Development Of Cardiac Dysfunction Research Articles

M6A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation.

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction (MI) can lead to heart failure. RNA N6-methyladenosine (m6A) methylation has been shown to play a pivotal role in the occurrence and development of many illnesses. In investigating the biological function of the m6A reader YTHDF1 in cardiac fibrosis, adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts, and MI surgery in vivo and transforming growth factor-β (TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models. Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis, whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development. Mechanistically, zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter. YTHDF1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway, thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis. Consistently, our data indicated that YTHDF1 was involved in activation, proliferation, and migration to participate in cardiac fibrosis in vitro. Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

Regulation of Myocardial Lipid Accumulation in the Development of Obesity

Energy metabolism is important in the development of heart disease, which is the leading cause of death worldwide. The importance of energy metabolism in disease is becoming even more clear with the rise in obesity, metabolic diseases, and the recognition that they all fit together as with the recent offcial report of a new syndrome named Cardiovascular-Kidney-Metabolic (CKM) Syndrome. A complete understanding of myocardial lipid storage and subsequent utilization of lipids is essential to understanding the impact of these metabolic diseases in the heart and on the development of cardiac dysfunction and hypertrophy. In this study we investigate how the heart controls fuel storage by taking advantage of the impact of the transcription factor peroxisome proliferator activated receptor α (PPARα) on 1) fatty acid metabolism and lipid accumulation, 2) its key role in sex differences in cardiac hypertrophy which we previously reported, and 3) the regulation of lipid droplets. It is controversial whether a decline in myocardial PPARα mediates cardiac hypertrophy and whether it increases or reduces lipid accumulation. Using our tamoxifen inducible cardiac-specific PPARα knockout mouse (cPPAR−/−) we see less cardiac lipid accumulation in response to a 5 week high fat diet. Our data indicate that this difference in triglyceride levels is present in both males and females. Importantly, this is not driven by a difference in fatty acid supply to these hearts. Serum fatty acid levels are not lower in cPPAR−/− vs Control mice fed a high fat diet. Further, we have not observed a difference in high fat diet induced body weight gain between cPPAR−/− and Control mice. We have begun to examine how these differences in high fat diet-induced lipid accumulation correlate with cardiac hypertrophy by looking at heart weight normalized to tibia length. While we did not expect 5 weeks of a high fat diet to induce cardiac hypertrophy, it is possible that the difference in cardiac lipid storage in the cPPAR−/− hearts could impact this. This measurement did not indicate a difference in cardiac hypertrophy between high fat diet fed cPPAR−/− and Control mice. We are utilizing this mouse as a model to investigate the regulation of lipid droplets and the lipid droplet proteome. So far, our results are indicating that the regulation of lipid droplet proteins is not affected in a uniform manner. For example, our data is suggesting that the expression of different members of the perilipin family are affected in distinct ways. Overall, these data indicate that a reduction in cardiac PPARα protects against obesity induced cardiac lipid accumulation. Going forward, it will be interesting to see how these changes occur in relation to the lipid droplet proteome and whether any changes that occur differentially in males vs female may be involved in sex differences in cardiac hypertrophy. Better understanding these factors will be essential for the development of safe and effective future therapies for CKM syndrome and other cardiovascular diseases. ND-EPSCoR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardiac CARE study: How the ESC Cardio-Oncology guidelines fo 2022 affect the study population

Abstract Introduction The new 2022 ESC Guidelines in Cardio-Oncology focused on cancer therapy-related cardiac dysfunction (CT-RCD), with the formal introduction of biomarkers in the classification and risk stratification of CTR-CD in addition to structural imaging . We here, investigated how these changes affect the classification of patients in the Cardiac CARE study and the value of high sensitivity troponin I (hSTrop-I). Methods The Cardiac CARE study prospectively recruited 191 patients who underwent anthracycline therapy for breast cancer or non-Hodgkin’s lymphoma. All patients underwent regular hSTrop-I levels throughout their anthracycline therapy as well as a baseline and 6-month cardiac magnetic resonance scans including assessment of left ventricular ejection fraction and global longitudinal strain. A post-hoc analysis assessed the association between hSTrop-I and the development of cardiac dysfunction (defined as a reduction in left ventricular ejection fraction <50% or a reduction in GLS by >15%) using logistic regression with data corrected for age and gender. In addition, receiver operator curves (ROC) were drawn and area under the curve (AUC) analysis was performed to assess the value of hSTrop-I as an addition to the classification model. Finally, to compare our data with the new guidelines, a confusion matrix was performed. Results 11 patients were diagnosed as having cardiotoxicity in the Cardiac CARE study but using the 2022 ESC guidelines in Cardio-Oncology, 53 patients were re-classified into the ‘asymptomatic mild cardiotoxicity’ group (95% CI of 0.5162 and 0.6823; kappa value 0.157). Using a logistic regression model, a difference in hSTrop-I measured at the first cycle of anthracycline therapy had an odds ratio of 1.37 (95% CI 0.37-5.10) which when corrected for age dropped to 1.18 (95% CI of 0.28-5.01) and with combined age and sex correction, fell further, to 0.83 (95% CI of 0.12 and 5.56). A ROC analysis looking at the performance of hSTrop-I at predicting cardiac dysfunction demonstrated an area under the curve of 0.605 and when corrected for age and sex, was 0.640. Conclusion The addition of cardiac biomarkers to the new classification, significantly reclassified 53 of 191 (27.7%) of patients who were previously normal, to having asymptomatic mild cancer therapy-related cardiac dysfunction, mostly due to the inclusion of hSTrop I. HSTrop-I prior to anthracycline treatment was not a robust predictor of the development of anthracycline-induced cardiotoxicity in our cohort of patients. Of note, the Cardiac CARE patients are a low-risk group of patients and follow-up data is limited to 6 months.

Association between epicardial adipose tissue and cardiac dysfunction in subjects with severe obesity.

Epicardial adipose tissue (EAT) plays a role in obesity-related heart failure with preserved ejection fraction. However, the association of EAT thickness with the development of cardiac dysfunction in subjects with severe obesity without known cardiovascular disease is unclear. Determine the association between EAT thickness and cardiac dysfunction and describe the potential value of EAT as an early marker of cardiac dysfunction. Subjects with BMI ≥35 kg/m2 aged 35 to 65 years, who were referred for bariatric surgery, without suspicion of or known cardiac disease, were enrolled. Conventional transthoracic echocardiography and strain analyses were performed. A total of 186 subjects were divided into tertiles based on EAT thickness, of whom 62 were in EAT-1 (EAT <3.8 mm), 63 in EAT-2 (EAT 3.8-5.4 mm), and 61 in EAT-3 (EAT >5.4 mm). Parameters of systolic and diastolic function were comparable between tertiles. Patients in EAT-3 had the lowest global longitudinal strain (GLS) and left atrial contractile strain (LASct). Linear regression showed that a one-unit increase in EAT thickness (mm) was independently associated with a decrease in GLS (%) (β-coefficient - 0.404, p = 0.002), and a decrease in LASct (%) (β-coefficient - 0.544, p = 0.027). Furthermore, EAT-3 independently predicted cardiac dysfunction as defined by a GLS < 18% (OR 2.8, p = 0.013) and LASct<14% (OR 2.5, p = 0.045). Increased EAT thickness in subjects with obesity without known cardiac disease was independently associated with subclinical cardiac dysfunction. Our findings suggest that EAT might play a role in the early stages of cardiac dysfunction in obesity before this may progress to overt clinical disease. This article is protected by copyright. All rights reserved.

Protective effect of the dexrazoxane against cardiotoxicity of the anthracycline in the treatment of the childhood cancers.

e22001 Background: Cardiovascular diseases have become the most important cause of morbidity and mortality in the long-term follow-up of childhood cancer survivors. Dexrazoxane (DEX) is the only FDA-approved drug to prevent Anthracycline-induced cardiotoxicity. In this study, we aimed to evaluate the cardioprotective efficacy of DEX in patients using Anthracycline in the treatment of childhood cancer. Methods: 142 patients aged 0-18 years, who were treated with cancer diagnosis in Ankara University Faculty of Medicine, Department of Pediatrics, Department of Pediatric Oncology, and who had been treated with Anthracycline group agents, were evaluated retrospectively. The cardiac functions of 87 patients who received only Anthracycline between November 2009 and March 2019 and 55 patients who received DEX + Anthracycline between March 2019 and June 2021 were compared. An ejection fraction (EF) of less than 50% in cardiac evaluation was defined as 'cardiac dysfunction'. Results: The group that received anthracycline with DEX; While 50.9% were girls, 49.1% were boys, and the mean age was 98.42 months, 48.3% of the group that took only Anthracycline was girls and 51.7% were boys, with a mean age of 105.75 months. There was no difference between the two groups in terms of diagnosis distribution. EF values of both groups before anthracycline were normal. While none of the patients in the DEX + Anthracycline group developed cardiac dysfunction during the follow-up, 11 (12.6%) patients in the Anthracycline group with no DEX had cardiac problems. Six Of the 11 patients (54.5%) who developed cardiac dysfunction died(p=0.012). There was a significant difference between the two groups with or without DEX patients in the manner of cardiac dysfunction(p=0.006) and death(p=0.009). Cardiac dysfunction development and mortality rates were higher in patients using only Anthracycline. Conclusions: In this study, it has been shown that DEX is very effective for preventing Anthracycline-related cardiac dysfunction, which is one of the most important causes of mortality and morbidity in childhood cancer survivors.

Extracellular Vesicles and Cardiac Aging.

Global population aging is a major challenge to health and socioeconomic policies. The prevalence of diseases progressively increases with aging, with cardiovascular disease being the major cause of mortality among elderly people. The allostatic overload imposed by the accumulation of cardiac senescent cells has been suggested to play a pivotal role in the aging-related deterioration of cardiovascular function. Senescent cells exhibit intrinsic disorders and release a senescence-associated secretory phenotype (SASP). Most of these SASP compounds and damaged molecules are released from senescent cells by extracellular vesicles (EVs). Once secreted, these EVs can be readily incorporated by recipient neighboring cells and elicit cellular damage or otherwise can promote extracellular matrix remodeling. This has been associated with the development of cardiac dysfunction, fibrosis, and vascular calcification, among others. The molecular signature of these EVs is highly variable and might provide important information for the development of aging-related biomarkers. Conversely, EVs released by the stem and progenitor cells can exert a rejuvenating effect, raising the possibility of future anti-aging therapies.

523 MITOAKAP PLAY A ROLE IN THE PROGRESSION TOWARDS HEART FAILURE MODULATING GUT INTEGRITY AND COMPOSITION DURING AGING

Abstract Background Mitochondrial A-kinase anchoring proteins (mitoAKAP) encoded by the Akap1 gene promote Protein Kinase A mitochondrial targeting, regulating mitochondrial structure and function, reactive oxygen species production and cardiomyocyte survival. Whether mitoAKAP levels play a role in cardiac aging, gut barrier integrity and gut microbiota composition is currently unknown. Purpose The aim of this study was to highlight the complex interplay between cardiac dysfunction, gut barrier integrity, gut microbiota composition and aging in young (6-month-old, 6m) and old (24-month-old, 24m) wild type (wt) and Akap1 heterozygous mice (Akap1+/-). Methods Cardiac function was noninvasively analyzed by echocardiography in 6m and 24m wt and Akap1+/- mice. Gut microbial DNA was extracted and gut microbiota composition was analyzed by Illumina Mi-Seq analysis. Bioinformatics analysis was carried out to identify major intestinal populations. Alpha diversity within each sample was determined, and then analyzed according to genotype and age; then, inter-sample diversity was determined. For each dataset, we used UniFrac to calculate the differences between microbial communities based on phylogenetic distance between taxa sets in a phylogenetic tree. Bioinformatics analyses were performed using the analysis of similarities (ANOSIM). To evaluate the role of mitoAKAPs in intestinal permeability, we analyzed intestinal junction proteins expression levels in colon samples of all groups. Variance analysis was performed to determine significance among the groups. Results Partial loss of Akap1 accelerated the progression of cardiac dysfunction in 24m mice, as demonstrated by a significantly lower % fractional shortening (%FS) compared to 24m wt mice (%FS, wt 6m: 60±3; Akap1-/+ 6m: 58±5; wt 24m: 49±6*; Akap1-/+ 24m: 39±12*§; *p&amp;lt;0.05 vs. wt 6m; §p&amp;lt;0.05 vs. wt 24m). In 24m Akap1+/- mice, aging was associated to enhanced colon permeability, as shown by reduced levels of Ocln and Tjp1 mRNA expression. A principal coordinate analysis of fecal samples based on their unweighted UniFrac distances revealed that samples from Akap1+/- 24m mice cluster apart from wt 24m samples, suggesting that Akap1+/- 24m mice exhibit a different assortment of microbial communities. This observation was supported by ANOSIM R statistic that revealed significant differences in gut microbiota composition between wt and Akap1+/- 24m mice (ANOSIM R=0.475, P=0.023), while no significant differences in bacterial assortment were identified between wt and Akap1+/- 6m mice. We analyzed the differences in abundance of all 2,042 Operational Taxonomic Units (OTUs) between age-matched wt and Akap1+/-. We identified 10 OTUs differently represented in wt and Akap1+/- 6m mice, while a bigger set of bacterial OTUs (19) were different between wt and Akap1+/-24m mice. Consistent with previous results in patients with heart failure, we identified Clostridiales, Blautia producta and R. Torques among differently regulated species. These results are in accordance with previous data on patients with heart failure (HF). Conclusion Partial Akap1 deletion plays an important role in the progression toward HF and modulates colon permeability and gut microbiota composition during aging. This work highlights the complex interplay between gut microbiota and development of cardiac dysfunction, and characterization of these processes might lead to the development of new diagnostic and therapeutic approaches for cardiac dysfunction.

Abstract 11262: Effect of Active Cancer/Cachexia on the Development of Cardiac Dysfunction in Mice

Introduction: Cancer is independently associated with the alteration of cardiac function prior to cardiotoxic chemotherapy (CCT) exposure. Similar to cancer associated cachexia (CAC), the elevation and the deleterious role of IL-6 in plasma was associated with a reduced cardiac function in heart failure (HF) patients subpopulation. Cancer cells manipulate BCL-2-associated athanogene 3 (BAG3)-HSP70-regulated pathways in tumor cells, which is a key regulator of protein turnover and contractility in cardiomyocyte. Hypothesis: Here, we aimed to characterize the progression of cardiac dysfunction and the expression of BAG3 and HSP70 in tumor-bearing mice. Methods: Colon-26 adenocarcinoma cells (C26; n=22) with/without shIL-6 (C26 shIL-6; n=22) were injected subcutaneously adult male BALB/c mice. Control mice were injected with PBS (n=13). Echocardiographic examinations and invasive hemodynamic measurements ( in vivo and ex vivo using isolated working hearts system) were performed at 10 (early) and 20 (late) days post injection, respectively. The expression of BAG3 and Hsp70 were determined by Western blot. Results: The tumor size was comparable between the cancer groups. However, only C26 group showed a significant loss of subcutaneous fat and skeletal muscle (p&lt;0.05, respectively), confirming cachectic condition. Echocardiography results show a tendency to decline of ejection fraction at the early phase (p~0.08 vs Control), and turned significance lower at late stage (p&lt;0.05 vs Control) in tumor-bearing mice. In line with that, invasive hemodynamic and isolated working heart measurements confirmed LV systolic and diastolic dysfunction (late stage, p&lt;0.05 vs Control, respectively). Interestingly, heart rate and aortic flow were predominantly declined in cachectic animals (p&lt;0.05 vs Control). Importantly, cardiac dysfunction was associated with a significant reduction in both BAG3 and Hsp70 in the myocardium independently of cachexia. Conclusions: Cancer rather than CAC is a main driver for the development of cardiac contractile dysfunction prior to CCT exposure. In addition, our data suggest that targeting BAG3-Hsp70 complex in the cardiomyocytes may provide a novel strategy to improve the cancer associated cardiac dysfunction.

Body mass index associated differences in cardiac stress energetics in type 2 diabetes

Abstract Background Patients with T2D and heart disease have normal body mass index (BMI), suggesting that diabetes and obesity mediate cardiovascular change by different mechanisms. Changes in cardiac energy metabolism in lean diabetic patients during exercise stress have not been previously reported. Objectives We aimed to assess if there are BMI-associated differences in cardiac stress metabolism in patients with T2D. Methods Twenty-five overweight T2D patients (O-T2D) and eleven lean T2D patients (LnT2D), age- and ethnicity-matched and with no other comorbidities were studied. Patients were on oral hypoglycaemics only and were free of diabetes complications. Participants underwent rest and dobutamine stress phosphorus magnetic resonance spectroscopy (31P-MRS) and cardiovascular magnetic resonance (CMR) at 3T for the assessment of myocardial phosphocreatine to ATP ratio (PCr/ATP) as a measure of myocardial energetics, biventricular volumes, rest and stress left ventricular (LV) ejection fraction, global longitudinal shortening, and mitral in-flow E/A ratio for assessment of diastolic function and perfusion. Intravenous Dobutamine was administered at a dose of 10μg/kg/min, increasing at 90 second intervals up to a maximum of 40 μg/kg/min to achieve a target heart rate of 65% of the age-predicted maximal heart rate. Mean rate pressure product (RPP) was recorded at rest and stress. Heart rate was maintained at target for the duration of the 31P-MRS and stress CMR cine, mitral in-flow and perfusion acquisitions. Results The cardiac volumes, systolic or diastolic function and LV mass were similar between LnT2D and O-T2D. Although the O-T2D patients had a numerically lower rest and stress PCr/ATP ratio, this did not reach statistical significance. Resting PCr/ATP was reduced in LnT2D and O-T2D patients similarly. However, LnT2D showed a greater reduction in PCr/ATP (stress PCr/ATP LnT2D 1.51±0.2 vs O-T2D 1.41±0.25, p=0.02) despite similar increases in RPP. Stress myocardial blood flow (MBF) was also significantly lower in the O-T2D patients. There were significant correlations of BMI with LV mass (r=0.35, p=0.03); stress LVEF (r=−0.34, p=0.04); stress MBF stress (r=−0.53, p=0.001) and stress E/A (r=0.46, p=0.01) (figure 1). Conclusions Despite their better stress perfusion and similar glycaemic control, LnT2D show worse metabolic reserve characterised by more significant decrements in energetics in response to hemodynamic stress compared to overweight patients with T2D. Higher BMI correlates inversely with stress myocardial blood flow and with stress left ventricular ejection fraction. The presence of these subtle alterations in measures of stress metabolism and perfusion might signify a distinct metabolic phenotype of “lean diabetic cardiomyopathy”. Future studies are needed to further delineate alterations in cardiac energy metabolism in lean and overweight/obese type 2 diabetes patients, and their role in the development of cardiac dysfunction. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Wellcome TrustBHF

Alterations of Lipid Metabolism in the Heart in Spontaneously Hypertensive Rats Precedes Left Ventricular Hypertrophy and Cardiac Dysfunction.

Disturbances in cardiac lipid metabolism are associated with the development of cardiac hypertrophy and heart failure. Spontaneously hypertensive rats (SHRs), a genetic model of primary hypertension and pathological left ventricular (LV) hypertrophy, have high levels of diacylglycerols in cardiomyocytes early in development. However, the exact effect of lipids and pathways that are involved in their metabolism on the development of cardiac dysfunction in SHRs is unknown. Therefore, we used SHRs and Wistar Kyoto (WKY) rats at 6 and 18 weeks of age to analyze the impact of perturbations of processes that are involved in lipid synthesis and degradation in the development of LV hypertrophy in SHRs with age. Triglyceride levels were higher, whereas free fatty acid (FA) content was lower in the LV in SHRs compared with WKY rats. The expression of de novo FA synthesis proteins was lower in cardiomyocytes in SHRs compared with corresponding WKY controls. The higher expression of genes that are involved in TG synthesis in 6-week-old SHRs may explain the higher TG content in these rats. Adenosine monophosphate-activated protein kinase phosphorylation and peroxisome proliferator-activated receptor α protein content were lower in cardiomyocytes in 18-week-old SHRs, suggesting a lower rate of β-oxidation. The decreased protein content of α/β-hydrolase domain-containing 5, adipose triglyceride lipase (ATGL) activator, and increased content of G0/G1 switch protein 2, ATGL inhibitor, indicating a lower rate of lipolysis in the heart in SHRs. In conclusion, the present study showed that the development of LV hypertrophy and myocardial dysfunction in SHRs is associated with triglyceride accumulation, attributable to a lower rate of lipolysis and β-oxidation in cardiomyocytes.

Abstract P2028: A Role For Pannexin 1 In Heart Failure Induced By Acute And Chronic Isoproterenol Administration

Pannexin 1 (Panx1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation and blood pressure regulation. Panx1 channel function is inhibited by spironolactone, a frontline therapy for heart failure patients. Despite this, the function of Panx1 in cardiomyocytes and a possible role in heart failure has not yet been studied. To investigate if Panx1 is involved in the development of cardiac dysfunction and fibrosis, we use an acute (14 day) and a chronic (28 day) model of adrenergic stimulation to induce heart failure in two novel mouse models: 1) We have generated mice with constitutive deletion of Panx1 in cardiomyocytes by crossing mice expressing loxP-flanked alleles of Panx1 to mice expressing Cre recombinase under the control of the cardiomyocyte specific MyHC6 promoter (Panx1 MyHC6-Cre ). 2) Using mice expressing the tamoxifen-inducible MerCreMer system under the control of the Tnnt2 promoter we generated mice with tamoxifen-inducible deletion of Panx1 in cardiomyocytes (Panx1 Tnnt2-MerCreMer ). Constitutive deletion of Panx1 in cardiomyocytes had no effect on heart function at baseline as measured by echocardiography. However, after acute isoproterenol treatment (15 mg/kg/day, i.p.), Panx1 MyHC6-Cre mice were protected from systolic and diastolic dysfunction and cardiac hypertrophy. Furthermore, after chronic administration of isoproterenol (15 mg/kg/day, osmotic pump) Panx1 MyHC6-Cre mice were still protected from cardiac hypertrophy compared to Panx1 fl/fl littermates. In vitro , treatment of H9c2 cardiomyocytes with isoproterenol led to Panx1-dependent release of ATP in a dose-dependent manner. This was demonstrated with both pharmacological blockade by spironolactone and siRNA-mediated knock-down of Panx1. Taken together, these data demonstrates that Panx1 deficiency in cardiomyocytes protects against isoproterenol-induced cardiac dysfunction and that ATP is released through Panx1 in response to isoproterenol. Further elucidating the role of Panx1 in cardiomyocytes in regulating cardiac function and fibrosis will identify Panx1 as a novel therapeutic target to prevent heart failure.

Long Non-Coding RNA HOTTIP is Elevated in Patients with Sepsis and Promotes Cardiac Dysfunction

ABSTRACT Background Cardiac dysfunction is the most common clinical complication of sepsis. Herein, the study explored the clinical importance of long non-coding RNA (lncRNA) HOXA terminal transcript antisense RNA (HOTTIP) in the onset of sepsis and the development of cardiac dysfunction. Methods 120 patients with sepsis were recruited and divided into cardiac dysfunction group and non-cardiac dysfunction group. Serum HOTTIP levels were measured via RT-qPCR. AC16 cells were treated with lipopolysaccharide (LPS) for cell experiments and detected for cell viability and apoptosis. Results High serum HOTTIP levels were tested in sepsis patients, which was associated with procalcitonin (PCT) level. Serum HOTTIP can identify sepsis cases from healthy people with the AUC of 0.927. 72 cases developed into cardiac dysfunction, accompanied by elevated levels of HOTTIP. ROC curve displayed the predictive ability of serum HOTTIP in the development of cardiac dysfunction in patients with sepsis. After adjusting for other clinical parameters, HOTTIP can independently affect the development of cardiac dysfunction. In vitro, HOTTIP knockdown promoted the recovery of cell viability and reversed LPS-induced cell apoptosis and excessive interleukin-6 (IL-6) release. Conclusion LncRNA HOTTIP is closely related to the condition of patients with sepsis and the development of cardiac dysfunction, possibly owing to its function in LPS-induced myocardial apoptosis and inflammation.

The first clinical pig heart transplant: Was IVIg or pig cytomegalovirus detrimental to the outcome?

The clinical course of the first patient to receive a gene-edited pig heart transplant was recently reported by the University of Maryland team. Although the pig heart functioned well for >40 days, serum anti-pig antibodies then increased, and the patient sadly died after 60 days. Because of his debilitated pre-transplant state, the patient never thrived despite excellent graft function for several weeks, and the cause of his demise continues to be uncertain. A few days before an increase in anti-pig antibodies was observed, the patient had received intravenous human immunoglobulin (IVIg), and whether this played a role in his cardiac deterioration has been discussed. Furthermore, mcfDNA testing indicated an increase in pig cytomegalovirus (CMV), and its possible role in the development of cardiac dysfunction has also been considered. On the basis of the limited data provided in the publication and on our previous investigations into whether IVIg contains anti-TKO pig antibodies and therefore might be deleterious to TKO pig organ xenografts, we suggest that the steady rise in anti-pig antibody titer was more consistent with the failure of the immunosuppressive regimen to prevent elicited anti-TKO pig antibody production, rather than from the passive transfusion of IVIg or the presence of pig CMV in the graft. Although the outcome of the Maryland experience was disappointing, valuable lessons were learned. Our attention was drawn to the potential risks of heart transplantation in a "deconditioned" patient, the administration of IVIg, the transmission of pig CMV, and of the difficulties in interpreting myocardial biopsy findings.

The effect of breast radiotherapy parameters (XRT), chemotherapy regimens (CT) and dual anti-HER2 monoclonal antibodies (MoAb) on the development of cardiac dysfunction (CD) among patients with HER2-positive breast cancer from Saudi Arabia.

e12508 Background: Treatment with anti-HER2 therapy can cause CD. The effect of breast XRT, heart dose and V25 of the heart and CT regimen on developing CD is controversial. The impact of these variables in developing CD among patients with HER2-positive breast cancer (BC), receiving CT plus anti-HER2 MoAb was evaluated in routine clinical practice. Methods: Patients with HER2-positive BC between 2015-2019 were included, retrospectively. CD is defined as a drop in (EF%) of at least 10 % points from baseline and/or below 50% at any point of the time during follow-up. The association of CD and various variables was examined with a significance level of &lt; 0.05. Results: Data from 224 female patients were analyzed with a mean age at diagnosis of 51 +12, BMI 29.6 ± 6.4, BSA 1.74 ± 0.19, 53% with left BC, 63% had non-metastatic BC, 52% with comorbidities, 11% had prior IHD medication use in 48%; metformin in 15% and B-blockers in 5%, 9.4% smoker, 70% had a mastectomy, 18% lumpectomy and 12% no surgery, 58% received XRT. The cumulative incidence of CD was 33% during follow-up noting that the first and subsequent drops of EF at any point of time during the follow-up was counted as a new event even for the same patient. The univariate analysis of factors influencing the risk of CD is shown in Table. However, the initial significance of CT regimen and whether the patient received breast XRT or otherwise, did not translate into significance on multivariate analysis with a P-value = 0.198 &amp; 0.326, respectively. Conclusions: XRT mean heart dose and V25 of the heart, anthracycline-based CT did not influence the risk of CD among this cohort. Likewise, the dual anti-HER2 therapy with trastuzumab and pertuzumab and the number of trastuzumab cycles did not influence CD. It is reassuring to demonstrate the safety of these approaches in real-life clinical practice.[Table: see text]

Predictors of cardiac dysfunction in children with HIV/AIDS attending University of Nigeria Teaching Hospital Enugu

Cardiac dysfunction, though common as a primary effect of HIV infection or its treatment in HIV-infected children, is often clinically masked by pulmonary disease in patients with HIV infection and AIDS. The objective of the study was to determine the prevalence and predictors of cardiac dysfunction in children with HIV/AIDS infection. This was a cross-sectional comparative case - control study of clinical and echocardiographic findings in 90 pediatric HIV/AIDS children aged 18 months to 14years and their age and gender - matched HIV – negative controls attending the University of Nigeria Teaching Hospital, Enugu. Relevant clinical information including demographics, investigations including echocardiography and treatment, were captured using a datasheet designed for the study. Data analysis was done using SPSS version 20.0. A p value of &lt;0.05 was considered significant. The majority of the subjects had cardiac abnormalities and was on HAART. The pattern of cardiac abnormalities in HIV – infected and AIDS groups were left ventricular diastolic dysfunction (33.8% and 36.4% in the HIV – infected and the AIDS groups respectively, followed by dilated cardiomyopathy (6.8%) seen only in AIDS group (p=0.03). A strong linear relationship between cardiac dysfunction and CD4+ counts (R2=0.8642) and age (R2=0.4203) among the patients were observed. Cardiac dysfunction is common in children with HIV/AIDS and predicted by CD4+ count and increasing age. Need exists to monitor the development of cardiac dysfunction using appropriate clinical details and echocardiography is recommended to improve their quality of life.

Immune cells play a crucial role in the development of a cardiac dysfunction in cardiac p38 MAPKa KO mice after pressure overload

QuestionCardiac metabolic remodeling is one of the early changes driving the progression of heart failure and is present even before overt cardiac dysfunction. Previously we showed that the tamoxifen inducible deletion of cardiomyocyte specific p38 MAPKa (KO) leads to a pronounced left ventricular dilation with a strongly impaired heart function just within 2 days of angiotensin II (ANGII) treatment. Additionally, a strong infiltration of immune cells in the cardiac tissue can be observed.Methods and ResultsUnder baseline conditions no impairment of the heart function in KO mice can be observed. ANGII treatment for 2 days induces a strong left ventricular dilation and poor heart function, indicated by a reduced ejection fraction and an increase in end‐systolic and end‐diastolic volume. KO mice do not get used to constant ANGII treatment even after 7 days of ANGII treatment and cardiac function continues to deteriorate. KO mice transiently loose weight as a consequence of ANGII treatment. On the fourth to fifth day of ANGII treatment, KO animals gain weight again, although the heart function continues to deteriorate. FACS analysis of cardiac tissue revealed a strong infiltration of neutrophils in KO hearts after 48h of ANGII treatment (4.5‐fold increase compared to control hearts). A strong correlation between reduced ejection fraction and increasing amount of neutrophils in the cardiac tissue suggests a particularly important role of neutrophils in the development of cardiac dysfunction. Also an increase of macrophages (1.6‐fold increase), CD4+ T‐helper cells (2.5‐fold increase) and CD8+ cytotoxic T‐cells (2.5‐fold increase) as well as B‐cells (2‐fold increase) could be shown in KO hearts compared to control hearts. After long term ANGII treatment for 7 days, however, the number of neutrophils in the hearts decreased (10‐fold decrease in control hearts and 73‐fold decrease in KO hearts compared to 48h of ANGII treatment) and a strong increase in M2‐like macrophage infiltration, mainly in control hearts (1.6‐fold increase compared to 48h ANGII treatment), could be observed. The infiltrated macrophages were also positive for CCR2, which indicates they originated from monocytes. B‐ and T‐cells were still elevated in KO hearts after 7 days of ANGII treatment. Also in control hearts an increase of B‐ and T‐cells could be observed. In addition, fibrosis developed in the cardiac tissue, which could be shown by histological staining of collagen I and FACS analysis targeting αSMA+ cardiac fibroblasts.ConclusionImmune cells and in particular neutrophils play an important role in the development of cardiac dysfunction after ANGII induced pressure overload in p38 MAPKa KO mice. Over time, however, the number of immune cells in control mice also increases, which underlines the peculiarity of the first neutrophil influx after 48h ANGII treatment for the impairment of cardiac function.

A Critical Role for Pannexin 1 in Heart Failure Induced by Acute and Chronic Isoproterenol Administration

Pannexin 1 (Panx1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation and blood pressure regulation. Panx1 channel function is inhibited by spironolactone, a frontline therapy for heart failure patients. Despite this, the function of Panx1 in cardiomyocytes and a possible role in heart failure has not yet been studied. To investigate if Panx1 is involved in the development of cardiac dysfunction and fibrosis, we use a model of chronic adrenergic stimulation to induce heart failure in two novel mouse models. We have generated mice with constitutive deletion of Panx1 in cardiomyocytes by crossing mice expressing loxP‐flanked alleles of Panx1 to mice expressing Cre recombinase under the control of the cardiomyocyte specific MyHC6 promoter (Panx1MyHC6‐Cre). Using the same approach with mice expressing the tamoxifen‐inducible MerCreMer system under the control of the Tnnt2 promoter we generated mice with tamoxifen‐inducible deletion of Panx1 in cardiomyocytes (Panx1Tnnt2‐MerCreMer). Constitutive deletion of Panx1 in cardiomyocytes had no effect on heart function at baseline as measured by echocardiography. However, after acute isoproterenol treatment (15 mg/kg/day, i.p.), Panx1MyHC6‐Cre mice were protected from systolic and diastolic dysfunction and cardiac hypertrophy. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to Panx1‐dependent release of ATP. Furthermore, siRNA‐mediated knock down of Panx1 in H9c2 cells attenuated basal and maximal extracellular acidification rate (a measure of glycolysis) after 24 hours of isoproterenol treatment, indicating a role for Panx1 in regulation of cardiomyocyte metabolism. Taken together, these data demonstrates that Panx1 deficiency protects against isoproterenol‐induced cardiac dysfunction and pathological glycolytic shift in stressed cardiomyocytes. Further elucidating the role of Panx1 in cardiomyocytes in regulating cardiac function and fibrosis will identify a novel therapeutic target to prevent heart failure.

186 Partial loss of AKAP1 promotes cardiac dysfunction, gut barrier abnormalities, and alteration of gut microbiota composition during ageing

Abstract Aims Mitochondrial A-kinase anchoring proteins (mitoAKAP) encoded by the Akap1 gene promote Protein Kinase A mitochondrial targeting, regulating mitochondrial structure and function, reactive oxygen species production, and cardiomyocyte survival. Whether mitoAKAP levels play a role in cardiac ageing, gut barrier integrity and gut microbiota composition is currently unknown. The aim of this study was to highlight the complex interplay between cardiac dysfunction, gut barrier integrity, gut microbiota composition and ageing in young (6-month-old, 6 m) and old (24-month-old, 24 m) wild type (wt) and Akap1 heterozygous mice (Akap1+/−). Methods and results Cardiac function was noninvasively analysed by echocardiography in 6 m and 24 m wt and Akap1+/− mice. Gut microbial DNA was extracted and gut microbiota composition was analysed by Illumina Mi-Seq analysis. Bioinformatics analysis was carried out to identify major intestinal populations. Alpha diversity within each sample was determined, and then analysed according to genotype and age; then, inter-sample diversity was determined. For each dataset, we used UniFrac to calculate the differences between microbial communities based on phylogenetic distance between taxa sets in a phylogenetic tree. Bioinformatics analyses were performed using the analysis of similarities (ANOSIM). To evaluate the role of mitoAKAPs in intestinal permeability, we analysed intestinal junction proteins expression levels in colon samples of all groups. Variance analysis was performed to determine significance among the groups. Partial loss of Akap1 accelerated the progression of cardiac dysfunction in 24 m mice, as demonstrated by a significantly lower % fractional shortening (%FS) compared to 24 m wt mice (%FS, wt 6 m: 60 ± 3; Akap1−/+ 6 m: 58 ± 5; wt 24 m: 49 ± 6*; Akap1−/+ 24 m: 39 ± 12*§; *P &amp;lt; 0.05 vs. wt 6 m; §P &amp;lt; 0.05 vs. wt 24 m). In 24 m Akap1+/− mice, ageing was associated to enhanced colon permeability, as shown by reduced levels of Ocln and Tjp1 mRNA expression. A principal Co-ordinate analysis of faecal samples based on their unweighted UniFrac distances revealed that samples from Akap1+/− 24 m mice cluster apart from wt 24 m samples, suggesting that Akap1+/− 24 m mice exhibit a different assortment of microbial communities. This observation was supported by ANOSIM R statistic that revealed significant differences in gut microbiota composition between wt and Akap1+/− 24 m mice (ANOSIM R = 0.475, P = 0.023), while no significant differences in bacterial assortment were identified between wt and Akap1+/− 6 m mice. We analysed the differences in abundance of all 2042 Operational Taxonomic Units (OTUs) between age-matched wt and Akap1+/−. We identified 10 OTUs differently represented in wt and Akap1+/− 6 m mice, while a bigger set of bacterial OTUs (19) were different between wt and Akap1+/− 24 m mice. Consistent with previous results in patients with heart failure, we identified Clostridiales, Blautia producta, and R. Torques among differently regulated species. These results are in accordance with previous data on patients with heart failure (HF). Conclusions Partial Akap1 deletion plays an important role in the progression towards HF and modulates colon permeability and gut microbiota composition during ageing. This work highlights the complex interplay between gut microbiota and development of cardiac dysfunction, and characterization of these processes might lead to the development of new diagnostic and therapeutic approaches for cardiac dysfunction.

Cardiac rest and stress metabolism in type 2 diabetes (T2D): can the diabetic heart flex under stress?

Abstract Background Efficient matching of energy supply to demand is essential for maintaining normal cardiac function. Altered cardiac metabolism may contribute to the development of cardiac dysfunction by impairing metabolic flexibility in type 2 diabetes (T2D). Purpose We aimed to evaluate the effect of T2D on myocardial substrate preferences in response to acute increases in cardiac workload and the effects on contractile function utilising simultaneous coronary sinus (CS) and aorta blood sampling and cardiac magnetic resonance (CMR) imaging Methods Eligible participants without obstructive coronary artery disease (&amp;gt;50% luminal coronary artery stenosis on coronary angiography) underwent transmyocardial arteriovenous blood sampling. Metabolites in paired coronary sinus and arterial samples were quantified to determine myocardial fuel selection at rest and during a stress protocol with intravenous dobutamine. Free fatty acid (FFA), glucose, 3-hydroxybutyric acid (3HBA) and lactate utilisation at rest and haemodynamic stress was calculated as an extraction fraction % (EF). Participants underwent dobutamine stress multiparametric CMR imaging at 3.0 Tesla (Skyra, Siemens, Germany) on a separate visit within 21 days to quantify cardiac volumes, function and perfusion. Results Two thousand and sixty-one participants were screened and due to stringent inclusion and exclusion criteria for this mechanistic study, three T2D patients and five matching controls were enrolled. Baseline demographics and metabolic and CMR results are documented in Table 1. At peak stress levels there was a significant increase in FFA use from rest to stress in controls only (p=0.002). There were no significant differences in FA or glucose uptake between T2D patients and controls at rest or stress. 3HBA EF was significantly increased in T2D during stress (25.04% vs 5.31%, p=0.007). Mean FFA and 3-HBA changes calculated as extraction fraction at stress and rest are illustrated in Figure 1. Conclusions We demonstrate for the first time in vivo that the diabetic heart switches to ketone bodies during increased workloads as a significant fuel source. At present, it is unknown whether enhanced ketone body metabolism in T2D is beneficial, maladaptive, or a bystander. As the energetic properties of ketones are favourable, increased myocardial ketone oxidation could be an adaptive change designed to compensate for defects in myocardial energy metabolism in diabetes. Further, larger studies are warranted. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation - Clinical Research Training FellowshipWellcome Trust Seed Grant Table 1Figure 1

Psoriasis and Atherosclerosis-Skin, Joints, and Cardiovascular Story of Two Plaques in Relation to the Treatment with Biologics.

It is known that both psoriasis (PSO) limited to the skin and psoriatic arthritis (PSA) increase the risk of cardiovascular complications and atherosclerosis progression by inducing systemic inflammatory response. In recent decades, the introduction of biological medications directed initially against TNF-α and, later, different targets in the inflammatory cascade brought a significant breakthrough in the efficacy of PSO/PSA treatment. In this review, we present and discuss the most recent findings related to the interplay between the genetics and immunology mechanisms involved in PSO and PSA, atherosclerosis and the development of cardiac dysfunction, as well as the current PSO/PSA treatment in view of cardiovascular safety and prognosis.