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).

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.

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.

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).

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.

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.

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.

An acetylation switch regulates SUMO-dependent protein interaction networks.

The attachment of the SUMO modifier to proteins controls cellular signaling pathways through noncovalent binding to SUMO-interaction motifs (SIMs). Canonical SIMs contain a core of hydrophobic residues that bind to a hydrophobic pocket on SUMO. Negatively charged residues of SIMs frequently contribute to binding by interacting with a basic surface on SUMO. Here we define acetylation within this basic interface as a central mechanism for the control of SUMO-mediated interactions. The acetyl-mediated neutralization of basic charges on SUMO prevents binding to SIMs in PML, Daxx, and PIAS family members but does not affect the interaction between RanBP2 and SUMO. Acetylation is controlled by HDACs and attenuates SUMO- and PIAS-mediated gene silencing. Moreover, it affects the assembly of PML nuclear bodies and restrains the recruitment of the corepressor Daxx to these structures. This acetyl-dependent switch thus expands the regulatory repertoire of SUMO signaling and determines the selectivity and dynamics of SUMO-SIM interactions.

Heart Failure Symptom Biology in Response to Ventricular Assist Device Implantation.

BACKGROUND: We have a limited understanding of the biological underpinnings of symptoms in heart failure (HF), particularly in response to left ventricular assist device (LVAD) implantation. OBJECTIVE: The aim of this study was to quantify the degree to which symptoms and biomarkers change in parallel from before implantation through the first 6 months after LVAD implantation in advanced HF. METHODS: This was a prospective cohort study of 101 patients receiving an LVAD for the management of advanced HF. Data on symptoms (dyspnea, early and subtle symptoms [HF Somatic Perception Scale], pain severity [Brief Pain Inventory], wake disturbance [Epworth Sleepiness Scale], depression [Patient Health Questionnaire], and anxiety [Brief Symptom Inventory]) and peripheral biomarkers of myocardial stretch, systemic inflammation, and hypervolumetric mechanical stress were measured before implantation with a commercially available LVAD and again at 30, 90, and 180 days after LVAD implantation. Latent growth curve and parallel process modeling were used to describe changes in symptoms and biomarkers and the degree to which they change in parallel in response to LVAD implantation. RESULTS: In response to LVAD implantation, changes in myocardial stretch were closely associated with changes in early and subtle physical symptoms as well as depression, and changes in hypervolumetric stress were closely associated with changes in pain severity and wake disturbances. Changes in systemic inflammation were not closely associated with changes in physical or affective symptoms in response to LVAD implantation. CONCLUSIONS: These findings provide new insights into the many ways in which symptoms and biomarkers provide concordant or discordant information about LVAD response.

Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD.

Acute lymphoblastic leukemia (ALL) persisting or relapsing following bone marrow transplantation (BMT) has a dismal prognosis. Success with chimeric antigen receptor (CAR) T cells offers an opportunity to treat these patients with leukemia-redirected donor-derived T cells, which may be more functional than T cells derived from patients with leukemia but have the potential to mediate graft-versus-host disease (GVHD). We, together with others, have previously demonstrated tumor-specific T-cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using an immunocompetent murine model of minor mismatched allogeneic transplantation followed by donor-derived CD19-CAR T cells. Allogeneic donor-derived CD19-CAR T cells eliminated residual ALL with equal potency to those administered after syngeneic BMT. Surprisingly, allogeneic CAR T cells mediated lethal acute GVHD with early mortality, which is atypical for this minor mismatch model. We demonstrated that both allogeneic and syngeneic CAR T cells show initial expansion as effector T cells, with a higher peak but rapid deletion of allogeneic CAR T cells. Interestingly, CAR-mediated acute GVHD was only seen in the presence of leukemia, suggesting CAR-target interactions induced GVHD. Indeed, serum interleukin (IL)-6 was elevated only in the presence of both leukemia and CAR T cells, and IL-6 neutralization ameliorated the severity of GVHD in a delayed donor lymphocyte infusion model. Finally, allogeneic CD4(+) CAR T cells were responsible for GVHD, which correlated with their ability to produce IL-6 upon CAR stimulation. Altogether, we demonstrate that donor-derived allogeneic CAR T cells are active but have the capacity to drive GVHD.

Depressive symptoms in couples living with heart failure: the role of congruent engagement in heart failure management.

OBJECTIVES: The life-threatening context of heart failure (HF), high variability of the illness and complexity of care place considerable demands on both the adult patient and his/her spouse. The current study examines the role of congruent engagement in HF management behaviors on the depressive symptoms of the couple living with HF. METHOD: A cross-sectional design was used to examine 60 couples living with HF. Multilevel modeling was used to examine partner and within-dyad effects of engagement in HF behaviors on depressive symptoms. RESULTS: Just over one quarter (27%) of couples had both members experiencing at least mild depressive symptoms. Controlling for stage of HF and one's own level of engagement, one's partner's level of engagement was significantly associated with one's level of depressive symptoms; higher levels of engagement by one's partner were associated with lower levels of depressive symptoms. Additionally, spouses had lower levels of depressive symptoms when they had similar levels of engagement to their partner with HF; spouses had higher levels of depressive symptoms when they had higher levels of engagement than their partner with HF. CONCLUSION: Findings confirm the importance of screening both members of the couple for depression and fostering collaboration within the couple.

Implant Strategy-Specific Changes in Symptoms in Response to Left Ventricular Assist Devices.

BACKGROUND: Although we know that the quality of life generally improves after left ventricular assist device (LVAD) implantation, we know little about how symptoms change in response to LVAD. METHODS: The purpose of this study was to compare the changes in symptoms between bridge and destination therapy patients as part of a prospective cohort study. Physical (dyspnea and wake disturbances) and affective symptoms (depression and anxiety) were measured before LVAD and at 1, 3, and 6 months after LVAD. Multiphase growth modeling was used to capture the 2 major phases of change: initial improvements between preimplant and 1 month after LVAD and subsequent improvements between 1 and 6 months after LVAD. RESULTS: The sample included 64 bridge and 22 destination therapy patients as the preimplant strategy. Destination patients had worse preimplant dyspnea and wake disturbances, and they experienced greater initial improvements in these symptoms compared with bridge patients (all P < .05); subsequent change in both symptoms were similar between groups (both P > .05). Destination patients had worse preimplant depression (P = .042) but experienced similar initial and subsequent improvements in depression in response to LVAD compared with bridge patients (both P > .05). Destination patients had similar preimplant anxiety (P = .279) but experienced less initial and greater subsequent improvements in anxiety after LVAD compared with bridge patients (both P < .05). CONCLUSION: There are many differences in the magnitude and timing of change in symptom responses to LVAD between bridge and destination therapy patients. Detailed information on changes in specific symptoms may better inform shared decision-making regarding LVAD.

Quality of Life, Depression, and Anxiety in Ventricular Assist Device Therapy: Longitudinal Outcomes for Patients and Family Caregivers.

BACKGROUND: Patients who receive ventricular assist device (VAD) therapy typically rely on informal caregivers (family members or friends) to assist them in managing their device. OBJECTIVE: The purpose of this study is to characterize changes in person-oriented outcomes (quality of life [QOL], depression, and anxiety) for VAD patients and their caregivers together from pre-implantation to 3 months post-implantation. METHODS: This was a formal interim analysis from an ongoing prospective study of VAD patients and caregivers (n = 41 dyads). Data on person-oriented outcomes (QOL: EuroQol 5 Dimensions Visual Analog Scale; depression: Patient Health Questionnaire-8; anxiety: Brief Symptom Inventory) were collected at 3 time points (just prior to implantation and at 1 and 3 months post-implantation). Trajectories of change for patients and caregivers on each measure were estimated using latent growth modeling with parallel processes. RESULTS: Patients' QOL improved significantly over time, whereas caregiver QOL worsened. Depression and anxiety also improved significantly among patients but did not change among caregivers. There was substantial variability in change on all outcomes for both patients and their caregivers. CONCLUSIONS: This is the first quantitative study of VAD patient-caregiver dyads in modern devices that describes change in person-oriented outcomes from pre-implantation to post-implantation. This work supports the need for future studies that account for the inherent relationships between patient and caregiver outcomes and examine variability in patient and caregiver responses to VAD therapy.

Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD.

Selective targeting of non-T cells, including antigen-presenting cells (APCs), is a potential strategy to prevent graft-versus-host-disease (GVHD) but to maintain graft-versus-tumor (GVT) effects. Because type I and II interferons signal through signal transducer and activator of transcription-1 (STAT1), and contribute to activation of APCs after allogeneic bone marrow transplant (alloBMT), we examined whether the absence of STAT1 in donor APCs could prevent GVHD while preserving immune competence. Transplantation of STAT1(-/-) bone marrow (BM) prevented GVHD induced by STAT1(+/+) T cells, leading to expansion of B220(+) cells and regulatory T cells. STAT1(-/-) BM also preserved GVT activity and enhanced overall survival of tumor-challenged mice in the setting of GVHD. Furthermore, recipients of allogeneic STAT1(-/-) BM demonstrated increased CD9(-)Siglec H(hi) plasmacytoid dendritic cells (pDCs), and depletion of pDCs after STAT1(-/-) BM transplantation prevented GVHD resistance. STAT1(-/-) pDCs were found to produce decreased free radicals, IFNα, and interleukin (IL)-12, and increased IL-10. Additionally, STAT1(-/-) pDCs that were isolated after alloBMT showed increased gene expression of S100A8 and S100A9, and transplantation of S100A9(-/-) BM reduced GVHD-free survival. Finally, elevated STAT3 was found in STAT1(-/-) pDCs isolated after alloBMT. We conclude that interfering with interferon signaling in APCs such as pDCs provides a novel approach to regulate the GVHD/GVT axis.

Gender-Specific Physical Symptom Biology in Heart Failure.

BACKGROUND: There are several gender differences that may help explain the link between biology and symptoms in heart failure (HF). OBJECTIVE: The aim of this study was to examine gender-specific relationships between objective measures of HF severity and physical symptoms. METHODS: Detailed clinical data, including left ventricular ejection fraction and left ventricular internal end-diastolic diameter, and HF-specific physical symptoms were collected as part of a prospective cohort study. Gender interaction terms were tested in linear regression models of physical symptoms. RESULTS: The sample (101 women and 101 men) averaged 57 years of age and most participants (60%) had class III/IV HF. Larger left ventricle size was associated with better physical symptoms for women and worse physical symptoms for men. CONCLUSION: Decreased ventricular compliance may result in worse physical HF symptoms for women and dilation of the ventricle may be a greater progenitor of symptoms for men with HF.

Physical and psychological symptom biomechanics in moderate to advanced heart failure.

BACKGROUND: There is a common dissociation between objective measures and patient symptomatology in heart failure (HF). OBJECTIVE: The aim of this study was to explore the relationship between cardiac biomechanics and physical and psychological symptoms in adults with moderate to advanced HF. METHODS: We performed a secondary analysis of data from 2 studies of symptoms among adults with HF. Stepwise regression modeling was performed to examine the influence of cardiac biomechanics (left ventricular internal diastolic diameter, right atrial pressure [RAP], and cardiac index) on symptoms. RESULTS: The average age of the sample (n = 273) was 57 ± 16 years, 61% were men, and 61% had class III or IV HF. Left ventricular internal diastolic diameter (ß = 4.22 ± 1.63, P = .011), RAP (ß = 0.71 ± 0.28, P = .013), and cardiac index (ß = 7.11 ± 3.19, P = .028) were significantly associated with physical symptoms. Left ventricular internal diastolic diameter (ß = 0.10 ± 0.05, P = .038) and RAP (ß = 0.03 ± 0.01, P = .039) were significantly associated with anxiety. There were no significant biomechanical determinants of depression. CONCLUSION: Cardiac biomechanics were related to physical symptoms and anxiety, providing preliminary evidence of the biological underpinnings of symptomatology among adults with HF.

Symptom-Hemodynamic Mismatch and Heart Failure Event Risk.

BACKGROUND: Heart failure (HF) is a heterogeneous condition of both symptoms and hemodynamics. OBJECTIVE: The goals of this study were to identify distinct profiles among integrated data on physical and psychological symptoms and hemodynamics and quantify differences in 180-day event risk among observed profiles. METHODS: A secondary analysis of data collected during 2 prospective cohort studies by a single group of investigators was performed. Latent class mixture modeling was used to identify distinct symptom-hemodynamic profiles. Cox proportional hazards modeling was used to quantify difference in event risk (HF emergency visit, hospitalization, or death) among profiles. RESULTS: The mean age (n = 291) was 57 ± 13 years, 38% were female, and 61% had class III/IV HF. Three distinct symptom-hemodynamic profiles were identified: 17.9% of patients had concordant symptoms and hemodynamics (ie, moderate physical and psychological symptoms matched the comparatively good hemodynamic profile), 17.9% had severe symptoms and average hemodynamics, and 64.2% had poor hemodynamics and mild symptoms. Compared with those in the concordant profile, both profiles of symptom-hemodynamic mismatch were associated with a markedly increased event risk (severe symptoms hazards ratio, 3.38; P = .033; poor hemodynamics hazards ratio, 3.48; P = .016). CONCLUSIONS: A minority of adults with HF have concordant symptoms and hemodynamics. Either profile of symptom-hemodynamic mismatch in HF is associated with a greater risk of healthcare utilization for HF or death.

Comorbidity profiles and inpatient outcomes during hospitalization for heart failure: an analysis of the U.S. Nationwide inpatient sample.

BACKGROUND: Treatment of heart failure (HF) is particularly complex in the presence of comorbidities. We sought to identify and associate comorbidity profiles with inpatient outcomes during HF hospitalizations. METHODS: Latent mixture modeling was used to identify common profiles of comorbidities during adult hospitalizations for HF from the 2009 Nationwide Inpatient Sample (n = 192,327). RESULTS: Most discharges were characterized by "common" comorbidities. A "lifestyle" profile was characterized by a high prevalence of uncomplicated diabetes, hypertension, chronic pulmonary disorders and obesity. A "renal" profile had the highest prevalence of renal disease, complicated diabetes, and fluid and electrolyte imbalances. A "neurovascular" profile represented the highest prevalence of cerebrovascular disease, paralysis, myocardial infarction and peripheral vascular disease. Relative to the common profile, the lifestyle profile was associated with a 15% longer length of stay (LOS) and 12% greater cost, the renal profile was associated with a 30% higher risk of death, 27% longer LOS and 24% greater cost, and the neurovascular profile was associated with a 45% higher risk of death, 34% longer LOS and 37% greater cost (all p < 0.001). CONCLUSIONS: Comorbidity profiles are helpful in identifying adults at higher risk of death, longer length of stay, and accumulating greater costs during hospitalizations for HF.