Publications by authors named "Lawrence S C Czer"

55 Publications

The Effects of Donor-Specific Antibody Characteristics on Cardiac Allograft Vasculopathy.

Clin Transplant 2021 Sep 21:e14483. Epub 2021 Sep 21.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Cardiac allograft vasculopathy (CAV) causes late graft dysfunction and post-transplant mortality. Currently, the effects of different donor-specific antibodies (DSA) on the severity of CAV remain unclear.

Method: We evaluated 526 adult heart transplant recipients at a single center between January 2010 and August 2015. Subjects were divided into those with DSA (n = 142) and those without DSA (n = 384, control). The DSA group was stratified into persistent DSA (n = 34), transient DSA (n = 105), 1:8 dilution DSA (n = 45), complement-binding (C1q) DSA (n = 36), Class I DSA (n = 37), and Class II DSA (n = 105). The primary outcome was the incidence of moderate-to-severe CAV (CAV 2/3) at 5-year follow-up.

Results: Subjects with persistent DSA, 1:8 dilution DSA, and C1q DSA had higher incidence of CAV 2/3 compared the control group (17.6%, 13.3%, and 16.7% vs. 3.1%, respectively; p≤0.001). The incidence of CAV 2/3 between subjects with transient DSA and the control group was similar (2.8% vs. 3.1%; p = 0.888). Subjects with Class II DSA also had higher incidence of CAV 2/3 (7.6% vs. 3.1%; p = 0.039).

Conclusion: DSA that are persistent, 1:8 dilution positive, C1q positive, and Class II are associated with more severe grades of CAV. These DSA characteristics may prognosticate disease and warrant consideration for treatment. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/ctr.14483DOI Listing
September 2021

Hypothermia promotes mitochondrial elongation In cardiac cells via inhibition of Drp1.

Cryobiology 2021 Jul 29. Epub 2021 Jul 29.

Cedars-Sinai Smidt Heart Institute, Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Hypothermia is a valuable clinical tool in mitigating against the consequences of ischemia in surgery, stroke, cardiac arrest and organ preservation. Protection is afforded principally by a reduction of metabolism, manifesting as reduced rates of oxygen uptake, preservation of ATP levels, and a curtailing of ischemic calcium overload. The effects of non-ischemic hypothermic stress are relatively unknown. We sought to investigate the effects of clinically mild-to-severe hypothermia on mitochondrial morphology, oxygen consumption and protein expression in normoxic hearts and cardiac cells. Normoxic perfusion of rat hearts at 28-32 °C was associated with inhibition of mitochondrial fission, evidenced by a reduced abundance of the active phosphorylated form of the fission receptor Drp1 (pDrp1). Abundance of the same residue was reduced in H9c2 cells subjected to hypothermic culture (25-32 °C), in addition to a reduced abundance of the Drp1 receptor MFF. Hypothermia-treated H9c2 cardiomyocytes exhibited elongated mitochondria and depressed rates of mitochondrial-associated oxygen consumption, which persisted upon rewarming. Hypothermia also promoted a reduction in mRNA expression of the capsaicin receptor TRPV1 in H9c2 cells. When normothermic H9c2 cells were transfected with TRPV1 siRNA we observed reduced pDrp1 and MFF abundance, elongated mitochondria, and reduced rates of mitochondrial-associated oxygen consumption, mimicking the effects of hypothermic culture. In conclusion hypothermia promoted elongation of cardiac mitochondria via reduced pDrp1 abundance which was also associated with suppression of cellular oxygen consumption. Silencing of TRPV1 in H9c2 cardiomyocytes reproduced the morphological and respirometric phenotype of hypothermia. This report demonstrates a novel mechanism of cold-induced inhibition of mitochondrial fission.
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http://dx.doi.org/10.1016/j.cryobiol.2021.07.013DOI Listing
July 2021

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

J Heart Lung Transplant 2021 Sep 10;40(9):970-980. Epub 2021 Jun 10.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD.

Methods: We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression.

Results: PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD.

Conclusions: Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.
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http://dx.doi.org/10.1016/j.healun.2021.06.002DOI Listing
September 2021

Heart Transplantation for Giant Cell Myocarditis: A Case Series.

Transplant Proc 2021 Jan-Feb;53(1):348-352. Epub 2020 Dec 29.

Advanced Heart Disease and Heart Transplant Programs, Cedars-Sinai Smidt Heart Institute, Los Angeles, California.

Background: Giant cell myocarditis (GCM) has a poor prognosis without heart transplant, but post-transplant survival is unknown.

Purpose: To describe the post-transplant survival of patients with GCM at a large transplant center.

Methods: Seven patients underwent heart transplant for histologically confirmed GCM of the explanted heart. The median age was 59 years, and 43% (3 of 7) were female. All patients had cardiogenic shock, multiorgan failure, elevated troponin, and recurrent ventricular tachycardia, and some required mechanical circulatory support. All patients received rabbit antithymocyte globulin (rATG) in the perioperative period at a dose of 1.5 mg/kg daily for 1 to 5 days and 4 received intravenous immunoglobulin 1 g/kg daily for 2 days after rATG. All patients had early initiation of tacrolimus by first to third postoperative day depending on renal function, early mycophenolate, and high dose steroid. All were maintained using tacrolimus, mycophenolate, and prednisone.

Results: One patient had asymptomatic recurrence of GCM at 3 months, managed by up-titration of tacrolimus, and had asymptomatic 2R cellular rejection at 4 months, managed with steroid bolus. No patient had high-grade rejection. One patient died at 267 days, possibly of GCM. Six of 7 (86%) remain alive at a median of 842 days (2.3 years) post transplant.

Conclusions: Patients with GCM have excellent post-transplant survival with use of rATG and triple drug immunosuppressive therapy; however, some patients remain at risk for GCM recurrence after transplant, which may respond to augmented immunosuppression.
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http://dx.doi.org/10.1016/j.transproceed.2020.10.047DOI Listing
April 2021

Successful Treatment of Severe COVID-19 Pneumonia With Clazakizumab in a Heart Transplant Recipient: A Case Report.

Transplant Proc 2020 Nov 7;52(9):2711-2714. Epub 2020 Jun 7.

Comprehensive Transplant Center, Transplant Immunotherapy Program, Cedars Sinai Medical Center, Los Angeles, California.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by an overwhelming cytokine response. Various treatment strategies have been attempted.

Methods And Results: A 61-year-old man with heart transplantation in 2017 presented with fever, cough, and dyspnea, and was confirmed positive for coronavirus disease 2019 (COVID-19). Laboratory tests showed significant elevations in C-reactive protein and interleukin-6 (IL-6). Echocardiogram showed left ventricular ejection fraction 58% (with ejection fraction 57% 6 months prior). Given the lack of clear management guidelines, the patient was initially managed symptomatically. However, the patient subsequently had a rapid respiratory deterioration with worsening inflammatory markers on day 5 of admission. Tocilizumab (anti-IL-6R) was in low supply in the hospital. The patient was offered clazakizumab (anti-IL-6) for compassionate use. Patient received 25 mg intravenously × 1 dose. Within 24 hours, he showed significant improvement in symptoms, oxygen requirements, radiological findings, and inflammatory markers. There was a transient leukopenia that improved in 4 days. He was discharged home on day 11, with negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, development of positive serum COVID-19 IgG antibody, and he continued to do well on day 60, with no heart-related symptoms.

Conclusion: Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19. Although not yet FDA approved, it is being investigated for treatment of renal antibody-mediated rejection. Clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide.
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http://dx.doi.org/10.1016/j.transproceed.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275980PMC
November 2020

Platelet Mapping by Thromboelastography and Whole Blood Aggregometry in Adult Patients Supported by Mechanical Circulatory Support Device on Aspirin Therapy.

J Extra Corpor Technol 2020 Mar;52(1):13-21

Cedars Sinai Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, California.

Patients on mechanical circulatory support (MCS) devices are placed on aspirin and may require platelet function testing (PFT) to monitor the adequacy of therapy. Routine laboratory PFT is performed using whole blood aggregation (WBA) which typically has a long turnaround time (4-5 hours) and may not be readily available. By contrast, platelet mapping by thromboelastography (TPM) can provide results within 45 minutes. The objective of this study was to compare the results of TPM with WBA. We compared platelet mapping maximal amplitude (MA) by TPM with that of arachidonic acid (AA) to WBA with AA by impedance. We analyzed paired samples where both TPM and WBA were available. Of 45 paired samples, 34 were from 29 MCS patients and 11 were from non-MCS patients. When applying institutional interpretation guidelines with an MA cutoff of ≤40 mm, WBA vs TPM MA in non-MCS and MCS patients correlated well with an accuracy of 100 and 94.4%, respectively. MA >40 had poor correlation with an accuracy of 37.5%. Irrespective of MA value, TPM AA inhibition expressed in percent of inhibition had poor accuracy. When used with proper guidelines for interpretation, specifically when MA ≤ 40 mm, TPM is a suitable and reliable test to use for MCS patients on aspirin.
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http://dx.doi.org/10.1182/ject-1900029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138126PMC
March 2020

Combined Heart and Kidney Transplantation: Clinical Experience in 100 Consecutive Patients.

J Am Heart Assoc 2019 02;8(4):e010570

1 Division of Cardiology Cedars-Sinai Smidt Heart Institute the Multiorgan Transplant Program Cedars-Sinai Medical Center Los Angeles CA.

Background Combined heart and kidney transplantation ( HKT x) is performed in patients with severe heart failure and advanced renal insufficiency. We analyzed the long-term survival after HKT x, the influence of age and dialysis status, the rates of cardiac rejection, and the influence of sensitization. Methods and Results From June 1992 to December 2016, we performed 100 HKT x procedures. We compared older (≥60 years, n=53) with younger (<60 years, n=47) recipients, and recipients on preoperative dialysis (n=49) and not on dialysis (n=51). We analyzed actuarial freedom from any cardiac rejection, acute cellular rejection, and antibody-mediated rejection, and survival rates by sensitized status with panel-reactive antibody levels <10%, 10% to 50%, and >50%, and compared these survival rates with those from the United Network for Organ Sharing database. There was no difference in 15-year survival between the 2 age groups (35±12.4% and 49±17.3%, ≥60 versus <60 years; P=0.45). There was no difference in 15-year survival between the dialysis and nondialysis groups (44±13.4% and 37±15.2%, P=0.95). Actuarial freedom from any cardiac rejection ( acute cellular rejection >0 or antibody-mediated rejection >0) was 92±2.8% and 84±3.8%, acute cellular rejection (≥2R/3A) 98±1.5% and 94±2.5%, and antibody-mediated rejection (≥1) 96±2.1% and 93±2.6% at 30 days and 1 year after HKT x. There was no difference in the 5-year survival among recipients by sensitization status with panel-reactive antibody levels <10%, 10% to 50%, and >50% (82±5.9%, 83±10.8%, and 92±8.0%; P=0.55). There was no difference in 15-year survival after HKT x between the United Network for Organ Sharing database and our center (38±3.2% and 40±10.1%, respectively; P=0.45). Conclusions HKT x is safe to perform in patients 60 years and older or younger than 60 years and with or without dialysis dependence, with excellent outcomes. The degree of panel-reactive antibody sensitization did not appear to affect survival after HKT x.
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http://dx.doi.org/10.1161/JAHA.118.010570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405671PMC
February 2019

Predicted heart mass is the optimal metric for size match in heart transplantation.

J Heart Lung Transplant 2019 02 27;38(2):156-165. Epub 2018 Sep 27.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Donor-recipient size match is traditionally assessed by body weight. We assessed the ability of 5 size match metrics-predicted heart mass (PHM), weight, height, body mass index (BMI) and body surface area (BSA)-to predict 1-year mortality after heart transplant and to assess the effect of size match on donor heart turn down for size.

Methods: The study cohort comprised 19,168 adult heart transplant recipients in the United Network for Organ Sharing registry between 2007 and 2016. Each size match metric was divided into 7 equally sized groups using the donor-recipient ratio for each metric. Single and multivariable Cox proportional hazard models for mortality 1 year after transplant were constructed.

Results: Recipients in the severely (donor-recipient PHM ratio 0.54-0.86) undersized group for PHM experienced increased mortality, with a hazard ratio of 1.34 (95% confidence interval, 1.13-1.59; p < 0.001). There was no increased risk of death at 1 year if donors were undersized for weight, height, BMI, or BSA. We found that 32% of heart offers turned down for donor size would be acceptable using a PHM threshold of 0.86 or greater and that 14% of offers accepted (most of which are female donor to male recipient) were below this threshold.

Conclusions: PHM is the optimal donor-recipient size match metric for prediction of mortality after heart transplant. Many offers turned down for donor size were above the threshold for adequacy of size match by PHM identified, and thus, the use of PHM could improve donor heart utilization and post-transplant survival.
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http://dx.doi.org/10.1016/j.healun.2018.09.017DOI Listing
February 2019

Combining Stem Cell Therapy for Advanced Heart Failure and Ventricular Assist Devices: A Review.

ASAIO J 2018 Sep/Oct;64(5):e80-e87

Cardiology, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.

The use of stem cell therapy in combination with a left ventricular assist device (LVAD) for patients with advanced heart failure (HF) is an attractive concept with the potential to alter the natural history of HF. Cell therapy trials for HF have demonstrated excellent safety and encouraging results, but current rates of myocardial recovery after LVAD implantation are limited. Early trials combining these 2 therapies to increase the likelihood of recovery and to potentially obviate the need for subsequent transplantation appear promising. Additionally, the application of cell therapy to patients undergoing LVAD implantation as a bridge to cardiac transplantation creates an opportunity to examine cardiac tissue before and after treatment and to study the mechanism of benefit. Despite the promise, there is a paucity of data for the combination of stem cell therapy with LVAD insertion in patients with HF. Of 11 case series or clinical trials, the largest enrolled 30 patients. We highlight clinical trials using stem cell therapy for end-stage HF most relevant to an LVAD patient population and comprehensively review the preclinical and clinical studies of combined stem cell therapy and long-term mechanical circulatory support. Based on the available clinical trials, the combination of stem cell therapy and LVAD support is a promising approach but requires further clinical refinement, with additional clinical data and larger numbers of patients required to support its clinical application.
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http://dx.doi.org/10.1097/MAT.0000000000000782DOI Listing
March 2019

Left Ventricular Reconstruction for Postinfarction Left Ventricular Aneurysm: Review of Surgical Techniques.

Tex Heart Inst J 2017 Oct 1;44(5):326-335. Epub 2017 Oct 1.

Different surgical techniques, each with its own advantages and disadvantages, have been used to reverse adverse left ventricular remodeling due to postinfarction left ventricular aneurysm. The most appropriate surgical technique depends on the location and size of the aneurysm and the scarred tissue, the patient's preoperative characteristics, and surgeon preference. This review covers the reconstructive surgical techniques for postinfarction left ventricular aneurysm.
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http://dx.doi.org/10.14503/THIJ-16-6068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731585PMC
October 2017

Role of Thromboelastography Platelet Mapping and International Normalized Ratio in Defining "Normocoagulability" During Anticoagulation for Mechanical Circulatory Support Devices: A Pilot Retrospective Study.

ASAIO J 2017 Jan/Feb;63(1):24-31

From the *Department of Pathology, Cedars Sinai Medical Center, Los Angeles, California; ‡Cedars-Sinai Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, California; §School of Pharmacy, University of California, San Francisco, California; and ¶Cedars - Sinai Research Institute (CSHI), Cedars Sinai Medical Center, Los Angeles, California.

Thromboembolic (TE) events and hemorrhagic complications continue to remain as frequent adverse events and causes of death after mechanical circulatory support device (MCSD) implantation. To counterbalance this postimplant multifactorial hypercoagulable state, antithrombotic therapy given postimplant must be individually tailored to keep patient adequately anticoagulated yet normocoagulable. Prior studies describing different anticoagulation protocols do not define normocoagulability for patients on MCSDs. We evaluated the role of thromboelastography platelet mapping (TEG PM) in defining "normocoagulability" for MCS patients on anticoagulant (warfarin) and antiplatelet agents. Ninety-eight MCSD patients who underwent TEG PM assay at our institution from 2012 to 2014 were included for retrospective analysis. Eleven (11.2%) subjects developed at least one TE event during the study period. Of the 13 TE events, 8 occurred in patients with total artificial heart (TAH). TEG parameters closest to the event or when patient was clinically adequately anticoagulated and corresponding international normalized ratio (INR) were measured. Thromboelastography coagulation index (CI) appears to be the single most statistically significant parameter that can be used to designate a patient as normocoagulable. Based on our results, patients with HeartMate II (HM II) and Heart Ware (HW) devices should be maintained at a CI value of less than or equal to 1.5 whereas patients with TAH devices should be maintained at a CI less than or equal to 1.2. The CI should be correlated with the degree of Vitamin K-dependent coagulation factor inhibition that is achieved using device-specific goal INR ranges. A recent modification, TEG PM assesses the effects of antiplatelet drug. Maximal amplitude arachidonic acid (MA-AA) < 50 and maximal amplitude adenosine diphosphate (MA-ADP) < 50 are desired for normocoagulable state.
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http://dx.doi.org/10.1097/MAT.0000000000000445DOI Listing
October 2017

Pathology of Chronic Chagas Cardiomyopathy in the United States:  A Detailed Review of 13 Cardiectomy Cases.

Am J Clin Pathol 2016 Aug 17;146(2):191-8. Epub 2016 Jul 17.

Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA.

Objectives: The pathologic features of chronic Chagas cardiomyopathy may not be widely appreciated in the United States. We sought to describe the gross, microscopic, immunohistochemical, and molecular pathology features useful to diagnose chronic Chagas cardiomyopathy.

Methods: The features from a case series of cardiectomy specimens of patients undergoing heart transplantation (12 patients) or mechanical circulatory support device implantation (one patient) for chronic Chagas cardiomyopathy at three institutions in the United States are reported and analyzed.

Results: Gross findings included enlarged and dilated ventricles (100% of cases), mural thrombi (54%), epicardial plaques (42%), and left ventricular aneurysm (36%). Microscopic evaluation revealed myocarditis (100% of cases) characterized by mononuclear cell infiltration, fibrosis (100%), nonnecrotizing granulomas (62%), and giant cells (38%). Two specimens (15%) showed rare intracellular amastigotes. Immunohistochemical assays for Trypanosoma cruzi organisms were negative in all cardiectomy specimens, whereas tissue polymerase chain reaction was positive in six (54%) of 11 cases.

Conclusions: The gross and microscopic features of chronic Chagas cardiomyopathy in the United States appear similar to those reported in endemic countries. Importantly, tissue polymerase chain reaction may be useful to confirm the diagnosis.
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http://dx.doi.org/10.1093/ajcp/aqw098DOI Listing
August 2016

Combined Lung-Kidney Transplantation: An Analysis of the UNOS/OPTN Database.

Am Surg 2015 Oct;81(10):1047-52

Cedars-Sinai Heart Institute, Los Angeles, California, USA.

Poor outcomes after thoracic transplantation with concurrent renal dysfunction are well described: without transplantation or with thoracic-only transplantation, patients face unacceptably high mortality. Outcomes after combined lung-kidney transplantation (LKT) remain largely uninvestigated. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database was queried to identify all LKTs, lung transplantations (LTs), and kidney transplantations (KTs) performed in the United States from 1995 to 2013. Survival was calculated using the Kaplan-Meier method and compared using log-rank tests or Cox regression models. Thirty-one LKTs were performed. Mean recipient age was 45.4 ± 13.5 years; 48.3 per cent were male. Retransplantation for graft failure was the leading indication for LT (n = 13) and the most common renal indication was calcineurin inhibitor nephrotoxicity (n = 11). Mean lung allocation score was 46.6 ± 14.4, mean creatinine was 3.7 ± 2.8 g/dL, and glomerular filtration rate was 23.1 (interquartile range 11.9, 38.3) mL/min/1.7 m(2), and 11 (35.5%) were dialysis dependent. Patient survival after LKT was 92.9 per cent, 71.0 per cent, and 71.0 per cent at one month, six months, and one year, with a median survival of 95.2 months. One- and five-year survival after LKT, 71.0 per cent and 59.9 per cent, were similar to LT (n = 23,913), 81.7 per cent and 51.4 per cent (P = 0.061 and 0.55), and inferior to KT (n = 175,269), 94.9 per cent and 82.8 per cent (P < 0.0001), respectively. Patient survival after LKT was similar to isolated LT, and these results suggest that LKT is a feasible therapeutic option for LT candidates with significant renal dysfunction.
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October 2015

Response.

Transplant Proc 2015 Jul-Aug;47(6):2077

Cedars-Sinai Heart Institute, and the Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

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http://dx.doi.org/10.1016/j.transproceed.2015.07.011DOI Listing
October 2015

Prevalence of Warfarin Genotype Polymorphisms in Patients with Mechanical Circulatory Support.

ASAIO J 2015 Jul-Aug;61(4):391-6

From the *Division of Cardiology, Cedars Sinai Heart Institute, Los Angeles, California; †Section of Biostatistics, Cedars-Sinai Medical Center, Los Angeles, California; and ‡Division of Cardiothoracic Surgery, Cedars Sinai Heart Institute, Los Angeles, California.

Polymorphisms for VKORC1 and CYP2C9 are associated with increased warfarin sensitivity. The prevalence of these polymorphisms in patients with mechanical circulatory support (MCS) is unknown. Polymorphisms for VKORC1 and CYP2C9 were determined in 65 patients undergoing MCS surgery. Postoperative warfarin dose, international normalized ratio (INR), and bleeding events were measured until discharge, 6 months, or composite end point (in-hospital MCS recovery, heart transplant, or death). A total of 67.7% (44/65) had at least one polymorphism: VKORC1 (44.6%), CYP2C9*2 (7.7%), CYP2C9*3 (4.6%), CYP2C9*2 and VKORC1 (3.1%), or CYP2C9*3 and VKORC1 (7.7%). At discharge or before composite end point, patients with any polymorphism received a lower mean warfarin dosage than patients having no polymorphism (3.21 ± 1.47 vs. 5.57 ± 3.72 mg, p = 0.015) and achieved a similar mean INR (2.20 ± 0.67 vs. 2.19 ± 0.69, p = 0.96). There was no significant difference in bleeding rates within 6 months or before composite end point (6.13 vs. 8.02 events/patient-year, p = 0.13). One or more polymorphisms for VKORC1 or CYP2C9 (associated with warfarin sensitivity) were found in 67.7% of MCS patients. By using a warfarin genotype-guided approach, MCS patients with polymorphisms received a lower warfarin dosage to achieve a similar INR, with similar bleeding rates, in comparison with no polymorphisms. A warfarin genotype-guided approach avoided excessive anticoagulation and its attendant bleeding risks.
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http://dx.doi.org/10.1097/MAT.0000000000000231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487870PMC
April 2016

Prevalence of hypertension in the Gambia and Sierra Leone, western Africa: a cross-sectional study.

Cardiovasc J Afr 2014 Nov-Dec;25(6):269-78. Epub 2014 Sep 29.

Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, California.

Background: Hypertension (HTN) is one of the causes of cardiovascular disease (CVD) in Africa, and may be associated with lower socio-economic status (SES). The prevalence of HTN is not well established in the Gambia or in Sierra Leone.

Methods: A cross-sectional, population-based study of adults was conducted in the Gambia in 2000 and in Sierra Leone from 2001 to 2003 and in 2009. The study was conducted as part of the annual visit to countries in western Africa sponsored by a medical delegation from California. People from the Gambia and Sierra Leone were examined by the medical delegation and blood pressures were measured.

Results: A total of 2 615 adults were examined: 1 400 females and 1 215 males. The mean systolic blood pressure (SBP) of the females was 134.3 ± 29.7 mmHg, mean diastolic blood pressure (DBP) was 84.5 ± 17.5 mmHg, and 46.2% were hypertensive. The mean SBP of the males was 132.8 ± 28.5 mmHg, mean DBP was 82.8 ± 16.2 mmHg, and 43.2% were hypertensive. Overall prevalence of HTN in the subjects was 44.8%. Mean SBP, mean DBP and HTN prevalence increased with age decade, both in males and females. In addition, after age adjustment (known age), females had higher mean SBP (p = 0.042), mean DBP (p = 0.001) and rate of occurrence of HTN (p = 0.016) when compared with males.

Conclusions: Prevalence rates of HTN in the Gambia and Sierra Leone were higher than 40% in males and females, and may be a major contributor to CVD in both countries. Due to the association of HTN with low SES, improvements in educational, public health, economic, non-governmental and governmental efforts in the Gambia and Sierra Leone may lead to a lower prevalence of HTN. The cause of the higher prevalence in women may be due to post-menopausal hormonal changes.
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http://dx.doi.org/10.5830/CVJA-2014-058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327182PMC
December 2015

Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair.

JACC Heart Fail 2014 Feb;2(1):49-61

Cedars-Sinai Heart Institute, Los Angeles, California.

Objectives: This study sought to compare the regenerative potency of cells derived from healthy and diseased human hearts.

Background: Results from pre-clinical studies and the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial support the notion that cardiosphere-derived cells (CDCs) from normal and recently infarcted hearts are capable of regenerating healthy heart tissue after myocardial infarction (MI). It is unknown whether CDCs derived from advanced heart failure (HF) patients retain the same regenerative potency.

Methods: In a mouse model of acute MI, we compared the regenerative potential and functional benefits of CDCs derived from 3 groups: 1) non-failing (NF) donor: healthy donor hearts post-transplantation; 2) MI: patients who had an MI 9 to 35 days before biopsy; and 3) HF: advanced cardiomyopathy tissue explanted at cardiac transplantation.

Results: Cell growth and phenotype were identical in all 3 groups. Injection of HF CDCs led to the greatest therapeutic benefit in mice, with the highest left ventricular ejection fraction, thickest infarct wall, most viable tissue, and least scar 3 weeks after treatment. In vitro assays revealed that HF CDCs secreted higher levels of stromal cell-derived factor (SDF)-1, which may contribute to the cells' augmented resistance to oxidative stress, enhanced angiogenesis, and improved myocyte survival. Histological analysis indicated that HF CDCs engrafted better, recruited more endogenous stem cells, and induced greater angiogenesis and cardiomyocyte cell-cycle re-entry. CDC-secreted SDF-1 levels correlated with decreases in scar mass over time in CADUCEUS patients treated with autologous CDCs.

Conclusions: CDCs from advanced HF patients exhibit augmented potency in ameliorating ventricular dysfunction post-MI, possibly through SDF-1–mediated mechanisms.
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http://dx.doi.org/10.1016/j.jchf.2013.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914736PMC
February 2014

Staged approach to mechanical circulatory support and recovered allograft function after transplantation rejection with cardiogenic shock.

Tex Heart Inst J 2013 ;40(5):596-9

Divisions of Cardiothoracic Surgery (Drs. Caceres, Esmailian, and Ramzy) and Cardiology (Drs. Czer and Moriguchi), Cedars-Sinai Heart Institute; and Department of Pathology (Dr. Luthringer), Cedars-Sinai Medical Center; Los Angeles, California 90048.

Cardiogenic shock resulting from acute rejection after heart transplantation is an infrequent but life-threatening condition. Intensified immunosuppressive therapy and the timely initiation of properly selected mechanical circulatory support can be life-saving and enable recovery of graft function. The few published reports on mechanical circulatory support for acute transplantation rejection have focused on short-term devices. We present the case of a 48-year-old woman who developed cardiogenic shock due to severe allograft rejection after heart transplantation. She underwent staged mechanical circulatory support: extracorporeal membrane oxygenation for 10 days and then biventricular assist device support for 5 weeks. Allograft function recovered completely, and this enabled removal of the assist device. The patient was alive 18 months after biventricular assist device insertion. To our knowledge, this is the first description of a successful staged approach involving short- and long-term mechanical circulatory support to resolve allograft rejection and refractory cardiogenic shock after heart transplantation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853834PMC
October 2014

Are different mechanical circulatory support devices important factors maximizing patient survival after heart transplant?

Ann Thorac Surg 2013 Oct;96(4):1530-1531

Cedars-Sinai Medical Center, Cedars-Sinai Heart-Institute, Division of Cardiothoracic Surgery, Saperstein Critical Care Tower, Room 2S04C, 8700 Beverly Blvd, Los Angeles, CA90048.

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http://dx.doi.org/10.1016/j.athoracsur.2013.03.075DOI Listing
October 2013

Combined heart and kidney transplantation: what is the appropriate surgical sequence?

Interact Cardiovasc Thorac Surg 2013 Aug 24;17(2):416-8. Epub 2013 Apr 24.

Division of Cardiothoracic Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.

Combined heart and kidney transplantation is increasing in frequency but there are no guidelines to establish the indications, contraindications and sequence for this surgical procedure. We report our single-centre experience on 30 consecutive patients who underwent combined heart and kidney transplant in comparison with heart transplant alone. Patients had similar preoperative characteristics in both groups. Combined heart and kidney transplant is associated with the same long-term survival rate, low cellular rejection and antibody-mediated rejection rates when compared with heart transplant alone. We did not observe any difference in the outcomes related to preoperative patient characteristics. We suggest the staged surgical approach as the preferred method for transplant.
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http://dx.doi.org/10.1093/icvts/ivt172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715178PMC
August 2013

Significant reduction of ATP production in PHA-activated CD4+ cells in 1-day-old blood from transplant patients.

Transplantation 2012 Dec;94(12):1243-9

Transplant Immunology Laboratory, Comprehensive Transplant Center, Cedars-Sinai Medical Center/UCLA School of Medicine, Los Angeles, CA 90048, USA.

Background: Global immunosuppression can be measured by assessing adenosine triphospate (ATP) levels in mitogen-stimulated CD4+ T cells.

Methods: We investigated the effect of storage time on ATP levels in 234 blood samples from 18 healthy individuals and 152 transplant patients. The difference between day 0 (<13 hours post-blood draw) and day 1 (24-37 hours) measurements was analyzed and compared with various factors; a subset of samples was also analyzed in 6-hour intervals.

Results: The ATP levels were significantly lower on day 1 compared with that on day 0 in healthy individuals (279±159 vs 414±159 ng/mL, P<0.001) and patients (356±209 vs 455±221 ng/mL, P<0.0001). Of the 18 healthy individuals, 17 showed ATP reduction, whereas 192 (89%) of 216 patients did so on day 1 (24.8±24.1%). In the time course analysis, ATP levels decreased with the blood storage time in healthy and patient samples, and the reduction began as early as 7 hours post-blood draw. The reduction rate was significantly higher in patient samples with low day 0 ATP levels compared with samples with moderate or high levels (44.7±31.3% vs 23.2±23.6% or 18.7±15.7%; P<0.001). The reduction rate in patients treated with alemtuzumab induction was slightly higher than that in daclizumab-treated patients (28.8±24.6% vs 21.3±21.3%, P=0.09). CD4+ cell number did not change within 24 hours post-blood draw, but CD4 expression decreased 2.0±2.8% (P<0.05).

Conclusions: The ATP levels are significantly lower in 1-day-old blood compared with fresh blood, suggesting that fresh blood should be used for assessing the T cell immune function to obtain the most accurate results.
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http://dx.doi.org/10.1097/TP.0b013e318270f322DOI Listing
December 2012

Impact of virtual cross match on waiting times for heart transplantation.

Ann Thorac Surg 2011 Dec;92(6):2104-10; discussion 2111

Division of Cardiothoracic Surgery, Cedars-Sinai Heart Institute, Los Angeles, California, USA.

Background: Heart transplantation for sensitized patients has been a significant challenge. In this study, outcome of heart transplantation in sensitized patients with virtual cross match was compared with prospective cross match.

Methods: Prior to July 2007, prospective cross match was used and afterward, virtual cross match with Luminex (One Lambda, Inc, Canoga Park, CA) based antibody analysis was used for potential heart transplant recipients. Prospectively collected data for the 3 years before and after July 2007, in sensitized (panel reactive antibody greater than 10%) and nonsensitized heart transplant recipients were reviewed.

Results: One hundred sixty-eight patients met inclusion criteria for analysis (78 patients for prospective cross match and 90 patients for virtual cross match). Multiple parameters were compared for the prospective cross match and virtual cross match eras. Three-year survivals in nonsensitized patients were 84.6% and 77.2% and in sensitized patients were 76.9% and 77.4% (p = 0.49) for prospective cross match and virtual cross match eras, respectively. Freedom from 3A (2R) cellular rejection in nonsensitized patients was 96.9% and 95.3%, and in sensitized patients was 90.9% and 100% (p = 0.83). Freedom from antibody-mediated rejection in nonsensitized patients was 95.3% and 96.8%, and in sensitized patients was 90.9% and 90.5% (p = 0.65). Mean waiting time was 129 ± 246 days (mean ± SD) for the period before virtual cross match and 59 ± 78 days with virtual cross match (p = 0.018). Donor geographic area was similar for prospective and virtual cross match.

Conclusions: In sensitized heart transplant candidates, virtual cross match may shorten waiting time to heart transplantation without increasing subsequent occurrence of cellular rejection, antibody mediated rejection, and mortality after heart transplantation.
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http://dx.doi.org/10.1016/j.athoracsur.2011.07.082DOI Listing
December 2011

Intrinsic cardiac origin of human cardiosphere-derived cells.

Eur Heart J 2013 Jan 9;34(1):68-75. Epub 2011 Jun 9.

Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Aims: Cardiosphere-derived cells (CDCs) are in clinical development as a regenerative cell product which can be expanded ex vivo from patient cardiac biopsies. Cardiosphere-derived cells are clonogenic, exhibit multilineage differentiation, and exert functional benefits in preclinical models of heart failure. The origin of CDCs remains unclear: are these cells endogenous to the heart, or do they arise from cells that populate the heart via blood-borne seeding?

Methods And Results: Right ventricular endomyocardial biopsies were obtained from cardiac transplant recipients (n = 10, age 57 ± 15 years), and CDCs expanded from each biopsy. Donor-recipient mismatches were used to probe the origin of CDCs in three complementary ways. First, DNA analysis of short-tandem nucleotide repeats (STRs) was performed on genomic DNA from donor and recipient, then compared with the STR pattern of CDCs. Second, in two cases where the donor was male and the recipient female, CDCs were examined for the presence of X and Y chromosomes by fluorescence in situ hybridization. Finally, in two cases, quantitative PCR (qPCR) was performed for individual-specific polymorphisms of a major histocompatability locus to quantify the contribution of recipient cells to CDCs. In no case was recipient DNA detectable in the CDCs by STR analysis. In the two cases in which a female patient had received a male heart, all CDCs examined had an X and Y chromosome, similarly indicating exclusively donor origin. Likewise, qPCR on CDCs did not detect any recipient DNA.

Conclusion: Cardiosphere-derived cells are of endogenous cardiac origin, with no detectable contribution from extra-cardiac seeding.
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http://dx.doi.org/10.1093/eurheartj/ehr172DOI Listing
January 2013

Vehicle safety features, especially airbags, may account for the recent decline in heart donors.

J Heart Lung Transplant 2011 Sep 28;30(9):1068-70. Epub 2011 May 28.

Cedars-Sinai Heart Institute, Los Angeles, California, USA.

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http://dx.doi.org/10.1016/j.healun.2011.04.010DOI Listing
September 2011

Changes in left and right ventricular function of donor hearts during the first year after heart transplantation.

Heart 2011 Oct 17;97(20):1681-6. Epub 2011 May 17.

Heart Institute, Kaplan Medical Center, Rehovot 76100, Israel.

Objective: Expected values of tissue Doppler imaging (TDI) velocities and myocardial performance index (MPI) after heart transplantation (HTx) have not been evaluated. This study assessed left and right ventricular (LV and RV) structure and function during the first year after HTx using these indexes.

Methods And Results: Echocardiography including MPI and TDI systolic (S'), early (E') and late (A') diastolic velocities of RV and LV were performed in 20 donors (mean age 35 ± 13 years) and serially in 20 recipients (mean age 59 ± 9 years) during the first year after HTx. Increase in LV mass occurred at 7 days, with normalisation at 3 months (p < 0.001). An increase in MPI (p<0.001) and a decrease in E', S' velocities on TDI occurred at week 1 with gradual improvement during the first year (p < 0.001). Normalisation of LV and RV MPI occurred at 6 months (p < 0.001) and LV TDI velocities at 1 year (p < 0.001). TDI velocities of both ventricles, however, at 1 year remained lower than at baseline. No patient had greater than grade IA rejection during the follow-up. No significant change was found in myocyte size within the first year. However, there was a 3.3-fold increase in fibrosis.

Conclusions: This study is the first to identify the normal changes of TDI and MPI of both ventricles during the first year after HTx. An increase in LV mass and impairment of bi-ventricular systolic and diastolic function occur early after HTx with gradual improvement during the first year. No significant changes in myocyte size were observed, but there was a substantial increase in fibrosis.
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http://dx.doi.org/10.1136/hrt.2010.220871DOI Listing
October 2011

Heart transplantation in the elderly: why cardiac transplantation does not need to be limited to younger patients but can be safely performed in patients above 65 years of age.

Ann Transplant 2010 Oct-Dec;15(4):110-9

Division of Cardiology, Department of Medicine, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, U.S.A.

Within the last forty years, heart transplantation as the ultimate option for the treatment of end-stage heart disease has undergone dramatic changes and advances in operative techniques, postoperative care, immunosuppression, and rejection management which resulted in reduced morbidity and mortality. As the heart failure epidemic worsens and the population grows older, cardiac transplantation criteria have expanded for end-stage heart disease refractory to medical management. Although outcomes after cardiac transplantation have improved, the critical organ shortage is a limitation to its efficacy. The demand-supply disparity for heart transplantations has led to clinical and ethical issues examining adequate candidacy for organ transplantation. Cardiac transplantation in the elderly recipient was considered a contraindication due to poor survival rates compared to younger recipients. Given the increase in life expectancy over the last decades, single-center studies have assessed the outcome of transplantation among elderly recipients and comparable survival and quality of life have been described among older heart transplantation recipients. Alternatives to cardiac transplantation which have become more common, such as mechanical circulatory support, and further investigation of the viability of transplantation in the elderly may help determine the proper allocation of the limited organ supply.
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April 2011

An agonist of liver X receptor slows valvular disease in a hypercholesterolemia mouse model.

J Heart Valve Dis 2010 Sep;19(5):653-64

Division of Cardiothoracic Surgery, Department of Surgery, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Davis Building Room 6014, Los Angeles, California 90048, USA.

Background And Aim Of The Study: Cholesterol is a known risk factor in aortic stenosis and valve degeneration, and the liver X receptor (LXR) is a regulator of cholesterol and phospholipid metabolism. It was hypothesized that an LXR agonist would reduce calcium and lipid deposition in aortic valves.

Methods: Apolipoprotein E-/- (ApoE-/-) mice fed a high-fat diet were implanted with glutaraldehyde-fixed porcine valve fragments. The animals were treated with either the LXR agonist T1317 or vehicle for eight weeks.

Results: The LXR agonist reduced lipid deposition in native aortic roots and sinuses about two-fold (p < 0.05), and echocardiography revealed lower transvalvular velocities in vivo (p < 0.05). Similarly, treatment with the LXR agonist significantly reduced the calcium content (by ca. 50%, p < 0.05) and lipid content (by ca. 20%, p < 0.01) of explanted porcine valve tissue. Serum low-density lipoprotein (LDL) and total cholesterol levels were also lower in treated mice (p < 0.01). Serum levels of the inflammatory chemokine platelet factor 4 were reduced by 30% compared to controls. Cultured valvular cells treated with oxidized LDL (ox-LDL) developed greater numbers of calcific nodules. The ox-LDL treatment of valvular endothelial cells increased adhesion to mononuclear cells, while the LXR agonist reversed both the increase in adhesion and vascular cell adhesion protein-1 expression mediated by ox-LDL.

Conclusion: The data acquired suggested that calcium and lipid deposition in heart valves can be altered by inhibiting lipid metabolism via LXR, and that the mechanism may involve inflammatory cell signaling. These results indicate that enhancement of cholesterol efflux activity may have the potential to reduce bioprosthetic and native valve degeneration.
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September 2010
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