Publications by authors named "Amrut V Ambardekar"

76 Publications

Association Between Variants in Calcineurin Inhibitor Pharmacokinetic and Pharmacodynamic Genes and Renal Dysfunction in Adult Heart Transplant Recipients.

Front Genet 2021 1;12:658983. Epub 2021 Apr 1.

Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States.

: The goal of the study was to assess the relationship between single nucleotide variants (SNVs) in calcineurin inhibitor (CNI) pharmacokinetic and pharmacodynamic genes and renal dysfunction in adult heart transplant (HTx) recipients. : This retrospective analysis included = 192 patients receiving a CNI at 1-year post-HTx. Using a candidate gene approach, 93 SNVs in eight pharmacokinetic and 35 pharmacodynamic genes were chosen for investigation. The primary outcome was renal dysfunction 1-year after HTx, defined as an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m. Renal dysfunction was present in 28.6% of patients 1-year after HTx. Two SNVs [transforming growth factor beta 1 () rs4803455 C > A and phospholipase C beta 1 () rs170549 G > A] were significantly associated with renal dysfunction after accounting for a false discovery rate (FDR) of 20%. In a multiple-SNV adjusted model, variant A allele carriers of rs4803455 had lower odds of renal dysfunction compared to C/C homozygotes [odds ratio (OR) 0.28, 95% CI 0.12-0.62; = 0.002], whereas rs170549 variant A allele carriers had higher odds of the primary outcome vs. patients with the G/G genotype (OR 2.66, 95% CI 1.21-5.84, = 0.015). : Our data suggest that genetic variation in and may contribute to the occurrence of renal dysfunction in HTx recipients receiving CNIs. Pharmacogenetic markers, such as rs4803455 and rs170549, could help identify patients at increased risk of CNI-associated renal dysfunction following HTx, potentially allowing clinicians to provide more precise and personalized care to this population.
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http://dx.doi.org/10.3389/fgene.2021.658983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047196PMC
April 2021

Reverse Remodeling the Transplanted Heart by Remodeling Immunosuppression?

JACC Heart Fail 2021 Apr;9(4):314-316

Division of Cardiology, University of Colorado, Aurora, Colorado, USA.

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http://dx.doi.org/10.1016/j.jchf.2021.02.003DOI Listing
April 2021

Maturation of Pluripotent Stem Cell-Derived Cardiomyocytes Enables Modeling of Human Hypertrophic Cardiomyopathy.

Stem Cell Reports 2021 Mar 25;16(3):519-533. Epub 2021 Feb 25.

Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; The Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for biomedical research. However, they are immature, which is a barrier to modeling adult-onset cardiovascular disease. Here, we sought to develop a simple method that could drive cultured hiPSC-CMs toward maturity across a number of phenotypes, with the aim of utilizing mature hiPSC-CMs to model human cardiovascular disease. hiPSC-CMs were cultured in fatty acid-based medium and plated on micropatterned surfaces. These cells display many characteristics of adult human cardiomyocytes, including elongated cell morphology, sarcomeric maturity, and increased myofibril contractile force. In addition, mature hiPSC-CMs develop pathological hypertrophy, with associated myofibril relaxation defects, in response to either a pro-hypertrophic agent or genetic mutations. The more mature hiPSC-CMs produced by these methods could serve as a useful in vitro platform for characterizing cardiovascular disease.
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http://dx.doi.org/10.1016/j.stemcr.2021.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940251PMC
March 2021

Predictive Value of Cardiopulmonary Exercise Testing Parameters in Ambulatory Advanced Heart Failure.

JACC Heart Fail 2021 Mar 3;9(3):226-236. Epub 2021 Feb 3.

Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Objectives: This study sought to determine cardiopulmonary exercise (CPX) predictors of the combined outcome of durable mechanical circulatory support (MCS), transplantation, or death at 1 year among patients with ambulatory advanced heart failure (HF).

Background: Optimal CPX predictors of outcomes in contemporary ambulatory advanced HF patients are unclear.

Methods: REVIVAL (Registry Evaluation of Vital Information for ventricular assist devices [VADs] in Ambulatory Life) enrolled 400 systolic HF patients, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles 4-7. CPX was performed by 273 subjects 2 ± 1 months after study enrollment. Discriminative power of maximal (peak oxygen consumption [peak VO]; VO pulse, circulatory power [CP]; peak systolic blood pressure • peak VO], peak end-tidal pressure CO [PEtCO], and peak Borg scale score) and submaximal CPX parameters (ventilatory efficiency [VE/VCO slope]; VO at anaerobic threshold [VOAT]; and oxygen uptake efficiency slope [OUES]) to predict the composite outcome were assessed by univariate and multivariate Cox regression and Harrell's concordance statistic.

Results: At 1 year, there were 39 events (6 transplants, 15 deaths, 18 MCS implantations). Peak VO, VOAT, OUES, peak PEtCO, and CP were higher in the no-event group (all p < 0.001), whereas VE/VCO slope was lower (p < 0.0001); respiratory exchange ratio was not different. CP (hazard ratio [HR]: 0.89; p = 0.001), VE/VCO slope (HR: 1.05; p = 0.001), and peak Borg scale score (HR: 1.20; p = 0.005) were significant predictors on multivariate analysis (model C-statistic: 0.80).

Conclusions: Among patients with ambulatory advanced HF, the strongest maximal and submaximal CPX predictor of MCS implantation, transplantation, or death at 1 year were CP and VE/VCO respectively. The patient-reported measure of exercise effort (Borg scale score) contributed substantially to the prediction of outcomes, a surprising and novel finding that warrants further investigation. (Registry Evaluation of Vital Information for VADs in Ambulatory Life [REVIVAL]; NCT01369407).
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http://dx.doi.org/10.1016/j.jchf.2020.11.008DOI Listing
March 2021

Bariatric Surgery Is Associated With Decreased Calcineurin Inhibitor Time in Therapeutic Range After Heart Transplantation.

Transplant Proc 2021 Mar 3;53(2):681-685. Epub 2021 Feb 3.

Department of Medicine, Division of Cardiology, University of Colorado, Aurora, Colorado. Electronic address:

Bariatric surgery (BSg) is an effective treatment for morbid obesity, but little is known about the outcomes of BSg patients who undergo orthotopic heart transplantation (OHT). The aim of this study was to determine if BSg alters calcineurin inhibitor (CNI) level variability after OHT. Data were collected from 58 consecutive patients who underwent OHT at a single center from 1/2018 to 4/2019: 4 with BSg prior to OHT (BSg + OHT) and 54 without prior BSg (OHT). CNI level, cardiac biopsy, and left ventricular ejection fraction (LVEF) data were collected during the first 6 months post-OHT. Comparisons were made for 3 measures of CNI variability: coefficient of variation, time in therapeutic range (TTR), and TTR by the Rosendaal method. A Pearson's correlation coefficient was calculated to assess the relationship between CNI TTR, episodes of rejection, and LVEF. The results show TTR was lower in BSg + OHT compared to OHT (12.5% vs 31.3%, P < .05). For the entire cohort, greater TTR correlated with fewer episodes of rejection (r = 0.31, P < .05). In conclusion, these findings suggest BSg + OHT patients may warrant closer monitoring of CNI levels post-OHT. Furthermore, episodes of rejection and LVEF were similar for BSg + OHT patients, indicating that BSg should not be a contraindication to transplant.
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http://dx.doi.org/10.1016/j.transproceed.2021.01.020DOI Listing
March 2021

Impairments in Blood Pressure Regulation and Cardiac Baroreceptor Sensitivity Among Patients With Heart Failure Supported With Continuous-Flow Left Ventricular Assist Devices.

Circ Heart Fail 2021 Jan 19;14(1):e007448. Epub 2021 Jan 19.

Department of Medicine-Cardiology (C.S., G.C., M.B., A.V.A., E.W., W.K.C.), University of Colorado Anschutz Medical Campus, Aurora.

Background: Continuous-flow (CF) left ventricular assist devices (LVADs) improve outcomes for patients with advanced heart failure (HF). However, the lack of a physiological pulse predisposes to side-effects including uncontrolled blood pressure (BP), and there are little data regarding the impact of CF-LVADs on BP regulation.

Methods: Twelve patients (10 males, 60±11 years) with advanced heart failure completed hemodynamic assessment 2.7±4.1 months before, and 4.3±1.3 months following CF-LVAD implantation. Heart rate and systolic BP via arterial catheterization were monitored during Valsalva maneuver, spontaneous breathing, and a 0.05 Hz repetitive squat-stand maneuver to characterize cardiac baroreceptor sensitivity. Plasma norepinephrine levels were assessed during head-up tilt at supine, 30 and 60. Heart rate and BP were monitored during cardiopulmonary exercise testing.

Results: Cardiac baroreceptor sensitivity, determined by Valsalva as well as Fourier transformation and transfer function gain of Heart rate and systolic BP during spontaneous breathing and squat-stand maneuver, was impaired before and following LVAD implantation. Norepinephrine levels were markedly elevated pre-LVAD and improved-but remained elevated post-LVAD (supine norepinephrine pre-LVAD versus post-LVAD: 654±437 versus 323±164 pg/mL). BP increased during cardiopulmonary exercise testing post-LVAD, but the magnitude of change was modest and comparable to the changes observed during the pre-LVAD cardiopulmonary exercise testing.

Conclusions: Among patients with advanced heart failure with reduced ejection fraction, CF-LVAD implantation is associated with modest improvements in autonomic tone, but persistent reductions in cardiac baroreceptor sensitivity. Exercise-induced increases in BP are blunted. These findings shed new light on mechanisms for adverse events such as stroke, and persistent reductions in functional capacity, among patients supported by CF-LVADs. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03078972.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818348PMC
January 2021

Right ventricular function and cardiopulmonary performance among patients with heart failure supported by durable mechanical circulatory support devices.

J Heart Lung Transplant 2021 Feb 22;40(2):128-137. Epub 2020 Nov 22.

Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address:

Background: Patients with continuous-flow left ventricular assist devices (CF-LVADs) experience limitations in functional capacity and frequently, right ventricular (RV) dysfunction. We sought to characterize RV function in the context of global cardiopulmonary performance during exercise in this population.

Methods: A total of 26 patients with CF-LVAD (aged 58 ± 11 years, 23 males) completed a hemodynamic assessment with either conductance catheters (Group 1, n = 13) inserted into the right ventricle to generate RV pressure‒volume loops or traditional Swan‒Ganz catheters (Group 2, n = 13) during invasive cardiopulmonary exercise testing. Hemodynamics were collected at rest, 2 sub-maximal levels of exercise, and peak effort. Breath-by-breath gas exchange parameters were collected by indirect calorimetry. Group 1 participants also completed an invasive ramp test during supine rest to determine the impact of varying levels of CF-LVAD support on RV function.

Results: In Group 1, pump speed modulations minimally influenced RV function. During upright exercise, there were modest increases in RV contractility during sub-maximal exercise, but there were no appreciable increases at peak effort. Ventricular‒arterial coupling was preserved throughout the exercise. In Group 2, there were large increases in pulmonary arterial, left-sided filling, and right-sided filling pressures during sub-maximal and peak exercises. Among all participants, the cardiac output‒oxygen uptake relationship was preserved at 5.8:1. Ventilatory efficiency was severely abnormal at 42.3 ± 11.6.

Conclusions: Patients with CF-LVAD suffer from limited RV contractile reserve; marked elevations in pulmonary, left-sided filling, and right-sided filling pressures during exercise; and severe ventilatory inefficiency. These findings explain mechanisms for persistent reductions in functional capacity in this patient population.
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http://dx.doi.org/10.1016/j.healun.2020.11.009DOI Listing
February 2021

Standardized Definitions for Evaluation of Heart Failure Therapies: Scientific Expert Panel From the Heart Failure Collaboratory and Academic Research Consortium.

JACC Heart Fail 2020 12 13;8(12):961-972. Epub 2020 Nov 13.

Inova Heart and Vascular Institute, Falls Church, Virginia, USA; Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina, USA.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation.
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http://dx.doi.org/10.1016/j.jchf.2020.10.002DOI Listing
December 2020

An immunosuppression tightrope: Successful heart transplantation after giant cell myocarditis in a patient with HIV complicated by recurrent giant cell myocarditis and Kaposi sarcoma.

J Heart Lung Transplant 2020 12 29;39(12):1506-1508. Epub 2020 Sep 29.

Section of Advanced Heart Failure and Transplantation, Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.

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http://dx.doi.org/10.1016/j.healun.2020.09.014DOI Listing
December 2020

Standardized definitions for evaluation of heart failure therapies: scientific expert panel from the Heart Failure Collaboratory and Academic Research Consortium.

Eur J Heart Fail 2020 12 13;22(12):2175-2186. Epub 2020 Nov 13.

Inova Heart and Vascular Institute, Falls Church, VA, USA.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation.
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http://dx.doi.org/10.1002/ejhf.2018DOI Listing
December 2020

Universal Depression Screen of Ambulatory Heart Transplant Recipients With Referral for Mental Health Intervention: A Quality Improvement Project.

J Nurs Care Qual 2021 Jul-Sep 01;36(3):236-241

Section of Advanced Heart Failure and Transplantation, Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (Drs Peters, Ambardekar, and McIlvennan); College of Nursing, University of Colorado, Aurora (Dr Rosenthal); and Adult and Child Consortium for Health Outcomes Research and Delivery Science, University of Colorado School of Medicine, Aurora (Dr McIlvennan).

Background: Patients with a heart transplant and depression have higher rates of graft failure and noncompliance.

Local Problem: The heart transplant clinic had no standardized approach to assess for depression.

Methods: The heart transplant clinic implemented routine use of the Patient Health Questionnaire (PHQ).

Interventions: Team members were educated via an online module about depression. A process for depression screening and follow-up was developed and implemented.

Results: From July 2018 to February 2019, there were 834 visits; PHQ2 screens were completed during 779 (93%) of those visits with 40 (5%) positive screens. All 40 patients had PHQ9 assessment, with 33 patients (4%) exhibiting moderate or severe depressive symptoms. All 33 patients were provided with mental health resources and received follow-up. Median time to administer PHQ2 was 2 minutes (range 1-3 minutes).

Conclusions: Implementation of universal depression screening in a heart transplant clinic is feasible, identifies patients with depression, and does not add significant clinical burden.
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http://dx.doi.org/10.1097/NCQ.0000000000000514DOI Listing
September 2020

Presence of any degree of coronary artery disease among liver transplant candidates is associated with increased rate of post-transplant major adverse cardiac events.

Clin Transplant 2020 11 28;34(11):e14077. Epub 2020 Sep 28.

Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA.

The impact of coronary artery disease (CAD) among liver transplant candidates (LTC) on post-LT clinical outcomes remains unclear. The aim of this study is to determine association of presence and severity of CAD on post-LT major adverse cardiac events (MACE) including cardiac-associated mortality. We conducted a retrospective cohort analysis of 231 patients who underwent diagnostic coronary angiogram (DCA) during their LT evaluation at a tertiary medical center from 2012-2017. Patients were analyzed based on degree of CAD (no CAD, non-obstructive CAD [< 50% stenosis], obstructive CAD [≥50% stenosis]) per DCA results. MACE were noted at 30 days, 1 year, 3 years, and 5 years post-LT, and Kaplan-Meier curves were used to determine post-LT MACE-free probability. LTC with any CAD, including non-obstructive CAD, had lower MACE-free probability at all post-LT time points (0.94 vs 0.65 at 30 days, P = .001; 0.87 vs 0.59 at 1 year, P = .002; 0.87 vs 0.41 at 3 years, P < .001; 0.87 vs 0.37 at 5 years, P < .001). Identification of and medical intervention for non-obstructive CAD should be considered in all LTC, though further studies are necessary to determine optimal medical interventions to mitigate MACE risk in this cohort.
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http://dx.doi.org/10.1111/ctr.14077DOI Listing
November 2020

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association.

Circulation 2020 Jul 1;142(1):e7-e22. Epub 2020 Jun 1.

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirmatory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.
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http://dx.doi.org/10.1161/CIR.0000000000000792DOI Listing
July 2020

New insights into resting and exertional right ventricular performance in the healthy heart through real-time pressure-volume analysis.

J Physiol 2020 07 18;598(13):2575-2587. Epub 2020 May 18.

Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Key Points: Despite growing interest in right ventricular form and function in diseased states, there is a paucity of data regarding characteristics of right ventricular function - namely contractile and lusitropic reserve, as well as ventricular-arterial coupling, in the healthy heart during rest, as well as submaximal and peak exercise. Pressure-volume analysis of the right ventricle, during invasive cardiopulmonary exercise testing, demonstrates that that the right heart has enormous contractile reserve, with a three- or fourfold increase in all metrics of contractility, as well as myocardial energy production and utilization. The healthy right ventricle also demonstrates marked augmentation in lusitropy, indicating that diastolic filling of the right heart is not passive. Rather, the right ventricle actively contributes to venous return during exercise, along with the muscle pump. Ventricular-arterial coupling is preserved during submaximal and peak exercise in the healthy heart.

Abstract: Knowledge of right ventricular (RV) function has lagged behind that of the left ventricle and historically, the RV has even been referred to as a 'passive conduit' of lesser importance than its left-sided counterpart. Pressure-volume (PV) analysis is the gold standard metric of assessing ventricular performance. We recruited nine healthy sedentary individuals free of any cardiopulmonary disease (42 ± 12 years, 78 ± 11 kg), who completed invasive cardiopulmonary exercise testing during upright ergometry, while using conductance catheters inserted into the RV to generate real-time PV loops. Data were obtained at rest, two submaximal levels of exercise below ventilatory threshold, to simulate real-world scenarios/activities of daily living, and maximal effort. Breath-by-breath oxygen uptake was determined by indirect calorimetry. During submaximal and peak exercise, there were significant increases in all metrics of systolic function by three- to fourfold, including cardiac output, preload recruitable stroke work, and maximum rate of pressure change in the ventricle (dP/dt ), as well as energy utilization as determined by stroke work and pressure-volume area. Similarly, the RV demonstrated a significant, threefold increase in lusitropic reserve throughout exercise. Ventricular-arterial coupling, defined by the quotient of end-systolic elastance and effective arterial elastance, was preserved throughout all stages of exercise. Maximal pressures increased significantly during exercise, while end-diastolic volumes were essentially unchanged. Overall, these findings demonstrate that the healthy RV is not merely a passive conduit, but actively participates in cardiopulmonary performance during exercise by accessing an enormous amount of contractile and lusitropic reserve, ensuring that VA coupling is preserved throughout all stages of exercise.
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http://dx.doi.org/10.1113/JP279759DOI Listing
July 2020

Relationship between nocturnal blood pressure patterns and end organ damage and diastolic dysfunction in heart transplant recipients.

Clin Transplant 2020 05 13;34(5):e13842. Epub 2020 Mar 13.

Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.

Background: We assessed the relationship between circadian blood pressure (BP) patterns and clinical outcomes in a contemporary cohort of adult heart transplant recipients.

Methods: This retrospective, cross-sectional study included adult heart transplant recipients at least 6 months post-transplant. Ambulatory BP measurements were recorded over 24 hours. Nondippers were defined as a decline in average nighttime BP ≤ 10% compared with daytime. Primary outcomes were the presence of end organ damage, that is, microalbuminuria, chronic kidney disease, and/or left ventricular hypertrophy. Secondary outcomes were measures of diastolic dysfunction (ie, mitral valve deceleration time, e/e', E/A, and isovolumetric relaxation time), microalbumin/creatinine ratio, eGFR, interventricular septal thickness, and left ventricular posterior wall thickness.

Results: Of 30 patients, 53.3% (n = 16) were systolic nondippers and 40% (n = 12) were diastolic nondippers. Diastolic nondippers had three times higher urine microalbumin/creatinine ratios than diastolic dippers (P = .03). Systolic nondippers had 16.3% lower mitral valve deceleration time (P = .05) than systolic dippers, while diastolic nondippers had 20.4% higher e/e' (P = .05) than diastolic dippers. There were no significant relationships between BP dipping status and any of the primary outcomes.

Conclusions: These data suggest that systolic and diastolic nondipping BP patterns are associated with subclinical kidney damage and diastolic dysfunction in heart transplant recipients.
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http://dx.doi.org/10.1111/ctr.13842DOI Listing
May 2020

Transcriptome signature of ventricular arrhythmia in dilated cardiomyopathy reveals increased fibrosis and activated TP53.

J Mol Cell Cardiol 2020 02 18;139:124-134. Epub 2020 Jan 18.

Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA; Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA. Electronic address:

Aims: One-third of DCM patients experience ventricular tachycardia (VT), but a clear biological basis for this has not been established. The purpose of this study was to identify transcriptome signatures and enriched pathways in the hearts of dilated cardiomyopathy (DCM) patients with VT.

Methods And Results: We used RNA-sequencing in explanted heart tissue from 49 samples: 19 DCM patients with VT, 16 DCM patients without VT, and 14 non-failing controls. We compared each DCM cohort to the controls and identified the genes that were differentially expressed in DCM patients with VT but not without VT. Differentially expressed genes were evaluated using pathway analysis, and pathways of interest were investigated by qRT-PCR validation, Western blot, and microscopy. There were 590 genes differentially expressed in DCM patients with VT that are not differentially expressed in patients without VT. These genes were enriched for genes in the TGFß1 and TP53 signaling pathways. Increased fibrosis and activated TP53 signaling was demonstrated in heart tissue of DCM patients with VT.

Conclusions: Our study supports that distinct biological mechanisms distinguish ventricular arrhythmia in DCM patients.
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http://dx.doi.org/10.1016/j.yjmcc.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144813PMC
February 2020

Defining decreased protein succinylation of failing human cardiac myofibrils in ischemic cardiomyopathy.

J Mol Cell Cardiol 2020 01 10;138:304-317. Epub 2019 Dec 10.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:

Succinylation is a post-translational modification of protein lysine residues with succinyl groups derived from succinyl CoA. Succinylation is considered a significant post-translational modification with the potential to impact protein function which is highly conserved across numerous species. The role of succinylation in the heart, especially in heart failure and myofibril mechanics, remains largely unexplored. Mechanical parameters were measured in myofibrils isolated from failing hearts of ischemic cardiomyopathy patients and non-failing donor controls. We employed mass spectrometry to quantify differential protein expression in myofibrils from failing ischemic cardiomyopathy hearts compared to non-failing hearts. In addition, we combined peptide enrichment by immunoprecipitation with liquid chromatography tandem mass spectrometry to quantitatively analyze succinylated lysine residues in these myofibrils. Several key parameters of sarcomeric mechanical interactions were altered in myofibrils isolated from failing ischemic cardiomyopathy hearts, including lower resting tension and a faster rate of activation. Of the 100 differentially expressed proteins, 46 showed increased expression in ischemic heart failure, while 54 demonstrated decreased expression in ischemic heart failure. Our quantitative succinylome analysis identified a total of 572 unique succinylated lysine sites located on 181 proteins, with 307 significantly changed succinylation events. We found that 297 succinyl-Lys demonstrated decreased succinylation on 104 proteins, while 10 residues demonstrated increased succinylation on 4 proteins. Investigating succinyl CoA generation, enzyme activity assays demonstrated that α-ketoglutarate dehydrogenase and succinate dehydrogenase activities were significantly decreased in ischemic heart failure. An activity assay for succinyl CoA synthetase demonstrated a significant increase in ischemic heart failure. Taken together, our findings support the hypothesis that succinyl CoA production is decreased and succinyl CoA turnover is increased in ischemic heart failure, potentially resulting in an overall decrease in the mitochondrial succinyl CoA pool, which may contribute to decreased myofibril protein succinylation in heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2019.11.159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058372PMC
January 2020

Quality of life and treatment preference for ventricular assist device therapy in ambulatory advanced heart failure: A report from the REVIVAL study.

J Heart Lung Transplant 2020 01 20;39(1):27-36. Epub 2019 Nov 20.

University of Michigan Medical School, Ann Arbor, Michigan.

Background: The Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life study is a prospective multicenter cohort of 400 ambulatory patients with advanced chronic systolic heart failure (HF). The aim of the study is to better understand disease trajectory and optimal timing of advanced HF therapies. We examined patient health-related quality of life (HRQOL) data collected at enrollment and their association with patient treatment preferences for VAD placement.

Methods: Baseline assessment of HRQOL included the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQol EQ-5D-3L Visual Analogue Scale (VAS), along with patient self-assessment of remaining life (PSARL). Descriptive statistics were used to present baseline HRQOL data and Spearman correlation tests to assess the association between KCCQ, VAS, and VAD treatment preference with patient clinical characteristics of interest.

Results: The median age was 60 years, 75% were male, and the median left ventricular ejection fraction was 20%. The median (25th percentile, 75th percentile), baseline KCCQ summary score was 64 (48, 78), VAS score 65 (50, 75), and PSARL 7 years (5, 10). There were statistically significant associations of baseline KCCQ and VAS with New York Heart Association class and Interagency Registry of Mechanically Assisted Circulatory Support profile (p < 0.005 for all comparisons). Baseline KCCQ and VAS revealed a modest association with PSARL (correlation = 0.45 and 0.35, respectively; p < 0.001), and many patients were overly optimistic about their expected survival. VAD treatment preference was associated with KCCQ scores (p < 0.031), but the absolute differences were small. VAD treatment preference was independent of other key clinical characteristics such as subject age, VAS, and PSARL.

Conclusions: We found a lack of strong association between HRQOL and patient preference for VAD therapy. Better understanding of patients' perceptions of their illness and how this relates to HRQOL outcomes, clinician risk assessment, and patient decision-making is needed. This may in turn allow better guidance toward available HF therapies in this vulnerable population.
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http://dx.doi.org/10.1016/j.healun.2019.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942204PMC
January 2020

Transcription-independent Induction of ERBB1 through Hypoxia-inducible Factor 2A Provides Cardioprotection during Ischemia and Reperfusion.

Anesthesiology 2020 04;132(4):763-780

From the Department of Anesthesiology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas (J.W.L., J.L.B., X.Y., J.L., H.K.E.) Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University Tübingen, Tübingen, Germany (M.K.) Department of Anesthesiology, University of New Mexico School of Medicine, Albuquerque, New Mexico (S.-W.S.) Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China (J.L.) Institute for Cancer Research, Department of Medicine, Medical University of Vienna, Vienna, Austria (M.S.) Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado (A.V.A.) Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, Texas (X.Z.) Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado (T.E.) Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas (S.-H.Y.).

Background: During myocardial ischemia, hypoxia-inducible factors are stabilized and provide protection from ischemia and reperfusion injury. Recent studies show that myocyte-specific hypoxia-inducible factor 2A promotes myocardial ischemia tolerance through induction of epidermal growth factor, amphiregulin. Here, the authors hypothesized that hypoxia-inducible factor 2A may enhance epidermal growth factor receptor 1 (ERBB1) expression in the myocardium that could interface between growth factors and its effect on providing tolerance to ischemia and reperfusion injury.

Methods: Human myocardial tissues were obtained from ischemic heart disease patients and normal control patients to compare ERBB1 expression. Myocyte-specific Hif2a or ErbB1 knockout mice were generated to observe the effect of Hif2a knockdown in regulating ERBB1 expression and to examine the role of ERBB1 during myocardial ischemia and reperfusion injury.

Results: Initial studies of myocardial tissues from patients with ischemic heart disease showed increased ERBB1 protein (1.12 ± 0.24 vs. 13.01 ± 2.20, P < 0.001). In contrast, ERBB1 transcript was unchanged. Studies using short hairpin RNA repression of Hif2A or Hif2a Myosin Cre+ mice directly implicated hypoxia-inducible factor 2A in ERBB1 protein induction during hypoxia or after myocardial ischemia, respectively. Repression of RNA-binding protein 4 abolished hypoxia-inducible factor 2A-dependent induction of ERBB1 protein. Moreover, ErbB1 Myosin Cre+ mice experienced larger infarct sizes (22.46 ± 4.06 vs. 46.14 ± 1.81, P < 0.001) and could not be rescued via amphiregulin treatment.

Conclusions: These findings suggest that hypoxia-inducible factor 2A promotes transcription-independent induction of ERBB1 protein and implicates epidermal growth factor signaling in protection from myocardial ischemia and reperfusion injury.
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http://dx.doi.org/10.1097/ALN.0000000000003037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072004PMC
April 2020

Increased myocyte calcium sensitivity in end-stage pediatric dilated cardiomyopathy.

Am J Physiol Heart Circ Physiol 2019 12 18;317(6):H1221-H1230. Epub 2019 Oct 18.

Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado.

Dilated cardiomyopathy (DCM) is the most common cause of heart failure (HF) in children, resulting in high mortality and need for heart transplantation. The pathophysiology underlying pediatric DCM is largely unclear; however, there is emerging evidence that molecular adaptations and response to conventional HF medications differ between children and adults. To gain insight into alterations leading to systolic dysfunction in pediatric DCM, we measured cardiomyocyte contractile properties and sarcomeric protein phosphorylation in explanted pediatric DCM myocardium ( = 8 subjects) compared with nonfailing (NF) pediatric hearts ( = 8 subjects). Force-pCa curves were generated from skinned cardiomyocytes in the presence and absence of protein kinase A. Sarcomeric protein phosphorylation was quantified with Pro-Q Diamond staining after gel electrophoresis. Pediatric DCM cardiomyocytes demonstrate increased calcium sensitivity (pCa =5.70 ± 0.0291), with an associated decrease in troponin (Tn)I phosphorylation compared with NF pediatric cardiomyocytes (pCa =5.59 ± 0.0271, = 0.0073). Myosin binding protein C and TnT phosphorylation are also lower in pediatric DCM, whereas desmin phosphorylation is increased. Pediatric DCM cardiomyocytes generate peak tension comparable to that of NF pediatric cardiomyocytes [DCM 29.7 mN/mm, interquartile range (IQR) 21.5-49.2 vs. NF 32.8 mN/mm, IQR 21.5-49.2 mN/mm; = 0.6125]. In addition, cooperativity is decreased in pediatric DCM compared with pediatric NF (Hill coefficient: DCM 1.56, IQR 1.31-1.94 vs. NF 1.94, IQR 1.36-2.86; = 0.0425). Alterations in sarcomeric phosphorylation and cardiomyocyte contractile properties may represent an impaired compensatory response, contributing to the detrimental DCM phenotype in children. Our study is the first to demonstrate that cardiomyocytes from infants and young children with dilated cardiomyopathy (DCM) exhibit increased calcium sensitivity (likely mediated by decreased troponin I phosphorylation) compared with nonfailing pediatric cardiomyocytes. Compared with published values in adult cardiomyocytes, pediatric cardiomyocytes have notably decreased cooperativity, with a further reduction in the setting of DCM. Distinct adaptations in cardiomyocyte contractile properties may contribute to a differential response to pharmacological therapies in the pediatric DCM population.
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http://dx.doi.org/10.1152/ajpheart.00409.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960778PMC
December 2019

When You Hear Hoof Beats, Think of the Treatable Zebras.

JACC Heart Fail 2019 11 9;7(11):967-969. Epub 2019 Oct 9.

Division of Cardiology, University of Colorado, Aurora, Colorado. Electronic address:

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http://dx.doi.org/10.1016/j.jchf.2019.08.002DOI Listing
November 2019

Pediatric Heart Transplantation: Transitioning to Adult Care (TRANSIT): Feasibility of a Pilot Randomized Controlled Trial.

J Card Fail 2019 Dec 2;25(12):948-958. Epub 2019 Jul 2.

Department of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.

Background: Young-adult heart transplant recipients transferring to adult care are at risk for poor health outcomes. We conducted a pilot randomized controlled trial to determine the feasibility of and to test a transition intervention for young adults who underwent heart transplantation as children and then transferred to adult care.

Methods: Participants were randomized to the transition intervention (4 months long, focused on heart-transplant knowledge, self-care, self-advocacy, and social support) or usual care. Self-report questionnaires and medical records data were collected at baseline and 3 and 6 months after the initial adult clinic visit. Longitudinal analyses comparing outcomes over time were performed using generalized estimating equations and linear mixed models.

Results: Transfer to adult care was successful and feasible (ie, excellent participation rates). The average patient standard deviation of mean tacrolimus levels was similar over time in both study arms and < 2.5, indicating adequate adherence. There were no between-group or within-group differences in percentage of tacrolimus bioassays within target range (> 50%). Average overall adherence to treatment was similarly good in both groups. Rates of appointment keeping through 6 months after transfer declined over time in both groups.

Conclusions: The feasibility of the study was demonstrated. Our transition intervention did not improve outcomes.
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http://dx.doi.org/10.1016/j.cardfail.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904510PMC
December 2019

Elamipretide Improves Mitochondrial Function in the Failing Human Heart.

JACC Basic Transl Sci 2019 Apr 29;4(2):147-157. Epub 2019 Apr 29.

Department of Medicine/Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado.

Negative alterations of mitochondria are known to occur in heart failure (HF). This study investigated the novel mitochondrial-targeted therapeutic agent elamipretide on mitochondrial and supercomplex function in failing human hearts ex vivo. Freshly explanted failing and nonfailing ventricular tissue from children and adults was treated with elamipretide. Mitochondrial oxygen flux, complex (C) I and CIV activities, and in-gel activity of supercomplex assembly were measured. Mitochondrial function was impaired in the failing human heart, and mitochondrial oxygen flux, CI and CIV activities, and supercomplex-associated CIV activity significantly improved in response to elamipretide treatment. Elamipretide significantly improved failing human mitochondrial function.
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http://dx.doi.org/10.1016/j.jacbts.2018.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488757PMC
April 2019

Outcomes with ambulatory advanced heart failure from the Medical Arm of Mechanically Assisted Circulatory Support (MedaMACS) Registry.

J Heart Lung Transplant 2019 04 1;38(4):408-417. Epub 2018 Oct 1.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Background: The outlook for ambulatory patients with advanced heart failure (HF) and the appropriate timing for left ventricular assist device (LVAD) or transplant remain uncertain. The aim of this study was to better understand disease trajectory and rates of progression to subsequent LVAD therapy and transplant in ambulatory advanced HF.

Methods: Patients with advanced HF who were New York Heart Association (NYHA) Class III or IV and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Profiles 4 to 7, despite optimal medical therapy (without inotropic therapy), were enrolled across 11 centers and followed for the end-points of survival, transplantation, LVAD placement, and health-related quality of life. A secondary intention-to-treat survival analysis compared outcomes for MedaMACS patients with a matched group of Profile 4 to 7 patients with LVADs from the INTERMACS registry.

Results: Between May 2013 and October 2015, 161 patients were enrolled with INTERMACS Profiles 4 (12%), 5 (32%), 6 (49%), and 7 (7%). By 2 years after enrollment, 75 (47%) patients had reached a primary end-point with 39 (24%) deaths, 17 (11%) undergoing LVAD implantation, and 19 (12%) receiving a transplant. Compared with 1,753 patients with Profiles 4 to 7 receiving LVAD therapy, there was no overall difference in intention-to-treat survival between medical and LVAD therapy, but survival with LVAD therapy was superior to medical therapy among Profile 4 and 5 patients (p = 0.0092). Baseline health-related quality of life was lower among patients receiving a LVAD than those enrolled on continuing oral medical therapy, but increased after 1 year for survivors in both cohorts.

Conclusions: Ambulatory patients with advanced HF are at high risk for poor outcomes, with only 53% alive on medical therapy after 2 years of follow-up. Survival was similar for medical and LVAD therapy in the overall cohort, which included the lower severity Profiles 6 and 7, but survival was better with LVAD therapy among patients in Profiles 4 and 5. Given the poor outcomes in this group of advanced HF patients, timely consideration of transplant and LVAD is of critical importance.
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http://dx.doi.org/10.1016/j.healun.2018.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452871PMC
April 2019

Rebuttal from William K. Cornwell III, Takashi Tarumi, Justin Lawley and Amrut V. Ambardekar.

J Physiol 2019 01 17;597(2):363-364. Epub 2018 Dec 17.

Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

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http://dx.doi.org/10.1113/JP277244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332768PMC
January 2019

CrossTalk opposing view: Blood flow pulsatility in left ventricular assist device patients is not essential to maintain normal brain physiology.

J Physiol 2019 01 17;597(2):357-359. Epub 2018 Dec 17.

Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

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http://dx.doi.org/10.1113/JP276730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332755PMC
January 2019

Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure.

BMC Genomics 2018 Nov 12;19(1):812. Epub 2018 Nov 12.

Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA.

Background: Current heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures.

Results: RNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets.

Conclusions: Our results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM.
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http://dx.doi.org/10.1186/s12864-018-5213-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233272PMC
November 2018

Association of Variants in BAG3 With Cardiomyopathy Outcomes in African American Individuals.

JAMA Cardiol 2018 10;3(10):929-938

Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.

Importance: The prevalence of nonischemic dilated cardiomyopathy (DCM) is greater in individuals of African ancestry than in individuals of European ancestry. However, little is known about whether the difference in prevalence or outcomes is associated with functional genetic variants.

Objective: We hypothesized that Bcl2-associated anthanogene 3 (BAG3) genetic variants were associated with outcomes in individuals of African ancestry with DCM.

Design: This multicohort study of the BAG3 genotype in patients of African ancestry with dilated cardiomyopathy uses DNA obtained from African American individuals enrolled in 3 clinical studies: the Genetic Risk Assessment of African Americans With Heart Failure (GRAHF) study; the Intervention in Myocarditis and Acute Cardiomyopathy Trial-2 (IMAC-2) study; and the Genetic Risk Assessment of Cardiac Events (GRACE) study. Samples of DNA were also acquired from the left ventricular myocardium of patients of African ancestry who underwent heart transplant at the University of Colorado and University of Pittsburgh.

Main Outcomes And Measures: The primary end points were the prevalence of BAG3 mutations in African American individuals and event-free survival in participants harboring functional BAG3 mutations.

Results: Four BAG3 genetic variants were identified; these were expressed in 42 of 402 African American individuals (10.4%) with nonischemic heart failure and 9 of 107 African American individuals (8.4%) with ischemic heart failure but were not present in a reference population of European ancestry (P < .001). The variants included 2 nonsynonymous single-nucleotide variants; 1 three-nucleotide in-frame insertion; and 2 single-nucleotide variants that were linked in cis. The presence of BAG3 variants was associated with a nearly 2-fold (hazard ratio, 1.97 [95% CI, 1.19-3.24]; P = .01) increase in cardiac events in carriers compared with noncarriers. Transfection of transformed adult human ventricular myocytes with plasmids expressing the 4 variants demonstrated that each variant caused an increase in apoptosis and a decrease in autophagy when samples were subjected to the stress of hypoxia-reoxygenation.

Conclusions And Relevance: This study demonstrates that genetic variants in BAG3 found almost exclusively in individuals of African ancestry were not causative of disease but were associated with a negative outcome in patients with a dilated cardiomyopathy through modulation of the function of BAG3. The results emphasize the importance of biological differences in causing phenotypic variance across diverse patient populations, the need to include diverse populations in genetic cohorts, and the importance of determining the pathogenicity of genetic variants.
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http://dx.doi.org/10.1001/jamacardio.2018.2541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233818PMC
October 2018

Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures.

JACC Clin Electrophysiol 2018 04 2;4(4):504-514. Epub 2018 Feb 2.

Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver, Aurora, Colorado. Electronic address:

Objectives: The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype.

Background: Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement.

Methods: A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry.

Results: A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell-cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa.

Conclusions: We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.
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http://dx.doi.org/10.1016/j.jacep.2017.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074050PMC
April 2018