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Pubblicazioni recenti - dilated cardiomyopathy
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BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes.
Sci Rep2020 May;10(1):8755. doi: 10.1038/s41598-020-65664-z.
Adriaenssens Elias, Tedesco Barbara, Mediani Laura, Asselbergh Bob, Crippa Valeria, Antoniani Francesco, Carra Serena, Poletti Angelo, Timmerman Vincent,
Abstract
Three missense mutations targeting the same proline 209 (Pro209) codon in the co-chaperone Bcl2-associated athanogene 3 (BAG3) have been reported to cause distal myopathy, dilated cardiomyopathy or Charcot-Marie-Tooth type 2 neuropathy. Yet, it is unclear whether distinct molecular mechanisms underlie the variable clinical spectrum of the rare patients carrying these three heterozygous Pro209 mutations in BAG3. Here, we studied all three variants and compared them to the BAG3_Glu455Lys mutant, which causes dilated cardiomyopathy. We found that all BAG3_Pro209 mutants have acquired a toxic gain-of-function, which causes these variants to accumulate in the form of insoluble HDAC6- and vimentin-positive aggresomes. The aggresomes formed by mutant BAG3 led to a relocation of other chaperones such as HSPB8 and Hsp70, which, together with BAG3, promote the so-called chaperone-assisted selective autophagy (CASA). As a consequence of their increased aggregation-proneness, mutant BAG3 trapped ubiquitinylated client proteins at the aggresome, preventing their efficient clearance. Combined, these data show that all BAG3_Pro209 mutants, irrespective of their different clinical phenotypes, are characterized by a gain-of-function that contributes to the gradual loss of protein homeostasis.
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Silencing of CCR4-NOT complex subunits affect heart structure and function.
Dis Model Mech2020 May;():. doi: dmm.044727.
Elmén Lisa, Volpato Claudia B, Kervadec Anaïs, Pineda Santiago, Kalvakuri Sreehari, Alayari Nakissa N, Foco Luisa, Pramstaller Peter P, Ocorr Karen, Rossini Alessandra, Cammarato Anthony, Colas Alexandre R, Hicks Andrew A, Bodmer Rolf,
Abstract
Genome wide association studies (GWAS) have identified variants that associate with QT-interval length. Three of the strongest associating variants (SNPs) are located in the putative promotor region of , a gene encoding the central subunit of CCR4-NOT, a multi-functional, conserved complex regulating gene expression and mRNA stability and turnover. We isolated the minimum fragment of the promoter containing all three variants from individuals homozygous for the QT-risk alleles and demonstrated that the haplotype associating with longer QT-interval caused reduced reporter expression in a cardiac cell line, suggesting that reduced expression may contribute to abnormal QT-intervals. Systematic siRNA-mediated knockdown of CCR4-NOT components in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) revealed that silencing and other genes reduced their proliferative capacity. Silencing also shortened action potential duration. Furthermore, cardiac-specific knockdown of orthologs of CCR4-NOT genes and , , was either lethal or resulted in dilated cardiomyopathy, reduced contractility, or a propensity for arrhythmia. Silencing , and also affected cardiac chamber size and contractility. Developmental studies suggested that and are required during cardiac remodeling from larval to adult stages. In sum, we have demonstrated how disease associated genes identified by GWAS can be investigated, by combining human cardiomyocyte cell-based and whole organism heart models. Our results also suggest a potential link of and to QT alterations and further establish a critical role of the CCR4-NOT complex in heart development and function.
© 2020. Published by The Company of Biologists Ltd.
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High expression levels and localization of Sox5 in dilated cardiomyopathy.
Mol Med Rep2020 May;():. doi: 10.3892/mmr.2020.11180.
Liu Yafeng, Jiang Ben, Cao Yide, Chen Wen, Yin Li, Xu Yueyue, Qiu Zhibing,
Abstract
Dilated cardiomyopathy (DCM) is a disease that can lead to heart expansion and severe heart failure, but the specific pathogenesis remains unclear. Sox5 is a member of the Sox family with a key role in cardiac function. However, the role of Sox5 in DCM remains unclear. In the present study, wild?type mice were intraperitoneally injected with doxorubicin (Dox) to induce DCM, and heart specimens from human patients with DCM were used to investigate the preliminary role of Sox5 in DCM. The present study demonstrated that, compared with control human hearts, the hearts of patients with DCM exhibited high expression levels of Sox5 and activation of the wnt/??catenin pathway. This result was consistent with Dox?induced DCM in mice. Furthermore, in Dox?treated mice, apoptosis was activated during the development of DCM. Inflammation and collagen deposition also increased in DCM mice. The results of the present study indicate that Sox5 may be associated with the development of DCM. Sox5 may be a novel potential factor that regulates DCM.
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A Population-Based Registry of Patients With Inherited Cardiac Conditions and Resuscitated Cardiac Arrest.
J Am Coll Cardiol2020 Jun;75(21):2698-2707. doi: S0735-1097(20)34871-3.
Rucinski Cynthia, Winbo Annika, Marcondes Luciana, Earle Nikki, Stiles Martin, Stiles Rachael, Hooks Darren, Neas Kate, Hayes Ian, Crawford Jackie, Martin Andrew, Skinner Jonathan R,
Abstract
BACKGROUND:
The relative proportion of each cardiac inherited disease (CID) causing resuscitated sudden cardiac arrest (RSCA) on a population basis is unknown.
OBJECTIVES:
This study describes the profile of patients with CIDs presenting with RSCA; their data were collected by the national Cardiac Inherited Diseases Registry New Zealand (CIDRNZ).
METHODS:
Data were collated from CIDRNZ probands presenting with RSCA (2002 to 2018).
RESULTS:
CID was identified in 115 (51%) of 225 RSCA cases: long QT syndrome (LQTS) (n = 48 [42%]), hypertrophic cardiomyopathy (HCM) (n = 28 [24%]), Brugada syndrome (BrS) (n = 16 [14%]), catecholaminergic polymorphic ventricular tachycardia (CPVT) (n = 9 [8%]), arrhythmogenic right ventricular cardiomyopathy (ARVC) (n = 9 [8%]), and dilated cardiomyopathy (n = 5 [4%]). Seventy-one (62%) of 115 were male. Of 725 probands from the CIDRNZ with CID, the proportion presenting with RSCA was: CPVT, 9 (53%) of 17; BrS, 16 (33%) of 49; ARVC, 9 (25%) of 36; LQTS, 48 (20%) of 238; dilated cardiomyopathy, 5 (9%) of 58; and HCM, 28 (8%) of 354. Incident activity was: normal everyday activities, 44 (40%); exercising, 33 (30%); concurrent illness, 13 (12%); sleeping, 10 (9%); drugs/medication, 9 (8%); and emotion, 2 (2%). LQTS and CPVT predominated in those <24 years of age, 30 (77%) of 39; cardiomyopathies and BrS predominated in those >24 years of age, 49 (64%) of 76. For those >40 years of age, HCM was the most common (33%) CID. A genetic diagnosis in patients with CID was made in 48 (49%) of 98 tested. Diagnosis by age range was as follows: age 1 to 14 years, 78%; age 15 to 24 years, 53%; age 25 to 39 years, 54%; and age >40 years, 26%.
CONCLUSIONS:
The commonest CID identified after RSCA was LQTS; the most common CID cause of RSCA for those >40 years of age was HCM. CPVT was the CID most likely to present with RSCA and HCM the least. Genetic yield decreases with age. Only one-third of RSCA cases due to CID occurred while exercising.
Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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Cost-Effectiveness of Immediate Ventricular Assist Device Implantation in Children with Inotrope-Dependent Heart Failure.
J Heart Lung Transplant2020 Apr;39(4S):S87. doi: S1053-2498(20)31335-8.
Avancena A L, Peng D M, Lee J, Si M, Schumacher K R, Hutton D W,
Abstract
PURPOSE:
Ventricular assist devices (VADs) have improved wait list survival in children with end-stage heart failure. However, questions remain about the optimal timing of VAD implantation. In this cost-effectiveness analysis, we compared immediate intracorporeal continuous VAD implantation to a watchful waiting approach using continuous inotropic therapy.
METHODS:
Using a Markov model, we simulated a cohort of pediatric patients with dilated cardiomyopathy. We used a monthly cycle and 20-year time horizon. We estimated cost and benefits (in terms of quality-adjusted life years, QALYs) from a healthcare perspective discounted at 3% per year. Transition probabilities, costs, and utility weights were taken from published and grey literature, which we supplemented with expert opinion where there were gaps. We calculated the incremental cost-effectiveness ratio (ICER) and performed one-way and probabilistic sensitivity analyses (PSA) using 10,000 Monte Carlo simulations to understand the impact of parameter uncertainty in the main findings. Cost variables were assigned gamma distributions, while transition probabilities and utilities were assigned beta distributions.
RESULTS:
In a base case analysis, the incremental costs and benefits of immediate intracorporeal continuous VAD implantation compared to medical management was $221,269 (2017 US$) and 0.21 QALYs, respectively, resulting in an ICER of $1.04 million per QALY. One-way sensitivity analysis found that the discount rate, the probability of heart transplant among patients on VAD and medical management, and the cost of VAD implantations exerted the most influence on the ICER, though varying any of the parameters to their lowest and highest values did not bring the ICER close a $100,000 per QALY willingness-to-pay (WTP) threshold. The PSA showed a 3% chance of immediate VAD implantation to be cost-effective at a WTP of $500,000 per QALY and a 36% chance at $1 million per QALY.
CONCLUSION:
Though VADs provide a net health benefit as a bridge to transplant, immediate implantation in children with inotrope-dependent heart failure is not likely to be a cost-effective strategy compared to medical management based on commonly used ICER thresholds. Future analyses should explore the cost-effectiveness of VAD implantation in children with other disease states, diagnoses and device types.
Copyright © 2020. Published by Elsevier Inc.
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Intracorporeal VAD Outcomes in the ACTION Quality Improvement Network.
J Heart Lung Transplant2020 Apr;39(4S):S84. doi: S1053-2498(20)31329-2.
Sutcliffe D L, Barnes A P, Davies R R, Machado D S, Shezad M F, Hawkins B M, Almond C S, Murray J M, Villa C R,
Abstract
PURPOSE:
The initial project of ACTION (Advanced Cardiac Therapies Improving Outcomes Network) is focused on improving stroke rates in patients implanted with a ventricular assist devices (VAD) in participating centers. The initial interventions targeted improving communication, anticoagulation, and blood pressure management. We sought to describe the characteristics and outcomes of patients implanted with intracorporeal, continuous flow VADs (cfVAD).
METHODS:
The ACTION registry was used to determine the stroke frequency in cfVAD implanted patients between April 2018 and September 2019, the time from development of the quality improvement bundle to the present.
RESULTS:
Sixty two patients (33 Heartmate3 [HM3] and 29 Heartware [HVAD]) were identified (Table). The majority had dilated cardiomyopathy (76%). Of the 12 (20%) patients with congenital heart disease (CHD), 9 (75%) had single ventricle (SV) physiology. The HM3 patients were older (16.5 yr vs 12.8 yr) and larger (64.2 kg vs 51.9 kg) than the HVAD patients. No significant difference was observed in diagnosis, duration of support, device strategy, or clinical outcome. One patient (2%) experienced a stroke during 6,920 days of support. Forty of the 45 (89%) patients to reach a clinical endpoint experienced a positive outcome (transplant or explant for recovery) while 17 (27%) patients remain on device.
CONCLUSION:
The stroke rate is low and survival good among patients implanted with an intracorporeal cfVAD at ACTION centers using the clinical protocols developed within the network. The HVAD is currently being used more frequently in younger and smaller patients. There has been an appreciable increase in the number and frequency of implants in patients with CHD, especially SV disease, as compared to previous reports. Future efforts within ACTION will focus on improving clinical outcomes as devices are increasingly used at individual centers and as the number of VAD-supported patients with congenital heart disease continues to grow.
Copyright © 2020. Published by Elsevier Inc.
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Genetic Profiling of Combined Post-Capillary and Pre-Capillary Pulmonary Hypertension in Left Heart Diseases.
J Heart Lung Transplant2020 Apr;39(4S):S512. doi: S1053-2498(20)30147-9.
Chomette L, Caravita S, Dewachter C, Abramowicz M, Vachiery J, Bondue A,
Abstract
PURPOSE:
Pulmonary hypertension (PH) in left heart diseases (LHD) has been redefined as isolated post-capillary PH (IpcPH) and combined post-capillary and pre-capillary PH (CpcPH). CpcPH's pathophysiology is not well understood. Predisposing constitutional factors may play a role in CpcPH development, as suggested by the variability in the adaptation of the pulmonary circulation to the elevation of pulmonary artery wedge pressure (PAWP). We sought to determine whether a genetic predisposition to CpcPH could be identified, suggesting a common pathway with pulmonary arterial hypertension (PAH).
METHODS:
Based on Erasme's hospital right heart catheterization database from January 2007 to January 2015, we selected PH-LHD patients to further identify CpcPH patients. Clinical and hemodynamic variables were used to compare IpcPH to CpcPH patients. A small cohort of CpcPH patients underwent genetic testing for genes predisposing to heritable PAH using a gene panel approach and MLPA analysis.
RESULTS:
93 patients presented with PH-LHD, of which 32% met the definition of CpcPH. Clinical data was similar in both IpcPH and CpcPH groups except for higher morphometric features in CpcPH patients. Missense variations of the BMPR2 gene (c.1749C>A, p.Asn583Lys) and of the ENG gene (c.1316A>C, p.Lys439Thr) were identified in one CpcPH patient presenting with heart failure due to dilated cardiomyopathy. Based on current knowledge, both variants were classified as variants of unknown significance (VUS).
CONCLUSION:
Our study uncovered genomic variations in the BMPR2 and ENG genes of a CpcPH patient, which may support the concept that a predisposing genetic background could modulate the precapillary component in CpcPH, potentially suggesting common genetic pathways between CpcPH and PAH, although this has to be further confirmed by functional testing, studies in bigger cohorts and with IpcPH control populations.
Copyright © 2020. Published by Elsevier Inc.
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Safety and Feasibility of Home INR Monitoring for Outpatient Ventricular Assist Device Support in Children.
J Heart Lung Transplant2020 Apr;39(4S):S495. doi: S1053-2498(20)30096-6.
Hawkins B M, Ventresco C, Hellinger A, VanderPluym C, Knoll C,
Abstract
PURPOSE:
The use of intracorporeal continuous flow (CF) ventricular assist devices- namely the Heartware? HVAD?- has expanded dramatically in the children, with many being discharged home. We sought to evaluate the feasibility and outcomes of children discharged home with point of care (POC) INR monitors for their warfarin anticoagulation management.
METHODS:
This is a retrospective single center review of all pediatric patients, aged ?19 years at time of implantation, who were discharged home for longer than 1 week. Efficacy of warfarin anticoagulation and outcomes were evaluated in those with home POC monitors as compared to children who went to laboratory.
RESULTS:
Between November 11, 2012 and January 1, 2018, a total of 12 patients, 33% female, aged median 14.5 years (range 10-18 years), weighing median 65.8kg (range 18.0-89.5 kg) were discharged home or to rehab with HeartWare as a bridge to transplantation. Underlying diagnosis included dilated cardiomyopathy in 67% (n=8), arrhythmogenic right ventricular dysplasia (ARVD) in 8% (n=1), and biventricular congenital heart disease (CHD) in 25% (n=3).Two patients were discharged to rehab before returning home. All patients were discharged with Coagucheck XS? POC INR machines, with goal INR of 2-3 in first 3 patients (23%) and goal INR of 2.5-3.5 in later 10 patients. There were a median number of INR tests of 27 (range 1-99) at home, over the course of a median 185 days (25-625) outpatient VAD support days. Overall median time in the therapeutic range(TTR) was 62.1%(range 20.0-70.7%). There was 100% adherence to clinician recommended INR testing at home. There was 4 bridging events with low molecular weight heparin for sub-therapeutic INR. There were no pump thrombosis or other thrombotic events. There were no major bleeding or clinically relevant non major bleeding events. Epistaxis was the most common minor bleeding event that was mitigated by dose reductions and preventative strategies. All patients were bridged to transplantation with no mortality.
CONCLUSION:
Use if home POC INR machines in children with intracorporeal VADs, in the outpatient setting was associated with 100% adherence to recommended testing regime. Despite low TTR, there was no major bleeding or thrombotic events.
Copyright © 2020. Published by Elsevier Inc.
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Adverse Events Following Cardiac Catheterization among Infants, Children, and Young Adults on Ventricular Assist Device Support.
J Heart Lung Transplant2020 Apr;39(4S):S465-S466. doi: S1053-2498(20)30336-3.
Power A, Murray J M, Peng L F, Rosenthal D N, Dykes J C, Shui A A, Yarlagadda V V, Navaratnam M, Maeda K, Almond C S, Chen S,
Abstract
PURPOSE:
Children on ventricular assist device (VAD) support often present unique challenges, such as small size, univentricular or biventricular congenital heart disease (1V- or 2V-CHD), and need for biventricular (BiVAD) support. While cardiac catheterization (cath) can provide valuable information in the management of pediatric patients on VAD support, it is an invasive procedure with inherent risks. We sought to evaluate the safety of cath in this population.
METHODS:
We performed a retrospective review of patients on VAD support who underwent cath at a single pediatric VAD center between 2014 and 2019. Using definitions based on Pedimacs, adverse events (AEs) following cath were identified, including respiratory failure (persistent need for intubation ? 48 hours post-cath), acute kidney injury (AKI), or arrhythmia within 24 hours, and stroke, pericardial effusion, device malfunction, infection, and death within 7 days. AEs were reviewed by two cardiologists, blinded to each other's assessments, and categorized as directly related or unrelated to cath. Strokes were unrelated to cath if there was documentation of baseline neurologic status after cath but prior to stroke. Descriptive statistics were employed.
RESULTS:
There were 60 caths on 39 patients. Median age was 11 years (range 2 months - 22 years) and median weight was 36 kg (3.8 - 99.2). Underlying diagnoses included dilated cardiomyopathy (DCM) (54%), 1V-CHD (31%), 2V-CHD (10%), hypertrophic cardiomyopathy (2.5%) and re-transplant (2.5%); 10% were on BiVAD support. Devices were paracorporeal pulsatile (20%), durable continuous flow (72%), and temporary continuous flow (8%). Caths were performed at a median 50 days (6 - 311) from VAD implant; 60% (36/60) were performed on patients in the intensive care unit. Of the 60 caths, there were 7 AEs following cath believed to be directly or possibly related to cath (12%, 7/60), occurring in 6 patients (2 DCM, 3 1V-CHD, 1 other): 1 major bleeding event, 1 AKI, 2 moderate pericardial effusions, and 3 episodes of respiratory failure. There were no strokes, arrhythmia, infections, or mortality attributable to cath.
CONCLUSION:
Despite medical complexity such as small size, complex CHD and intensive care needs, cardiac catheterization can be performed with an acceptable adverse event profile in infants, children and young adults on VAD support.
Copyright © 2020. Published by Elsevier Inc.
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Natural History of Hemodynamic Maturation Post Heart Transplantation in the Absence of Rejection.
J Heart Lung Transplant2020 Apr;39(4S):S463. doi: S1053-2498(20)30329-6.
Deshpande S R, Simpson P M, Zhang L, -Mitchell A Tomita, Mitchell M E,
Abstract
PURPOSE:
Routine catheterization is a part of transplant surveillance, however there is extremely limited data on evolution of hemodynamic parameters post heart transplant. Knowledge of these normative data will be useful in interpretation of individual catheterization results, assessment of graft performance and identification of risk factors.
METHODS:
Prospectively collected transplant and hemodynamic data for patients enrolled in the Quantitative Detection of Circulating Donor-Specific DNA in Organ Transplant Recipients (DTRT Study) was secondarily analyzed.
RESULTS:
A total of 265 patients were included in the analysis. The patient population was representative for heart transplant population, with majority being White (64%), male (59%), listed as IA (61.4%) with dilated cardiomyopathy (31 % of cardiomyopathy group) or Hypoplastic left heart syndrome (43.8% of CHD group) as the common diagnosis. 83 (31%) were supported with LVAD at the time of transplantation. 8.5% of the transplants were performed in ABO incompatible group. Serial changes in hemodynamics in the absence of rejection are shown in figure 1. RAP and PCWP were significant predictors of outcomes. An RAP of > 10 mmHg and PCWP of > 15 mmHg at first available catheterization were significantly associated with mortality at 6 months, 1 and 2 years post-transplant (p=0.001). Mean survival for RAP was associated with overall mortality at one year post transplant in a cox proportional hazard model (p=0.012) while other recipient factors were not. Pairwise comparison and survival curves for elevated pressures are shown in figure 1.
CONCLUSION:
This is the first, large scale, prospectively collected data on the hemodynamic evolution post-transplant in the absence of rejection. RAP greater than 10 mmHg and PCWP pressure greater than 15mmHg are significant markers of early graft loss and mortality and may warrant increased monitoring and modified treatment strategies.
Copyright © 2020. Published by Elsevier Inc.
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Heightened Immune Response and Increased Risk of Infections in Pediatric Fontan Patients after Heart Transplantation.
J Heart Lung Transplant2020 Apr;39(4S):S452-S453. doi: S1053-2498(20)30300-4.
Ahmed H, Lee J, Profita E, Dykes J, Hollander S, Kaufman B, Bernstein D, Rosenthal D N, Barkoff L, Lee D, Chen S,
Abstract
PURPOSE:
Infectious complications are a major cause of morbidity & mortality after heart transplantation (HT). Patients who have undergone Fontan palliation may have a higher susceptibility to post HT infections given thymectomy in infancy and known depletions of T-cell subsets.
METHODS:
This was a single-center, retrospective cohort analysis of pediatric patients undergoing HT for dilated cardiomyopathy (DCM) or failing Fontan physiology, who underwent post HT induction with anti-thymoglobulin (ATG). Repeat HTs and multi organ transplants were excluded. The primary endpoint was infection in the first 180 days post HT, defined as 1) positive blood, urine, or respiratory culture; 2) positive viral PCR (excluding CMV and EBV); 3) skin or wound infection; or 4) culture-negative infection if a full antibiotic course (? 5 days) was completed. Secondary endpoints included sensitivity to ATG as defined by 1) absolute lymphocyte (ALC) and CD3 counts after 5 doses; 2) the incidence of post transplant lymphoproliferative disorder (PTLD); and 3) rejection (>/= Grade 2R ACR or pAMR2) in the first 180 days post HT.
RESULTS:
From 1/2014 to 9/2019, 63 patients (30 Fontan, 33 DCM) underwent HT at a median of 15.4 (IQR 10.8, 20.1) and 11.7 (IQR 1.4, 13.6) years, respectively. The median total ATG received was 7.5 (IQR 6.7, 8.2) mg/kg vs 7.2 (IQR 4.7, 9.2) mg/kg (p=NS), respectively. The median CD3 [9 (IQR 3,14) vs 12 (IQR 6, 26); p=0.04, Figure 1A] and lymphocyte counts [172 (IQR 98, 354) vs 427 (IQR 205, 662); p=0.02] after ATG were lower in Fontan vs DCM patients. 28 patients (41%) developed at least one infection within 180 days after HT, with a higher rate of infection in Fontan patients (60% vs 24%, p=0.005; Figure 1B). There was no difference in the incidence of PTLD (10% vs 0%; p=0.1) or rejection (17% vs 27%; p=0.31) between Fontan vs DCM patients, respectively.
CONCLUSION:
Compared to DCM patients, Fontan patients have a more pronounced suppression of CD3 counts after induction, as well as a higher risk of infection.
Copyright © 2020. Published by Elsevier Inc.
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High Dosage of Carvedilol is Effective to Induce Remodeling and Improve of Survival in Children with Dilated Cardiomyopathy.
J Heart Lung Transplant2020 Apr;39(4S):S451. doi: S1053-2498(20)30295-3.
Adorisio R, Cantarutti N, Cicenia M, Drago F,
Abstract
PURPOSE:
We aim to evaluate clinical outcomes, echocardiographic changes, heart rate (HR) modifications and side effects in children with dilated cardiomyopathy (DCM) and chronic heart failure (HF) treated by high dosage of carvedilol.
METHODS:
We prospectively enrolled pediatric patients with DCM and ventricular dysfunction (EF <45%) referred to our institute. All enrolled patients were treated with high dosage of carvedilol coupled to heart failure therapy (ace inhibitors; diuretics, aldosterone blockade) in order to achieve a reduction of heart rate > 20% from baseline. Conventional treatment should be started from at least 1 month. Initial dosage of carvedilol was 0.1 mg/kg/day, up-titrated every 2 weeks to a maximum dose of 1 mg/kg/day. All data were compared to an historical control group treated with low dose of carvedilol or without beta-blockers. Data were collected before and after one year of maximum tolerated treatment.
RESULTS:
65 patients (58% male) were enrolled, mean age was 13.4 +/- 9 years. 72 patients (48% male) were enrolled in the control group, mean age was 3.9 +/- 3.7. Mean duration of treatment was 50 months. HR reduction and EF improvement were statistically significant after treatment (mean HR reduction was 23%, p<0,0001; mean EF improvement 11,9%, p<0,0001); as well as decrease in LV diameters (p=0.001), volumes (p=0.029) and BNP levels (p=0.029) compared to control group. All patients survived, and 4 out of 4 were delisted from transplant list; on the contrary 32 patients of group 2 were transplanted and 11 died. Blood pressure remained stable for all patients treated with carvedilol and no side effects were recorded.
CONCLUSION:
High dosage of carvedilol up-titrated to achieve a reduction of heart rate of 20%, in addition to standard therapy, significantly improve ventricular function and survival in pediatric patients with DCM.
Copyright © 2020. Published by Elsevier Inc.
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Outcomes in Patients with Smaller Left Ventricular End Diastolic Diameter Following HeartMate 3 (HM3) Left Ventricular Assist Device (LVAD) Implantation.
J Heart Lung Transplant2020 Apr;39(4S):S434. doi: S1053-2498(20)30250-3.
Molina E J, Sheikh F H, Ahmed S, Rodrigo M E, Hofmeyer M, Kadakkal A, Mohammed S F, Lam P H, Kitahara H, Najjar S S,
Abstract
PURPOSE:
Outcomes in patients with small left ventricular end diastolic diameter (LVEDD) following HM3 LVAD implantation have not been well characterized. We sought to compare the clinical outcomes of patients with small LVEDD to those with dilated left ventricles.
METHODS:
Patients who received a HeartMate 3 LVAD at our institution between October 1, 2015 and June 30, 2019 were analyzed. Patients who received a HM3 LVAD as a pump exchange were excluded. The cohort was divided in 2 groups: smaller LVEDD (?60 mm in males and ?58 mm in females) and larger LVEDD (>60 mm in males and >58 mm in females).
RESULTS:
One hundred and nineteen patients underwent HeartMate 3 LVAD implantation at our institution. Patients in the smaller LVEDD group (n: 22) had a mean LVEDD of 55.7±5 mm and patients in the larger LVEDD group had a mean LVEDD of 70.6±8 mm (p=<0.0001). Patients in the smaller LVEDD group tended to be older (60±11 vs 56±11 years, p=0.07), and included more males (82% vs. 68%, p=0.3) and fewer African-Americans (59% vs. 79%, p=0.08). Patients in the smaller LVEDD group were more likely to have a history of ischemic cardiomyopathy (50% vs. 23%, p=0.01), CAD (82% vs. 30%, p<0.001)) and diabetes (73% vs. 47%, p=0.03). INTERMACS class 1?+?2 was similar between groups (72% vs. 68%, p=0.9). Mean days on the ventilator (2.4±3 vs. 3.2±5 days, p=0.5), on inotropes (16±12 vs. 15±8 days, p=0.69) and vasopressors (9±9 vs. 7±11 days, p=0.6) was similar between groups. Mean length of stay (25±14 vs. 29±17 days, p=0.2) and readmissions days (25±52 vs. 27±46 days, p=0.8) were also similar. One-year survival was 90% for the smaller LVEDD group and 95% for the larger LVEDD group (Figure, log rank 0.696).
CONCLUSION:
Adult patients with smaller LVEDD who received a HeartMate 3 LVAD have comparable clinical outcomes to patients with larger LVEDD. A small left ventricle should not be a contraindication to implantation of this particular durable device in adult patients.
Copyright © 2020. Published by Elsevier Inc.
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Cerebrovascular Events in Pediatric Population on Intracorporeal Continuous-Flow Ventricular Assist Devices: Single Center Experience.
J Heart Lung Transplant2020 Apr;39(4S):S409. doi: S1053-2498(20)30184-4.
Sert D E, Kocabeyoglu S S, Karahan M, Beyazal O F, Akdi M, Yilmaz A, Kervan U,
Abstract
PURPOSE:
Continuous flow intracorporeal left ventricular assist devices(CF-LVAD) are used more frequently in pediatric population. One of the major complications of CF-LVAD includes cerebrovascular events(CVE) and little is known about this complication in pediatric patients.
METHODS:
We performed a retrospective, single center review of 21 patients younger than 19 years of age who underwent CF-LVAD implantation between June 2014 and September 2018. Patients on biventricular support, extracorporeal device were excluded. Cerebrovascular accidents-ischemic or hemorrhagic-were investigated. CVE was confirmed by brain computed tomographic scan. Target international normalized ratio was 2.0-3.0.
RESULTS:
Of twenty-one pediatric patients, 11 was male. Mean BSA was 1.05±0.41(0.77-1.78) m2 and mean age was 11.05±4.07 years. Dilated cardiomyopathy was the leading cause of heart failure. The patients were implanted HeartWare hVAD (Heartware Ltd, Framingham, MA, USA n=19), Heartmate II(Thoratec Corp., Pleasanton, CA, USA n=1) and Heartmate III (n=1). Mean follow-up time was 421±448(18-1460) days. Nine(43%) patients underwent transplantation, 1 patient recovered with subsequent device explantation. Four(17%) patients were still on support. One patient(5%) died in early postoperative period and 6(28%) patients died on VAD support after mean duration of 194 days. There were overall 5 cerebral hemorrhagic strokes in 4 patients(0.2 events per patient-year). CVA occurred between 250 and 1320 days(mean 600 days). No ischemic stroke was documented. Only one(20%) patient died after hemorrhagic stroke; other 3 patients recovered and were discharged from the hospital with minor sequelaes.
CONCLUSION:
Incidence of CVE in children on CF-LVAD is relatively low compared with adults on VAD and severity of stroke is milder than adult population.
Copyright © 2020. Published by Elsevier Inc.
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Clinical Utility of Using Next Generation Sequencing in Life Threatening Ventricular Arrhythmia.
J Heart Lung Transplant2020 Apr;39(4S):S360. doi: S1053-2498(20)30449-6.
Akilzhanova A, Guelly C, Abilova Z, Rakhimova S, Akhmetova A, Kairov U, Kozhamkulov U, Nuralinov O, Abdrakhmanov A, Akilzhanova S, Trajanoski S, Bekbosynova M, Zhumadilov Z,
Abstract
PURPOSE:
Ventricular fibrillation (VF) and ventricular tachycardia (VT) are major causes of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (iVT). Recent achievements in molecular genetics has unveiled the complex molecular basis of many cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. We aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias using targeted next-generation sequencing (NGS) approach in Kazakhstani patients with arrhythmias.
METHODS:
The study included 92 Kazakhstani patients (mean age of 31.2 years at the time of the VT event), diagnosed with iVT, VT and coronary heart disease (CHD), VT and dilated cardiomyopathy (DCM). We developed a targeted panel of 96 known cardiac disease genes, associated with cardiomyopathy and arrhythmia.
RESULTS:
We observed 168 mutations (61 distinct) listed in the Human Genome Mutation Database and another 256 rare/unique variants with elevated pathogenic potential. Also we analyzed observed mutations according to ACMG guidelines. The majority of VT/CHD patients carried known mutations and rare variants with high pathogenetic potential in the same genes and at a comparable frequency as observed for VT/DCM and iVT patients. The most abundant mutations observed for the CHD group locate to MYBPC3, DMD, LAMA2, MYH6 and GAA. A subset of patients originally diagnosed with iVT carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies.
CONCLUSION:
Our study indicates that individuals presenting with VT either secondary to CHD, DCM or of idiopathic etiology carry multiple rare mutations and potentially pathogenic sequence variants in classical cardiac risk genes in a similar pattern and at a comparable frequency. Molecular genetic testing of patients with life-threatening ventricular arrhythmia with NGS identifies a molecular-genetic cause in a significant proportion of patients.
Copyright © 2020. Published by Elsevier Inc.
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Dysregulation of H11 Kinase in the Failing Human Left Ventricular Myocardium.
J Heart Lung Transplant2020 Apr;39(4S):S357. doi: S1053-2498(20)30442-3.
Gupta R C, Singh-Gupta V, Sabbah H N,
Abstract
PURPOSE:
Mitochondrial dysfunction and ongoing cardiomyocyte loss from apoptosis contribute to the progressive LV dysfunction characteristic of the heart failure (HF) state. H11 kinase (H11K) is a 22-kD serine/threonine kinase protein abundantly expressed in the heart. Dysregulation of H11K occurs in HF but its potential contribution to the progression of HF is not fully understood. Cardiac deletion of H11K in mice with LV pressure overload has been shown to result in LV dilation, reduced hypertrophy, impaired contractile function, increased interstitial fibrosis and faster transition to HF. In this study, we examined the expression of H11K in LV myocardium and separately in cytosolic and mitochondrial fractions of explanted failing human hearts.
METHODS:
Sodium-dodecyl sulfate (SDS) extracts were prepared from LV tissue of 7 explanted failed human hearts due to idiopathic dilated cardiomyopathy (IDC), 7 due to ischemic cardiomyopathy (ICM) and of 7 non-failing human donor hearts (DNR). Western blotting and specific antibodies were used to assess protein levels of H11K normalized to the internal control GAPDH in homogenate and cytosolic fractions and protein levels of H11K normalized to the internal control porin in mitochondrial fractions.
RESULTS:
There were no differences in GAPDH and porin among the 3 groups. H11K protein levels were significantly increased in LV homogenate and cytosolic fractions but significantly decreased in mitochondrial fractions of both IDC and ICM failed human hearts compared to DNR hearts (Table).
CONCLUSION:
The failing human LV manifests increased H11K protein levels independent of HF etiology. The reduced H11K protein level in mitochondria and its increase in the cytosolic compartment of failing cardiomyocytes represents an adverse maladaptation capable of reducing ATP synthesis by mitochondria and activation of cardiomyocyte pro-apoptotic cell death pathways in the cytosol respectively thus likely contributing to the progression of HF.
Copyright © 2020. Published by Elsevier Inc.
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Real World Experience with the HeartMate 3 (HM3) Left Ventricular Assist Device (LVAD): Analysis of the First 125 Consecutive Patients at a Single Institution.
J Heart Lung Transplant2020 Apr;39(4S):S338. doi: S1053-2498(20)30390-9.
Molina E J, Najjar S S, Ahmed S, Rodrigo M E, Hofmeyer M, Kadakkal A, Mohammed S F, Lam P H, Kitahara H, Sheikh F H,
Abstract
PURPOSE:
Excellent outcomes following HM3 LVAD implantation have been reported in the setting of a large multicenter randomized controlled trial. Real world experience reports with this device are still limited. We sought to review our experience with this fully magnetically levitated LVAD.
METHODS:
The first 125 consecutive patients who received a HM3 LVAD at our institution from October 1, 2015 to August 30, 2019 were analyzed. Pump exchange procedures were excluded. We investigated clinical outcomes including survival and the development of postoperative complications.
RESULTS:
All devices were implanted via median sternotomy. Mean patient age was 57.5 ± 11 years, 72 % were males and 74% African-Americans. Idiopathic dilated cardiomyopathy was the most common diagnosis (73%). 67 % of the patients were INTERMACS profiles 1 or 2. 19 % of devices were implanted as bridge to transplant and 59% as destination therapy. Mean body-mass index at the time of implant was 30.5 ± 8 Kg/m. Mean creatinine level was 1.29 ± 0.4 mg/dl and mean bilirubin was 1.45 ± 1.6 mg/dl. The mean length of stay during index admission for LVAD was 30 ± 17 days and the mean follow-up time was 411 ± 34 days. The rate of complications measured as EPPY was 0.42 for GI bleeding, 0.03 for ischemic stroke, 0.01 for hemorrhagic stroke, 0 for clinically suspected pump thrombosis or confirmed pump thrombosis, 0.22 for LVAD related infection, 0.16 for other systemic infection and 0.59 for acute heart failure. Survival was estimated at 96%, 91%, 88%, 81% and 74% at 30-day, 90-day, 1-year, 2-year, and overall 3-year follow-up, respectively (Figure).
CONCLUSION:
In this single center, real world experience, HeartMate 3 implantation was associated with excellent survival comparable to those demonstrated in a recent clinical trial. The incidence of complications was also low, including no episodes of suspected or confirmed pump thrombosis.
Copyright © 2020. Published by Elsevier Inc.
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Patient Outcomes after Heart Transplantation in Sweden between 1988 and 2017: Continuous Improvement in Survival.
J Heart Lung Transplant2020 Apr;39(4S):S284. doi: S1053-2498(20)30643-4.
Esmaily S, Dellgren G, Bobbio E, Nilsson J, Rådegran G, Braun O, Gjesdal G, Löfman I, Melin M, Karason K,
Abstract
PURPOSE:
To investigate the survival of heart transplant (HTx) recipients during different time periods in Sweden. We hypothesized that the survival for HTx recipients has improved following advancements in the management of these patients.
METHODS:
Data was obtained through the database of the organ exchange organization Scandiatransplant. All patients who underwent HTx in Sweden between Jan 1988 and Dec 2017 were included. Patients were divided into five cohorts of six-year periods each.
RESULTS:
A total of 1137 HTx recipients were included. Main causes of transplantation were dilated cardiomyopathy (44 %) and ischemic heart disease (18 %). Retransplantation constituted a small portion of the overall total (2 %). The cohorts were similar in terms of age and gender, while later cohorts had higher BMI, lower GFR and longer ischemia time (Tab. 1). The later cohorts received organs from older donors (Tab. 1). The amount of heart transplantations performed in Sweden has increased with time (Tab. 1). Log-rank test comparing the survival curves was able to show improved survival during later eras (Fig. 1).
CONCLUSION:
Survival among HTx recipients has significantly improved in Sweden over time, despite less favorable recipients and donor characteristics. This was related to both reduced postoperative mortality and also improved long-time survival.
Copyright © 2020. Published by Elsevier Inc.
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Heart Transplant Outcomes for Patients with Myocarditis.
J Heart Lung Transplant2020 Apr;39(4S):S261. doi: S1053-2498(20)30585-4.
Li J P, Kingsford P, Grazette L, Nattiv J, Liu G S, Genyk P A, Lum C, Vucicevic D, Pandya K, Fong M, Banankhah P, DePasquale E C, Vaidya A S,
Abstract
PURPOSE:
Myocarditis is a known etiology of both acute fulminant heart failure and chronic dilated cardiomyopathy requiring heart transplantation. We sought to evaluate the long-term post-transplant outcomes of pts with myocarditis.
METHODS:
We evaluated the UNOS registry for all heart transplant (HT) recipients from 1987 to 2019. Comparisons between pt characteristics of HT recipients with myocarditis (N=649) and HT recipients without a diagnosis of myocarditis (N=62,493) are reported using standard statistical methods including Cox proportional hazards regression for survival analysis.
RESULTS:
Myocarditis HT recipients were younger (29.6 ± 20.7 vs. 46.8 ± 19.1, p<0.001) and more likely to be female (44.1% vs. 26.0%, p<0.001). Myocarditis HT recipients were less likely to be DM (6.6% vs. 20.7%, p<0.001) and to have undergone prior cardiac surgery (7.6% vs. 18.4%, p<0.001). In terms of transplant related factors, myocarditis HT recipients were likely to receive a younger donor (23.3 ± 15.0 vs. 28.3 ± 13.9, p<0.001) and have shorter ischemic times (p<0.001). Prior to transplant, the myocarditis HT recipients were a sicker cohort and more likely to require ECMO [6.0% vs. 1.0%, p<0.001), VAD support (34.4% vs. 25.0%, p<0.001), and MV (13.4% vs. 4.2%, p<0.001). Median (interquartile range) time on the wait list was significantly shorter for myocarditis HT recipients [37.0 (12.0, 100.0) days vs. 83.0 (26.0, 231.0) days, p<0.001]. There was a lower overall post-transplant mortality in the myocarditis HT recipients (26.0% vs. 34.2%, p<0.001).
CONCLUSION:
Myocarditis HT recipients tend to be a younger population with less underlying co-morbidities such as DM and prior cardiac surgery, but they are more likely to be more acutely sick at the time of heart transplantation requiring mechanical ventilation, ECMO, or VAD support. Myocarditis HT recipients have shorter organ wait times and have more favorable transplant related factors, and ultimately have a lower overall mortality compared to recipients without myocarditis.
Copyright © 2020. Published by Elsevier Inc.
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The Predictive Scoring Systems for Outcomes of Heart Transplantation in Patients with Pre-Existing Liver Cirrhosis.
J Heart Lung Transplant2020 Apr;39(4S):S257-S258. doi: S1053-2498(20)30576-3.
Kim H, Kim J, Joo H, Lee S, Lee S, Yoo K, Youn Y,
Abstract
PURPOSE:
There are few data assessing factors and clinical outcomes in patients with liver cirrhosis for heart transplantation. The aim of this study was to compare the Model for End-Stage Liver Disease (MELD) score, the MELD-XI score and Child-Turcotte-Pugh (CTP) score risk prediction in cirrhotic patients undergoing heart transplantation.
METHODS:
Between 1994 and 2018, forty-nine consecutive patients (19 men and 30 women, median age 46 years, range 12-68 years) had liver cirrhosis, among 170 patients underwent heart transplantations in our institution. Potential preoperative predictors of outcomes, as well as preoperative MELD score, MELD-XI score and CTP classification were calculated.
RESULTS:
Causes of heart failure were dilated cardiomyopathy in 26, ischemic disease in 7, congenital heart disease in 6 and valvular heart disease 7 patients. Cause of liver cirrhosis was majority of cardiac origin, except hepatitis in two and alcoholism in one patient. The median follow-up duration was 45.2 months. The MELD score (p=0.010) and MELD-XI score (p=<0.001) were significantly differed between survivors and non-survivors. Cox regression analysis showed high MELD score (HR 1.211; 95% CI, 1.059-1.386; p=0.005), MELD-XI score (HR, 1.184; 95% CI, 1.042-1.345; p=0.010) and CTP score (HR, 1.694; 95% CI, 1.040-2.760; p=0.034) were associated with the risk of all-cause mortality. Receiver operating characteristic (ROC) curve analysis revealed the optimal cut-off value of MELD, MELD-XI and CTP score was 12.2, 12.0 and 7.5, respectively (sensitivity: 69.2 vs. 61.5 vs. 69.2%, specificity 68.6 vs. 60.0 vs. 62.9%) for all-cause mortality (AUC: 0.745 vs. 0.690, 0.729).
CONCLUSION:
The patients with advanced heart failure and liver cirrhosis were high mortality and morbidity of heart transplantation. However, these scoring systems can be a tool to risk-stratification for liver cirrhotic patients undergoing heart transplantation.
Copyright © 2020. Published by Elsevier Inc.
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