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Summary Background Previous studies have suggested that haemodynamic-guided management using an implantable pulmonary artery pressure monitor reduces heart failure hospitalisations in patients with moderately symptomatic (New York Heart Association [NYHA] functional class III) chronic heart failure and a hospitalisation in the past year, irrespective of ejection fraction. It is unclear if these benefits extend to patients with mild (NYHA functional class II) or severe (NYHA functional class IV) symptoms of heart failure or to patients with elevated natriuretic peptides without a recent heart failure hospitalisation. This trial was designed to evaluate whether haemodynamic-guided management using remote pulmonary artery pressure monitoring could reduce heart failure events and mortality in patients with heart failure across the spectrum of symptom severity (NYHA funational class II–IV), including those with elevated natriuretic peptides but without a recent heart failure hospitalisation. Methods The randomised arm of the haemodynamic-GUIDEed management of Heart Failure (GUIDE-HF) trial was a multicentre, single-blind study at 118 centres in the USA and Canada. Following successful implantation of a pulmonary artery pressure monitor, patients with all ejection fractions, NYHA functional class II–IV chronic heart failure, and either a recent heart failure hospitalisation or elevated natriuretic peptides (based on a-priori thresholds) were randomly assigned (1:1) to either haemodynamic-guided heart failure management based on pulmonary artery pressure or a usual care control group. Patients were masked to their study group assignment. Investigators were aware of treatment assignment but did not have access to pulmonary artery pressure data for control patients. The primary endpoint was a composite of all-cause mortality and total heart failure events (heart failure hospitalisations and urgent heart failure hospital visits) at 12 months assessed in all randomly assigned patients. Safety was assessed in all patients. A pre-COVID-19 impact analysis for the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov , NCT03387813 . Findings Between March 15, 2018, and Dec 20, 2019, 1022 patients were enrolled, with 1000 patients implanted successfully, and follow-up was completed on Jan 8, 2021. There were 253 primary endpoint events (0·563 per patient-year) among 497 patients in the haemodynamic-guided management group (treatment group) and 289 (0·640 per patient-year) in 503 patients in the control group (hazard ratio [HR] 0·88, 95% CI 0·74–1·05; p=0·16). A prespecified COVID-19 sensitivity analysis using a time-dependent variable to compare events before COVID-19 and during the pandemic suggested a treatment interaction (pinteraction=0·11) due to a change in the primary endpoint event rate during the pandemic phase of the trial, warranting a pre-COVID-19 impact analysis. In the pre-COVID-19 impact analysis, there were 177 primary events (0·553 per patient-year) in the intervention group and 224 events (0·682 per patient-year) in the control group (HR 0·81, 95% CI 0·66–1·00; p=0·049). This difference in primary events almost disappeared during COVID-19, with a 21% decrease in the control group (0·536 per patient-year) relative to pre-COVID-19, virtually no change in the treatment group (0·597 per patient-year), and no difference between groups (HR 1·11, 95% CI 0·80–1·55; p=0·53). The cumulative incidence of heart failure events was not reduced by haemodynamic-guided management (0·85, 0·70–1·03; p=0·096) in the overall study analysis but was significantly decreased in the pre-COVID-19 impact analysis (0·76, 0·61–0·95; p=0·014). 1014 (99%) of 1022 patients had freedom from device or system-related complications. Interpretation Haemodynamic-guided management of heart failure did not result in a lower composite endpoint rate of mortality and total heart failure events compared with the control group in the overall study analysis. However, a pre-COVID-19 impact analysis indicated a possible benefit of haemodynamic-guided management on the primary outcome in the pre-COVID-19 period, primarily driven by a lower heart failure hospitalisation rate compared with the control group. Funding Abbott.

Increased left ventricular dilation and reduced systolic function are consistently associated with a poor prognosis and worse clinical outcomes. In this review, we discuss the pathophysiological me...

A previously healthy 39-year-old man presented in cardiogenic shock with evidence of multisystem inflammatory syndrome of adults 2 months after a mild case of coronavirus disease 2019. He was treated with intravenous immunoglobulin and pulse-dose corticosteroids with rapid resolution of his symptoms and normalization of biventricular function. (Level of Difficulty: Intermediate.), Central Illustration

Aims Over decades, left ventricular assist device (LVAD) technology has transitioned from less durable bulky pumps to smaller continuous‐flow pumps which have substantially improved long‐term outcomes and quality of life. Contemporary LVAD therapy is beleaguered by haemocompatibility‐related adverse events including thrombosis, stroke and bleeding. A fully magnetically levitated pump, the HeartMate 3 (HM3, Abbott, USA) LVAD, has been shown to be superior to the older HeartMate II (HMII, Abbott, USA) pump by improving haemocompatibility. Experience with the HM3 LVAD suggests near elimination of de‐novo pump thrombosis, a marked reduction in stroke rates, and only a modest decrease in bleeding complications. Since the advent of continuous‐flow LVAD therapy, patients have been prescribed a combination of aspirin and anticoagulation therapy on the presumption that platelet activation and perturbations to the haemostatic axis determine their necessity. Observational studies in patients implanted with the HM3 LVAD who suffer bleeding have suggested a signal of reduced subsequent bleeding events with withdrawal of aspirin. The notion of whether antiplatelet therapy can be avoided in an effort to reduce bleeding complications has now been advanced. Methods To evaluate this hypothesis and its clinical benefits, the Antiplatelet Removal and Hemocompatibility Events with the HeartMate 3 Pump (ARIES HM3) has been introduced as the first‐ever international prospective, randomized, double‐blind and placebo‐controlled, non‐inferiority trial in a patient population implanted with a LVAD. Conclusion This paper reviews the biological and clinical role of aspirin (100 mg) with LVADs and discusses the rationale and design of the ARIES HM3 trial., This figure incorporates the rationale for ARIES HM3 (Antiplatelet Removal and Hemocompatibility Events with the HeartMate 3 Pump), the principal study hypothesis and a summary of its design. LVAD, left ventricular assist device.

Background Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. Methods ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. Results A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n = 37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n = 16), renin-angiotensin-aldosterone system-related therapies (12.3%; n = 14), and colchicine (8.8%; n = 10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n = 5) and 9.6% (n = 11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n = 100), enrollment of less than 1000 participants (86.8%; n = 99), single site implementation (55.3%; n = 63), and had a primary outcome of mortality or a composite including mortality (56.1%; n = 64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n = 93). At the time of database query, 28.9% (n = 33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n = 78). Most lead sponsors were located in North America (43.9%; n = 50) or Europe (36.0%; n = 41). Conclusions A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.

Purpose of review Timely referral of eligible candidates for consideration of advanced therapies, such as a heart transplantation or mechanical circulatory support is essential. The characteristics of heart transplantation candidates have changed significantly over the years, leading to a more complex evaluation process. The present review summarizes recent advances in the evaluation process for heart transplantation eligibility. Recent findings The heart transplantation allocation policy was recently reviewed in the USA in an effort to reduce waitlist mortality and to ensure fair geographic allocation of organs to the sickest patients. Moreover, patients with chronic infectious diseases, as well as malignancies, are being currently considered acceptable candidates for transplantation. Listing practices for heart transplantation vary between programmes, with a greater willingness to consider high-risk candidates at higher-volume centres. Summary The ultimate decision to place high-risk candidates on the heart transplantation waitlist should be based on a combination of quantitative and qualitative data analysis informed by clinical judgement, and the chronic shortage of organ donors makes this process an important ethical concern for any society. Future guidelines should discuss approaches to achieve fair organ allocation while preserving improved outcomes after transplantation.

Cardiac allografts from donors with a history of cocaine use (DHCU) are often discarded owing to concerns regarding organ quality. We investigated long-term outcomes of de novo adult heart transplantation (HTx) using DHCU.Using the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry, we identified 24,430 adult recipients of primary, deceased donor, heart-alone transplants between January 1, 2000, and June 30, 2013. Transplants were categorized on the basis of DHCU. Survival rates were compared using Kaplan-Meier curves and log-rank tests.A total of 3,246 (13.3%) HTx were performed using DHCU during the study period. Of these, 1,477 (45.5%) were classified as current users. Organs from DHCU were transplanted at a later sequence number (data from a sub-group of patients transplanted in the United States) than those from the non-cocaine use group (mean sequence number 16.1 ± 55.6 vs 11.5 ± 38.2; p0.001), suggesting higher decline rates by centers. Kaplan-Meier estimates of survival were not different between groups (p = 0.16), with post-transplant survival rates at 1, 5, and 10 years of 88.1%, 75.8%, and 58.5%, respectively, in the non-cocaine use group and 90.0%, 76.7%, and 59.7%, respectively, in the DHCU group. On multivariate analysis, DHCU were not associated with mortality (hazard ratio [HR]: 0.94; 95% CI: 0.88-1.00; p = 0.050), cardiac allograft vasculopathy (HR: 1.02; 95% CI: 0.94-1.11; p = 0.56), or allograft rejection (HR: 0.98; 95% CI: 0.92-1.05; p = 0.61).Our findings demonstrate that adult HTx performed using DHCU is not associated with an adverse impact on long-term clinical outcomes. These findings should spur efforts to reduce discard rates of organs from DHCU.

Objectives This study sought to determine the frequency, incidence rates over time, association with mortality, and potential risk factors for hemocompatibility-related adverse events (HRAEs) occurring during venoarterial-extracorporeal life support (VA-ECLS). Background HRAEs are common complications of VA-ECLS. Studies examining relevant clinical predictors and the association of HRAEs with survival are limited by small sample size and single-center setting. Methods We queried adult patients supported with VA-ECLS from 2010 to 2017 in the Extracorporeal Life Support Organization database to assess the impact of HRAEs on in-hospital mortality. Results Among 11,984 adults meeting study inclusion, 8,457 HRAEs occurred; 62.1% were bleeding events. The HRAE rate decreased significantly over the study period (p trend Conclusions Although decreasing, HRAEs remain common during VA-ECLS and have a cumulative association with survival. Bleeding events are twice as common as thrombotic events, with a hierarchy of HRAEs influencing survival. Differential risk factors for bleeding and thrombotic complications exist and raise the possibility of a tailored approach to ECLS management.

Substantial progress in the field of mechanical circulatory support (MCS) has expanded the treatment options for patients with advanced-stage heart failure (HF). Currently available MCS devices can be implanted percutaneously or surgically. They can also be configured to support the left, right, or both ventricles, offering varying levels of circulatory support. Short-term temporary MCS devices are primarily used in high-risk percutaneous coronary intervention, cardiogenic shock, and post-cardiac arrest, while durable left ventricular assist systems (LVAS) are increasingly utilized either as a bridge-to-transplant, bridge to decision, or as a destination therapy. The evolution from older pulsatile devices to continuous-flow LVAS and the incorporation of smaller pumps, with no valves, fewer moving parts, and improved hemocompatibility has translated into improved clinical outcomes, greater durability, fewer adverse events, and reduced overall cost of care. However, despite marked advances in device design and clinical management, determining MCS candidacy is often difficult and requires the integration of clinical, biomarker, imaging, exercise, and hemodynamic data. This review aims to provide a summary of the current use of short-term and durable MCS devices in the treatment of advanced-stage HF, highlighting several aspects of LVAS support and the challenges that remain.

To understand the challenges for thoracic transplantation and mechanical circulatory support during the current coronavirus disease 2019 pandemic, we propose separating the effects of the pandemic into 5 distinct stages from a healthcare system perspective. We discuss how the classical ethical principles of utility, justice, and efficiency may need to be adapted, and we give specific recommendations for thoracic transplantation and mechanical circulatory support centers to balance their clinical decisions and strategies for advanced heart and lung disease during the current pandemic.

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

Author(s): Anker, Stefan D; Butler, Javed; Khan, Muhammad Shahzeb; Abraham, William T; Bauersachs, Johann; Bocchi, Edimar; Bozkurt, Biykem; Braunwald, Eugene; Chopra, Vijay K; Cleland, John G; Ezekowitz, Justin; Filippatos, Gerasimos; Friede, Tim; Hernandez, Adrian F; Lam, Carolyn SP; Lindenfeld, JoAnn; McMurray, John JV; Mehra, Mandeep; Metra, Marco; Packer, Milton; Pieske, Burkert; Pocock, Stuart J; Ponikowski, Piotr; Rosano, Giuseppe MC; Teerlink, John R; Tsutsui, Hiroyuki; Van Veldhuisen, Dirk J; Verma, Subodh; Voors, Adriaan A; Wittes, Janet; Zannad, Faiez; Zhang, Jian; Seferovic, Petar; Coats, Andrew JS | Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

Objectives This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial. Background Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide ≥200 ng/l or N-terminal pro–B-type natriuretic peptide ≥800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria. Methods We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death. Results A total of 5,022 patients with left ventricular ejection fraction ≤40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints. Conclusions In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (COMMANDER HF [A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure] NCT01877915)

Early generation left ventricular assist devices (LVAD) for treatment of refractory heart failure attempted to mimic the pulsatility of a native heart and were bulky and less durable due to valves within the inflow and outflow pathways. The next disruption came with the introduction of continuous flow pumps characterized by a low-pulse pressure circulation. Since the mechanism of action did not involve displacement of blood, these pumps were much smaller and less noisy in part due to fewer moving parts. Such devices include the HeartMate II axial-flow pathway pump which is implanted thoraco-abdominally and the HVAD, a centrifugal-flow pathway pump which is smaller and is implanted entirely within the thoracic cavity and uses a combination of hydrodynamic and magnetic levitation of the internal rotor. These pumps improved survival compared with the early generation LVADs and in a trial, the HVAD demonstrated non-inferiority compared with the HeartMate II but with an increase in ischemic and hemorrhagic strokes. The HeartMate 3 LVAD is an intrapericardial centrifugal-flow pathway pump with a full magnetically levitated, frictionless rotor with a fixed intrinsic pulse. In a randomized trial, the HeartMate 3 "hybrid" pump was associated with near-elimination of pump thrombosis, a reduction in strokes of any type or severity and lower mucosal bleeding rates. Despite improvements in hemocompatibility, right heart failure and infections contribute to significant morbidity, and devices designed to be internally contained with a wireless power source and physiological flow characteristics are still required despite great strides in the field.

Anticoagulation before, during, and after heart transplantation (HT) presents unique challenges to clinicians. Bleeding and thrombotic morbidity continues to affect this patient population throughout all phases of the HT journey. Reversal is commonly required since patients are commonly bridged to HT with left ventricular assist devices, which require chronic anti platelet and anticoagulation. Caution must be exercised in patients requiring cardiopulmonary bypass during surgery who are at risk of complications from heparin induced thrombocytopenia. The reported incidence of venous thromboembolism following HT is high, particularly during the first post-HT year, most likely due to surgery, biopsies, specific immunosuppression (mTOR inhibitors) and immobilization. It is crucial to maintain long-term oral anticoagulation after the first venous thromboembolism event, especially when risk factors exist. A major issue, and one for which there remains considerable debate, is the optimal treatment of such complications, particularly upper extremity venous thrombosis. For both warfarin and the thrombin inhibitors or Factor Xa inhibitors, the clinician must determine potential drug interactions based on the HT drug regimen, and then develop a patient-specific management strategy.

Cardiac allograft vasculopathy (CAV)-mediated by a heterogeneous myriad of immune and non-immune factors, which contribute to the progressive and diffuse thickening of the arterial allograft's tunica intima in one distinct form of CAV, and the build-up of plaque in another-is a major limiting factor of long-term survival post heart transplantation. Information on the optimal pharmacotherapeutic approaches for the prevention and management of CAV is conflicting, scattered, and inconsistent, with numerous recent studies adding to the literature. In this paper, we present a go-to clinical resource with the most updated and comprehensive information on the topic. Immunosuppressant therapy remains a staple, with mTOR inhibitors and mycophenolate mofetil (MMF) showing direct correlation with CAV prevention. More data is now available with calcineurin inhibitor (CNI) minimizing or sparing regimens. More novel approaches are being investigated for the roles of monoclonal antibodies, anti-thymocyte globulin, and bortezomib in preventing or delaying CAV. On the other hand, statins' established efficacy is attributed to lipid-lowering and lipid-independent immunomodulatory effects, with early initiation associated with improved outcomes. The choice of statin is dependent on drug-drug interactions. Other aiding approaches for the prevention of CAV include antioxidant vitamins, aspirin, vasodilators, folate therapy, and, most pertinently, cytomegalovirus prophylaxis. Larger clinical trials are needed before these options are institutionalised. For management of established CAV, early initiation of augmented immunosuppressive therapies may be effective, as well as CNI conversion to mTOR inhibitors with or without standard MMF and azathioprine therapy. Risk of acute rejection needs to be monitored during conversion. Finally, preclinical investigations highlight novel potential therapies for CAV prevention and attenuation, however robust clinical trials are needed to test their efficacy and safety.

Alternations in gut microbial composition (i.e. loss of microbial diversity or 'gut dysbiosis') have been associated with heart failure with reduced ejection fraction (HFrEF). It has also been suggested that increased chronic low-level inflammation and immune system dysregulation seen in patients with HFrEF could be related to gut dysbiosis and increased intestinal permeability. Hence, the concept of modulating gut microbial composition with the goal of reducing systemic inflammation and controlling HFrEF progression has generated a substantial interest in the scientific community. However, several challenges to the gut dysbiosis theory remain as the exact gut microbial composition in HFrEF patients in these studies is not the same and a common microbiome linked to HFrEF is not yet established. With the advances in culture independent sequencing techniques it has also become evident that the gut microbiome may be much more diverse than previously believed. Further, various 'omic' technologies have enabled us to appreciate the potential role of gut microbial metabolites in various physiological processes in the host. Hence, identification of specific gut microbial metabolites may offer an alternative approach at solving this gut microbiome-HFrEF puzzle. In the current review, we evaluate the concept of gut symbiosis, the potential role of gut dysbiosis in systemic inflammation and HFrEF, and finally highlight the challenges faced by the gut dysbiosis theory in HFrEF and provide a framework for the possible solutions.

Aims The prognostic importance of post-diagnosis assessment of cardiorespiratory fitness (CRF) in cancer patients is not well established. We sought to examine the association between CRF and mortality in cancer patients. Methods and results This was a single-centre cohort analysis of 1632 patients (58% male; 64 ± 12 years) with adult-onset cancer who were clinically referred for exercise treadmill testing a median of 7 [interquartile range (IQR): 3–12] years after primary diagnosis. Cardiorespiratory fitness was defined as peak metabolic equivalents (METs) achieved during standard Bruce protocol and categorized by tertiles. The association between CRF and all-cause and cause-specific mortality was assessed using multivariable Cox proportional hazard models adjusting for important covariates. Median follow-up was 4.6 (IQR: 2.6–7.0) years; a total of 411 deaths (229, 50, and 132 all-cause, cardiovascular (CV), and cancer related, respectively) occurred during this period. Compared with low CRF (range: 1.9–7.6 METs), the adjusted hazard ratio (HR) for all-cause mortality was 0.38 [95% confidence interval (CI): 0.28–0.52] for intermediate CRF (range: 7.7–10.6 METs) and 0.17 (95% CI: 0.11–0.27) for high CRF (range: 10.7–22.0 METs). The corresponding HRs were 0.40 (95% CI: 0.19–0.86) and 0.41 (95% CI: 0.16–1.05) for CV mortality and 0.40 (95% CI: 0.26–0.60) and 0.16 (95% CI: 0.09–0.28) for cancer mortality, respectively. The adjusted risk of all-cause, CV, and cancer mortality decreased by 26%, 14%, and 25%, respectively with each one MET increment in CRF. Conclusion Cardiorespiratory fitness is a strong, independent predictor of all-cause, CV, and cancer mortality, even after adjustment for important clinical covariates in patients with certain cancers.

Background: \ud Patients with coronary artery disease (CAD) are at increased risk of developing and being hospitalised for heart failure (HFH). However, the risk of HFH versus ischemic events may vary among patients with CAD, depending on whether acute myocardial infarction (MI), left ventricular dysfunction or decompensated HF is present at baseline.\ud \ud Aims: \ud We aim to explore the risk of non-fatal events (HFH, MI, stroke) and subsequent death in 3 landmark trials, COMMANDER-HF, EPHESUS and EXAMINE that, together, included patients with CAD with and without reduced ejection fraction and acute MI.\ud \ud Methods: \ud Events, person-time metrics and time-updated Cox models.\ud \ud Results: \ud In COMMANDER-HF the event-rate for the composite of AMI, stroke or all-cause death was 13.5 (12.8–14.3) events/100 py. Rates for AMI and stroke were much lower (2.2 [2.0–2.6] and 1.3 [1.1–1.6] events/100 py, respectively) than the rate of HFH (16.9 [16.1–17.9] events/100 py). In EPHESUS, the rates of MI and stroke were also lower than the rate of HFH: 7.2 (6.7–7.8), 1.9 (1.7–2.3), and 10.6 (9.9–11.3) events/100 py, but this was not true for EXAMINE with 4.4 (4.0–4.9), 0.7 (0.6–0.9), and 2.4 (2.0–2.7) events/100 py, respectively. In all 3 trials, a non-fatal event (HFH, MI or stroke) during follow-up doubled the risk of subsequent mortality. This most commonly followed a HFH.\ud \ud Conclusions: \ud A first or recurrent HFH is common in patients with CAD and AMI or HFrEF and indicates a poor prognosis. Preventing the development of heart failure after AMI and control of congestion in patients with CAD and HFrEF are key unmet needs and therapeutic targets.\ud \ud Registration: \ud ClinicalTrials.gov Identifier: NCT01877915. URL: https://clinicaltrials.gov/ct2/show/NCT01877915.

Background: Heart failure disproportionately affects Black patients. Whether differences among race influence outcomes in advanced heart failure with use of a fully magnetically levitated continuous-flow left ventricular assist device remains uncertain. Methods: We included 515 IDE (Investigational Device Exemption) clinical trial patients and 500 Continued Access Protocol patients implanted with the HeartMate 3 left ventricular assist device in the MOMENTUM 3 study (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3). Outcomes were compared between Black and White left ventricular assist device recipients for the primary end point of survival free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years, overall survival, adverse events, 6-minute walk distance, and quality of life scores. Results: Of 1015 HeartMate 3 patients, 675 were self-identified as White and 285 as Black individuals. The Black patient cohort was younger, more obese and with a history of hypertension, and more nonischemic cause of heart failure, relative to the White patient group. Black and White patients did not experience a difference in the primary end point (81.1% versus 77.9%; hazard ratio, 1.08 [95% CI, 0.76–1.54], P =0.6568). Black patients were at higher risk of adverse events (calculated as events per 100 patient-years), including bleeding (75.4 versus 63.5; P P =0.0183), and hypertension (10.1 versus 3.2; P P =0.01). The absolute quality of life measurement (EuroQoL group, 5-dimension, 5-level instrument visual analog scale) at baseline and 6 months was better in the Black patient group, but relative improvement from baseline to 6 months was greater in White patients (median: +20.0 [interquartile range, 5.0–40.0] versus +25.0 [interquartile range, 10.0–45.0]; P =0.0298). Conclusions: Although the survival free of disabling stroke or reoperation to replace/remove a malfunctioning device at 2 years with the HM 3 left ventricular assist device did not differ by race, Black HeartMate 3 patients experienced a higher morbidity burden and smaller gains in functional capacity and quality of life when compared with White patients. These findings require efforts designed to better understand and overcome these gaps through systematic identification and tackling of putative factors. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02224755 and NCT02892955.

Aim: The clinical and cost-effectiveness of left ventricular assist device (LVAD) therapy for patients with advanced heart failure (HF) who are ineligible for heart transplantation is debated in UK. This study develops an indirect comparison between the fully magnetically levitated HeartMate 3 (HM 3) LVAD and medical therapy (MT) to evaluate expected clinical and cost-effectiveness in the UK National Health Service (NHS) context. Methods: We performed an economic analysis comparing the HM3 pump against the HeartMate II LVAD (MOMENTUM 3), and then another analysis comparing MT with the first and second generation HeartMate XVE pump LVAD and HeartMate II LVAD for the same patient population (REMATCH and ROADMAP, respectively). By bridging those two analyses, an indirect comparison between HM3 and MT in the form of a network meta-analysis was developed. A literature search was performed to select the most appropriate pair of studies for this purpose. Outcomes were adjusted to produce Kaplan-Meier curves for the cost-effectiveness evaluation by using a decision-analytic model. Data were extrapolated linearly over a 5-year time horizon. Uncertainty and additional scenarios were addressed by one-way and probabilistic sensitivity analysis. Local costs and health utility were used from England, thereby representing the UK context. Results: The incremental cost-effectiveness ratio (ICER) for LVAD versus MT in transplant ineligible patients with advanced HF was estimated to be £47,361 per quality-adjusted life year (QALY) gained, with a 97.1% probability of being cost-effective at £50,000. In a sub-group of patients who are inotropic therapy dependent (INTERMACS 1-3 severity profile), the ICER was £45,616, while for a population with less-ill ambulatory HF (INTERMACS profile 4-7) the ICER changed to £65,018. Conclusion: This study provides evidence that HM3 LVAD therapy in advanced HF patients ineligible for heart transplantation may be cost-effective compared to MT in the NHS UK-England context. The ICER is lowest for patients dependent on inotropic support, but exceeds the willingness to pay threshold of £50,000 in ambulatory non-inotropic therapy dependent advanced HF patients.

Background Early aspirin (ASA) use after orthotopic heart transplantation (OHT) has been associated with lower rates of cardiac allograft vasculopathy (CAV). We hypothesized that the inverse association between ASA use and CAV incidence may be most pronounced in patients with allograft rejection. Methods Patients receiving OHT at a single center 2004-2010 (n = 120) were categorized by early ASA use post-transplant (ASA use for > 6 months in the first year) and the presence of biopsy-defined acute cellular rejection (ACR) and/or antibody-mediated rejection (AMR) during 5 year followup. Propensity scores for ASA treatment were estimated using boosting models and applied by inverse probability of treatment weighting. The association between ASA use and time to moderate/severe CAV (ISHLT ≥ 2) was investigated. Results Among patients with ACR or AMR, ASA therapy was associated with significantly lower rates of CAV≥ 2 (3.3 vs 30.1%; p = 0.001; HRadj 0.07; 95% CI 0.01-0.52) whereas ASA therapy was not associated with lower rates of CAV in patients with no rejection (5.6 vs 5.3%; p = 0.90; HRadj 1.26; 95% CI 0.08-20.30; pinteraction = 0.09). Conclusions Early ASA use after OHT was associated with lower rates of moderate to severe CAV only in those patients with episodes of allograft rejection. This article is protected by copyright. All rights reserved.

BACKGROUND: Gut microbial imbalance may contribute to endotoxemia, inflammation, and oxidative stress in heart failure (HF). Changes occurring in the intestinal microbiota and inflammatory/oxidative milieu during HF progression and following left ventricular assist device (LVAD) or heart transplantation (HT) are unknown. We aimed to investigate variation in gut microbiota and circulating biomarkers of endotoxemia, inflammation, and oxidative stress in patients with HF (New York Heart Association, Class I–IV), LVAD, and HT. METHODS: We enrolled 452 patients. Biomarkers of endotoxemia (lipopolysaccharide and soluble [sCD14]), inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-α, and endothelin-1 adiponectin), and oxidative stress (isoprostane) were measured in 644 blood samples. A total of 304 stool samples were analyzed using 16S rRNA sequencing. RESULTS: Gut microbial community measures of alpha diversity were progressively lower across worsening HF class and were similarly reduced in patients with LVAD and HT (p < 0.05). Inflammation and oxidative stress were elevated in patients with Class IV HF vs all other groups (all p < 0.05). Lipopolysaccharide was elevated in patients with Class IV HF (vs Class I–III) as well as in patients with LVAD and HT (p < 0.05). sCD14 was elevated in patients with Class IV HF and LVAD (vs Class I–III, p < 0.05) but not in patients with HT. CONCLUSIONS: Reduced gut microbial diversity and increased endotoxemia, inflammation, and oxidative stress are present in patients with Class IV HF. Inflammation and oxidative stress are lower among patients with LVAD and HT relative to patients with Class IV HF, whereas reduced gut diversity and endotoxemia persist in LVAD and HT.

Author(s): Rizk, John G; Kalantar-Zadeh, Kamyar; Mehra, Mandeep R; Lavie, Carl J; Rizk, Youssef; Forthal, Donald N

OBJECTIVES: The purpose of this study was to describe our experience with fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET/CT) in diagnosing left ventricular assist device (LVAD) infections and perform a meta-analysis of published studies to determine overall diagnostic accuracy. BACKGROUND: Device-related infections are a common complication of LVADs and are linked to worse outcomes. Diagnosis of LVAD infections remains challenging. FDG PET/CT has demonstrated good diagnostic accuracy in several other infectious conditions. METHODS: This was a single-center, retrospective case series of FDG PET/CT scans in suspected LVAD infection between September 2015 and February 2018. A systematic review of PubMed from database inception through March 2018 was also conducted to identify additional studies. RESULTS: Nineteen FDG PET/CT scans were identified for the retrospective case series. The systematic review identified an additional 3 publications, for a total of 4 studies involving 119 scans assessing diagnostic performance. Axial (n = 36) and centrifugal (n = 83) flow LVADs were represented. Pooled sensitivity was 92% (95% confidence interval [CI]: 82% to 97%) and specificity was 83% (95% CI: 24% to 99%) for FDG PET/CT in diagnosing LVAD infections. Summary receiver-operating characteristic curve analysis demonstrated an AUC of 0.94 (95% CI: 0.91 to 0.95). CONCLUSIONS: FDG PET/CT for suspected LVAD infections demonstrates good diagnostic accuracy, with overall high sensitivity but variable specificity.

Aims Stroke is often a devastating event among patients with heart failure with reduced ejection (HFrEF). In COMMANDER HF, rivaroxaban 2.5 mg b.i.d. did not reduce the composite of first occurrence of death, stroke, or myocardial infarction compared with placebo in patients with HFrEF, coronary artery disease (CAD), and sinus rhythm. We now examine the incidence, timing, type, severity, and predictors of stroke or a transient ischaemic attack (TIA), and seek to establish the net clinical benefit of treatment with low-dose rivaroxaban. Methods and results In this double-blind, randomized trial, 5022 patients who had HFrEF(≤40%), elevated natriuretic peptides, CAD, and who were in sinus rhythm were treated with rivaroxaban 2.5 mg b.i.d. or placebo in addition to antiplatelet therapy, after an episode of worsening HF. The primary neurological outcome for this post hoc analysis was time to first event of any stroke or TIA. Over a median follow-up of 20.5 (25th–75th percentiles 20.0–20.9) months, 150 all-cause stroke (127) or TIA (23) events occurred (ischaemic stroke in 82% and haemorrhagic stroke in 11% of stroke events). Overall, 47.5% of first-time strokes were either disabling (16.5%) or fatal (31%). Prior stroke, low body mass index, geographic region, and the CHA2DS2-VASc score were predictors of stroke/TIA. Rivaroxaban significantly reduced the primary neurological endpoint of all-cause stroke or TIA compared with placebo by 32% (1.29 events vs. 1.90 events per 100 patient-years), adjusted for the time from index HF event to randomization and stratified by geographic region (adjusted hazard ratio 0.68, 95% confidence interval 0.49–0.94), with a number needed to treat of 164 patients per year to prevent one stroke/TIA event. The principal safety endpoint of fatal bleeding or bleeding into a critical space, occurred at a similar rate on rivaroxaban and placebo (0.44 events vs. 0.55 events per 100 patient-years). Conclusions Patients with HFrEF and CAD are at risk for stroke or TIA in the period following an episode of worsening heart failure in the absence of atrial fibrillation. Most strokes are of ischaemic origin and nearly half are either disabling or fatal. Rivaroxaban at a dose of 2.5 mg b.i.d. reduced rates of stroke or TIA compared with placebo in this population. Trial Registration COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure); ClinicalTrials.gov NCT01877915.

Background Hemodynamic-guided heart failure (HF) management using pulmonary artery (PA) pressures reduces HF hospitalizations (HFHs) in previously hospitalized HF patients with New York Heart Association (NYHA) class III symptoms. It remains uncertain whether this approach reduces not only HFHs but all-cause mortality and if benefits extend to patients with NYHA class II and IV HF or to those symptomatic patients with elevated natriuretic peptides without recent HFH. Methods GUIDE-HF is a prospective trial with 2 arms enrolling patients with HF regardless of ejection fraction (EF). The randomized arm is a single-blind, randomized, controlled trial of PA pressure-guided therapy in NYHA class II-IV patients (n = 1,000) with either a previous HFH or elevated natriuretic peptides (B-type natriuretic peptide/NT-pro–B-type natriuretic peptide). All consenting subjects will receive an implantable PA pressure sensor (CardioMEMS HF System) followed by randomization to either a treatment group, managed with provider remote access to the hemodynamic data, or a control group, managed without provider access to these data. Subjects in the control group will receive scheduled, scripted, sham contacts from the study team to maintain blinding as to their study group assignment. The primary study end point is the composite of cumulative HF events and all-cause mortality at 12 months. Secondary end points include quality-of-life and functional assessments. The single arm of the trial is an observational arm in which NYHA class III patients (n = 2,600) with either a previous HFH or elevated natriuretic peptides (but no recent HFH) will be implanted with a PA pressure sensor and observed for occurrence of the primary composite end point of cumulative HF events and mortality at 12 months. This arm will test the hypothesis that hemodynamic-guided care is similarly effective in HF patients enrolled on the basis of elevated natriuretic peptide levels but no recent HFH and those with a recent HFH. Conclusions GUIDE-HF is the largest clinical trial of hemodynamic-guided HF management across a broad population of HF patients, with a study design and sample size adequate to examine survival, cumulative HF events, quality of life, and functional capacity.

Increased shear stress conferred upon the circulation by continuous-flow pumps is associated with hemocompatibility-related adverse events, principally bleeding within the gastrointestinal system, and linked to the degradation of high-molecular-weight multimers (HMWMs) of von Willebrand factor (vWF). We evaluated the structure and functional characteristics of vWF HMWMs in patients with the fully magnetically levitated centrifugal-flow HeartMate 3 (HM3) and the continuous axial-flow HeartMate II (HMII) pump. Findings were correlated with bleeding events.In a prospective, multicenter, comparative cohort study, 60 patients from the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 Continued Access Protocol (NCT02892955) with an HM3 pump were compared with 30 randomly selected HMII patients from the PREVENtion of HeartMate II Pump Thrombosis study (NCT02158403) biobank. The primary end point was the difference in the normalized vWF HMWM ratio (ratio of the HMWMs to the intermediate- and low-molecular-weight multimers, normalized to pooled plasma from healthy volunteers) between the HM3 and the HMII pump at 90 days after implantation. Assay tests for vWF activity, vWF antigen, vWF activity to antigen ratio, coagulation factor VIII activity, and ADAMTS13 activity were measured by using standard protocols. Differences in these markers were compared in the context of clinical characteristics and correlated with adjudicated bleeding events within the HM3 group.Of 51 and 29 evaluable patients in the HM3 and HMII arms, respectively, those implanted with the HM3 pump exhibited greater preservation of the vWF HMWM ratio than those with the HMII pump at 90 days after implantation (54.1% vs 42.4%, p0.0001). Laboratory values for all vWF assays (antigen, activity, and coagulation factor VIII activity) remained within the normal functional range with no significant differences observed between the pumps at 90 days after implantation. At baseline, there was a decrease in the structural integrity of vWF HMWMs that correlated with increasing heart failure severity as measured by the Interagency Registry for Mechanically Assisted Circulatory Support profile. Multivariable modeling identified the HM3 pump as the only independent variable that determined post-implantation preservation of the structural integrity of vWF HMWMs.This prospective, multicenter comparative analysis study demonstrates that the fully magnetically levitated centrifugal-flow HM3 left ventricular assist device is associated with greater preservation of the structure of vWF HMWMs than the HMII mechanical bearing axial-flow pump.

BACKGROUND In this study we sought to evaluate risk factors (RFs) for death or heart transplantation (D-HT) in single-ventricle (SV) physiology due to tricuspid atresia (TA), pulmonary atresia‒intact ventricular septum (PA-IVS), and heterotaxy with SV (HX), clinical conditions for which outcome data are limited. METHODS To conduct a systematic review, we included citations that evaluated occurrence of D-HT in SV physiology of TA, PA-IVS, and HX in English articles published between January 1998 and December 2017 based on inclusion and exclusion criteria, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The Cochrane Risk of Bias in Non-Randomized Studies-Interventions (ROBINS-I) tool for non-randomized studies was used to assess the risk of bias. Meta-analysis was performed if RF data were available in more than 3 studies. RESULTS Of 11,629 citations reviewed, 30 met inclusion criteria. All 30 were observational, retrospective studies. In all, 1,770 patients were included, 481 died and 21 underwent HT (63 lost to follow-up); 723 patients reached Fontan completion. We found that systemic ventricular dysfunction (odds ratio [OR] 20.7, confidence interval [CI] 10.0–42.5, I2 = 0%) and atrioventricular valve regurgitation (AVR) were associated with risk of D-HT (OR 3.7, CI 1.9–6.9, I2 = 14%). RF associations with D-HT could not be derived for right ventricle‒dependent coronary circulation, pulmonary arteriovenous malformations, total anomalous pulmonary venous return, arrhythmias, and pulmonary atresia. CONCLUSIONS This systematic review and meta-analysis has identified a high mortality rate in children born with non-HLHS SV heart disease and points to potential under-utilization of HT. Systemic ventricular dysfunction and AVR were identified as RFs for D-HT in this subset of patients SV with TA, PA-IVS, and HX.

In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device were less likely to have pump thrombosis or nondisabling stroke than were patients treated with a mechanical-bearing axial-flow left ventricular assist device.We randomly assigned patients with advanced heart failure to receive either the centrifugal-flow pump or the axial-flow pump irrespective of the intended goal of use (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or remove a malfunctioning device. The principal secondary end point was pump replacement at 2 years.This final analysis included 1028 enrolled patients: 516 in the centrifugal-flow pump group and 512 in the axial-flow pump group. In the analysis of the primary end point, 397 patients (76.9%) in the centrifugal-flow pump group, as compared with 332 (64.8%) in the axial-flow pump group, remained alive and free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years (relative risk, 0.84; 95% confidence interval [CI], 0.78 to 0.91; P0.001 for superiority). Pump replacement was less common in the centrifugal-flow pump group than in the axial-flow pump group (12 patients [2.3%] vs. 57 patients [11.3%]; relative risk, 0.21; 95% CI, 0.11 to 0.38; P0.001). The numbers of events per patient-year for stroke of any severity, major bleeding, and gastrointestinal hemorrhage were lower in the centrifugal-flow pump group than in the axial-flow pump group.Among patients with advanced heart failure, a fully magnetically levitated centrifugal-flow left ventricular assist device was associated with less frequent need for pump replacement than an axial-flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.).

Background Hearts and lungs from donors with hepatitis C viremia are typically not transplanted. The advent of direct-acting antiviral agents to treat hepatitis C virus (HCV) infection has raised the possibility of substantially increasing the donor organ pool by enabling the transplantation of hearts and lungs from HCV-infected donors into recipients who do not have HCV infection. Methods We conducted a trial involving transplantation of hearts and lungs from donors who had hepatitis C viremia, irrespective of HCV genotype, to adults without HCV infection. Sofosbuvir-velpatasvir, a pangenotypic direct-acting antiviral regimen, was preemptively administered to the organ recipients for 4 weeks, beginning within a few hours after transplantation, to block viral replication. The primary outcome was a composite of a sustained virologic response at 12 weeks after completion of antiviral therapy for HCV infection and graft survival at 6 months after transplantation. Results A total of 44 patients were enrolled: 36 received lung transplants and 8 received heart transplants. The median viral load in the HCV-infected donors was 890,000 IU per milliliter (interquartile range, 276,000 to 4.63 million). The HCV genotypes were genotype 1 (in 61% of the donors), genotype 2 (in 17%), genotype 3 (in 17%), and indeterminate (in 5%). A total of 42 of 44 recipients (95%) had a detectable hepatitis C viral load immediately after transplantation, with a median of 1800 IU per milliliter (interquartile range, 800 to 6180). Of the first 35 patients enrolled who had completed 6 months of follow-up, all 35 patients (100%; exact 95% confidence interval, 90 to 100) were alive and had excellent graft function and an undetectable hepatitis C viral load at 6 months after transplantation; the viral load became undetectable by approximately 2 weeks after transplantation, and it subsequently remained undetectable in all patients. No treatment-related serious adverse events were identified. More cases of acute cellular rejection for which treatment was indicated occurred in the HCV-infected lung-transplant recipients than in a cohort of patients who received lung transplants from donors who did not have HCV infection. This difference was not significant after adjustment for possible confounders. Conclusions In patients without HCV infection who received a heart or lung transplant from donors with hepatitis C viremia, treatment with an antiviral regimen for 4 weeks, initiated within a few hours after transplantation, prevented the establishment of HCV infection. (Funded by the Mendez National Institute of Transplantation Foundation and others; DONATE HCV ClinicalTrials.gov number, NCT03086044.).

Background: The MOMENTUM 3 study (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3) has demonstrated that the HeartMate 3 (HM3) pump is associated with reduced strokes compared with the HeartMate II (HMII) device. We now perform a comprehensive analysis of stroke events to evaluate their longitudinal occurrence, clinical correlates, patterns, and impact on outcome across the 2-year duration of support. Methods: MOMENTUM 3 is a randomized controlled trial of the HM3 centrifugal-flow pump versus the HMII axial-flow pump in patients with advanced heart failure, regardless of the intended goal of support (bridge to transplantation or destination therapy). Baseline and postimplantation clinical correlates of stroke events were assessed with multivariable analyses. Longitudinal patterns, including device association, type of stroke (hemorrhagic versus ischemic), changing severity of impairment assessed with the modified Rankin Scale (disabling [modified Rankin Scale score >3] versus nondisabling [modified Rankin Scale score ≤3]) over time, and association with outcome, were determined. Results: In 361 patients with the intended implant (189 HM3 and 172 HMII), 65 strokes (40 ischemic strokes and 25 hemorrhagic strokes) occurred in 52 patients at a median of 131 (range, 1–733) days. No difference in stroke rate was noted between 0 and 180 days of follow-up between devices. However, stroke incidence in the long-term period (181–730 days after left ventricular assist device) was 3.3 times lower for the HM3 group (HM3: 0.04 versus HMII: 0.13 events per patient-year; odds ratio, 0.23; 95% CI, 0.08–0.63; P =0.01). Treatment with the HM3 pump was the only independent predictor of lower stroke events. We found no direct association of blood pressure or antithrombotic regimens with observed stroke rates. A stroke event significantly lowered 2-year postimplantation survival regardless of subtype or initial severity of neurological impairment compared with patients without a stroke (43±12% for hemorrhagic stroke, 57±9% for ischemic stroke, 51±11% for disabling, and 51±11% for nondisabling compared with 85±2% 2-year survival for patients without stroke). Conclusions: The HM3 pump is associated with a marked reduction in stroke rates compared with the HMII device, with benefits observed in the long-term period (>6 months). The occurrence of stroke of any type (hemorrhagic and ischemic) or of any functional severity (disabling and nondisabling) is predictive of a poor 2-year clinical outcome. Clinical Trial Registration: URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT02224755.

Background Mechanisms underlying impaired exercise capacity and increased cardiovascular mortality observed in breast cancer (BC) patients remain unclear. The prevalence, functional, and prognostic significance of elevated resting heart rate (HR) and abnormal heart rate recovery (HRR) in breast cancer (BC) requires evaluation. Methods In a single‐center, retrospective, case‐control study of women referred for exercise treadmill testing (ETT), 448 BC patients (62.6 ± 10.0 years) were compared to 448 cancer‐free, age‐matched controls. Elevated resting HR was defined as HR ≥80 bpm at rest. Abnormal HRR at 1‐minute following exercise was defined as ≤12 bpm if active recovery or ≤18 bpm if passive recovery. Association of these parameters with exercise capacity and all‐cause mortality was evaluated. Results Elevated resting HR (23.7% vs 17.0%, P = 0.013) and abnormal HRR (25.9% vs 20.3%, P = 0.048) were more prevalent in BC cohort than controls. In adjusted analyses, BC patients with elevated resting HR (−0.9 METs (SE 0.3); P = 0.0003) or abnormal HRR (−1.3 METs (SE 0.3); P

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.

Secondary (or functional) mitral regurgitation (SMR) occurs frequently in chronic heart failure (HF) with reduced left ventricular (LV) ejection fraction, resulting from LV remodelling that prevents coaptation of the valve leaflets. Secondary mitral regurgitation contributes to progression of the symptoms and signs of HF and confers worse prognosis. The management of HF patients with SMR is complex and requires timely referral to a multidisciplinary Heart Team. Optimization of pharmacological and device therapy according to guideline recommendations is crucial. Further management requires careful clinical and imaging assessment, addressing the anatomical and functional features of the mitral valve and left ventricle, overall HF status, and relevant comorbidities. Evidence concerning surgical correction of SMR is sparse and it is doubtful whether this approach improves prognosis. Transcatheter repair has emerged as a promising alternative, but the conflicting results of current randomized trials require careful interpretation. This collaborative position statement, developed by four key associations of the European Society of Cardiology—the Heart Failure Association (HFA), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Association of Cardiovascular Imaging (EACVI), and European Heart Rhythm Association (EHRA)—presents an updated practical approach to the evaluation and management of patients with HF and SMR based upon a Heart Team approach., Graphical abstract

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.

We present the hypothesis that advanced stage cancer is also a heart failure syndrome. It can develop independently of or in addition to cardiotoxic effects of anti-cancer therapies. This includes an increased risk of ventricular arrhythmias. We suggest the pathophysiologic link for these developments includes generalized muscle wasting (i.e. sarcopenia) due to tissue homeostasis changes leading to cardiac wasting associated cardiomyopathy. Cardiac wasting with thinning of the ventricular wall increases ventricular wall stress, even in the absence of ventricular dilation. In addition, arrhythmias may be facilitated by cellular wasting processes affecting structure and function of electrical cells and conduction pathways. We submit that in some patients with advanced cancer (but not terminal cancer), heart failure therapy or defibrillators may be relevant treatment options. The key points in selecting patients for such therapies may be the predicted life expectancy, quality of life at intervention time, symptomatic burden, and consequences for further anti-cancer therapies. The cause of death in advanced cancer is difficult to ascertain and consensus on event definitions in cancer is not established yet. Clinical investigations on this are called for. Broader ethical considerations must be taken into account when aiming to target cardiovascular problems in cancer patients. We suggest that focused attention to evaluating cardiac wasting and arrhythmias in cancer will herald a further evolution in the rapidly expanding field of cardio-oncology. This article is protected by copyright. All rights reserved.