Specific methylation marks in promoter regions are associated to the pathogenic process of Chronic Chagas disease Cardiomyopathy by modifying transcription factor binding patterns

Chagas disease, caused by Trypanosoma cruzi, is an endemic parasitical disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including Chronic Chagasic Cardiomyopathy (CCC), which ranges from moderate to severe stages depending on the cardiac ejection fraction. The pathogenic process remains poorly understood, although genetic and epigenetic factors have already been proposed. Based on bulk RNA-seq and EPIC methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. We identified 4 main biological processes associated with the pathology development, including immune response, ion transport, cardiac muscle processes and nervous system. An in-depth study of the transcription factors binding sites in the differentially methylated regions corroborated the importance of these processes. We also conducted a methylation study on blood to identify potential biomarkers for CCC. Our data revealed 198 differentially methylated positions (DMPs) that could serve as biomarkers of the disease, of which 61 are associated with disease severity.

Pediatric Heart Failure: Cardiac Ejection Fraction with Cardiomyopathy Decreased to 21% in Iron Deficient from 37% in Iron Sufficient Children

Introduction: The overall aim of our study was to determine if iron deficiency has harmful effects on cardiac function in children with chronic heart failure. Heart failure in children is a complex, heterogeneous disorder leading to a final common pathway of cardiomyocyte dysfunction and attrition. Cellular, animal, and human studies have shown that iron deficiency causes cardiomyocyte dysfunction that can be reversed with iron treatment. Cellular studies of human iron-deficient cardiomyocytes have shown that supplemental iron restores impaired contractility and relaxation. Animal studies have found that cardiomyocyte-specific deletions or alterations of critical iron proteins (transferrin receptor 1, hepcidin, ferroportin) produce cardiomyocyte iron deficiency (without anemia) and result in ultimately fatal cardiac dysfunction that can be rescued with intravenous (IV) iron. Over half of adults with chronic heart failure are iron deficient. Meta-analysis of small randomized clinical trials has shown that IV iron significantly reduces recurrent hospitalization, cardiovascular mortality, and all-cause mortality in iron deficient adults with heart failure. European Society of Cardiology, American College of Cardiology and American Heart Association guidelines recommend consideration of IV iron therapy for adult iron-deficient patients with heart failure. The prevalence and consequences of iron deficiency in children with heart failure have not been established. Previously, two small retrospective studies of children with heart failure have reported that 56% to 96% were iron deficient, with increased morbidity and mortality. The goals of our study of children with heart failure were to determine (i) how often iron status is assessed, (ii) the prevalence of iron deficiency, and (iii) the effects of iron deficiency on cardiac function in patients with cardiomyopathy. Methods: We retrospectively reviewed electronic medical records to identify pediatric patients ages 1-21 years old seen at Columbia University Irving Medical Center Pediatric Heart Failure clinic with absolute iron deficiency during 2010-2020. Heart failure was defined as presence of symptoms or systolic dysfunction by echocardiography. Patients were excluded with a history of heart transplant, isolated diastolic failure, or renal failure requiring dialysis. In adults with heart failure, a transferrin saturation <20% has a sensitivity of 94% and a specificity of 84% in identifying absolute iron deficiency, as determined from a bone marrow aspirate, and iron stores were present in 100% of patients with a transferrin saturation ≥30% (Circ Heart Fail. 2018;11:e0045). In children with heart failure, we used these criteria to define absolute iron deficiency as a transferrin saturation <20% and iron sufficiency as a transferrin saturation ≥30%. Patients with an intermediate transferrin saturation are likely a mixture of absolute and functional iron deficiency, and of iron sufficiency and were excluded from our analysis of cardiomyopathy. Cardiac ejection fraction was evaluated by an echocardiogram performed within 3 months of measurement of transferrin saturation. Results: Of 579 patients with heart failure, only 159 (27%) had any type of laboratory iron studies. Of patients with iron studies, 81 (51%) were evaluated as outpatients; 49% as inpatients. The cause of heart failure was cardiomyopathy (52%), congenital heart disease (34%), acute myocarditis (6%), and other (8%). In the 82 patients with heart failure due to cardiomyopathy, 39 (48%) were iron deficient and 16 (20%) iron sufficient. In the iron deficient children with cardiomyopathy, the left ventricular ejection fraction was lower than in the iron sufficient patients (median 21% vs. 37%; p=0.03 (Mann-Whitney); Figure). The groups did not differ significantly with respect to hemoglobin (Figure), sex, age, or New York Heart Association class. Conclusion: We report a clinically important decrease in cardiac ejection fraction in children with heart failure due to cardiomyopathy who have absolute iron deficiency. Potentially, iron treatment could safely and effectively reverse the harmful effect of iron deficiency on heart function and prospective randomized trials of oral and intravenous iron therapy are urgently needed. Measurement of iron status should routinely be included in the evaluation of children with heart failure. Figure 1 Figure 1. Disclosures Neunert: Novartis: Research Funding.

Cardiac Function Index as a Possible Target Parameter Hemodynamic Correction in Abdominal Sepsis (Pilot Study)

Aim of the study: to determine the predictive value of central hemodynamic parameters in relation to mortality and evaluate their potential acceptability for goal-directed therapy during days 1-4 of treatment in patients with sepsis.Material and methods. The results of investigation and treatment of 62 patients aged 50.9±2.13 years with abdominal sepsis were analyzed. The patient severity on admission to the intensive care unit was 13 [10-15] on the APACHE II scale, 8 [6.75-9.25] on the SOFA scale. Lethal outcome 15.6±1.4 days after admission occurred in 19 (31%) patients. Central hemodynamic parameters were studied by transpulmonary thermodilution according to the standard technique. Infusions and administration of sympathomimetic drugs were performed according to Sepsis-3 guidelines. Statistical analysis was performed using logistic regression and ROC analysis.Results. The median values of the main circulatory parameters during days 1-4 of sepsis treatment were within normal ranges. Cardiac index, afterload-related cardiac performance, global cardiac ejection fraction and cardiac function index were predictors of mortality at all stages of treatment. However, the first three parameters did not provide either sufficient model quality at the study stages or a stable cutoff value with acceptable sensitivity and specificity. The cardiac function index maintained good model quality (area under the ROC curve 0.708-0.753) and a stable cutoff value (≤5.75 to ≤5.81 min-1) with acceptable and balanced sensitivity and specificity of about 70% at all study stages.Conclusion. The cardiac index, afterload cardiac performance, global cardiac ejection fraction and cardiac function index during days 1-4 of intensive care of sepsis are predictors of lethal outcome. At the same time, only the cardiac function index maintains good model quality and consistent cut-off point value with acceptable sensitivity and specificity at all stages of the study. The feasibility of using the cardiac function index as one of the parameters of goal-directed therapy aimed at cardiovascular function improvement in sepsis needs further investigation.

Abstract 14793: Association Between Cardiac Ejection Fraction and the Size of Stroke

Introduction: Heart failure with low ejection fraction (EF) is a known risk factor for stroke. Low EF is associated with increased risk of thrombus formation and is accompanied with 2 to 3 fold increased risk of stroke. This can happen even in the absence of atrial fibrillation. Hypothesis: Our hypothesis was that size of the stroke will be larger in patients with reduction in EF as compared with cardioembolic strokes in preserved EF. The worse the EF, the more stagnation of blood and poor cardiac output leading higher risk of thrombus formation. It’s also likely that the group with reduced EF form a larger thrombus leading to larger stroke as compared to the group with preserved EF. Methods: For our analysis, we retrospectively reviewed charts for 49 acute ischemic stroke patients without atrial fibrillation. We used transthoracic echocardiogram to determine the EF. There are 25 patients with preserved EF, cutoff > 50%. There were 24 patients in reduced EF group. Both groups were matched for age and cardiovascular risk factors. Infarct volume was manually calculated from T1 MRI using BrainLab software. Results: There is an inverse correlation between EF and infarct volume (r=-.283, p=.048) meaning patients with reduced EF had greater infarct volume. Median infarct volume is higher in reduced EF group (median volume = 36 cm 3 ) compared to patients with preserved EF (median volume = 11 cm 3 ) (p=.117). Conclusions: In our patient’s sample, there seems to be an inverse correlation between EF and size of stroke. Patients with reduced EF were associated with larger strokes. Larger studies need to be performed to establish a correlation.

The role of parathyroid hormone and cardiac output in pulmonary hypertension in hemodialysis patients

Introduction: High prevalence of pulmonary hypertension has been reported in patients with chronic renal failure, especially those undergoing hemodialysis. Objectives: Considering the high prevalence of pulmonary hypertension in hemodialysis patients and uncertainty about the causes, the present study planned to investigate the role of parathyroid hormone (PTH) and cardiac ejection fraction (EF %) in development of pulmonary hypertension. Patients and Methods: By simple census sampling, all patients on hemodialysis in the hemodialysis center of Birjand University of Medical Sciences were enrolled. After obtaining written consent, the EF% and systolic pulmonary artery pressure (sPAP) were determined using echocardiography (MEDISON V10 model, Korea). The cut-point of less than 35 mm Hg was considered for normal sPAP. The blood sample was prepared to assay PTH using COBAS411 and ROCH kit. Independent t test or Man-Whitney test were used to compare means. P value <0.05 was considered significant. Results: A totsl of 114 patients were enrolled in the study. Finally 89 patients, including 49 (55.1%) male and 40 (44.9%) female completed the study. The mean age and mean sPAP of the studied patients were 55.14 ± 15.68 years and 30.65 ± 12.10 mm Hg respectively. Among the studied patients, normal and high sPAP were reported in 60 (67.4%) and 29 (32.6%) cases respectively. Cardiac EF% in patients with normal and high sPAP was 59.08 ± 2.83 versus 56.37 ± 4.79 respectively (P = 0.01). PTH was determined 275.12 ± 218.44 versus 395.67 ± 332.05(pg/mL) (P = 0.03), in patients with normal and high sPAP respectively. Conclusion: The prevalence of pulmonary hypertension in the studied patients was 32.6%. Patients in the pulmonary hypertension group had higher levels of PTH and lower cardiac EF%.