End-stage Dilated Cardiomyopathy Research Articles

Association between anti-cardiac autoantibodies in acute myocarditis and downstream clinical outcomes

Abstract Introduction Myocarditis is an inflammatory heart muscle disease that can result in cardiac dysfunction and arrhythmias. Its aetiology includes infectious, toxic or autoimmune causes. Myocarditis is responsible for sudden cardiac death in young adults (1) and can result in heart failure due to dilated cardiomyopathy in 20% of patients (2). The pathogenesis of myocarditis may involve immune system dysregulation leading to a cascade of inflammation and myocardial damage (3). For those patients that rapidly progress to end-stage dilated cardiomyopathy, an important dilemma is whether there is any prospect of heart function recovery. Therefore, there is an unmet need for a better understanding of key causal pathways and for developing a biological signature of disease progression. Hypothesis The progression of acute myocarditis depends on a persistent adaptive immune response against the heart, leading to ongoing inflammation, myocardial fibrosis and ultimately tissue destruction and remodelling. Aims We sought to explore anti-cardiac IgG serum levels, their temporal profile throughout follow up and their association with clinical and imaging data, in patients presenting with acute myocarditis. Methods We prospectively recruited 80 patients with a clinical diagnosis of acute myocarditis. We measured their total anti-cardiac IgG levels at admisssion, 3- and 12-months follow-up using an enzyme-linked immunosorbent assay (ELISA). We explored the association between the anti-cardiac IgG levels, cardiac MRI parameters (CMR) and clinical data. Results We detect an adaptive immune response against the heart in a subgroup of patients with acute myocarditis. 20% of patients develop high systemic titres of anti-cardiac IgG (OD threshold >0.65), within the first 7 days of presentation (Figure 1a). These patients continue to have persistent and significantly higher anti-cardiac IgG levels at 12 months (Figure 1b). Importantly, patients that mount a strong initial adaptive immune response against the heart, are more likely to show evidence of persistent oedema on CMR at 12 months(Figure 1c). Clinical event rates in our cohort have remained low at five-year follow-up. A small signal exists to indicate potentially higher rates of persistent symptoms (70% vs 47%), hospitalisations for heart failure (12% vs 8%) and new heart failure diagnosis (18% vs 11%), in patients that mount a strong adaptive immune response compared to those that do not. Conclusion A subset of patients with acute myocarditis develops a strong and persistent adaptive immune response against the heart. This may be associated with more myocardial oedema on cardiac MRI, persistent symptoms and higher rates of heart failure diagnoses and hospitalisations. Further work Plasma proteomics (targeted and un-targeted discovery) with validation in myocardial tissue. Analysis of CMR data with a focus on fibrosis assessment. ELISA for IgG subtypes and total IgG against myosin and troponin I.

Starting Pediatric VAD Program: Transforming Challenges into Opportunities; A Case Series of a Single Center

Background: The prevalence of heart failure is constantly increasing in both children and adults. End-stage heart failure in children unresponsive to medical therapy has limited treatment options. Surgical options include heart transplantation or implantation of durable ventricular assist devices (VADs). To start the VAD program, it was necessary to train core team members, invite experienced proctors and adjust the organizational approach. Methods: We present our first seven pediatric patients who underwent a VAD implantation with primary indication end-stage dilated cardiomyopathy. Results: The median age on implant was four and a half years and the median duration of VAD support was 39 days with long term survival achieved in three patients. The causes of death were multiorgan failure, thromboembolic events, sepsis, and low cardiac output syndrome. Ischemic stroke was the reason for successful neurointervention during VAD support in two patients. Conclusions: To establish a VAD program, numerous specialties must be included with adequate training and learning for all team members.

COX5A Alleviates Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress, Mitochondrial Dysfunction and Cardiomyocyte Apoptosis.

Doxorubicin (DOX) as a chemotherapeutic agent can cause mitochondrial dysfunction and heart failure. COX5A has been described as an important regulator of mitochondrial energy metabolism. We investigate the roles of COX5A in DOX-induced cardiomyopathy and explore the underlying mechanisms. C57BL/6J mice and H9c2 cardiomyoblasts were treated with DOX, and the COX5A expression was assessed. An adeno-associated virus serum type 9 (AAV9) and lenti-virus system were used to upregulate COX5A expression. Echocardiographic parameters, morphological and histological analyses, transmission electron microscope and immunofluorescence assays were used to assess cardiac and mitochondrial function. In a human study, we found that cardiac COX5A expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to the control group. COX5A was significantly downregulated following DOX stimulation in the heart of mice and H9c2 cells. Reduced cardiac function, decreased myocardium glucose uptake, mitochondrial morphology disturbance, reduced activity of mitochondrial cytochrome c oxidase (COX) and lowered ATP content were detected after DOX stimulation in mice, which could be significantly improved by overexpression of COX5A. Overexpression of COX5A effectively protected against DOX-induced oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, the phosphorylation of Akt (Thr308) and Akt (Ser473) were also decreased following DOX treatment, which could be reserved by the upregulation of COX5A. Furthermore, PI3K inhibitors abrogated the protection effects of COX5A against DOX-induced cardiotoxicity in H9c2 cells. Thus, we identified that PI3K/Akt signaling was responsible for the COX5A-mediated protective role in DOX-induced cardiomyopathy. These results demonstrated the protective effect of COX5A in mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis, providing a potential therapeutic target in DOX-induced cardiomyopathy.

Cardiac iron overload in pediatric oncology and bone marrow transplant survivors.

e22022 Background: Cardiovascular late effects are a leading cause of mortality and morbidity in childhood cancer and Bone Marrow Transplant (BMT) survivors. In patients receiving chronic red blood cell transfusions, excess iron may be deposited in the liver, heart, and pituitary gland. Iron overload cardiomyopathy is characterized as a restrictive physiology with early diastolic dysfunction ultimately progressing to end-stage dilated cardiomyopathy. Iron loading in the heart can also lead to arrhythmias and increase myocardial ischemia reperfusion injury due to increased formation of reactive oxygen species. It is not yet known whether high transfused packed red blood cell (PRBC) volumes in cancer and BMT patients leads to cardiac iron deposition, and whether iron-induced cardiac injury contributes to the known cardiovascular late effects in these patients. Methods: 83 childhood cancer and BMT survivors with elevated serum ferritin levels and subsequent liver Magnetic Resonance (MR) imaging were identified. 18 patients (21.7%) who had liver iron content of > 12mg/g (mean 16.0 ± 7.36 mg/g) also underwent Cardiac MRI (CMR) to determine cardiac iron content. Results: Median transfused blood volume was 393 ml/kg [95% Confidence Interval (CI) 170-780 ml/kg]. All 18 patients had at least one echocardiogram showing normal ventricular ejection fractions [mean 65.1 ± Standard Deviation (SD) 3.53%] and normal shortening fractions (mean 35.4 ± 3.67%). All patients had myocardial iron content within normal ranges (T2* relaxation time mean 35.1 msec ± 7.1 [normal >20 msec], mean ± SD iron content 0.63± 0.2 mg/g dry weight, range 0.5-1.1). There was no association of cardiac iron content with transfused blood volume, anthracycline dose (mg/m2) or liver iron content (Pearson Correlation Coefficients 0.27, 0.29 and 0.89 respectively). Conclusions: Childhood cancer and BMT patients receive multiple PRBC transfusions to treat symptomatic anemia. It is currently unknown whether excess iron deposition in the heart contributes to the cardiac effects of impaired diastolic function and ultimately systolic dysfunction. In this study, 11 of 18 patients (61.1%) with high levels of liver iron had at least 1 other risk factor for the development of future cardiac dysfunction (either anthracycline exposure, radiation to the chest or total body irradiation or both). Larger studies are needed to determine whether oncology patients with high levels of iron deposition in their liver are also at risk for clinically significant cardiac iron loading, and what risk factors may exist for elevated myocardial iron content.

Late left ventricular myocardial remodeling after pulmonary artery banding for end-stage dilated cardiomyopathy in infants: an imaging study

BackgroundUnderstanding the macroscopic biventricular changes induced by pulmonary artery banding (PAB) in children with dilated cardiomyopathy (DCM) represents the first step to unraveling the regenerative potential of the myocardium. We herein investigated the phases of left ventricular (LV) rehabilitation in PAB responders, using a systematic echocardiographic and cardiac magnetic imaging (CMRI) surveillance protocol. MethodsWe prospectively enrolled all patients with DCM treated with PAB from September-2015 at our institution. Among 9 patients, 7 positively responded to PAB and were selected. Transthoracic 2D echocardiography was performed before PAB; and 30, 60, 90, and 120 days after PAB; and at the last available follow-up. CMRI was performed before PAB (whenever possible) and one year after PAB. ResultsIn PAB responders, LV ejection fraction showed a modest 10% increase 30–60 days after PAB, followed by its almost complete normalization after 120 days (median of 20[10–26]% vs 56[44.5–63.5]%, at baseline and 120 days after PAB, respectively). Parallelly, the LV end-diastolic volume decreased from a median of 146(87–204)ml/m2 to 48(40–50)ml/m2. At the last available follow-up (median of 1.5 years from PAB), both echocardiography and CMRI showed a sustained positive LV response, although myocardial fibrosis was detected in all patients. ConclusionsEchocardiography and CMRI show that PAB can promote a LV remodeling process, which starts slowly and can culminate in the normalization of LV contractility and dimensions 4 months later. These results are maintained up to 1.5 years. However, CMRI showed residual fibrosis as evidence of a past inflammatory injury whose prognostic significance is still uncertain.

Alterated gene expression in dilated cardiomyopathy after left ventricular assist device support by bioinformatics analysis.

Heart transplantation is the best treatment for end-stage dilated cardiomyopathy (DCM). Left ventricular assist device (LVAD) support is becoming more prevalent and may delay heart transplantation. Gene expression of the left ventricular myocardium usually changes following LVAD implantation. In this study, we aimed to identify potential biomarkers to determine the prognosis of patients with DCM after receiving LVAD support. We extracted microarray datasets from Gene Expression Omnibus (GEO), including GSE430 and GSE21610. There were 28 paired DCM samples in the GSE430 and GSE21610 profiles. Differentially expressed genes (DEGs) were identified at LVAD implantation and heart transplantation. DEGs were annotated according to Gene Ontology (GO) and analyzed according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A protein-protein interaction (PPI) network was constructed. The top 10 crucial genes were predicted using Cytoscape plugin CytoHubba in conformity with the network degree algorithm. The levels of gene expression and the diagnostic values of crucial genes were confirmed in the clinical datasets. The 28 DEGs were clustered into the GSE datasets. GO annotations and KEGG pathway enrichment analyses revealed that inflammation might be involved. They were associated with correlative inflammation. Combined with PPI networks, these results revealed CytoHubba's top 10 hub genes, including CCL2, CXCL12, CXCL1, CTGF/CCN2, CX3CR1, POSTN, FKBP5, SELE, AIF1, and BMP2. Among them, CCL2, CXCL12, FKBP5, and BMP2 might be considered prognostic and diagnostic biomarkers after LVAD support and have confirmed their validity in clinical datasets. The area under the curve of the four main hub genes was more than 0.85, indicating high diagnostic ability and good prognosis for patients with DCM with LVAD implantation. However, a significant effect of CCL2, CXCL12, FKBP5, and BMP2 expression was not observed on the left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), cardiac index (CI), or support time of LVAD. CCL2, CXCL12, FKBP5, and BMP2 could be potential gene biomarkers for patients with DCM after LVAD support. These findings provide critical clues for the therapeutic management of patients with DCM and LVADs. LVEDD, LVEF, CI, and support time of LVAD were not correlated with the expression of these hub genes.

Clustering of Cardiac Transcriptome Profiles Reveals Unique: Subgroups of Dilated Cardiomyopathy Patients

Dilated cardiomyopathy is a heterogeneous disease characterized by multiple genetic and environmental etiologies. The majority of patients are treated the same despite these differences. The cardiac transcriptome provides information on the patient's pathophysiology, which allows targeted therapy. Using clustering techniques on data from the genotype, phenotype, and cardiac transcriptome of patients with early- and end-stage dilated cardiomyopathy, more homogeneous patient subgroups are identified based on shared underlying pathophysiology. Distinct patient subgroups are identified based on differences in protein quality control, cardiac metabolism, cardiomyocyte function, and inflammatory pathways. The identified pathways have the potential to guide future treatment and individualize patient care.

Time course, factors related to, and prognostic impact of venoarterial extracorporeal membrane flow in cardiogenic shock.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is currently one of the most used devices in refractory cardiogenic shock. However, there is a lack of evidence on how to set the 'optimal' flow. We aimed to describe the evolution of VA-ECMO flows in a cardiogenic shock population and determine the risk factors of 'high-ECMO flow'. A 7year database of patients supported with VA-ECMO was used. Based on the median flow during the first 48h of the VA-ECMO run, patients were classified as 'high-flow' or 'low-flow', respectively, when median ECMO flow was ≥3.6 or <3.6L/min. Outcomes included rates of ventilator-associated pneumonia, ECMO-related complications, days on ECMO, days on mechanical ventilation, intensive care unit and hospitalization lengths of stay, and in-hospital and 60day mortality. Risk factors of high-ECMO flow were assessed using univariate and multivariate cox regression. The study population included 209 patients on VA-ECMO, median age was 51 (40-59) years, and 78% were males. The most frequent aetiology leading to cardiogenic shock was end-stage dilated cardiomyopathy (57%), followed by acute myocardial infarction (23%) and fulminant myocarditis (17%). Among the 209 patients, 105 (50%) were classified as 'high-flow'. This group had a higher rate of ischaemic aetiology (16% vs. 30%, P=0.023) and was sicker at admission, in terms of worse Simplified Acute Physiology Score II score [40 (26-58) vs. 56 (42-74), P<0.001], higher lactate [3.6 (2.2-5.8) mmol/L vs. 5.2 (3-9.7) mmol/L, P<0.001], and higher aspartate aminotransferase [97 (41-375) U/L vs. 309 (85-939) U/L, P<0.001], among others. The 'low-flow' group had less ventilator-associated pneumonia (40% vs. 59%, P=0.007) and less days on mechanical ventilation [4 (1.5-7.5) vs. 6 (3-12) days, P=0.009]. No differences were found in lengths of stay or survival according to the ECMO flow. The multivariate analysis showed that risk factors independently associated with 'high-flow' were mechanical ventilation at cannulation [odds ratio (OR) 3.9, 95% confidence interval (CI) 2.1-7.1] and pre-ECMO lactate (OR 1.1, 95% CI 1.0-1.2). In patients with refractory cardiogenic shock supported with VA-ECMO, sicker patients had higher support since early phases, presenting thereafter higher rates of ventilator-associated pneumonia but similar survival compared with patients with lower flows.

Clinical Case 26—Is it possible to live with thrombosed left ventricular assist device (LVAD)?

Abstract LVAD HeartWare was implanted in a 63-year-old patient with end-stage dilated cardiomyopathy. The postoperative course was complicated by massive gastrointestinal (GI) bleeding that required surgical exploration of the GI tract. For the next 1.5 years, the patient has significantly improved functional capacity with proper LVAD function. A month before the incident, an alarm indicating a pump malfunction was recorded. The patient presents with congestive symptoms and an altered sound of LVAD. Laboratory indicates seven times elevated LDH values, low HGB and INR 3.03. Thrombophilia tests were negative. Echo examination does not indicate pump thrombosis, but the pump parameters show increased energy consumption (&amp;gt;6 W) and increased flow (&amp;gt;7 L/min). A diagnosis of LVAD thrombosis was made. Fibrinolytic therapy was contraindicated because of a history of GI bleeding, so a continuous infusion of heparin was started. Despite this, the patient's clinical condition deteriorates, and a decision was made to discontinue the LVAD, to prevent further hemolysis that led to acute kidney injury (AKI). The procedure was performed without endangering the patient. Massive hemolysis, however, leads to the progressive development of AKI requiring CVVHDF. Global respiratory insufficiency develops and mechanical ventilation was started. After six days of intensive treatment, the patient recovered and was discharged home with a thrombosed pump. For the next 2.5 years, the patient was in satisfactory condition during follow-ups, the pump was not explanted. Even sophisticated medical devices carry with them risks for the patient's life despite adequate management. Treatment of LVAD thrombosis depends on patient characteristics and pump-related factors.

Pulmonary Artery Banding for Dilated Cardiomyopathy in Children: Returning to the Bench from Bedside.

Current treatment paradigms for end-stage dilated cardiomyopathy (DCM) in children include heart transplantation and mechanical support devices. However, waitlist mortality, shortage of smaller donors, time-limited durability of grafts, and thrombo-hemorrhagic events affect long-term outcomes. Moreover, both these options are noncurative and cannot preserve the native heart function. Pulmonary artery banding (PAB) has been reinvented as a possible “regenerative surgery” to retrain the decompensated left ventricle in children with DCM. The rationale is to promote positive ventricular–ventricular interactions that result in recovery of left ventricular function in one out of two children, allowing transplantation delisting. Although promising, global experience with this technique is still limited, and several surgical centers are reluctant to adopt PAB since its exact biological bases remain unknown. In the present review, we summarize the clinical, functional, and molecular known and supposed working mechanisms of PAB in children with DCM. From its proven efficacy in the clinical setting, we described the macroscopic geometrical and functional changes in biventricular performance promoted by PAB. We finally speculated on the possible underlying molecular pathways recruited by PAB. An evidence-based explanation of the working mechanisms of PAB is still awaited to support wider adoption of this surgical option for pediatric heart failure.

Transcriptomic Signatures of End-Stage Human Dilated Cardiomyopathy Hearts with and without Left Ventricular Assist Device Support.

Left ventricular assist device (LVAD) use in patients with dilated cardiomyopathy (DCM) can lead to a differential response in the LV and right ventricle (RV), and RV failure remains the most common complication post-LVAD insertion. We assessed transcriptomic signatures in end-stage DCM, and evaluated changes in gene expression (mRNA) and regulation (microRNA/miRNA) following LVAD. LV and RV free-wall tissues were collected from end-stage DCM hearts with (n = 8) and without LVAD (n = 8). Non-failing control tissues were collected from donated hearts (n = 6). Gene expression (for mRNAs/miRNAs) was determined using microarrays. Our results demonstrate that immune response, oxygen homeostasis, and cellular physiological processes were the most enriched pathways among differentially expressed genes in both ventricles of end-stage DCM hearts. LV genes involved in circadian rhythm, muscle contraction, cellular hypertrophy, and extracellular matrix (ECM) remodelling were differentially expressed. In the RV, genes related to the apelin signalling pathway were affected. Following LVAD use, immune response genes improved in both ventricles; oxygen homeostasis and ECM remodelling genes improved in the LV and, four miRNAs normalized. We conclude that LVAD reduced the expression and induced additional transcriptomic changes of various mRNAs and miRNAs as an integral component of the reverse ventricular remodelling in a chamber-specific manner.

ELSO Interim Guidelines for Venoarterial Extracorporeal Membrane Oxygenation in Adult Cardiac Patients.

ELSO Interim Guidelines for Venoarterial Extracorporeal Membrane Oxygenation in Adult Cardiac Patients.

Heart Rate Reduction Strategy Improves Survival in Children with Severe Dilated Cardiomyopathy

Purpose Assess the long term cardiovascular outcomes of heart rate reduction strategy (HRR) using ivabradine in children with chronic heart failure (HF). Background Chronic heart failure (HF) due to dilated cardiomyopathy (DCM) remains a significant medical challenge in pediatric population. There is paucity of evidence about pharmacological management of this population. Methods We conducted a retrospective cohort study including all children with end stage dilated cardiomyopathy (DCM) with LV function Results 72 children were included in the study and 23 treated with HRR strategy. After 1 year, HRR strategy was able to reduce heart rate [from 109.2 ± 26.4 bpm to 79.04 ± 18.8 bpm (p Conclusion Treatment with HRR strategy, in addition to standard HF therapy, seemed to be effective in reducing the incidence of acute adverse events and improving ventricular function in children with DCM and chronic HF.

Transcatheter aortic valve implantation in moderate bicuspid aortic valve disease in a patient with end-stage dilated cardiomyopathy - bridge to heart transplantation.

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Mizia-Szubryt M, Hudziak D, Grabka M, Małyszek-Tumidajewicz J, Wojakowski W, Mizia-Stec K. Transcatheter aortic valve implantation in moderate bicuspid aortic valve disease in a patient with end-stage dilated cardiomyopathy – bridge to heart transplantation. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej. 2021. doi:10.5114/aic.2021.110930. APA Mizia-Szubryt, M., Hudziak, D., Grabka, M., Małyszek-Tumidajewicz, J., Wojakowski, W., & Mizia-Stec, K. (2021). Transcatheter aortic valve implantation in moderate bicuspid aortic valve disease in a patient with end-stage dilated cardiomyopathy – bridge to heart transplantation. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej. https://doi.org/10.5114/aic.2021.110930 Chicago Mizia-Szubryt, Magdalena, Damian Hudziak, Marek Grabka, Justyna Małyszek-Tumidajewicz, Wojciech Wojakowski, and Katarzyna Mizia-Stec. 2021. "Transcatheter aortic valve implantation in moderate bicuspid aortic valve disease in a patient with end-stage dilated cardiomyopathy – bridge to heart transplantation". Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej. doi:10.5114/aic.2021.110930. Harvard Mizia-Szubryt, M., Hudziak, D., Grabka, M., Małyszek-Tumidajewicz, J., Wojakowski, W., and Mizia-Stec, K. (2021). Transcatheter aortic valve implantation in moderate bicuspid aortic valve disease in a patient with end-stage dilated cardiomyopathy – bridge to heart transplantation. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej. https://doi.org/10.5114/aic.2021.110930 MLA Mizia-Szubryt, Magdalena et al. "Transcatheter aortic valve implantation in moderate bicuspid aortic valve disease in a patient with end-stage dilated cardiomyopathy – bridge to heart transplantation." Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej, 2021. doi:10.5114/aic.2021.110930. Vancouver Mizia-Szubryt M, Hudziak D, Grabka M, Małyszek-Tumidajewicz J, Wojakowski W, Mizia-Stec K. Transcatheter aortic valve implantation in moderate bicuspid aortic valve disease in a patient with end-stage dilated cardiomyopathy – bridge to heart transplantation. Advances in Interventional Cardiology/Postępy w Kardiologii Interwencyjnej. 2021. doi:10.5114/aic.2021.110930.

HeartMate II thrombosis treated without explantation in the waiting period for heart transplantation: a case report.

BackgroundThe HeartMate II (HMII) is a high speed, axial flow, rotary blood pump that restores systemic flow by draining blood from the left ventricular (LV) apex and ejecting into the aortic root. This LV assist device was previously used in patients with medically refractory advanced-stage heart failure, for both destination therapy and bridge to transplantation until the introduction of HeartMate III. Case summaryWe report herein a case of a 25-year-old patient with Interagency Registry for Mechanical Assisted circulatory 3 profile implanted with HMII device for an end-stage dilated cardiomyopathy, who experienced a pump thrombosis despite a well-conducted anticoagulant protocol. A thrombophilia with heterozygous mutation of factor II and V was diagnosed at that time. We chose to stop the device without explantation until heart transplantation.DiscussionPump thrombosis with HMII is associated with a prohibitive risk of morbidity and mortality. Pump thrombosis is suspected when haemolysis or congestive heart failure occurs, also in cases of overconsumption of pump power (>10 W). Pump thrombosis treatment is challenging in the case of clotting factors mutation. Pump exchange could be ineffective, exposing the patient to the recurrence of thrombo-embolic events. Intravenous thrombolysis may be used for patients not candidates for redo procedures but could be unsuccessful and expose patients to high bleeding risk. Heart transplantation remains a reliable option. In our case, pump explantation was considered too hazardous by the heart team due to a prohibitive risk of redo surgery. Then, we decided to turn off the HMII pump after the introduction of continuous intravenous dobutamine support. The haemodynamic stability allowed us to wait for heart transplantation in favourable conditions.

An epigenetic circuit linking oxidative stress and DNA hydroxymethylation in heart failure

Abstract Background Heart failure is a major cause of morbidity and mortality worldwide, but the underlying molecular mechanisms remain not well defined. Reactive oxygen species (ROS) in heart failure (HF) alter multitudes of mitochondrial enzymes and metabolites, such as α-ketoglutarate and its oxidised form L-2-hydroxyglutarate (L-2HG). These metabolites are cofactors for ten eleven translocation (TET) enzymes that convert DNA's 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Aim We hypothesize that oxidative stress during heart failure alters mitochondrial function through epigenetic remodeling, and that reduction of oxidative stress will improve cardiac function. Methods and results Targeted LC-MS/MS analysis of dilated cardiomyopathy (DCM) hearts obtained from MLP−/− and WT littermate controls showed a significant increase in the oxidized metabolite L-2HG (∼30%, p=0.004), with significant reduction of multiple TCA cycle intermediates. RNA sequencing revealed a significant reduction in mRNA levels of IDH2 in human TTN related DCM and MLP−/− HF mice. The altered activity of IDH2 contributes to ROS production in these hearts and to the production of L-2HG. No alteration in the mitochondria structures was observed. HF biopsies show decreased TET activity most likely due to increased L-2HG levels. Whole genome single base pair 5mC and 5hmC deep sequencing of gDNA from explanted human DCM heart biopsies and MLP−/− mouse model revealed significantly altered global distribution of both 5mC and 5hmC in comparison to control samples. Genes involved in hypertrophy, such as Myh7 and Fhl2 were among the top genes with differential 5mC levels. Global loss of 5hmC level was observed, especially in the intronic regions of genes involved in redox hemostasis. Reducing oxidative stress in vivo in MLP−/− using a small molecule (AZ14117925) improves heart function (EF) by 13% [EF=(Treated:47,44%, Placebo: 34,54%), n=5 (males per group), p=0.0373, unpaired t-test]. Additional bioinformatic analysis revealed that reduction of ROS most likely leads to activation of TET and activation of pro-survival pathways, anti-oxidative stress response, and significantly less activation of apoptotic pathways. Conclusion Alterations in TCA cycle metabolites may underlie changes in DNA methylation and gene expression in end-stage human DCM and mouse models and indicate a role for epigenetic regulation of mitochondrial function in HF. NRF2 activation may pose a novel therapeutic approach to treat this devastating disease. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): AstraZeneca

Heart Transplant Outcomes for Patients with Cardiac Sarcoidosis

Cardiac sarcoidosis (CS) is a known etiology of both end-stage dilated and restrictive cardiomyopathy requiring heart transplantation. We sought to evaluate the long-term post-transplant outcomes of patients with CS compared to patients without CS. We evaluated the United Network of Organ Sharing (UNOS) registry for all heart transplant (HT) recipients from 1987 to 2019. Comparisons between patient characteristics of HT recipients with CS (N=288) and HT recipients without a diagnosis of CS (N=62,854) were reported using standard statistical methods including Cox proportional hazards regression for survival analysis. Sarcoid HT recipients were significantly older (52.4 ± 9.0 vs. 46.6 ± 19.2, p<0.001) and were more likely to be female (35.8% vs. 26.2%, p<0.001). Sarcoid HT recipients were also less likely to have diabetes (15.4% vs. 20.6%, p=0.03) and to have undergone prior cardiac surgery (12.2% vs. 18.3%, p=0.01). In terms of transplant related factors, sarcoid HT recipients were more likely to receive an older donor (32.1 ± 11.8 vs. 28.2 ± 14.0, p<0.001), but had similar ischemic times. Prior to transplant, the CS patients were less likely to require mechanical ventilation (0.3% vs. 4.3%, p=0.001), but had similar rate of ventricular assist device (VAD) and extracorporeal membrane oxygenation (ECMO) requirements. Median time on the wait list was similar between both groups, however there was a lower overall post-transplant mortality in the sarcoid HT recipients (p<0.001). Cardiac sarcoidosis HT recipients tended to be an older population with less underlying co-morbidities such as diabetes and prior cardiac surgery. They were more likely to receive older donors. Although sarcoid HT recipients have similar organ wait times as non-CS recipients, they ultimately have a lower overall mortality.

Production of TRPV2-targeting functional antibody ameliorating dilated cardiomyopathy and muscular dystrophy in animal models

Abnormal Ca2+ handling is essential in the pathophysiology of degenerative muscle disorders, such as dilated cardiomyopathy (DCM) and muscular dystrophy (MD). Transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a candidate for Ca2+ entry and a potential therapeutic target for degenerative muscle disorders, there are few specific inhibitors for TRPV2. In this study, we produced a monoclonal antibody (designated mAb88-2) and two polyclonal antibodies (pAb591 and pAb592) that selectively recognize TRPV2 from the outside of cells and interact with the turret region of the pore-forming outer gate. These antibodies inhibited Ca2+ influx via TRPV2 in cultured cells and substantially reduced TRPV2 in the plasma membrane via cellular internalization. We evaluated the therapeutic efficacy of the functional antibody in δ-sarcoglycan-deficient hamster (J2N-k) models of DCM and MD and in the 4C30 DCM model of murine heart failure. The intraperitoneal administration of the functional antibody (0.5 mg/kg) for 2 weeks (once a week) prevented the progression of cardiac dysfunction, as evaluated by echocardiography and histological staining, and improved the abnormal Ca2+ handling (high diastolic Ca2+ level and small Ca2+ transient peak) in cardiomyocytes isolated from J2N-k hamsters and prevented skeletal muscle damage. Further, the antibody effectively prevented heart failure in the 4C30 mouse model with end-stage DCM. Interestingly, endogenous TRPV2 that accumulated in the cardiac and skeletal muscle sarcolemma disappeared upon antibody administration. Thus, the newly produced antibodies are capable of ameliorating DCM and MD by promoting the cellular internalization of TRPV2; antibodies specific to human TRPV2 may substantially improve the treatment of patients with degenerative muscle diseases.

P362 Antimalarial-induced cardiomyopathy: retrospective case series

Abstract Background Antimalarial drugs chloroquine and hydroxychloroquine represent an important therapeutic option in autoimmune diseases. Rare cases of potentially lethal antimalarial-induced cardiomyopathy (AMIC) have been described. Pattern of minimal changes with wall hypertrophy, followed by restrictive and end-stage dilative cardiomyopathy was proposed in AMIC. Purpose Our aim was to identify patients with definite AMIC and characterize their clinical and imaging findings. Methods Retrospective analysis of admissions to Cardiology department from January 2010 to January 2019 was done to identify patients with definite diagnosis of AMIC based on positive endomyocardial biopsy. Clinical, echocardiographic, and cardiac magnetic resonance (CMR) imaging findings were reviewed if available. Results Three patients with biopsy proven diagnosis of AMIC were identified. Two patients, 62 and 76-year-old females, presented with signs of congestive heart failure, while the third, a 41-year-old man presented with chest pain and cardiac conduction abnormalities necessitating pacemaker implantation. All were treated with chloroquine phosphate. Both females had a history of pacemaker due to atrioventricular block. All had positive troponin and coronary artery disease was excluded. Echocardiography in the first case showed a severely dilated left ventricle (LV) with global hypokinesia and severe systolic dysfunction (LVEF 30%). CMR confirmed dilative cardiomyopathy, furthermore subepicardial late gadolinium enhancement (LGE) of the inferolateral LV wall and of the right ventricle free wall was present. In the second case a restrictive cardiomyopathy pattern was observed with mild biventricular systolic dysfunction and biatrial enlargement. CMR of this case was not available. Echocardiography in the third case showed a normal sized LV with mild diastolic and systolic dysfunction (LVEF 50%), along with septal hypokinesia. CMR showed patchy subepicardial and mid-wall LGE of the septum that was falsely attributed to myocarditis. Additionally, a chemical shift artefact suggestive of myocardial fatty infiltration (Image 1) was visible in the apical septum. After discontinuation of chloroquine two patients improved, while the first patient deteriorated and eventually succumbed to refractory heart failure. Conclusions Our three cases confirm high diversity of cardiac imaging findings in AMIC. Even mild non-specific findings such as LV systolic dysfunction or wall motion abnormalities in patients on antimalarial drugs should therefore be thoroughly investigated. CMR with non-ischaemic LGE pattern may aid in diagnosis, however definite diagnosis is currently possible only with endomyocardial biopsy. Novel imaging techniques, such as T1 mapping, have a potential to increase the diagnostic yield given the known patohistological similarities between AMIC and Anderson-Fabry disease. Abstract P362 Figure. Chemical shift artefact (arrow) in AMIC

Long non-coding RNA HAND2-AS1 downregulation predicts poor survival of patients with end-stage dilated cardiomyopathy.

ObjectiveInsulin-like growth factor-1 (IGF-1) signaling is inhibited in end-stage dilated cardiomyopathy (DCM), and recombinant IGF-1 improves cardiac function in DCM patients. Long non-coding (lnc)RNA HAND2-AS1 was previously shown to be involved in cancer development, but its role in DCM is unknown. The present study investigated the involvement of IGF-1 and HAND2-AS1 in DCM.MethodsPlasma HAND2-AS1 was detected by quantitative real-time PCR. IGF-1 plasma levels were measured by a human IGF-1 enzyme-linked immunosorbent assay. All experiments were performed in triplicate. Pearson’s correlation coefficient analyzed correlations between levels of IGF-1 and HAND2-AS1. Patients were divided into high and low IGF-1 or lncRNA HAND2-AS1 groups, and survival curves were plotted and compared by the Kaplan–Meier method and log-rank test, respectively.ResultsPlasma levels of IGF-1 and lncRNA HAND2-AS1 were significantly lower in end-stage DCM patients than in healthy controls, and were only positively correlated in end-stage DCM patients. A follow-up study revealed that low levels of IGF-1 or lncRNA HAND2-AS1 were significantly associated with poor survival. In the human cardiomyocyte cell line AC16, lncRNA HAND2-AS1 overexpression failed to alter IGF-1 levels and IGF-1 overexpression did not affect lncRNA HAND2-AS1 expression.ConclusionsLncRNA HAND2-AS1 may participate in end-stage dilated cardiomyopathy.