Prevalence and Factors Associated with Echocardiographic Abnormalities in Children with Sickle Cell Disease; Results from the Displace Study

Introduction Cardiopulmonary complications remain a leading cause of morbidity and mortality in adults with sickle cell disease (SCD) particularly for people with sickle cell anemia (SCA) who have lower hemoglobin and higher baseline hemolysis. Many cardiovascular complications are not identified until adulthood when patients have developed irreversible pathology. Previous studies have suggested that SCD-specific therapies like hydroxyurea (HU) may be beneficial in reducing the hemolysis associated vascular dysfunction and reducing cardiopulmonary complications. This study describes the prevalence of and factors associated with left ventricular hypertrophy (LVH), left atrial dilation and high tricuspid regurgitant jet velocity (TRJV) in children with SCA. We also describe the association between patent foramen ovale (PFO) and ischemic stroke in children with SCA. Method This crossectional study used data collected as part of the Dissemination and Implementation Stroke Prevention Looking at the Care Environment (DISPLACE) study. American society of echocardiography (ASE) guidelines and cutoff values were used to define abnormalities in the echocardiographic variables. Results A total of 1414 children were included in the analysis. The median age was 9 years (range 5-12 years) and median hemoglobin of 8.6 g/dl. The most common abnormal findings on echocardiogram was left atrial dilatation (61% of the children), LVH (20% of children) and high TRJV (23% of children). Children with abnormal echocardiographic variables were more likely to have lower hemoglobin level. Children with LVH were more likely to have left atrial dilation, high TRJV and abnormal left ventricular end diastolic diameter (LVIDD). Multivariable analysis of LVH was conducted and included variables: age, sex, hemoglobin, reticulocyte count, treatment with chronic red cell transfusion therapy (CRCT) or hydroxyurea therapy (HU). Baseline hemoglobin levels were associated with the lower odds of having LVH (OR: 0.71, 95% CI: 0.60 - 0.84). The odds of LVH increases for every one-year increase in age (OR: 1.07, 95%CI: 1.02-1.13). Similarly, the odds of LVH was lower among males than females (OR:0.59, 95%CI: 0.38-0.93). The odds of LVH were higher among those on HU compared to no therapy (OR: 1.83, 95% CI: 1.41 - 2.37). Although not all children had a bubble, study, a total of 90(6.3%) had an identified PFO. We assessed the relationship between PFO and ischemic stroke. 102 (7.2%) of the 1414 children had an ischemic stroke. Out of this 5 (5.6%) had PFO. We also assessed the relationship between PFO and abnormal TCD. 142 (10.0%) of the 1414 had abnormal TCD and only 9 (10%) of the 142 had PFO. There is no evidence that the odds of having stroke was higher among those with PFO compared to those without (OR: 1.49, 95% CI: 0.20- 11.03, p = 0.6994). Similarly, no evidence that the odds of having abnormal TCD is higher among those with PFO compared to those without (OR: 0.85, 95% CI: 0.17- 4.25, p = 0.8463). Conclusion Overall results of the study showed echocardiographic abnormalities are common in and occur at an early age in children with SCA. The risk of LVH increases with increasing age and with lower hemoglobin. Further, we found higher use of HU among those with LVH, suggesting that possibly children with more severe disease requiring HU are also at increased risk of cardiopulmonary complications. Given the fact that high TRJV is an independent risk factor for death in adults with SCD and left atrial dilatation has been shown to be an independent predictor of cardiac events, our data support further investigation into identifying early biomarkers of cardiovascular morbidity in children with SCD. Figure 1 Figure 1. Disclosures Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy.

Abstract 1122‐000069: Left Atrial Dilatation, Atrial Fibrillation and Stroke; A 5 Year Follow Up Study

Introduction : Our prior study showed that Atrial Fibrillation (AFib) and not Left Atrial Dilatation (LAD) was associated with ischemic stroke (IS) in a cross‐sectional analysis. We sought to validate these findings in a prospective 5‐year follow up study. Methods : Patients with transthoracic Echocardiography (TTE) completed from March to September 2016 were selected . New diagnoses of Afib and IS over the interval period of 5 years (2016‐2021) were obtained. Regression models were used to analyze LAD, Afib and other covariates as they relate to IS, as well as the association of baseline LAD to subsequent AFib. Results : There were 7988 subjects analyzed. Of those; 578 had IS before 2016 and an additional 249 patients had no follow‐up information, who were excluded from the analysis. Of the remaining 7161, mean age was 65.1, 54% females, 52% Caucasian, 43% African American, 9% developed new AFib and3% had a new IS during follow‐up. The median follow‐up was 47 months (IQR 14–60). Also, 54% patients had a normal LA, 13% were mildly dilated, 13% were moderately and 20% were severely dilated, of which 6%, 11%, 13% and 15% were found to have new AFib, respectively (p<0.001). Mild and Severe LAD was more likely to experience IS when compared to normal LAD and moderate LAD showed a trend (Model‐1). Prior diagnosis of LAD or Afib was associated with a new IS on univariate analysis (Model‐2). However, on multivariate analysis, only Afib remained associated (Models‐3/4). Additionally, anticoagulant use was associated with a reduced risk of IS. (Model‐4) Conclusions : LAD increased the probability of AFib discovery during follow‐up and was associated with both Afib and IS. However, AFib, not LAD, was independently associated with IS. Medical treatment of AFib was associated with a reduction in future IS, reaffirming the need to identify and treat AFib. Our study suggests the presence of LAD on TTE is a useful marker for identification of high risk individuals for Afib and prospective investigations to identify Afib would provide primary IS prevention.

Abstract 17275: The SGLT2 Inhibitor Empagliflozin Ameliorates Left Atrial Dilatation in Non-Diabetic Patients With Heart Failure With Reduced Ejection Fraction: A Secondary Analysis of the EMPATROPISM Trial

Background: SGLT2 inhibitors (SGLT2i) improve prognosis in HFrEF patients. We recently demonstrated in a porcine model of non-diabetic HFrEF that empagliflozin (EMPA) ameliorates adverse cardiac remodeling and improves LV systolic function. However, the effect of EMPA on left atrial (LA) dilatation has not yet been studied Hypothesis:: Empagliflozin ameliorates left atrial dilatation in non-diabetic HFrEF patients Methods: The EMPATROPISM clinical trial investigated the efficacy and safety of EMPA in non-diabetic HFrEF patients. 84 patients were randomized to EMPA 10mg daily for 6 months or placebo on top of optimal medical treatment, and were evaluated with cardiac magnetic resonance (CMR). LA Volumes were quantified by CMR using the Simpson method (the number of slices in the usual short axis SSFP cine sequence was increased to cover both LV and the whole of LA. The primary endpoint was change in LVEDV. Prespecified secondary endpoints were changes in maximal and minimal LA volumes (ΔMax LA Vol and ΔMin LA Vol) at the end of 6 months between both arms Results: 80 patients completed the follow up period. There were no differences at baseline in LVEDV (220±75 vs 209±68mL for EMPA vs placebo, p=0.5) or LVEF (36±8 vs 37±8%, p=0.7). There were no differences at baseline in both groups in either maximal or minimal LA volume (Table). In the primary endpoint, EMPA-treated patients showed decrease in LVEDV and increase in LVEF (ΔLVEDV -25±25 vs -1±25mL, p<0.001; and ΔLVEF 6±4 vs 0±4%, p<0.001 for EMPA vs placebo). EMPA-treated patients exhibited a reduction of both maximal LA volume (ΔMax LA Vol -16.2±17.8 vs 11.4±25.9mL for EMPA vs placebo, p<0.001) and minimal LA volume (ΔMin LA Vol -11.3±13.3 vs 6.4±19.3mL for EMPA vs control, p<0.001) Conclusions: In HFrEF patients without diabetes, treatment with empagliflozin ameliorates left atrial dilatation. As LA volume is a surrogate for chronic filling pressures, this reduced LA volume suggest improved diastolic function with EMPA

Results of surgical correction of gigantic left atrium

We presented a clinical case of surgical treatment of gigantic left atrium in longstanding mitral regurgitation due to mitral valve disease diagnosed 23 years ago (patient refused surgery and was on medical treatment) and complicated by atrial fibrillation. The patient was referred for surgery with complaints on severe dyspnea on minimal exertion, weakness, fatigue, palpitations and massive leg edema. Diagnosis was established using electrocardiography, chest X-Ray, transthoracic and transesophageal echocardiography, and computed tomography. The patient underwent mitral valve replacement, tricuspid valve annuloplasty and left atrial reduction surgery (atrioplasty by Kawazoe). After surgery, left atrial volume decreased from 813 ml to 294 ml and antero-posterior size from 11.2 to 6.2 cm. The patient was discharged on 8th day after surgery. Control examinations after 6 months and 1 year showed reduction of left atrial volume (319 ml and 294 ml); patient feels well and has no complaints. Thus, our case demonstrated reduction of left atrium early in postoperative period and its slow reduction after surgery during 1 year. It is also showed human reserve capacity and possibility of left atrial dilatation to such sizes. Late diagnosis of such changes in heart is possibly related to the fact that patient was afraid to see doctors and undergo surgery. The left atrial cavity size determination can be done intraoperatively using method of surgical glove we suggested.

Abstract TP173: Reduced Ejection Fraction and Left Atrial Dilatation are Independently Associated With Cardioembolic Stroke

Introduction: The role of heart failure and left atrial dilatation as independent risk factors for ischemic stroke has remained controversial. The goal of this study is to evaluate the association between reduced ejection fraction (EF) and left atrial dilatation with cardioembolic stroke. Methods: Four hundred fifty-three patients with ischemic stroke admitted to the University of California, Irvine between 2016-2017 were included based on the following criteria: age >18 and availability of echocardiogram within 3 months of diagnosis. Stroke was subdivided into cardioembolic and non-cardioembolic based on MRI findings. EF was categorized into normal: 52-72% (male), 54-74% (female), mildly abnormal: 41-51%(male), 41-53% (female), moderately abnormal: 30-40% (same in both genders), and severely abnormal: <30% (same in both genders). Other variables included: left atrial volume size categorized into normal (≤34 ml/m 2 ) vs. enlarged (≥35 ml/m 2 ), gender, hypertension (SBP≥140 or DBP≥ 90), and known history of atrial fibrillation. Results: Two hundred eighteen patients were identified to have cardiomebmolic stroke and two hundred thirty-five with non-cardioembolic stroke. Among patients with cardiomebmolic stroke, 49 (22.4%) and 142 (65%) had reduced EF and enlarged left atrium, respectively, as compared to 19 (8.1%) and 65 (27.7%) in patients with non-cardioembolic stroke. The number of patients with reduced EF and left atrial enlargement were significantly higher in patients with cardioembolic stroke (P<0.001). The odds of cardioembolic stroke were 2.0 and 8.8 times higher in patients with moderately and severely reduced EF, respectively, when compared to patients with normal EF. The odds of cardioembolic stroke was 2.4 times higher in patients with enlarged left atrial size when compared to patients with normal left atrial size. Conclusions: Our results have shown an independent association between moderately and severely reduced EF and enlarged left atrial size with cardioembolic stroke. Heart failure and left atrial dilatation may increase the risk of stroke regardless of the presence of atrial fibrillation, which warrants further studies to determine the appropriate treatment for secondary stroke prevention such as anticoagulation.