Publications by authors named "Edward M Gilbert"

68 Publications

Quality of Life in Patients With Heart Failure With Recovered Ejection Fraction.

JAMA Cardiol 2021 Aug;6(8):957-962

University of Utah School of Medicine, Salt Lake City.

Importance: Heart failure with recovered ejection fraction (HFrecEF) is a recently recognized phenotype of patients with a history of reduced left ventricular ejection fraction (LVEF) that has subsequently normalized. It is unknown whether such LVEF improvement is associated with improvements in health status.

Objective: To examine changes in health-related quality of life in patients with heart failure with reduced ejection fraction (HFrEF) whose LVEF normalized, compared with those whose LVEF remains reduced and those with HF with preserved EF (HFpEF).

Design, Setting, And Participants: This prospective cohort study was conducted at a tertiary care hospital from November 2016 to December 2018. Consecutive patients seen in a heart failure clinic who completed patient-reported outcome assessments were included. Clinical data were abstracted from the electronic health record. Data analysis was completed from February to December 2020.

Main Outcomes And Measures: Changes in Kansas City Cardiomyopathy Questionnaire overall summary score, Visual Analog Scale score, and Patient-Reported Outcomes Measurement Information System domain scores on physical function, fatigue, depression, and satisfaction with social roles over 1-year follow-up.

Results: The study group included 319 patients (mean [SD] age, 60.4 [15.5] years; 120 women [37.6%]). At baseline, 212 patients (66.5%) had HFrEF and 107 (33.5%) had HFpEF. At a median follow-up of 366 (interquartile range, 310-421) days, LVEF had increased to 50% or more in 35 patients with HFrEF (16.5%). Recovery of systolic function was associated with heart failure-associated quality-of-life improvement, such that for each 10% increase in LVEF, the Kansas City Cardiomyopathy Questionnaire score improved by an mean (SD) of 4.8 (1.6) points (P = .003). Recovery of LVEF was also associated with improvement of physical function, satisfaction with social roles, and a reduction in fatigue.

Conclusions And Relevance: Among patients with HFrEF in this study, normalization of left ventricular systolic function was associated with a significant improvement in health-related quality of life.
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http://dx.doi.org/10.1001/jamacardio.2021.0939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100912PMC
August 2021

Dynamic Regulation of SARS-Cov-2 Binding and Cell Entry Mechanisms in Remodeled Human Ventricular Myocardium.

JACC Basic Transl Sci 2020 Sep 24;5(9):871-883. Epub 2020 Jun 24.

Division of Cardiology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, Colorado.

Using serial analysis of myocardial gene expression employing endomyocardial biopsy starting material in a dilated cardiomyopathy cohort, we show that mRNA expression of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) cardiac myocyte receptor ACE2 is up-regulated with remodeling and with reverse remodeling down-regulates into the normal range. The proteases responsible for virus-cell membrane fusion were expressed but not regulated with remodeling. In addition, a new candidate for SARS-CoV-2 cell binding and entry was identified, the integrin encoded by . Up-regulation in ACE2 in remodeled left ventricles may explain worse outcomes in patients with coronavirus disease 2019 who have underlying myocardial disorders, and counteracting ACE2 up-regulation is a possible therapeutic approach to minimizing cardiac damage.
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http://dx.doi.org/10.1016/j.jacbts.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314447PMC
September 2020

Impact of Shared Care in Remote Areas for Patients With Left Ventricular Assist Devices.

JACC Heart Fail 2020 04;8(4):302-312

Department of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah; George E. Wahlen Veterans' Affairs Medical Center, Salt Lake City, Utah. Electronic address:

Objectives: The aim of this study was to evaluate the impact of a shared-care model on outcomes in patients with left ventricular assist devices (LVADs) living in remote locations.

Background: Health care delivery through shared-care models has been shown to improve outcomes in patients with chronic diseases. However, the impact of shared-care models on outcomes in patients with LVAD is unknown.

Methods: LVAD recipients in the authors' program (2007 to 2018) were classified based on the levels of care provided and training and resources used: level 1, was defined as outpatient primary care without LVAD-specific care; level 2 was level 1 services and outpatient LVAD-specific care; level 3 was level 2 services and inpatient LVAD-specific care and implantation center (IC). The Kaplan-Meier method was used to compare rates of survival, bleeding, pump thrombosis, infection, neurologic events, and readmissions among levels of care.

Results: A total of 336 patients were included, with 255 patients (75.9%) cared for in shared-care facilities. Median follow-up was 810 (interquartile range: 321 to 1,096) days. In comparison to patients cared for by IC, patients at levels 2 and 3 shared-care centers had similar rates of death, bleeding, neurologic events, pump thromboses, and infections. However, the rates of death, pump thromboses, and infections were higher for level 1 patients than in IC patients.

Conclusions: Shared health care is an effective strategy to deliver care to patients with LVAD living in remote locations. However, patients in shared-care facilities unable to provide LVAD-specific care are at higher risk of unfavorable outcomes. Availability of LVAD-specific care should be strongly considered during patient selection and every effort made to ensure LVAD-specific training and resources are available at shared-care facilities.
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http://dx.doi.org/10.1016/j.jchf.2020.01.004DOI Listing
April 2020

Sequential analysis of myocardial gene expression with phenotypic change: Use of cross-platform concordance to strengthen biologic relevance.

PLoS One 2019 30;14(8):e0221519. Epub 2019 Aug 30.

Division of Cardiology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, Colorado, United States of America.

Objectives: To investigate the biologic relevance of cross-platform concordant changes in gene expression in intact human failing/hypertrophied ventricular myocardium undergoing reverse remodeling.

Background: Information is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices.

Methods: We measured mRNA expression in ventricular septal endomyocardial biopsies from 47 idiopathic dilated cardiomyopathy patients, at baseline and after 3-12 months of β-blocker treatment to effect left ventricular (LV) reverse remodeling as measured by ejection fraction (LVEF). Cross-platform gene expression change concordance was investigated in reverse remodeling Responders (R) and Nonresponders (NR) using 3 platforms (RT-qPCR, microarray, and RNA-Seq) and two cohorts (All 47 subjects (A-S) and a 12 patient "Super-Responder" (S-R) subset of A-S).

Results: For 50 prespecified candidate genes, in A-S mRNA expression 2 platform concordance (CcpT), but not single platform change, was directly related to reverse remodeling, indicating CcpT has biologic significance. Candidate genes yielded a CcpT (PCR/microarray) of 62% for Responder vs. Nonresponder (R/NR) change from baseline analysis in A-S, and ranged from 38% to 100% in S-R for PCR/microarray/RNA-Seq 2 platform comparisons. Global gene CcpT measured by microarray/RNA-Seq was less than for candidate genes, in S-R R/NR 17.5% vs. 38% (P = 0.036). For S-R global gene expression changes, both cross-cohort concordance (CccT) and CcpT yielded markedly greater values for an R/NR vs. an R-only analysis (by 22 fold for CccT and 7 fold for CcpT). Pathway analysis of concordant global changes for R/NR in S-R revealed signals for downregulation of multiple phosphoinositide canonical pathways, plus expected evidence of a β1-adrenergic receptor gene network including enhanced Ca2+ signaling.

Conclusions: Two-platform concordant change in candidate gene expression is associated with LV biologic effects, and global expression concordant changes are best identified in an R/NR design that can yield novel information.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221519PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716635PMC
March 2020

Post-transplant outcome in patients bridged to transplant with temporary mechanical circulatory support devices.

J Heart Lung Transplant 2019 08 20;38(8):858-869. Epub 2019 Apr 20.

Division of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah. Electronic address:

Background: The new heart allocation system in the United States prioritizes patients supported by temporary mechanical circulatory support (TMCS) devices over those with uncomplicated durable continuous-flow left ventricular assist devices (CF-LVADs), which may increase the number of patients bridged to transplant with TMCS. Limited data are available in guiding post-transplant outcomes with various TMCS devices. We sought to describe post-transplant outcome and identify clinical variables associated with post-transplant outcome in patients bridged to transplant with TMCS.

Methods: Using data from the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, we included subjects who underwent transplantation between 2005 and 2016 with known use of mechanical circulatory support. Pre-transplant recipient, donor, and transplant-specific variables were abstracted. The primary outcome was patient survival at 1-year post-transplant. Outcomes of patients bridged to transplant with TMCS were compared with those of patients bridged with CF-LVADs. Cox regression analyses were performed to identify clinical variables associated with the outcomes.

Results: There were 6,528 patients bridged to transplant with the following types of mechanical circulatory support: durable CF-LVADs (n = 6,206), extracorporeal membrane oxygenation (ECMO, n = 134), percutaneous temporary CF-LVADs (n = 75), surgically implanted temporary CF-LVADs (n = 38) or surgically implanted temporary BiVAD (n = 75). Bridging with ECMO (hazard ratio 3.79, 95% confidence interval [CI] 2.69-5.34, p < 0.001) or percutaneous temporary CF-LVADs (hazard ratio 1.83, 95% CI 1.09-3.08, p = 0.02) was independently associated with higher risk of mortality. Additional risk factors included older donor age, female/male donor-recipient match, older recipient age, higher recipient body mass index, higher recipient creatinine, and prolonged ischemic time.

Conclusions: This analysis of a large international cohort of patients bridged to transplant with mechanical circulatory support identified ECMO and percutaneous temporary CF-LVADs as predictors of mortality after transplant, along with additional donor and recipient clinical characteristics. These findings may provide guidance to clinicians in decisions on mechanical circulatory support device selection, transplant eligibility, and timing of transplant.
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http://dx.doi.org/10.1016/j.healun.2019.04.003DOI Listing
August 2019

Novel Model to Predict Gastrointestinal Bleeding During Left Ventricular Assist Device Support.

Circ Heart Fail 2018 11;11(11):e005267

Division of Cardiology, Department of Medicine (M.Y.Y., S.R., I.T., E.M.G., J.N.-N., J.S., G.J.S., J.C.F., S.G.D., O.W.-P.).

Background: Gastrointestinal bleeding (GIB) is a leading cause of morbidity during continuous-flow left ventricular assist device (CF-LVAD) support. GIB risk assessment could have important implications for candidate selection, informed consent, and postimplant therapeutic strategies. The aim of the study is to derive and validate a predictive model of GIB in CF-LVAD patients.

Methods And Results: CF-LVAD recipients at the Utah Transplantation Affiliated Hospitals program between 2004 and 2017 were included. GIB associated with a decrease in hemoglobin ≥2 g/dL was the primary end point. A weighted score comprising preimplant variables independently associated with GIB was derived and internally validated. A total of 351 patients (median age, 59 years; 82% male) were included. After a median of 196 days, GIB occurred in 120 (34%) patients. Independent predictors of GIB included age >54 years, history of previous bleeding, coronary artery disease, chronic kidney disease, severe right ventricular dysfunction, mean pulmonary artery pressure <18 mm Hg, and fasting glucose >107 mg/dL. A weighted score termed Utah bleeding risk score, effectively stratified patients based on their probability of GIB: low (0-1 points) 4.8%, intermediate (2-4) 39.8%, and high risk (5-9) 83.8%. Discrimination was good in the development sample (c-index: 0.83) and after internal bootstrap validation (c-index: 0.74).

Conclusions: The novel Utah bleeding risk score is a simple tool that can provide personalized GIB risk estimates in CF-LVAD patients. This scoring system may assist clinicians and investigators in designing tailored risk-based strategies aimed at reducing the burden posed by GIB in the individual CF-LVAD patient and healthcare systems.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005267DOI Listing
November 2018

Microvascular Loss and Diastolic Dysfunction in Severe Symptomatic Cardiac Allograft Vasculopathy.

Circ Heart Fail 2018 08;11(8):e004759

Division of Cardiovascular Medicine (A.D., D.X., Z.S., S.G.D., E.D., G.S., J.N.-N., E.M.G., O.W.-P., J.C.F., J.S.).

Background: Cardiac allograft vasculopathy (CAV) remains an important source of mortality after heart transplant. The aim of our study was to identify structural and microvasculature changes in severe CAV.

Methods And Results: The study group included heart transplant recipients with severe CAV who underwent retransplantation (severe CAV, n=20). Control groups included time from transplant matched cardiac transplant recipients without CAV (transplant control, n=20), severe ischemic cardiomyopathy patients requiring left ventricular assist device implantation (ischemic control, n=18), and normal hearts donated for research (donor control, n=10). We collected baseline demographic information, echocardiography data, and performed histopathologic examination of myocardial microvasculature. Echocardiographic features of severe CAV included lack of eccentric remodeling and presence of significant diastolic dysfunction. In contrast, diastolic function was preserved in transplant control subjects. Histopathologic examination showed increased interstitial fibrosis among severe CAV, transplant controls, and ischemic control patients. Compared with transplant controls, severe CAV subjects had reduced capillary density and increased capillary wall thickness ( P<0.05).

Conclusions: Our results suggest that the marked diastolic dysfunction and resultant symptoms in patients with severe CAV may be secondary to the loss of microvasculature and remodeling of remaining microvessels rather than a consequence of interstitial fibrosis. The clinical significance and potential therapeutic implications of these unique microvasculature characteristics warrant further investigation.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004759DOI Listing
August 2018

Structural and Functional Phenotyping of the Failing Heart: Is the Left Ventricular Ejection Fraction Obsolete?

JACC Heart Fail 2017 11;5(11):772-781

Division of Cardiology, Department of Medicine, Washington University Medical School, St. Louis, Missouri.

Diagnosis, prognosis, treatment, and development of new therapies for diseases or syndromes depend on a reliable means of identifying phenotypes associated with distinct predictive probabilities for these various objectives. Left ventricular ejection fraction (LVEF) provides the current basis for combined functional and structural phenotyping in heart failure by classifying patients as those with heart failure with reduced ejection fraction (HFrEF) and those with heart failure with preserved ejection fraction (HFpEF). Recently the utility of LVEF as the major phenotypic determinant of heart failure has been challenged based on its load dependency and measurement variability. We review the history of the development and adoption of LVEF as a critical measurement of LV function and structure and demonstrate that, in chronic heart failure, load dependency is not an important practical issue, and we provide hemodynamic and molecular biomarker evidence that LVEF is superior or equal to more unwieldy methods of identifying phenotypes of ventricular remodeling. We conclude that, because it reliably measures both left ventricular function and structure, LVEF remains the best current method of assessing pathologic remodeling in heart failure in both individual clinical and multicenter group settings. Because of the present and future importance of left ventricular phenotyping in heart failure, LVEF should be measured by using the most accurate technology and methodologic refinements available, and improved characterization methods should continue to be sought.
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http://dx.doi.org/10.1016/j.jchf.2017.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340335PMC
November 2017

Left ventricular perforation after Impella® placement in a patient with cardiogenic shock.

Catheter Cardiovasc Interv 2018 04 25;91(5):894-896. Epub 2017 Sep 25.

Division of Cardiovascular Medicine, University of Utah Hospital, Utah.

Mechanical cardiovascular support devices are now widely used both in the setting of cardiogenic shock as well as during high risk cardiac catheterization procedures. We report a case of a young female patient who presented with presumed myocarditis and rapidly deteriorating decompensated heart failure requiring the implantation of an Impella Circulatory Support System. Upon transfer to our facility it was discovered that during transport, the Impella device had migrated through the left ventricle. She was emergently taken to the operating room where the Impella was surgically removed and biventricular support devices were placed. The patient eventually expired after weeks of treatment in the intensive care unit. We believe this is the first recorded case of an Impella device perforating the left ventricle. Particularly in cases of newly discovered pericardial effusion, change in waveform on the Impella controller placement signal or rapid decompensation, physicians should consider this rare but potentially catastrophic complication associated with mechanical left ventricular support devices.
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http://dx.doi.org/10.1002/ccd.27329DOI Listing
April 2018

A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction.

Eur J Heart Fail 2017 10 5;19(10):1321-1332. Epub 2017 Jul 5.

Department of Cardiology, Kerckhoff-Klinik, Bad Nauheim, Germany.

Aims: This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS-986231, a novel second-generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction (HFrEF).

Methods And Results: Forty-six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose-escalation cohorts in this double-blind, randomized, placebo-controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure (PCWP) of ≥20 mmHg and a cardiac index of ≤2.5 L/min/m received one 6-h i.v. infusion of BMS-986231 (at 3, 5, 7 or 12 µg/kg/min) or placebo. BMS-986231 produced rapid and sustained reductions in PCWP, as well as consistent reductions in time-averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS-986231 increased non-invasively measured time-averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug-related arrhythmia or symptomatic hypotension with BMS-986231. Analyses of adverse events throughout the 30-day follow-up did not identify any toxicities specific to BMS-986231, with the potential exception of infrequent mild-to-moderate headaches during infusion. There were no treatment-related serious adverse events.

Conclusions: BMS-986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS-986231 should be further assessed in patients with heart failure.
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http://dx.doi.org/10.1002/ejhf.897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607490PMC
October 2017

Rationales and choices for the treatment of patients with NYHA class II heart failure.

Postgrad Med 2017 Aug 14;129(6):619-631. Epub 2017 Jul 14.

a Division of Cardiology , University of Utah , Salt Lake City , UT , USA.

Heart failure (HF) in the United States represents a significant burden for patients and a tremendous strain on the healthcare system. Patients receiving a diagnosis of HF can be placed into 1 of 4 New York Heart Association (NYHA) functional classifications; the greatest proportion of patients are in the NYHA class II category, which is defined as patients having a slight limitation of physical activity but who are comfortable at rest, and for whom ordinary physical activity results in symptoms of HF. Because the severity of NYHA class II HF may be perceived as mild or unalarming by this definition, the urgency to treat this type of HF may be overlooked. However, these patients are optimal candidates for active intervention because their HF is at a critical point on the disease progression continuum when untoward changes can be halted or reversed. This review discusses the physiological consequences of NYHA class II HF with reduced ejection fraction and describes recent clinical trials that have demonstrated a therapeutic benefit for patients in this population. In doing so, we hope to establish that patients with NYHA class II disease merit careful attention and to provide reassurance to the treating community that options are available for these patients.
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http://dx.doi.org/10.1080/00325481.2017.1344082DOI Listing
August 2017

Myocardial microRNAs associated with reverse remodeling in human heart failure.

JCI Insight 2017 01 26;2(2):e89169. Epub 2017 Jan 26.

Division of Cardiology, Department of Medicine.

Background: In dilated cardiomyopathies (DCMs) changes in expression of protein-coding genes are associated with reverse remodeling, and these changes can be regulated by microRNAs (miRs). We tested the general hypothesis that dynamic changes in myocardial miR expression are predictive of β-blocker-associated reverse remodeling.

Methods: Forty-three idiopathic DCM patients (mean left ventricular ejection fraction 0.24 ± 0.09) were treated with β-blockers. Serial ventriculography and endomyocardial biopsies were performed at baseline, and after 3 and 12 months of treatment. Changes in RT-PCR (candidate miRs) or array-measured miRs were compared based on the presence (R) or absence (NR) of a reverse-remodeling response, and a miR-mRNA-function pathway analysis (PA) was performed.

Results: At 3 months, 2 candidate miRs were selectively changed in Rs, decreases in miR-208a-3p and miR-591. PA revealed changes in miR-mRNA interactions predictive of decreased apoptosis and myocardial cell death. At 12 months, 5 miRs exhibited selective changes in Rs (decreases in miR-208a-3p, -208b-3p, 21-5p, and 199a-5p; increase in miR-1-3p). PA predicted decreases in apoptosis, cardiac myocyte cell death, hypertrophy, and heart failure, with increases in contractile and overall cardiac functions.

Conclusions: In DCMs, myocardial miRs predict the time-dependent reverse-remodeling response to β-blocker treatment, and likely regulate the expression of remodeling-associated miRs.

Trial Registration: ClinicalTrials.gov NCT01798992.

Funding: NIH 2R01 HL48013, 1R01 HL71118 (Bristow, PI); sponsored research agreements from Glaxo-SmithKline and AstraZeneca (Bristow, PI); NIH P20 HL101435 (Lowes, Port multi-PD/PI); sponsored research agreement from Miragen Therapeutics (Port, PI).
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http://dx.doi.org/10.1172/jci.insight.89169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256135PMC
January 2017

Immunologic effects of continuous-flow left ventricular assist devices before and after heart transplant.

J Heart Lung Transplant 2016 08 6;35(8):1024-30. Epub 2016 May 6.

Division of Cardiovascular Disease, University of Utah Health Sciences Center, Salt Lake City, Utah; George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah; Utah Transplant Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.

Background: Immune allosensitization can be triggered by continuous-flow left ventricular assist devices (CF LVAD). However, the effect of this type of allosensitization on post-transplant outcomes remains controversial. This study examined the post-transplant course in a contemporary cohort of patients undergoing transplantation with and without LVAD bridging.

Methods: We included consecutive patients who were considered for cardiac transplant from 2006 to 2015. Serum alloantibodies were detected with single-antigen beads on the Luminex platform (One Lambda Inc., Canoga Park, CA). Allosensitization was defined as calculated panel reactive antibody (cPRA) > 10%. cPRA was determined at multiple times. LVAD-associated allosensitization was defined as development of cPRA > 10% in patients with cPRA ≤ 10% before LVAD implantation. Post-transplant outcomes of interest were acute cellular rejection (ACR), antibody-mediated rejection (AMR), and survival.

Results: Allosensitization status was evaluated in 268 patients (20% female). Mean age was 52 ± 12 years, and 132 (49.3%) received CF LVADs. After LVAD implant, 30 patients (23%) became newly sensitized, and the level of sensitization appeared to diminish in many of these patients while awaiting transplant. During the study period, 225 of 268 patients underwent transplant, and 43 did not. A CF LVAD was used to bridge 50% of the transplant recipients. Compared with patients without new sensitization or those already sensitized at baseline, the patients with LVAD-associated sensitization had a higher risk of ACR (p = 0.049) and higher risk of AMR (p = 0.018) but a similar intermediate-term post-transplant survival. The patients who did not receive a transplant had higher level of allosensitization, with a baseline cPRA of 20% vs 6% in those who received an allograft and a high risk (40%) of death during follow-up.

Conclusions: New allosensitization takes place in > 20% of patents supported with CF LVADs. Among patients who undergo transplant, this results in a higher risk of ACR and AMR, but survival remains favorable, likely due to the efficacy of current management after transplant. However, mortality in sensitized patients who do not reach transplant remains high, and new approaches are necessary to meet the needs of this group of patients.
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http://dx.doi.org/10.1016/j.healun.2016.05.001DOI Listing
August 2016

Exertional Angina Due To Fused Aortic Bioprosthesis During Left Ventricular Assist Device Support: Two Cases and Review of the Literature.

ASAIO J 2017 Jan/Feb;63(1):e6-e9

From the Divisions of *Cardiovascular Medicine and †Cardiothoracic Surgery, Cardiac Mechanical Support Program; University of Utah, Salt Lake City, Utah.

We present the case of two patients with idiopathic dilated cardiomyopathy and moderate aortic valve regurgitation that were treated with a bioprosthetic valve at the time of the left ventricular assist device (LVAD) implantation. A few months later, patients revealed partial recovery in the left ventricle systolic function. Both patients, during the LVAD turndown protocol, reported the onset of chest pain. The transthoracic echocardiography revealed the presence of a new transaortic pressure gradient. We confirmed the presence of a fused bioprosthetic valve by further performing a transesophageal echocardiogram and a left and right heart catheterization. Replacement of aortic valve at the time of an LVAD implantation constitutes a challenging case. Although a mechanical valve is contraindicated due to the increased thromboembolic risk, selecting a bioprosthetic valve increases the risk of valve leaflets fusion. The consequences of this phenomenon should be acknowledged in LVAD patients undergoing aortic valve replacement with a bioprosthetic, especially under the view of LVAD explantation for those revealing myocardial recovery under mechanical unloading.
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http://dx.doi.org/10.1097/MAT.0000000000000369DOI Listing
October 2017

Mixed cellular and antibody-mediated rejection in heart transplantation: In-depth pathologic and clinical observations.

J Heart Lung Transplant 2016 Mar 23;35(3):335-341. Epub 2015 Oct 23.

Intermountain Heart Institute and Intermountain Healthcare, Murray, Utah; University of Utah School of Medicine, Salt Lake City, Utah; Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah.

Background: Little is known about mixed cellular and antibody-mediated rejection (MR) in heart transplantation. It remains unclear whether cardiac MR has distinctive pathologic and clinical features beyond those of simultaneous cellular rejection (CR) and antibody-mediated rejection (AMR). In this study we systematically explore the pathologic and clinical characteristics of MR in heart transplantation.

Methods: The UTAH Cardiac Transplant Program database was queried for transplant recipients who survived long enough to have at least one endomyocardial biopsy (EMB) between 1985 and 2014. Only EMBs with both CR and AMR scores documented were included. In addition to detailed pathologic analyses, we also examined the incidence and prevalence of MR, the likelihood to transition from and to MR, and mortality associated with MR.

Results: Patients (n = 1,207) with a total of 28,484 EMBs met the study inclusion criteria. The overall prevalence of MR was 7.8% and it was nearly twice as frequent within the first year post-transplant. Mild MR was by far the most common occurrence and was typically preceded by an immune active state. When CR increased in severity, AMR tended to follow, but the reverse was not true. On pathology, individual features of CR and AMR were more easily separated in cases of mild MR, whereas they substantially overlapped in more severe cases. MR was associated with a significant cardiovascular death risk that was incremental with severity.

Conclusions: MR is not common, usually occurs early after transplant, and is associated with worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity.
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http://dx.doi.org/10.1016/j.healun.2015.10.016DOI Listing
March 2016

Elevated resting heart rate in heart transplant recipients: innocent bystander or adverse prognostic indicator?

Clin Transplant 2015 Sep 27;29(9):829-34. Epub 2015 Jul 27.

School of Medicine, University of Utah, Salt Lake City, UT, USA.

Background: The elevated baseline heart rate (HR) of a heart transplant recipient has previously been considered inconsequential. However, we hypothesized that a resting HR above 100 beats per minute (bpm) may be associated with morbidity and mortality.

Methods: The U.T.A.H. Cardiac Transplant Program studied patients who received a heart transplant between 2000 and 2011. Outpatient HR values for each patient were averaged during the first year post-transplant. The study cohort was divided into two groups: the tachycardic (TC) (HR > 100 bpm) and the non-TC group (HR ≤ 100 bpm) in which mortality, incidence of rejection, and cardiac allograft vasculopathy were compared.

Results: Three hundred and ten patients were included as follows: 73 in the TC and 237 in the non-TC group. The TC group had a higher risk of a 10-yr all-cause mortality (p = 0.004) and cardiovascular mortality (p = 0.044). After adjustment for donor and recipient characteristics in multivariable logistic regression analysis, the hazard ratio was 3.9, (p = 0.03, CI: 1.2-13.2) and 2.6 (p = 0.02, CI: 1.2-5.5) for cardiovascular mortality and all-cause mortality, respectively.

Conclusion: Heart transplant recipients with elevated resting HR appear to have higher mortality than those with lower resting HR. Whether pharmacologically lowering the HR would result in better outcomes warrants further investigation.
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http://dx.doi.org/10.1111/ctr.12587DOI Listing
September 2015

Therapeutic Molecular Phenotype of β-Blocker-Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy.

Circ Cardiovasc Genet 2015 Apr 30;8(2):270-83. Epub 2015 Jan 30.

From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas, Little Rock (C.D.B.).

Background: When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal-adult/contractile protein, natriuretic peptide, SR-Ca(2+)-ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by β1-adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes.

Methods And Results: Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β1-selective), metoprolol+doxazosin (β1/α1), or carvedilol (β1/β2/α1). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by ≥0.08 at 12 months or by ≥0.05 at 3 months (Δ left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6, ATP2A2, PLN, RYR2, ADRA1A, ADRB1, MYL3, PDFKM, PDHX, and CPT1B. All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β1-adrenergic signaling.

Conclusions: In addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal-adult paradigm but may be because of reversal of gene expression controlled by a β1-adrenergic receptor gene network.

Clinical Trial Registration: URL: www.clinicaltrials.gov. Unique Identifier: NCT01798992.
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http://dx.doi.org/10.1161/CIRCGENETICS.114.000767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205443PMC
April 2015

Magnitude and time course of changes induced by continuous-flow left ventricular assist device unloading in chronic heart failure: insights into cardiac recovery.

J Am Coll Cardiol 2013 May 14;61(19):1985-94. Epub 2013 Mar 14.

Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program, Divisions of Cardiology and Cardiothoracic Surgery, University of Utah Health Sciences Center, Intermountain Medical Center, Salt Lake City, Utah 84132, USA.

Objectives: This study sought to prospectively investigate the longitudinal effects of continuous-flow left ventricular assist device (LVAD) unloading on myocardial structure and systolic and diastolic function.

Background: The magnitude, timeline, and sustainability of changes induced by continuous-flow LVAD on the structure and function of the failing human heart are unknown.

Methods: Eighty consecutive patients with clinical characteristics consistent with chronic heart failure requiring implantation of a continuous-flow LVAD were prospectively enrolled. Serial echocardiograms (at 1, 2, 3, 4, 6, 9, and 12 months) and right heart catheterizations were performed after LVAD implant. Cardiac recovery was assessed on the basis of improvement in systolic and diastolic function indices on echocardiography that were sustained during LVAD turn-down studies.

Results: After 6 months of LVAD unloading, 34% of patients had a relative LV ejection fraction increase above 50% and 19% of patients, both ischemic and nonischemic, achieved an LV ejection fraction ≥ 40%. LV systolic function improved as early as 30 days, the greatest degree of improvement was achieved by 6 months of mechanical unloading and persisted over the 1-year follow up. LV diastolic function parameters also improved as early as 30 days after LVAD unloading, and this improvement persisted over time. LV end-diastolic and end-systolic volumes decreased as early as 30 days after LVAD unloading (113 vs. 77 ml/m(2), p < 0.01, and 92 vs. 60 ml/m(2), p < 0.01, respectively). LV mass decreased as early as 30 days after LVAD unloading (114 vs. 95 g/m(2), p < 0.05) and continued to do so over the 1-year follow-up but did not reach values below the normal reference range, suggesting no atrophic remodeling after prolonged LVAD unloading.

Conclusions: Continuous-flow LVAD unloading induced in a subset of patients, both ischemic and nonischemic, early improvement in myocardial structure and systolic and diastolic function that was largely completed within 6 months, with no evidence of subsequent regression.
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http://dx.doi.org/10.1016/j.jacc.2013.01.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819804PMC
May 2013

Pulsatility and the risk of nonsurgical bleeding in patients supported with the continuous-flow left ventricular assist device HeartMate II.

Circ Heart Fail 2013 May 11;6(3):517-26. Epub 2013 Mar 11.

Utah Transplantation Affiliated Hospitals, Cardiac Transplant Program, Salt Lake City, UT, USA.

Background: Bleeding is an important cause of morbidity and mortality in patients with continuous-flow left ventricular assist devices (LVADs). Reduced pulsatility has been implicated as a contributing cause. The aim of this study was to assess the effects of different degrees of pulsatility on the incidence of nonsurgical bleeding.

Methods And Results: The Utah Transplantation Affiliated Hospitals (U.T.A.H.) heart failure and transplant program databases were queried for patients with end-stage heart failure who required support with the continuous-flow LVAD HeartMate II (Thoratec Corp, Pleasanton, CA) between 2004 and 2012. Pulsatility was evaluated by means of the LVAD parameter pulsatility index (PI) and by the echocardiographic assessment of aortic valve opening during the first 3 months of LVAD support. PI was analyzed as a continuous variable and also stratified according to tertiles of all the PI measurements during the study period (low PI: <4.6, intermediate PI: 4.6-5.2, and high PI: >5.2). Major nonsurgical bleeding associated with a decrease in hemoglobin ≥2 g/dL (in the absence of hemolysis) was the primary end point. A total of 134 patients (median age of 60 [interquartile range: 49-68] years, 78% men) were included. Major bleeding occurred in 33 (25%) patients (70% gastrointestinal, 21% epistaxis, 3% genitourinary, and 6% intracranial). In multivariable analysis, PI examined either as a categorical variable, low versus high PI (hazard ratio, 4.06; 95% confidence interval, 1.35-12.21; P=0.04), or as a continuous variable (hazard ratio, 0.60; 95% confidence interval, 0.40-0.92; P=0.02) was associated with an increased risk of bleeding.

Conclusions: Reduced pulsatility in patients supported with the continuous-flow LVAD HeartMate II is associated with an increased risk of nonsurgical bleeding, as evaluated by PI.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.112.000206DOI Listing
May 2013

Morbidity and mortality in heart transplant candidates supported with mechanical circulatory support: is reappraisal of the current United network for organ sharing thoracic organ allocation policy justified?

Circulation 2013 Jan 27;127(4):452-62. Epub 2012 Dec 27.

U.T.A.H. Cardiac Transplant Program, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.

Background: Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list.

Methods And Results: We analyzed mortality and morbidity in 33,073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, 1B, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P<0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P<0.0001) and similar to that in status 1B patients (HR, 1.04; P=0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P=0.12) and lower mortality compared with status 1A and 1B patients (HR, 0.24 and 0.47; P<0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P=0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P<0.0001) and temporary VADs (HR, 7.72; P<0.0001).

Conclusions: Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.100123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752367PMC
January 2013

Beta-adrenergic receptors, from their discovery and characterization through their manipulation to beneficial clinical application.

Cardiology 2012 3;122(2):104-12. Epub 2012 Jul 3.

Division of Cardiology, University of Utah, Salt Lake City, Utah, USA.

β-Adrenergic receptors (β-AR) are central to the overall regulation of cardiac function. From the first proposed receptor/transmitter concept to the latest clinical β-blocker trials β-AR have been shown to play an important role in cardiac disease and heart failure in particular. This study provides a historical perspective, reviews the latest discoveries and beliefs, and discusses the current clinical practices of β-AR and their modulation with their associated guanine-nucleotide regulatory protein/adenylylcyclasesignal transduction pathways.
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http://dx.doi.org/10.1159/000339271DOI Listing
November 2012

Longitudinal evaluation of microvessel density in survivors vs. nonsurvivors of cardiac pathologic antibody-mediated rejection.

Cardiovasc Pathol 2012 Nov-Dec;21(6):445-54. Epub 2012 Feb 29.

Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, UT, USA.

Background: Antibody-mediated rejection (AMR) of cardiac allografts is associated with reduced long-term graft survival, but not every patient with AMR develops premature graft failure. The tissue level mechanisms leading to graft failure in some patients with antibody-mediated rejection are poorly characterized.

Methods: We assessed changes in myocardial microvessel density (number of capillaries per unit area) in endomyocardial biopsies over time using whole-slide microscopic imaging of CD34-stained slides and computer-assisted image analysis. Changes were compared among eight heart transplant recipients with multiple episodes of pathologic AMR who died from cardiovascular causes, eight age- and gender-matched patients with pathologic AMR who were still alive at a similar follow-up interval, and six matched controls without AMR or cellular rejection.

Results: Microvessel density decreased in the last biopsies (mean 6.52 years post-transplant) from patients with pathologic AMR and cardiovascular mortality compared to their biopsies at 6 and 12 months post-transplant [respectively, -22% (P=.02) and -25% (P=.02)]. A similar decrease was not seen for the other groups.

Conclusions: Significantly reduced myocardial microvessel density does occur in a subset of patients with pathologic AMR who have a worse outcome. These data provide insights into the interplay between AMR, microvascular injury, and clinical outcomes.
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http://dx.doi.org/10.1016/j.carpath.2012.01.004DOI Listing
May 2013

A longitudinal study of the course of asymptomatic antibody-mediated rejection in heart transplantation.

J Heart Lung Transplant 2012 Jan;31(1):46-51

Intermountain Medical Center and Intermountain Healthcare, Salt Lake City, Utah, USA.

Background: Growing evidence suggests worse cardiac allograft vasculopathy and mortality in patients with asymptomatic antibody-mediated rejection (AMR). Debate continues about whether therapeutic intervention is warranted to avoid adverse outcomes. In this study we examine the course of individual episodes of untreated asymptomatic AMR on follow-up endomyocardial biopsy (EMB).

Methods: The U.T.A.H. Cardiac Transplant Program database was queried for transplant recipients between 1985 and 2009 who survived beyond 1 year and had at least 1 episode of lone AMR with a follow-up EMB. All EMBs were screened for AMR by immunofluorescence and graded for severity. Data were analyzed based on time from transplant (early, ≤12 months; late, >12 months).

Results: Nine hundred fifty-eight patients with a total of 15,448 biopsies qualified for the study. Average age at transplant was 46.7 years; 13% of the patients were female. Within the first year post-transplant, asymptomatic AMR was diagnosed in 13.6% of biopsies compared with 5.2% beyond 1 year. AMR resolved in 65% (early) vs 75% (late) on follow-up EMB. More severe AMR was less likely to improve regardless of time from transplant. Furthermore, after an episode of AMR had resolved, the recurrence rate at 3, 6 and 12 months was 44%, 50.1% and 56.2%, respectively.

Conclusions: The incidence of AMR is higher in the first year post-transplant and the likelihood of resolution is less on follow-up EMB, especially when more severe. A small but significant number of cases became worse or did not change. These new findings may be helpful in planning future studies that test whether therapeutic interventions on asymptomatic AMR favorably impact outcomes.
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http://dx.doi.org/10.1016/j.healun.2011.10.009DOI Listing
January 2012

Allograft rejection in patients supported with continuous-flow left ventricular assist devices.

Ann Thorac Surg 2011 Nov 22;92(5):1601-7; discussion 1607. Epub 2011 Sep 22.

UTAH (Utah Transplant Affiliated Hospitals) Cardiac Transplant Program, University of Utah, Salt Lake City, Utah 84132, USA.

Background: Both pulsatile-flow and continuous-flow left ventricular assist devices (LVADs) successfully provide patients a bridge to transplantation. Some data suggest that continuous-flow pumps increase the risk of allograft rejection, contributing to posttransplantation morbidity and mortality. We sought to analyze the relationship between LVAD flow characteristics and subsequent allograft rejection in bridge to transplant (BTT) patients.

Methods: Patients with LVADs from the UTAH Transplant Affiliated Hospitals were retrospectively analyzed. Rejection was determined pathologically according to the International Society for Heart and Lung Transplantation revised cardiac allograft rejection scale. Multimodal statistical analyses were applied.

Results: Of 1,076 patients who underwent transplantation over a 26-year period, 151 had LVADs. Of these, 111 (77 pulsatile flow, 34 continuous flow) patients had pathologic data available. There was no difference in overall rejection (grades 1R to 3R) between the pulsatile-flow LVAD and continuous-flow LVAD groups (2.00 ± 1.43 versus 1.50 ± 1.16 episodes/year; p = 0.076.) Patients with pulsatile-flow LVADs had more clinically relevant (grades 2R to 3R) rejection than did patients with continuous-flow LVADs (0.49 ± 0.72 versus 0.12 ± 0.33 episodes/year; p < 0.001). There was no survival difference at 1 year (p = 0.920) or 4 years (p = 0.721) after transplantation.

Conclusions: Patients with continuous-flow LVADs have similar overall rejection rates and a reduced rate of clinically relevant rejection compared with patients with pulsatile-flow LVADs during the first year after transplantation. Although there is theoretical concern that nonphysiologic, nonpulsatile flow could alter the neurohormonal profile of patients in heart failure, we are encouraged that the type of LVAD circulation does not influence posttransplantation allograft survival.
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http://dx.doi.org/10.1016/j.athoracsur.2011.05.119DOI Listing
November 2011

Can echocardiographic evaluation of cardiopulmonary hemodynamics decrease right heart catheterizations in end-stage heart failure patients awaiting transplantation?

Am J Cardiol 2010 Dec 14;106(11):1657-62. Epub 2010 Oct 14.

Division of Cardiology, University of Utah, Salt Lake City, Utah, USA.

Candidacy for heart transplantation is influenced by the severity of pulmonary hypertension. In this study, invasive hemodynamics from right-sided cardiac catheterization were compared with values obtained by validated equations from Doppler 2-dimensional transthoracic echocardiography. This prospective study was conducted in 40 patients with end-stage heart failure evaluated for heart transplantation or ventricular assist device implantation. Transthoracic echocardiography and right-sided cardiac catheterization were performed within 4 hours. From continuous-wave Doppler of the tricuspid regurgitation jet, pulmonary artery systolic pressure was calculated as the peak gradient across the tricuspid valve plus right atrial pressure estimated from inferior vena cava filling. Mean pulmonary artery pressure was calculated as (0.61 × pulmonary artery systolic pressure) + 2. Pulmonary vascular resistance (PVR) was calculated as (tricuspid regurgitation velocity/right ventricular outflow tract time-velocity integral × 10) + 0.16. Pulmonary capillary wedge pressure was calculated as 1.91 + (1.24 × E/E'). Pearson's correlation and Bland-Altman analysis of mean differences between echocardiographic and right-sided cardiac catheterization measurements were statistically significant for all hemodynamic parameters (pulmonary artery systolic pressure: r = 0.82, p < 0.05, mean difference 3.1 mm Hg, 95% confidence interval [CI] -0.2 to 6.3; mean pulmonary artery pressure: r = 0.80, p < 0.05, mean difference 2.5 mm Hg, 95% CI 0.3 to 4.6; PVR: r = 0.52, p < 0.05, mean difference 0.8 Wood units, 95% CI 0.3 to 1.4; pulmonary capillary wedge pressure: r = 0.65, p < 0.05, mean difference 2.2 mm Hg, 95% CI 0.1 to 4.3). Compared with right-sided cardiac catheterization, PVR by Doppler echocardiography identified all patients with PVR > 4 Wood units (n = 4), 73% of patients with PVR <2 Wood units (n = 8), and 52% of patients with PVR from 2 to 4 Wood units (n = 10). In conclusion, echocardiographic estimation of cardiopulmonary hemodynamics is reliable in patients with end-stage cardiomyopathy. The noninvasive assessment of hemodynamics by echocardiography may be able to decrease the number of serial right-sided cardiac catheterizations in selected patients awaiting heart transplantation. However, in patients with borderline PVR, right-sided cardiac catheterization is indicated to assess eligibility for transplantation.
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http://dx.doi.org/10.1016/j.amjcard.2010.07.022DOI Listing
December 2010

Double-blind placebo-controlled comparison of enoximone and dobutamine infusions in patients with moderate to severe chronic heart failure.

Congest Heart Fail 2010 Nov-Dec;16(6):265-70. Epub 2010 Oct 19.

Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.

Few data exist on the safety of transferring patients to standard oral therapy for chronic heart failure (CHF) after acute management with inotropic agents. This study compares hemodynamic responses and cardiac dysrhythmic effects of continuous infusion of enoximone, dobutamine, or placebo in patients with moderate to severe CHF. The authors enrolled 136 patients who were randomly assigned to either open-label dobutamine or double-blind enoximone vs placebo. After 24 hours of treatment, the study was unblinded. Patients receiving placebo completed the study. Patients receiving enoximone or dobutamine received the infusion for an additional 24 hours and were then switched to standard oral therapy for 72 hours. Compared with placebo, both enoximone and dobutamine increased cardiac index and decreased pulmonary capillary wedge pressure (PCWP). Compared with dobutamine, enoximone significantly increased cardiac index after the first 24 hours of infusion and significantly decreased PCWP throughout the infusion period. There was no difference in the incidence of arrhythmias between enoximone and dobutamine. More patients (65%) tolerated the switch to oral therapy in the enoximone group compared with dobutamine (49%; P =.12). Enoximone is effective in improving the hemodynamics in patients with moderate to severe CHF and is tolerated at least as well as dobutamine.
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http://dx.doi.org/10.1111/j.1751-7133.2010.00185.xDOI Listing
June 2011

Rationale and design of the treatment of hyponatremia based on lixivaptan in NYHA class III/IV cardiac patient evaluation (THE BALANCE) study.

Clin Transl Sci 2010 Oct;3(5):249-53

Division of Cardiovascular Medicine, The Ohio State University Heart Center, Columbus, USA.

Hyponatremia is a common electrolyte disorder in patients with heart failure (HF) associated with cognitive dysfunction and increased mortality and rehospitalization rates. Loop diuretics worsen renal function, produce neurohormonal activation, and induce electrolyte imbalances. Lixivaptan is a selective, oral vasopressin V(2) -receptor antagonist that improves hyponatremia by promoting electrolyte-free aquaresis without significant side effects. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE) study is a randomized, double-blind, placebo-controlled, phase 3 trial designed to evaluate the effects of lixivaptan on serum sodium in patients hospitalized with worsening heart failure (target N= 650), signs of congestion and serum sodium concentrations <135 mEq/L. Other endpoints include assessment of dyspnea, body weight, cognitive function, and days of hospital-free survival. Patients are randomized 1:1 to lixivaptan or matching placebo for 60 days, with a 30-day safety follow-up. Doses of lixivaptan or placebo are adjusted based on serum sodium and volume status. Lixivaptan was shown to increase serum sodium and reduce body weight, without renal dysfunction or hypokalemia. BALANCE seeks to address unmet questions regarding the use of vasopressin antagonists including their effects on cognitive function and clinical outcomes in patients with hyponatremia and worsening heart failure.
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http://dx.doi.org/10.1111/j.1752-8062.2010.00217.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439626PMC
October 2010

Antibody testing for cardiac antibody-mediated rejection: which panel correlates best with cardiovascular death?

J Heart Lung Transplant 2011 Feb 19;30(2):144-50. Epub 2010 Sep 19.

George E Wahlen Veterans Affairs Medical Center, Utah Transplantation Affiliated Hospitals, Salt Lake City, Utah, USA.

Background: Recent efforts are being undertaken to update and refine current diagnostic criteria for antibody-mediated rejection (AMR) in heart transplantation. We believe that the appropriate reactants are those that best predict the adverse consequences of AMR and therefore tested various models using different reactants to find the best predictors of cardiovascular mortality in pathologically defined AMR.

Methods: The study group included only patients in whom all immunofluorescence antibodies of interest had been tested on biopsy specimens obtained after 2002 when C4d was routinely added. We analyzed our data using 3 Cox proportional hazard models with time-varying covariates using an end point of cardiovascular mortality, as previously defined.

Results: In 3,712 biopsy specimens from 422 patients, the 2-antibody model achieved a value of R(2) = 0.930 using C3d and C4d antibodies alone. A model that used 4 antibodies--C3d, C4d, human leukocyte antigen-D related (HLA-DR) and fibrin--was superior (R(2) = 0.988). The model that best predicted cardiovascular mortality included all 6 antibodies: HLA-DR, immunoglobulin (Ig) G, IgM, C3d, C4d, and fibrin (R(2) = 0.989). The models using 4 or 6 antibodies were significantly superior to the model using only C3d and C4d (for each interaction, p < 0.0001).

Conclusions: The combination of complement components, HLA-DR and fibrin, is valuable in defining AMR in patients at risk for allograft loss from cardiovascular causes. Fibrin is particularly important for detecting the presence of severe AMR, with a high likelihood of poor long-term patient outcome.
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http://dx.doi.org/10.1016/j.healun.2010.06.019DOI Listing
February 2011
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