13. CONCLUSION: Our findings provide evidence that BNP directly induces CD8+ T cell apoptosis via a caspase 3 associated mechanism from cardiac transplant patients. This may impart significant consequences on immune mediated disease processes, such as allograft rejection.

Effect of antipsychotic medications on glucose and lipid levels.

Severe mental illnesses, such as schizophrenia and bipolar affective disorder, are associated with excess cardiovascular morbidity and mortality. Cardiovascular risk in psychiatric disorders is partly related to antipsychotic therapy, especially second-generation or atypical antipsychotics. Some antipsychotic medications are associated with proatherogenic conditions including insulin resistance and dyslipidemia. In particular, olanzapine and clozapine have been consistently demonstrated to promote insulin resistance and dyslipidemia. Ziprasidone and amisulpiride may be associated with more favorable metabolic effects. Many of the published data relating to metabolic effects of anti-psychotics originate from retrospective studies. However, prospective randomized-controlled data are emerging, and the latest evidence is described here.

The usefulness of chronic heart failure treatments in chronic cardiac graft failure.

Following cardiac transplantation, registry data has demonstrated a gradual improvement in survival over the last several decades, which is testament to continual improvement in aftercare strategy. However, a significant number of patients will eventually develop a new syndrome of chronic heart failure, owing to the multitude of physiological processes that occur after transplantation. This condition, referred to as chronic graft failure (CGF) should be regarded as a unique illness rather than one that is simply analogous with chronic heart failure. In particular, the unique pathophysiological (and pharmacological) environment in the setting of CGF presents a challenging situation to the transplant physician. There is uncertainty over which treatments to offer given a paucity of clinical trial data to support the use of standard heart failure treatments in CGF. In this review, we discuss which chronic heart failure treatments could be considered in the setting of CGF based on their mechanisms of action, benefits within the native heart failure setting, and the relevant issues within the posttransplant environment.

The effect of beta-blockers on the adaptive immune system in chronic heart failure.

It remains possible that the benefit from beta-blockers (BBs) in chronic heart failure (CHF) may not entirely be derived from a class-specific effect. Several experimental reports have alluded to the capability of immunomodulation by individual BBs. Given the increasingly recognized importance of the immune system in the pathogenesis of CHF, we studied the effects of BBs on the circulating immune system of these patients. Blood samples from CHF outpatients were prospectively analyzed using flow cytometry and gating software. Results were analyzed against comprehensive clinical details that were recorded during sample donation, including the type of BB administered. 273 blood samples were analyzed from 141 CHF patients, with an average ejection fraction of 31.9% and a mean age of 69.1 years. Patients taking carvedilol had a significantly lower expression of CD107a on cytotoxic T cells compared to bisoprolol (P= 0.001) and nebivolol (P= 0.008). They also had a significantly lower expression of HLA-DR on lymphocytes (P < 0.001 and P= 0.009 for bisoprolol and nebivolol, respectively). Cytotoxic T cells and lymphocytes expressing HLA-DR have been implicated in the pathogenesis of CHF. The fact that carvedilol, but not other commonly used beta-blockers, appears to modulate these important parameters, supports the concept that important differences exist between these agents, which may affect outcomes in CHF.

Neuroendocrine effects on the heart and targets for therapeutic manipulation in heart failure.

Chronic heart failure (CHF) involves derangements in multiple neurohormonal axes leading to a procatabolic state and wasting syndrome associated with significant mortality. Catabolic abnormalities include excess catecholamines and glucocorticoids. Anabolic defects include deficiencies of sex steroids, insulin resistance, and growth hormone (GH) resistance. These abnormalities are also correlated with increased morbidity and mortality in CHF. Anabolic axes have been augmented in pilot studies in CHF with testosterone, GH, insulin-like growth factor-1, and GH secretagogues. Results have been varied although some treatments have been associated with improved surrogate endpoints. This review article explores the current understanding of metabolic derangements in CHF and highlights potential neuroendocrine treatment strategies.

Beta-blocker use in heart failure patients with airways disease.

BACKGROUND: Beta-Blockers are often withheld from patients with obstructive airways disease, especially those with reversible airways disease due to fear of inducing bronchospasm. We report our single center experience of cautiously treating such patients who have concomitant chronic heart failure (CHF). HYPOTHESIS: The use of cardioselective beta-blockers under caution and specialist supervision may be tolerable in many CHF patients with obstructive airways disease, resulting in clinical improvement rather than detriment. METHODS: A retrospective case notes analysis was performed on CHF outpatients who had obstructive airways disease and been treated with beta-blockers. RESULTS: A total of 43 patients were identified, with an average ejection fraction of 31.8%; 18 of these patients had fixed obstructive airways disease, 15 patients had reversible obstructive airways disease, 10 patients had a label of obstructive airways disease (but no supporting evidence for the diagnosis in the hospital notes). In all 3 groups, beta-blockers had been initiated and maintained without any respiratory event over a median continuous exposure time of 135 days. Limitation of the dose was documented in only 2 patients because of worsening shortness of breath. New York Heart Association (NYHA) class significantly improved for the group with the use of these agents (p = 0.003). CONCLUSION: A cautious approach (under specialist supervision) to beta-blocker use in patients with heart failure and airways disease can result in successful treatment. The implications of withholding these agents may have more serious consequences than their administration.