Publications by authors named "Marlena Habal"

22 Publications

  • Page 1 of 1

Chronic intermittent intravenous immunoglobulin in heart transplant recipients with elevated donor-specific antibody levels.

Clin Transplant 2021 Oct 27:e14524. Epub 2021 Oct 27.

Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, New York, New York, USA.

Donor-specific antibodies (DSA) are associated with antibody-mediated rejection (AMR) and poor patient survival. In heart transplant, the efficacy of intermittent intravenous immunoglobulin (IVIg) in reducing de novo DSA levels and treating AMR has not been characterized. We retrospectively studied a cohort of 19 patients receiving intermittent IVIg for elevated DSA and examined changes in DSA levels and graft function. Intermittent IVIg infusions were generally safe and well tolerated. Overall, 23 of 62 total DSA (37%) were undetectable after treatment, 21 DSA (34%) had MFI decrease by more than 25%, and 18 (29%) had MFI decrease by less than 25% or increase. The average change in MFI was -51% ± 71% (P < .001). Despite reductions in DSA, among the six patients (32%) with biopsy-confirmed AMR, left ventricular ejection fraction (LVEF) decreased in five (83%) and cardiac index (CI) decreased in three (50%). Conversely, LVEF increased in 91% and CI increased in 70% of biopsy-negative patients. All six AMR patients were readmitted during treatment, four for confirmed or suspected rejection. IVIg infusions may stabilize the allograft in patients with elevated DSA and negative biopsies, but once AMR has developed does not appear to improve allograft function despite decreasing DSA levels.
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http://dx.doi.org/10.1111/ctr.14524DOI Listing
October 2021

Prolonged severe acute respiratory syndrome coronavirus 2 persistence, attenuated immunologic response, and viral evolution in a solid organ transplant patient.

Am J Transplant 2021 Sep 12. Epub 2021 Sep 12.

Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.

Unlike immunocompetent hosts, the duration of viral persistence after infection with severe acute respiratory syndrome coronavirus 2 can be prolonged in immunosuppressed patients. Here, we present a case of viral persistence for over 19 weeks in a patient with a history of solid organ transplant and explore the clinical, virologic, and immunologic course. Our patient still demonstrated viral persistence at 138 days with low polymerase chain reaction cycle threshold values and evidence of continuing viral sequence evolution indicative of ongoing virus replication. These findings have important implications for infection prevention and control recommendations in immunosuppressed patients. Immune response, including neutralizing antibody titers, T cell activity, and cytokine levels, peaked around days 44-72 after diagnosis. Anti-S trimer antibodies were low at all time points, and T cell response was attenuated by day 119. As immune response waned and viral load increased, increased genetic diversity emerged, suggesting a mechanism for the development of viral variants.
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http://dx.doi.org/10.1111/ajt.16837DOI Listing
September 2021

Current Desensitization Strategies in Heart Transplantation.

Authors:
Marlena V Habal

Front Immunol 2021 24;12:702186. Epub 2021 Aug 24.

Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, Columbia University, New York, NY, United States.

Heart transplant candidates sensitized to HLA antigens wait longer for transplant, are at increased risk of dying while waiting, and may not be listed at all. The increasing prevalence of HLA sensitization and limitations of current desensitization strategies underscore the urgent need for a more effective approach. In addition to pregnancy, prior transplant, and transfusions, patients with end-stage heart failure are burdened with unique factors placing them at risk for HLA sensitization. These include homograft material used for congenital heart disease repair and left ventricular assist devices (LVADs). Moreover, these risks are often stacked, forming a seemingly insurmountable barrier in some cases. While desensitization protocols are typically implemented uniformly, irrespective of the mode of sensitization, the heterogeneity in success and post-transplant outcomes argues for a more tailored approach. Achieving this will require progress in our understanding of the immunobiology underlying the innate and adaptive immune response to these varied allosensitizing exposures. Further attention to B cell activation, memory, and plasma cell differentiation is required to establish methods that durably abrogate the anti-HLA antibody response before and after transplant. The contribution of non-HLA antibodies to the net state of sensitization and the potential implications for graft longevity also remain to be comprehensively defined. The aim of this review is to first bring forth select issues unique to the sensitized heart transplant candidate. The current literature on desensitization in heart transplantation will then be summarized providing context within the immune response. Building on this, newer approaches with therapeutic potential will be discussed emphasizing the importance of not only addressing the short-term pathogenic consequences of circulating HLA antibodies, but also the need to modulate alloimmune memory.
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http://dx.doi.org/10.3389/fimmu.2021.702186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423343PMC
December 2021

How can we better inform our patients about post-heart transplantation survival? A conditional survival analysis.

Clin Transplant 2021 Nov 12;35(11):e14449. Epub 2021 Sep 12.

Department of Medicine, Milstein Division of Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.

Background: Conditional survival (CS) is a dynamic method of survival analysis that provides an estimate of how an individual's future survival probability changes based on time post-transplant, individual characteristics, and post-transplant events. This study sought to provide post-transplant CS probabilities for heart transplant recipients based on different prognostic variables and provide a discussion tool for the providers and the patients.

Methods: Adult heart transplant recipients from January 1, 2004, through October 18, 2018, were identified in the UNOS registry. CS probabilities were calculated using data from Kaplan-Meier survival estimates.

Results: CS probability exceeded actuarial survival probability at all times post-transplant. Women had similar short-term, but greater long-term CS than men at all times post-transplant (10-year CS 1.8-11.5% greater [95% CI 1.2-12.9]). Patients with ECMO or a surgical BiVAD had decreased survival at the time of transplant, but their CS was indistinguishable from all others by 1-year post-transplant. Rejection and infection requiring hospitalization during the first year were associated with a persistently decreased CS probability.

Conclusions: In this study, we report differential conditional survival outcomes based on time, patient characteristics, and clinical events post-transplant, providing a dynamic assessment of survival. The survival probabilities will better inform patients and clinicians of future outcomes.
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http://dx.doi.org/10.1111/ctr.14449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8697356PMC
November 2021

Exception Status Listing in the New Adult Heart Allocation System: A New Solution to an Old Problem?

Circ Heart Fail 2021 06 28;14(6):e007916. Epub 2021 May 28.

Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY (E.H., G.S., N.U.).

Background: One of the goals of the revised 6-tiered US adult heart allocation policy was to improve risk stratification of patients to lower exception status utilization for transplant listing. We sought to define the characteristics and outcomes of waitlisted patients using exception status and to examine region- and center-level differences in utilization of exception status in the new heart allocation system.

Methods: This retrospective cohort analysis of the United Network for Organ Sharing database included adult waitlisted patients for heart transplant between October 18, 2018, and June 30, 2020, in the United States, stratified by use of exception status versus standard criteria.

Results: Out of 6351 patients, 1907 (30.0%) were waitlisted under exception status. Patients using exception status were more likely to have a nonischemic cause of heart failure, blood type O, United Network for Organ Sharing status 2 at listing and were less likely to have a durable left ventricular assist device at listing. Exception status utilization varied significantly between and within United Network for Organ Sharing regions. Listing by exception criteria was associated with a significantly higher incidence of heart transplantation compared with listing by standard criteria (hazard ratio, 1.25 [1.15-1.38], <0.001), without increased risk of death or delisting for worsening clinical status (hazard ratio, 0.83 [0.65-1.05], =0.12) after multivariable adjustment.

Conclusions: The status tiers of the new heart allocation system may not fully capture medical urgency and complexity of waitlisted patients as assessed by transplant physicians and review committees and may limit the ability to develop a heart allocation score.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218576PMC
June 2021

Extracorporeal photopheresis and its role in heart transplant rejection: prophylaxis and treatment.

Clin Transplant 2021 07 27;35(7):e14333. Epub 2021 May 27.

Division of Cardiology, Department of Medicine, Columbia University, New York, NY, USA.

Heart transplantation is the gold standard therapeutic option for select patients with end-stage heart failure. Unfortunately, successful long-term outcomes of heart transplantation can be hindered by immune-mediated rejection of the cardiac allograft, specifically acute cellular rejection, antibody-mediated rejection, and cardiac allograft vasculopathy. Extracorporeal photopheresis is a cellular immunotherapy that involves the collection and treatment of white blood cells contained in the buffy coat with a photoactive psoralen compound, 8-methoxy psoralen, and subsequent irradiation with ultraviolet A light. This process is thought to cause DNA and RNA crosslinking, ultimately leading to cell destruction. The true mechanism of therapeutic action remains unknown. In the last three decades, extracorporeal photopheresis has shown promising results and is indicated for a variety of conditions. The American Society for Apheresis currently recommends the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma, scleroderma, psoriasis, pemphigus vulgaris, atopic dermatitis, graft-versus-host disease, Crohn's disease, nephrogenic systemic fibrosis, and solid organ rejection in heart, lung, and liver transplantation. In this review, we aim to explore the proposed effects of extracorporeal photopheresis and to summarize published data on its use as a prophylactic and therapy in heart transplant rejection.
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http://dx.doi.org/10.1111/ctr.14333DOI Listing
July 2021

De Novo Human Leukocyte Antigen Allosensitization in Heartmate 3 Versus Heartmate II Left Ventricular Assist Device Recipients.

ASAIO J 2021 Apr 19. Epub 2021 Apr 19.

From the Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, New York Division of Cardiothoracic Surgery, Department of Surgery, Columbia University Irving Medical Center, New York, New York.

Left ventricular assist devices (LVADs) are associated with the development of antihuman leukocyte antigen (HLA) antibodies, which can create a challenge for future transplantation in these patients. The differential effects of Heartmate 3 (HM3) versus Heartmate II (HMII) on de novo HLA allosensitization remain unknown. Patients who underwent HMII or HM3 implantation and had no prior HLA antibodies by solid-phase assay (Luminex) testing were included in this study. Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) levels and Luminex antibody profiles were followed until cardiac transplantation, device explantation, or death. Electronic medical records were reviewed to examine posttransplant outcomes. Thirty-eight HM3 and 34 HMII patients with complete data were followed for 1.5 ± 1.1 years on device support. HM3 and HMII groups had similar age at implant, female gender, ischemic heart failure etiology, bridge strategy at implant, as well as intraoperative and postoperative transfusion requirements. 39.5% of HM3 and 47.1% of HMII patients developed detectable HLA antibodies by Luminex testing (p = 0.516). Development of high-level (mean fluorescence intensity >10,000) antibodies was significantly lower in HM3 than HMII patients (5.3 vs. 20.6%, p = 0.049). CDC PRA testing showed fewer HM3 patients with a positive result (PRA > 0%) than HMII patients (39.4 vs. 70.0%, p = 0.015). Among transplanted patients, those who had developed de novo sensitization on LVAD support showed a trend toward incidence of moderate to severe grade rejection compared with unsensitized patients (23.8 vs. 4.8%, p = 0.078). HM3 is associated with lower risk of de novo HLA sensitization compared with HMII.
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http://dx.doi.org/10.1097/MAT.0000000000001451DOI Listing
April 2021

T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy.

Am J Transplant 2021 04 26;21(4):1465-1476. Epub 2020 Oct 26.

Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, New York.

T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T cell receptor β chain (TCRB) sequencing to study the T cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in four cases of CAV and compared it to the immunoglobulin heavy chain variable region (IGHV) repertoire from the same samples. High-dimensional flow cytometry coupled with single-cell PCR was also used to define the T cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4 and CD8 memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFβ) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA-4, and CD69). Importantly, high-frequency rearrangements were traced back to endomyocardial biopsies (2-6 years prior). Comparison with four HLA-mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described cross-reactive sequences. These findings provide supportive evidence for an active local intragraft bystander T cell response in late-stage CAV.
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http://dx.doi.org/10.1111/ajt.16333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672660PMC
April 2021

United network for organ sharing outcomes after heart transplantation for al compared to ATTR cardiac amyloidosis.

Clin Transplant 2020 10 24;34(10):e14028. Epub 2020 Jul 24.

Center for Advanced Cardiac Care, Division of Cardiology, Columbia College of Physicians & Surgeons, New York, NY, USA.

Light-chain (AL) cardiac amyloidosis (CA) has a worse prognosis than transthyretin (ATTR) CA. In this single-center study, we compared post-heart transplant (OHT, orthotopic heart transplantation) survival for AL and ATTR amyloidosis, hypothesizing that these differences would persist post-OHT. Thirty-nine patients with CA (AL, n = 18; ATTR, n = 21) and 1023 non-amyloidosis subjects undergoing OHT were included. Cox proportional hazards modeling was used to evaluate the impact of amyloid subtype and era (early era: from 2001 to 2007; late era: from 2008 to 2018) on survival post-OHT. Survival for non-amyloid patients was greater than ATTR (P = .034) and AL (P < .001) patients in the early era. One, 3-, and 5-year survival rates were higher for ATTR patients than AL patients in the early era (100% vs 75%, 67% vs 50%, and 67% vs 33%, respectively, for ATTR and AL patients). Survival in the non-amyloid cohort was 87% at 1 year, 81% at 3 years, and 76% at 5 years post-OHT. In the late era, AL and ATTR patients had unadjusted 1-year, 3-year, and 5-year survival rates of 100%, which was comparable to non-amyloid patients (90% vs 84% vs 81%). Overall, these findings demonstrate that in the current era, differences in post-OHT survival for AL compared to ATTR are diminishing; OHT outcomes for selected patients with CA do not differ from non-amyloidosis patients.
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http://dx.doi.org/10.1111/ctr.14028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744118PMC
October 2020

Desensitizing highly sensitized heart transplant candidates with the combination of belatacept and proteasome inhibition.

Am J Transplant 2020 12 7;20(12):3620-3630. Epub 2020 Jul 7.

Department of Medicine, Division of Cardiology, Columbia University Irving Medical Center, New York, New York, USA.

HLA antibodies pose a significant barrier to transplantation and current strategies to reduce allosensitization are limited. We hypothesized that augmenting proteasome inhibitor (PI) based desensitization with costimulation blockade (belatacept) to mitigate germinal center (GC) responses might increase efficacy and prevent rebound. Four highly sensitized (calculated panel reactive antibody [cPRA] class I and/or II >99%, complement-dependent cytotoxicity panel reactive antibody [CDC PRA+], C1q+) heart transplant candidates were treated with the combination of belatacept and PI therapy, which significantly reduced both class I and II HLA antibodies and increased the likelihood of identifying an acceptable donor. Three negative CDC crossmatches were achieved against 3, 6, and 8 donor-specific antibodies (DSA), including those that were historically C1q+ binding. Posttransplant, sustained suppression of 3 of 3, 4 of 6, and 8 of 8 DSA (cases 1-3) was achieved. Analysis of peripheral blood mononuclear cells before and after desensitization in one case revealed a decrease in naïve and memory B cells and a reduction in T follicular helper cells with a phenotype suggesting recent GC activity (CD38, PD1, and ICOS). Furthermore, a shift in the natural killer cell phenotype was observed with features suggestive of activation. Our findings support synergism between PI based desensitization and belatacept facilitating transplantation with a negative CDC crossmatch against historically strong, C1q binding antibodies.
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http://dx.doi.org/10.1111/ajt.16113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366746PMC
December 2020

Characteristics and Outcomes of Recipients of Heart Transplant With Coronavirus Disease 2019.

JAMA Cardiol 2020 10;5(10):1165-1169

Division of Cardiology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York.

Importance: Recipients of heart transplant (HT) may be at increased risk of adverse outcomes attributable to infection with coronavirus disease 2019 (COVID-19) because of multiple comorbidities and clinically significant immunosuppression.

Objective: To describe the characteristics, treatment, and outcomes of recipients of HT with COVID-19.

Design, Setting, And Participants: This case series from a single large academic heart transplant program in New York, New York, incorporates data from between March 1, 2020, and April 24, 2020. All recipients of HT followed up by this center who were infected with COVID-19 were included.

Interventions: Heart transplant and a confirmed diagnosis of COVID-19.

Main Outcomes And Measures: The primary measure was vital status at end of study follow-up. Secondary measures included patient characteristics, laboratory analyses, changes to immunosuppression, and treatment administered for COVID-19.

Results: Twenty-eight patients with HT received a confirmed diagnosis of COVID-19. The median age was 64.0 (interquartile range [IQR], 53.5-70.5) years, 22 (79%) were men, and the median time from HT was 8.6 (IQR, 4.2-14.5) years. Comorbid conditions included hypertension in 20 patients (71%), diabetes in 17 patients (61%), and cardiac allograft vasculopathy in 16 patients (57%). Twenty-two participants (79%) were admitted for treatment, and 7 (25%) required mechanical ventilation. Most (13 of 17 [76%]) had evidence of myocardial injury (median high-sensitivity troponin T, 0.055 [IQR, 0.0205-0.1345] ng/mL) and elevated inflammatory biomarkers (median peak high-sensitivity C-reactive protein, 11.83 [IQR, 7.44-19.26] mg/dL; median peak interleukin 6, 105 [IQR, 38-296] pg/mL). Among patients managed at the study institution, mycophenolate mofetil was discontinued in 16 patients (70%), and 6 (26%) had a reduction in the dose of their calcineurin inhibitor. Treatment of COVID-19 included hydroxychloroquine (18 patients [78%]), high-dose corticosteroids (8 patients [47%]), and interleukin 6 receptor antagonists (6 patients [26%]). Overall, 7 patients (25%) died. Among 22 patients (79%) who were admitted, 11 (50%) were discharged home, 4 (18%) remain hospitalized at the end of the study, and 7 (32%) died during hospitalization.

Conclusions And Relevance: In this single-center case series, COVID-19 infection was associated with a case fatality rate of 25% in recipients of HT. Immunosuppression was reduced in most of this group of patients. Further study is required to evaluate the optimal approach to management of COVID-19 infection in the HT population.
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http://dx.doi.org/10.1001/jamacardio.2020.2159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221850PMC
October 2020

Desensitization in the Era of Precision Medicine: Moving From the Bench to Bedside.

Transplantation 2019 08;103(8):1574-1581

Department of Surgery, University of Chicago, Chicago, IL.

Patients with antibodies to HLA wait longer for transplant and are at increased risk of adverse outcomes. For more than a decade, drug therapy approaches have been tested to modulate the immune system to prevent or reduce donor-specific antibody levels. Despite some studies reporting success in facilitating transplant, many patients do not respond or experience donor-specific antibody rebound, highlighting the diversity of the individual patient's immune response. While advances in immunomodulatory therapies have resulted in escalating efforts to successfully treat highly sensitized patients, further insight into the human immune system has uncovered its enormous complexity and diversity calling for a personalized approach. Yet, even defining the sensitized transplant candidate can be troublesome and much remains to be understood about the interaction between an individual's immune system as a whole and their response to our current desensitization strategies. The shift toward a personalized approach calls for a reevaluation of what we know and what remains to be determined; a process that will require iterative translational approaches. This review will focus on new insights into how the interaction between immune risk assessment, the patient's immunological history, and the clinical context can be reconciled to develop a precision-based approach to pretransplant management.
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http://dx.doi.org/10.1097/TP.0000000000002737DOI Listing
August 2019

Effect of Socioeconomic Status on Patients Supported with Contemporary Left Ventricular Assist Devices.

ASAIO J 2020 04;66(4):373-380

From the Division of Cardiology, Department of Medicine.

Continuous-flow left ventricular assist devices (CF-LVADs) are increasingly used in advanced heart failure patients. Recent studies suggest that low socioeconomic status (SES) predicts worst survival after heart transplantation. Both individual-level and neighborhood-level SES (nSES) have been linked to cardiovascular health; however, the impact of SES in CF-LVAD patients remains unknown. We hypothesized that SES is a major determinant of CF-LVAD candidacy and postimplantation outcomes. A retrospective chart review was conducted on 362 patients between February 2009 and May 2016. Neighborhood-level SES was measured using the American Community Survey data and the Agency for Healthcare Research and Quality SES index score. Individual-level SES was self reported. Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression determined survival statistics. Patients in the highest SES tertile were older (58 ± 13 vs. 53 ± 14; p < 0.001), less likely to be black or Hispanic (26% vs. 70%; p < 0.001), more likely to be married (87% vs. 65%; p < 0.001), more likely to have private insurance (50% vs. 39%; p < 0.001), and more likely to have employment (29% vs. 15%; p < 0.001) compared with patients in the lowest tertile. Low nSES was associated with a decreased risk of death (hazard ratio [HR], 0.580; 95% confidence interval [CI], 0.347-0.970; p = 0.038) in comparison to the high nSES. However, after adjusting for baseline clinical morbidities, the relationship was no longer present. When selecting patients for a LVAD, SES should not be thought of as an immutable risk factor. Carefully selected low-SES patients could be safely implanted with CF-LVAD with outcomes comparable to high-SES patients.
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http://dx.doi.org/10.1097/MAT.0000000000001009DOI Listing
April 2020

Advanced Therapies for Advanced Heart Failure in Women.

Heart Fail Clin 2019 Jan 24;15(1):97-107. Epub 2018 Oct 24.

Department of Medicine, Division of Cardiology, Center for Advanced Cardiac Care, Columbia University Medical Center, 622 West 168th Street PH1273, New York, NY 10032, USA.

Women with advanced heart failure (HF) are underrepresented in trials of short-term and durable mechanical circulatory support although they derive similar benefit. In acute HF, intensive medical and interventional therapies are effective but underutilized. The smaller, newer generation, left ventricular assist devices (LVADs) have increased the feasibility of durable support in women. Women frequently present late, with more comorbidities, emphasizing the need for timely referral. Compared with men, the stroke risk is higher in women with an LVAD. Increased representation in clinical trials and a better understanding of the psychosocial issues affecting women is essential.
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http://dx.doi.org/10.1016/j.hfc.2018.08.010DOI Listing
January 2019

Predictors of Survival for Patients with Acute Decompensated Heart Failure Requiring Extra-Corporeal Membrane Oxygenation Therapy.

ASAIO J 2019 Nov/Dec;65(8):781-787

Department of Surgery, Columbia University Medical Center, New York, New York.

Chronic systolic heart failure (HF) with acute decompensation can result in cardiogenic shock (CS) requiring short-term mechanical circulatory support. We sought to identify predictors of survival for acute decompensated HF (ADHF) patients requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Patients >18 years old treated at our institution with VA-ECMO from 2009 to 2018 for ADHF with CS were studied. Demographic, hemodynamic, and echocardiographic data were collected. The primary outcome was survival to discharge. Fifty-two patients received VA-ECMO for ADHF with CS; 24 (46.2%) survived. Seventeen (32.7%) had suffered cardiac arrest, and 37 (71.2%) were mechanically ventilated. Mean lactate was 4.33 ± 3.45 mmol/L, and patients were receiving 2.7 ± 1.2 vasopressor/inotropic infusions at ECMO initiation; these did not differ significantly between survivors and nonsurvivors. Pre-ECMO cardiac index was 1.84 ± 0.56L/min/m and 1.94 ± 0.63L/min/m in survivors and nonsurvivors, respectively (p = 0.57). In multivariable analysis, only diabetes mellitus (DM; OR, 13.25; CI, 1.42-123.40; p = 0.02) and mineralocorticoid receptor antagonist use (OR, 0.12; CI, 0.02-0.78; p = 0.03) were independent predictors of mortality. Nineteen (79.2%) survivors required durable ventricular assist device. Among ADHF patients receiving VA-ECMO, DM is a powerful predictor of outcomes while markers of clinical acuity including hemodynamics, vasopressor/inotrope use, and lactate are not. The vast majority of survivors required durable left-ventricular assist devices.
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http://dx.doi.org/10.1097/MAT.0000000000000898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456436PMC
June 2020

VA-ECMO for cardiogenic shock in the contemporary era of heart transplantation: Which patients should be urgently transplanted?

Clin Transplant 2018 09 13;32(9):e13356. Epub 2018 Aug 13.

Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York.

With the impending United Network for Organ Sharing (UNOS) heart allocation policy giving VA-ECMO supported heart transplant (HT) candidates highest priority status (Tier 1), identifying patients in cardiogenic shock (CS) with severe and irreversible heart failure (HF) appropriate for urgent HT is critically important. In a center where wait times currently preclude this approach, we retrospectively reviewed 119 patients (ages 18-72) with CS from 1/2014 to 12/2016 who required VA-ECMO for >24 hours. Underlying aetiologies included postcardiotomy shock (45), acute coronary syndromes (33), and acute-on-chronic HF (16). Eighty-four percent of patients (100) had ≥1 contraindication to HT with 61.3% (73) having preexisting contraindications (eg, multiorgan dysfunction and substance abuse), and 68.1% (81) experienced preclusive complications (eg, renal failure, coagulopathy, and infection). Potential HT candidates were significantly more likely to survive to discharge (potential HT candidates 84.2% vs preexisting contraindications 43.8% vs contraindications developing on VA-ECMO 33.3%, P = 0.001). Among potential HT candidates, 11 (68.8%) were discharged without advanced therapies and 4 received durable left ventricular assist device (25.0%). Importantly, 1-year survival was 100% for the 11 patients with follow-up. Thus, further work is critical to define appropriate candidates for HT from VA-ECMO while avoiding preemptive transplantation in those with otherwise favorable outcomes.
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http://dx.doi.org/10.1111/ctr.13356DOI Listing
September 2018

Heart rate in patients with reduced ejection fraction: relationship between single time point measurement and mean heart rate on prolonged implantable cardioverter defibrillator monitoring.

BMC Cardiovasc Disord 2018 01 31;18(1):17. Epub 2018 Jan 31.

University of Toronto, Toronto, ON, Canada.

Background: Heart rate (HR) is a prognostic marker that is increasingly used as a therapeutic target in patients with cardiovascular disease. The association between resting and mean HR remains unclear. We therefore set out to determine the relationship between resting HR on the electrocardiogram (ECG) obtained at a single time point, and mean HR on implantable cardioverter defibrillator (ICD) interrogation amongst patients with a reduced left ventricular ejection fraction (LVEF).

Methods: Prospective ICD data were obtained from 54 patients with LVEF < 40%. Mean HR determined using the ICD HR histograms was compared with resting HR measured on the ECG performed in the clinic.

Results: Average resting and ICD mean HRs were 67.9 ± 10.1 and 67.8 ± 9.6 bpm respectively. There was good correlation in the overall cohort (r = 0.79), in those with resting ECG HRs ≤ 70 bpm (r = 0.62), and amongst the 27 patients on intermediate-to-high dose beta-blockers (r = 0.91). However, Bland-Altman analysis demonstrated wide limits of agreement in the overall cohort (- 12.5, 12.7 bpm), at resting HRs ≤ 70 bpm (- 12.7, 9.8 bpm), and on intermediate-to-high dose beta-blockers (- 8.9, 7.4 bpm). Moreover, resting HR did not predict the 10-bpm interval where the most time was spent.

Conclusions: While resting HR correlated with mean HR in patients with reduced LVEF, and in important subgroups, the limits of agreement were unacceptably wide raising concern over the use of single time point resting HR as a therapeutic target.
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http://dx.doi.org/10.1186/s12872-018-0751-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793357PMC
January 2018

Long-term management of end-stage heart failure.

Best Pract Res Clin Anaesthesiol 2017 Jun 18;31(2):153-166. Epub 2017 Jul 18.

Columbia University Medical Center, 622 W 168th Street, New York, NY 10032, USA. Electronic address:

End-stage heart failure manifests as severe and often relentless symptoms that define the clinical syndrome of heart failure, namely congestion and hypoperfusion. These patients suffer from dyspnea, fatigue, abdominal discomfort, and ultimately cardiac cachexia. Renal and hepatic dysfunction frequently further complicates the process. Recurrent hospitalizations, cardiac arrhythmias, and intolerance to standard heart failure therapies are common as the disease progresses. Management focuses on controlling symptoms, correcting precipitants, avoiding triggers, and maximizing therapies with demonstrable survival benefit. Among appropriate candidates, advanced therapies such as orthotopic heart transplant (OHT) can significantly extend survival and improve the quality of life. Left ventricular assist devices have been used with increasing frequency as a bridge to OHT or as a destination therapy in appropriately selected candidates where they have a demonstrable mortality benefit over medical therapy. Importantly, a multidisciplinary patient-centered approach is crucial when considering these advanced therapies.
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http://dx.doi.org/10.1016/j.bpa.2017.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726453PMC
June 2017

Association of heart rate at hospital discharge with mortality and hospitalizations in patients with heart failure.

Circ Heart Fail 2014 Jan 2;7(1):12-20. Epub 2013 Dec 2.

Institute for Clinical Evaluative Sciences, Toronto, Canada.

Background: Heart failure (HF) is associated with a high burden of morbidity and mortality. Hospital discharge is an opportunity for identification of modifiable prognostic factors in the transition to chronic HF.

Methods And Results: We examined the association of discharge heart rate with 30-day and 1-year mortality and hospitalization outcomes in a cohort of 9097 patients with HF discharged from hospital. Discharge heart rate was categorized into predefined groups: 40 to 60 (n=1333), 61 to 70 (n=2170), 71 to 80 (n=2631), 81 to 90 (n=1700), and >90 bpm (n=1263). There was a significant increase in all-cause 30-day mortality with adjusted odds ratios of 1.59 (95% confidence interval [CI], 1.18-2.14; P=0.003) for discharge heart rates 81 to 90 bpm and 1.56 (95% CI, 1.13-2.16; P=0.007) for heart rates>90 bpm when compared with the reference group (heart rates, 61-70 bpm). Cardiovascular death risk at 30 days was also higher with adjusted odds ratio 1.59 (discharge heart rates, 81-90 bpm; 95% CI, 1.09-2.33; P=0.017) and 1.65 (discharge heart rates, >90 bpm; 95% CI, 1.09-2.48; P=0.017). One-year all-cause mortality (adjusted odds ratio, 1.41; 95% CI, 1.16-1.72; P<0.001) and cardiovascular death (adjusted odds ratio, 1.47; 95% CI, 1.12-1.92; P=0.005) were higher with discharge heart rates>90 bpm when compared with the reference group (heart rates, 40-60 bpm). Readmissions for HF (adjusted hazard ratio, 1.26; 95% CI, 1.04-1.54; P=0.021) and cardiovascular disease (adjusted hazard ratio, 1.29; 95% CI, 1.08-1.54; P=0.004) within 30 days were also higher with discharge heart rates>90 bpm.

Conclusions: Higher discharge heart rates were associated with greater risk of all-cause and cardiovascular mortality≤1-year follow-up and an elevated risk of 30-day readmission for HF and cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.113.000429DOI Listing
January 2014

How aware of advanced care directives are heart failure patients, and are they using them?

Can J Cardiol 2011 May-Jun;27(3):376-81. Epub 2011 Apr 22.

Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Background: The increasing prevalence of heart failure and its unpredictable trajectory highlight the need for patients to make their end-of-life care wishes known using advanced care directives (ACDs). The paucity of literature addressing heart failure patients' decision-making processes and knowledge of ACDs underscores the need for investigation. The purposes of this study were to (1) determine patients' awareness, comprehension, and utilization of ACDs and (2) determine their knowledge of the process of cardiopulmonary resuscitation and their current resuscitation preference.

Methods: A prospective, single-centre study was designed to collect quantitative data addressing patients' understanding of ACDs and cardiopulmonary resuscitation as well as their current resuscitation preference. Patients who consented were interviewed using a semistructured questionnaire. Data were analyzed using descriptive statistics.

Results: Of the 41 participants, 76% did not know what ACDs were and fewer recalled discussing them with their physician. Nearly 80% of the 37 queried participants would have preferred to discuss ACDs. More than 75% of participants wanted full resuscitation if they were to require it at this time. Most participants had not documented their resuscitation preference, and only slightly over half said their substitute decision maker was aware of their preference. Among the 19 with an implantable cardioverter-defibrillator, nearly half would want it deactivated should their condition worsen. Only 2 participants recalled having discussed this option with their physician.

Conclusions: There remains a lack of knowledge and utilization of ACDs among this heart failure population. Participants' preferences highlight the importance of discussing ACDs and exploring resuscitation preferences early and often in heart failure.
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http://dx.doi.org/10.1016/j.cjca.2010.12.067DOI Listing
July 2011

Murine hepatitis virus strain 1 produces a clinically relevant model of severe acute respiratory syndrome in A/J mice.

J Virol 2006 Nov;80(21):10382-94

Toronto General Hospital, 585 University Ave., NCSB-11-1236, Toronto, Ontario M5G 2N2, Canada.

Severe acute respiratory syndrome (SARS) is a life-threatening infectious disease which has been difficult to study and treat because of the lack of a readily available animal model. Intranasal infection of A/J mice with the coronavirus murine hepatitis virus strain 1 (MHV-1) produced pulmonary pathological features of SARS. All MHV-1-infected A/J mice developed progressive interstitial pneumonitis, including dense macrophage infiltrates, giant cells, and hyaline membranes, resulting in death of all animals. In contrast, other mouse strains developed only mild transitory disease. Infected A/J mice had significantly higher cytokine levels, particularly macrophage chemoattractant protein 1 (MCP-1/CCL-2), gamma interferon, and tumor necrosis factor alpha. Furthermore, FGL2/fibroleukin mRNA transcripts and protein and fibrin deposits were markedly increased in the lungs of infected A/J mice. These animals developed a less robust type I interferon response to MHV-1 infection than resistant C57BL/6J mice, and treatment with recombinant beta interferon improved survival. This study describes a potentially useful small animal model of human SARS, defines its pathogenesis, and suggests treatment strategies.
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http://dx.doi.org/10.1128/JVI.00747-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1641767PMC
November 2006
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