Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment.

Tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as "living drugs," their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post-translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic-based strategies to enhance T cell immunotherapy.

Depressive symptoms are associated with clinical outcomes in heart failure with reduced ejection fraction.

AIMS: The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours. METHODS AND RESULTS: One hundred forty-two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6 months, depressive symptoms were assessed by the Beck Depression Inventory-II (BDI-II) and HFrEF disease activity by B-type natriuretic peptide (BNP). The Self-Care of Heart Failure Index (SCHFI) was used to assess HF self-care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow-up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI-II scores were associated with poorer HF self-care maintenance behaviours (R = -0.30, P < 0.001) and fewer daily steps (R = -0.19, P = 0.04), suggesting that elevated depressive symptoms may diminish important health behaviours. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II and plasma BNP over 6 months were positively related (R = 0.25, P = 0.004). CONCLUSIONS: This study confirms that elevated depressive symptoms are associated with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Poor health behaviours may contribute to the adverse association of elevated depressive symptoms with the increased hazard of adverse clinical outcomes.

Manufacture of CD22 CAR T cells following positive versus negative selection results in distinct cytokine secretion profiles and γδ T cell output.

Chimeric antigen receptor T cells (CART) have demonstrated curative potential for hematological malignancies, but the optimal manufacturing has not yet been determined and may differ across products. The first step, T cell selection, removes contaminating cell types that can potentially suppress T cell expansion and transduction. While positive selection of CD4/CD8 T cells after leukapheresis is often used in clinical trials, it may modulate signaling cascades downstream of these co-receptors; indeed, the addition of a CD4/CD8-positive selection step altered CD22 CART potency and toxicity in patients. While negative selection may avoid this drawback, it is virtually absent from good manufacturing practices. Here, we performed both CD4/CD8-positive and -negative clinical scale selections of mononuclear cell apheresis products and generated CD22 CARTs per our ongoing clinical trial (NCT02315612NCT02315612). While the selection process did not yield differences in CART expansion or transduction, positively selected CART exhibited a significantly higher in vitro interferon-γ and IL-2 secretion but a lower in vitro tumor killing rate. Notably, though, CD22 CART generated from both selection protocols efficiently eradicated leukemia in NSG mice, with negatively selected cells exhibiting a significant enrichment in γδ CD22 CART. Thus, our study demonstrates the importance of the initial T cell selection process in clinical CART manufacturing.

Association of Depression Symptoms and Biomarkers of Risk on Clinical Outcomes in HFrEF.

BACKGROUND: Prior studies have demonstrated an association of depression with adverse clinical outcomes in patients with HFrEF, but the possible mechanisms responsible for the association are not unserstood. METHODS: 142 men and women with HFrEF were enrolled through HF clinics and followed over time. At baseline and 6-months, depression was assessed by the Beck Depression Inventory (BDI-II) and disease activity by B-type natriuretic peptide (BNP). Proportional Hazards Regression Models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. RESULTS: Over a median follow-up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% higher hazard of death or cardiovascular hospitalization. Greater baseline BDI-II scores were associated with poorer HF self-care maintenance (R=-0.30, p<0.001) and fewer daily steps (R=-0.19, p=0.04), suggesting that depression may adversely affect important health behaviors. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II score and plasma BNP over 6 months were positively correlated (R=0.25, p=0.004). CONCLUSIONS: This study underscores the importance of elevated depression symptoms and their association with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Health behaviors may play a greater role than direct biobehavioral pathways in the adverse effects of depression on the HF disease trajectory and resultant clinical outcomes.

Potent preclinical activity of FLT3-directed chimeric antigen receptor T-cell immunotherapy against FLT3- mutant acute myeloid leukemia and KMT2A-rearranged acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 or CD22 induce remissions in the majority of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), although relapse due to target antigen loss or downregulation has emerged as a major clinical dilemma. Accordingly, great interest exists in developing CAR T cells directed against alternative leukemia cell surface antigens that may help to overcome immunotherapeutic resistance. The fms-like tyrosine kinase 3 receptor (FLT3) is constitutively activated via FLT3 mutation in acute myeloid leukemia (AML) or wild-type FLT3 overexpression in KMT2A (lysine-specific methyltransferase 2A)-rearranged ALL, which are associated with poor clinical outcomes in children and adults. We developed monovalent FLT3-targeted CAR T cells (FLT3CART) and bispecific CD19xFLT3CART and assessed their anti-leukemia activity in preclinical models of FLT3-mutant AML and KMT2A-rearranged infant ALL. We report robust in vitro FLT3CART-induced cytokine production and cytotoxicity against AML and ALL cell lines with minimal cross-reactivity against normal hematopoietic and non-hematopoietic tissues. We also observed potent in vivo inhibition of leukemia proliferation in xenograft models of both FLT3-mutant AML and KMT2A-rearranged ALL, including a post-tisagenlecleucel ALL-to-AML lineage switch patient-derived xenograft model pairing. We further demonstrate significant in vitro and in vivo activity of bispecific CD19xFLT3CART against KMT2Arearranged ALL and posit that this additional approach might also diminish potential antigen escape in these high-risk leukemias. Our preclinical data credential FLT3CART as a highly effective immunotherapeutic strategy for both FLT3- mutant AML and KMT2A-rearranged ALL which is poised for further investigation and clinical translation.

Disparities in Practice Patterns by Sex, Race, and Ethnicity in Patients Referred for Advanced Heart Failure Therapies.

Advanced heart failure (HF) therapies improve survival in patients with stage D HF. We sought to evaluate differences by race/ethnicity and sex in advanced HF therapy referrals and decision-making across a multicenter survey. We performed a retrospective analysis of patients referred for evaluation for advanced HF therapies at 9 centers (n = 515) across the United States. The median age was 58 years, and 73% were male. White patients comprised 55.7% of referrals, whereas non-White patients comprised 44.3%. Non-ischemic etiology was more common in non-White patients (66.6% vs 47.4% p = 0.0005), and ischemic etiology was more common in men (37.8% vs 20.4% p = 0.0005). The primary reason for referral differed by race/ethnicity but not sex, with ventricular arrhythmias (7.6% vs 3%, p = 0.024) and pulmonary hypertension (3.4% vs 0.4% p = 0.018) being more common in White patients, whereas worsening HF was less common (25.4% vs 35.9%; p = 0.009). White patients were offered left ventricular assist devices (LVADs) (60.3% vs 54.7 p = 0.039) and heart transplants (51.8% vs 33.1% p = 0.0007) more often than non-White patients. The preference not to pursue LVAD therapy was more common in non-White patients (17.6% vs 9.6%; p = 0.049). Men were more often declined for a heart transplant because of psychosocial contraindications (34% vs 15%, p = 0.005). In conclusion, in this multicenter analysis of referrals for advanced HF therapies, we observed significant differences by race, ethnicity, and sex in both referral characteristics and evaluation outcomes. Further investigation is warranted to better understand why rates of LVAD and transplantation may be lower in non-White patients who are referred for advanced therapies.

CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR.

Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).

Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) - Phase I Evaluation of the Integration and Safety of the HeartLogic Multisensor Algorithm in Patients With Heart Failure.

BACKGROUND: Patients with heart failure (HF) and reduced ejection fraction suffer from a relapsing and remitting disease course, where early treatment changes may improve outcomes. We assessed the clinical integration and safety of the HeartLogic multisensor index and alerts in HF care. METHODS: The Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) study enrolled 200 patients with HF and reduced ejection fraction (<35%), New York Heart Association functional class II-III symptoms, implanted with a cardiac resynchronization therapy-defibrillator or and implantable cardioverter defibrillator, who had either a hospitalization for HF within 12 months or unscheduled visit for HF exacerbation within 90 days or an elevated natriuretic peptide concentration (brain natriuretic peptide [BNP] of ≥150 pg/mL or N-terminal pro-BNP [NT-proBNP] of ≥600 pg/mL). This phase included the development of an alert management guide and evaluated changes in medical treatment, natriuretic peptide levels, and safety. RESULTS: The mean age of participants was 67 years, 68% were men, 81% were White, and 61% had a HF hospitalization in prior 12 months. During follow-up, there were 585 alert cases with an average of 1.76 alert cases per patient-year. HF medications were augmented during 74% of the alert cases. HF treatment augmentation within 2 weeks from an initial alert was associated with more rapid recovery of the HeartLogic Index. Five serious adverse events (0.015 per patient-year) occurred in relation to alert-prompted medication change. NTproBNP levels decreased from median of 1316 pg/mL at baseline to 743 pg/mL at 12 months (P < .001). CONCLUSIONS: HeartLogic alert management was safely implemented in HF care and may optimize HF management. This phase supports further evaluation in larger studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03237858).

The GUIDE-HF trial of pulmonary artery pressure monitoring in heart failure: impact of the COVID-19 pandemic.

AIMS: During the coronavirus disease 2019 (COVID-19) pandemic, important changes in heart failure (HF) event rates have been widely reported, but few data address potential causes for these changes; several possibilities were examined in the GUIDE-HF study. METHODS AND RESULTS: From 15 March 2018 to 20 December 2019, patients were randomized to haemodynamic-guided management (treatment) vs. control for 12 months, with a primary endpoint of all-cause mortality plus HF events. Pre-COVID-19, the primary endpoint rate was 0.553 vs. 0.682 events/patient-year in the treatment vs. control group [hazard ratio (HR) 0.81, P = 0.049]. Treatment difference was no longer evident during COVID-19 (HR 1.11, P = 0.526), with a 21% decrease in the control group (0.536 events/patient-year) and no change in the treatment group (0.597 events/patient-year). Data reflecting provider-, disease-, and patient-dependent factors that might change the primary endpoint rate during COVID-19 were examined. Subject contact frequency was similar in the treatment vs. control group before and during COVID-19. During COVID-19, the monthly rate of medication changes fell 19.2% in the treatment vs. 10.7% in the control group to levels not different between groups (P = 0.362). COVID-19 was infrequent and not different between groups. Pulmonary artery pressure area under the curve decreased -98 mmHg-days in the treatment group vs. -100 mmHg-days in the controls (P = 0.867). Patient compliance with the study protocol was maintained during COVID-19 in both groups. CONCLUSION: During COVID-19, the primary event rate decreased in the controls and remained low in the treatment group, resulting in an effacement of group differences that were present pre-COVID-19. These outcomes did not result from changes in provider- or disease-dependent factors; pulmonary artery pressure decreased despite fewer medication changes, suggesting that patient-dependent factors played an important role in these outcomes. Clinical Trials.gov: NCT03387813.

Patterns and predictors of dyspnoea following left ventricular assist device implantation.

AIMS: Dyspnoea is a common symptom of heart failure (HF) that often prompts patients to seek treatment. Implantation of a left ventricular assist device (LVAD) has been associated with reduced dyspnoea but it is unclear if all patients experience similar improvements in dyspnoea over time following LVAD implantation. Our aim was to identify distinct trajectories of dyspnoea symptoms over time following LVAD implantation and predictors of dyspnoea trajectory. We hypothesized that at least two, distinct trajectories of dyspnoea would be observed following LVAD implantation. METHODS AND RESULTS: This was a secondary analysis of data from the Profiling Biobehavioral Responses to Mechanical Support in Advanced Heart Failure study. In the parent study, sociodemographic and clinical data were collected prior to LVAD implantation and at 1, 3, and 6 months following LVAD implantation from a sample (n = 101) of patients with advanced HF. Latent growth mixture modelling was performed to identify distinct trajectories of dyspnoea symptoms. Backwards stepwise logistic regression was used to identify predictors of dyspnoea trajectory. Two, distinct trajectories of dyspnoea symptoms were identified: sustained improvement and unsustained improvement. Participants who experienced sustained improvement (86.7% of sample) demonstrated large, significant improvement in dyspnoea from pre-implantation to 3 months post-implant followed by smaller, non-significant improvement from 3 to 6 months. Participants who experienced unsustained improvement (13.3% of sample) demonstrated initial improvement from pre-implantation to 3 months post-implantation followed by worsening of dyspnoea from 3 to 6 months. Greater depressive symptoms at baseline and living alone were significant predictors of unsustained improvement. CONCLUSION: Patients experience different patterns of dyspnoea over time following LVAD implantation. Clinicians should inquire about living arrangements and depressive symptoms at each visit to determine risk of unsustained improvement in dyspnoea.

Longitudinal Effects of Left Ventricular Assist Device Implantation on Global and Domain-Specific Cognitive Function.

BACKGROUND: Left ventricular assist devices (LVADs) are a common treatment of advanced heart failure, but cognitive dysfunction, which is common in heart failure, could limit the ability to perform postimplantation LVAD care. Implantation of an LVAD has been associated with improved cerebral perfusion and may improve cognitive function post implantation. OBJECTIVE: The aim of this study was to quantify longitudinal change in cognitive function after LVAD implantation. METHODS: A secondary analysis of data on 101 adults was completed to evaluate cognitive function before implantation and again at 1, 3, and 6 months post implantation of an LVAD. Latent growth curve modeling was conducted to characterize change over time. Serial versions of the Montreal Cognitive Assessment were used to measure overall (total) cognitive function and function in 6 cognitive domains. RESULT: There was moderate, nonlinear improvement from preimplantation to 6 months post implantation in Montreal Cognitive Assessment total score (Hedges' g = 0.50) and in short-term memory (Hedges' g = 0.64). There also were small, nonlinear improvements in visuospatial ability, executive function, and attention from preimplantation to 6 months post implantation (Hedges' g = 0.20-0.28). The greatest improvements were observed in the first 3 months after implantation and were followed by smaller, sustained improvements or no additional significant change. CONCLUSIONS: Implantation of an LVAD is associated with significant, nonlinear improvement in short-term memory and global cognitive function, with the most significant improvements occurring in the first 3 months after implantation. Clinicians should anticipate improvements in cognitive function after LVAD implantation and modify postimplantation education to maximize effectiveness of LVAD self-care.

Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design.

BACKGROUND: Successful development of chimeric antigen receptor (CAR) T cell immunotherapy for children and adults with relapsed/refractory acute myeloid leukemia (AML) is highly desired given their poor clinical prognosis and frequent inability to achieve cure with conventional chemotherapy. Initial experiences with CD19 CAR T cell immunotherapy for patients with B-cell malignancies highlighted the critical impact of intracellular costimulatory domain selection (CD28 vs 4-1BB (CD137)) on CAR T cell expansion and in vivo persistence that may impact clinical outcomes. However, the impact of costimulatory domains on the efficacy of myeloid antigen-directed CAR T cell immunotherapy remains unknown. METHODS: In this preclinical study, we developed six CAR constructs targeting CD33, a highly expressed and validated AML target, comprised of one of three single-chain variable fragments with CD3ζ and either CD28 or 4-1BB costimulatory domains. We systematically compared the preclinical in vitro and in vivo efficacy of T cells lentivirally transduced with CD33 CAR constructs (CD33CARTs) against human AML. RESULTS: We observed potent in vitro cytokine production and cytotoxicity of CD33CARTs incubated with human CD33+ AML cell lines, as well as robust in vivo antileukemia activity in cell line and childhood AML patient-derived xenograft (PDX) models. Gemtuzumab-based CD33CARTs were unexpectedly toxic in vivo in animal models despite observed in vitro anti-leukemia activity. CD28-based CD33CARTs consistently induced more robust inhibition of leukemia proliferation in AML cell line and PDX models than did 4-1BB-based CD33CARTs. A 'best-in-class' lintuzumab-CD28/CD3ζ CAR construct was thus selected for clinical translation. CONCLUSIONS: CD33 is a critical antigen for potential immunotherapeutic targeting in patients with AML. Based on this rigorous preclinical evaluation, our validated clinical grade lintuzumab-CD28/CD3ζ CD33CART immunotherapy is now under evaluation in a first-in-child/first-in-human phase 1 clinical trial for children and adolescents/young adults with relapsed/refractory AML. TRIAL REGISTRATION NUMBER: clinicaltrials.gov; NCT03971799.

Exploring gender differences in trajectories of clinical markers and symptoms after left ventricular assist device implantation.

AIMS: Despite well-known gender differences in heart failure, it is unknown if clinical markers and symptoms differ between women and men after left ventricular assist device (LVAD) implantation. Our aim was to examine gender differences in trajectories of clinical markers (echocardiographic markers and plasma biomarkers) and symptoms from pre- to post-LVAD implantation. METHODS AND RESULTS: This was a secondary analysis of data collected from a study of patients from pre- to 1, 3, and 6 months post-LVAD implantation. Data were collected on left ventricular internal end-diastolic diameter (LVIDd) and ejection fraction (LVEF), plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), and soluble suppressor of tumorigenicity (sST2). Physical and depressive symptoms were measured using the Heart Failure Somatic Perception Scale and Patient Health Questionnaire-9, respectively. Latent growth curve modelling was used to compare trajectories between women and men. The average age of the sample (n = 98) was 53.3 ± 13.8 years, and most were male (80.6%) and had non-ischaemic aetiology (65.3%). Pre-implantation, women had significantly narrower LVIDd (P < 0.001) and worse physical symptoms (P = 0.041) compared with men. Between pre- and 6 months post-implantation, women had an increase in plasma sST2 followed by a decrease, whereas men had an overall decrease (slope: P = 0.014; quadratic: P = 0.011). Between 1 and 6 months post-implantation, women had a significantly greater increase in LVEF (P = 0.045) but lesser decline in plasmoa NT-proBNP compared with men (P = 0.025). CONCLUSION: Trajectories of clinical markers differed somewhat between women and men, but trajectories of symptoms were similar, indicating some physiologic but not symptomatic gender differences in response to LVAD.

Practices of Referring Patients to Advanced Heart Failure Centers.

BACKGROUND: Therapies for advanced heart failure (AHF) improve the likelihood of survival in a growing population of patients with stage D heart failure (HF). Successful implementation of these therapies is dependent upon timely and appropriate referrals to AHF centers. METHODS: We performed a retrospective analysis of patients referred to 9 AHF centers for evaluation for AHF therapies. Patients' demographics, referring providers' characteristics, referral circumstances, and evaluation outcomes were collected. RESULTS: The majority of referrals (n = 515) were male (73.4%), and a majority of those were in the advanced state of the disease: very low left ventricular ejection fraction (<20% in 51.5%); 59.4% inpatient; and high risk Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles (74.5% profile 1-3). HF cardiologists (49.1%) were the most common originating referral source; the least common (4.9%) were electrophysiologists. Common clinical triggers for referral included worsening HF (30.0%), inotrope dependence (19.6%), hospitalization (19.4%), and cardiogenic shock (17.8%). Most commonly, AHF therapies were not offered because patients were too sick (38.0%-45.1%) or for psychosocial reasons (20.3%-28.6%). Compared to non-HF cardiologists, patients referred by HF cardiologists were offered an AHF therapy more often (66.8% vs 58.4%, P = 0.0489). Of those not offered any AHF therapy, 28.4% received home inotropic therapy, and 14.5% were referred to hospice. CONCLUSIONS: In this multicenter review of AHF referrals, HF cardiologists referred the most patients despite being a relatively small proportion of the overall clinician population. Late referral was prevalent in this high-risk patient population and correlates with worsened outcomes, suggesting a significant need for broad clinician education regarding the benefits, triggers and appropriate timing of referral to AHF centers for optimal patient outcomes.

Loss of daptomycin susceptibility in clinical Staphylococcus epidermidis infection coincided with variants in WalK.

Daptomycin (DAP) is key in treating multidrug-resistant Staphylococcus infections. Diminished susceptibility to DAP is emerging among Staphylococcus epidermidis strains although mechanisms for non-susceptibility (NS) remain poorly understood. We report a case of persistent S. epidermidis bacteremia in which loss of DAP susceptibility arose during prolonged treatment. Whole genome sequencing identified two mutations, Q371del and P415L, in a single-affected gene, WalK, that coincided with the emergence of DAP-NS. Protein modeling of the mutations predicted a disruption of WalK protein configuration. The emergence of mutations in a single-gene during DAP exposure raises concerns in an era of increasingly treatment-resistant infections. Lay summary: Daptomycin is an important antibiotic for fighting Staphylococcus infections. We identified variants in the WalK gene that were coincident with resistance in a clinical Staphylococcus epidermidis infection. Clinicians, hospital epidemiologists, and microbiology laboratories need to be aware of the potential for the evolution of drug resistance during prolonged daptomycin therapy.

A manifesto of collaborative longitudinal cardiovascular care in heart failure.

In this document, we outline the challenges faced by patients and clinicians in heart failure, specifically centered around the needed coordination of care among the various subspecialties within cardiovascular medicine. We call for a more organized and collaborative effort among clinicians in primary care, general cardiology, electrophysiology, interventional cardiology, cardiothoracic surgery, cardiac imaging, and heart failure-all caring for mutual patients. Care is contextualized within the framework of two phases: a cardiomyopathy phase and an advanced heart failure phase, each of which lends to different considerations in therapy. Ultimately multidisciplinary coordinated care within cardiovascular medicine may lead to greater patient and clinician satisfaction as well as improved outcomes, but this remains to be investigated.