Tricuspid Regurgitant Jet Velocity Research Articles

A case report of pulmonary atresia with intact ventricular septum: an extraordinary finding of subsystemic right ventricle

BackgroundMassive tricuspid regurgitation (TR) is the most common feature of pulmonary atresia with intact ventricular septum (PA/IVS), and mild or absent TR is observed in severe right ventricular (RV) dysplasia or RV-to-coronary fistulous connections, resulting in non-biventricular (BV) outcomes postnatally.Case summaryWe report a case of fetal severe pulmonary stenosis with IVS diagnosed at 26 weeks of gestation. The severity of RV hypoplasia did not worsen or reach indications for intrauterine intervention, while the jet velocity of TR decreased significantly during pregnancy. The fetus was definitely diagnosed with PA/IVS with mild RV dysplasia after birth. Unusually, the fetus did not experience severe TR and myocardial sinusoids, the TR jet velocity was maintained at 2.0 m/s, and the coronary artery was almost normal. The incapable RV cannot pump blood into pulmonary circulation after RV decompression from valvular perforation and balloon dilation. It may be an extraordinary finding of subsystemic RV.ConclusionPA/IVS is a heterogeneous disease with various degrees of RV dysplasia. Mild or no baseline TR is a reliable indicator with non-BV outcomes for fetal PA/IVS, even with acceptable dysplasia RV structures.

The Influence of Pericardial Fat on Left Ventricular Diastolic Function.

Heart failure is a major cause of morbidity and mortality worldwide; left ventricular diastolic dysfunction plays a leading role in this clinical context. Diastolic dysfunction may be predisposed by increased abdominal fat and, consequently, increased pericardial and epicardial adiposity. This study aimed to determine whether pericardial fat (PF) and epicardial fat (EF) are associated with left ventricular diastolic function. A total of 82 patients had their abdominal circumference measured and underwent transthoracic echocardiography to measure the thickness of PF and EF and assess the left ventricular diastolic function. Two groups were created based on mean pericardial fat (PF) thickness (4.644 mm) and were related to abdominal circumference and echocardiographic parameters. Subjects in the PF High group showed a significant decrease in septal e' (p < 0.0001), lateral e' (p < 0.0001), and E/A ratio (p = 0.003), as well as a significant increase in E/e' ratio (p < 0.0001), E wave deceleration time (p = 0.013), left atrial volume (p < 0.0001), the left ventricle mass (p = 0.003), tricuspid regurgitant jet velocity (p < 0.0001), and the left ventricle diameter (p = 0.014) compared to the PF Low group. Correlations were found between pericardial fat and nine echocardiographic parameters in the study, while epicardial fat (EP) only correlated with eight. Measurement of abdominal circumference, PF, and EF is an early indicator of diastolic changes with transthoracic echocardiography being the gold standard exam.

Effect of allogeneic hematopoietic stem cell transplantation on sickle cell disease-related organ complications: A systematic review and meta-analysis.

Sickle cell disease (SCD)-related organ complications are a major cause of morbidity and mortality in patients with SCD. We sought to assess whether hematopoietic stem cell transplantation (HSCT) stabilizes, attenuates, or exacerbates organ decline. We performed a systematic review and meta-analysis of trials investigating organ function before and after HSCT in patients with SCD. We searched MEDLINE/PubMed and EMBASE up to September 21, 2023. Continuous data were expressed as standardized mean difference (SMD) and pooled in a weighted inverse-variance random-effects model; binomial data were expressed as risk ratio (RR) using the Mantel-Haenszel random-effects meta-analyses. Of 823 screened studies, 34 were included in this review. Of these, 17 (774 patients, 23.6% adults, 86.3% HLA-identical sibling donor, 56.7% myeloablative conditioning regimen) were included in the meta-analyses. Pulmonary function remained stable. Mean tricuspid regurgitant jet velocity decreased but did not reach statistical significance. In children, estimated glomerular filtration rate decreased (SMD -0.80, p = .01), and the presence of proteinuria increased (RR 2.00, p = <.01), while splenic uptake and phagocytic function improved (RR 0.31, p = <.01; RR 0.23, p = <.01). Cerebral blood flow improved (SMD -1.39, p = <.01), and a low incidence of stroke after transplantation in high-risk patients was found. Retinopathy and avascular osteonecrosis were investigated in only one study, showing no significant changes. While HSCT can improve some SCD-related organ dysfunctions, transplantation-related toxicity may have an adverse effect on others. Future research should focus on identifying individuals with SCD who might benefit most from HSCT and which forms of organ damage are more likely to exacerbate post-transplantation.

Sickle Cell Disease Related Vasculopathies and Early Evaluation in a Pediatric Population.

Cardiovascular pathologies are ubiquitous in sickle cell disease (SCD). A targeted literature review was conducted to compare the overall epidemiology of selected vasculopathies seen in SCD (SCDVs) compared to the general population. Since many SCDV may originate in childhood, the study also focused on the retrospective investigation of SCDVs in a pediatric cohort at the Harbor-UCLA Medical Center. SCDVs were studied along patient age, β-globin genotypes, and fetal hemoglobin (HbF). Urine microalbumin/creatinine ratios (UM/Cr), trans-cranial doppler (TCD) and tricuspid regurgitant jet velocities (TRJV) were analyzed as well. Retinographies and overt vasculopathies were presented descriptively. Among 20 females and 20 males [average 8.3 years (2.3-19 years)], 70% had HbSS/Sβ0, 22.5% HbSC and 7.5%-HbSβ+. The mean(±SD) HbF% was 17.4±12.7% (30% higher in <10 vs. ≥10 y/o, and 3 times higher in SS/Sβ0). Twenty-six patients received hydroxyurea and 13/26, L-glutamine. Thirty-six patients had TCDs within 1.4±0.9 years and all laboratory values were obtained within the last 12 months. TCDs showed low-normal velocities, but 2 were higher for HbSS/Sβ0 vs. HbSC/Sβ+ (MCA-96 vs. 86 cm/s, p=0.03; and PCA-50 vs. 41, p<0.001). Nineteen of 28 patients with echocardiograms had measurable TRJV (2.46±0.19 m/s); 9 had TRJV ≥2.5-2.8 m/s, but BNP ≤80 pg/ml. SS/Sβ0 was associated with higher UM/Cr. There were 2 cases with silent infarcts, 1-Moyamoya, 2-persistent macroalbuminuria, and 1-hematuria/renal papillary necrosis. Most ≥9 y/o patients had retinographies without SCD-related changes. There was no correlation among TCD (MCA), TRJV, and UM/Cr (n=17); thus, in this subpopulation, pathologies of cerebral, cardiopulmonary, and renal vasculatures evolved independently. Patients with higher TRJV and/or overt vasculopathy (n=14) were older than ones without (12.5±4.7 vs. 6.1±3.1 y/o, p<0.001), and had lower HbF (11.4±7.6 vs. 20.6±13.8%, p=0.026). While overt SCDVs are less frequent in children, age-dependent trends/surrogate markers suggest their early origination in youth, justifying intense screening to prevent their progression with disease-modifying measures.

In vitro and clinical validation of different correction algorithms for the two-dimensional proximal isovelocity surface area method in a low-velocity flow field for quantifying tricuspid regurgitation.

The 2-dimensional proximal isovelocity surface area (2D PISA) method underestimates tricuspid regurgitation (TR) severity. Previously proposed correction algorithms should be further scrutinized. Two correction algorithms were tested. One approach involves dividing the 2D PISA effective regurgitant orifice area by a constant of 0.7 (EROA0.7). Another approach involves multiplying the unadjusted EROA by Vorifice/(Vorifice - Valiasing), where Vorifice denotes the TR jet velocity, and Valiasing represents the color aliasing velocity (EROAVo-Va). In vitro validation was performed on a commercially available multifunctional valve tester with different size orifices and peak pressure gradients. A true EROA was derived through the regurgitant volume (RVol) calculated from the tester. For clinical validation, RVol was calculated as the difference between the overall stroke volume and the forward stroke volume of the right ventricle. Volumetric EROA was derived by dividing the RVol by the TR velocity-time integral (VTI). The vena contracta area (VCA) was obtained through direct planimetry with 3D echocardiography. The mean of volumetric EROA and VCA served as the reference in clinical validation. Excellent correlation between the calculated EROAs and the true EROA was observed in vitro (r=0.98, r=0.97, and r=0.98 for uncorrected EROA, EROAVo-Va, and EROA0.7, respectively; all P values <0.0001). EROAVo-Va underestimated the true EROA and averaged 33% (P=0.3163), while EROA0.7 overestimated the true EROA and averaged 8% (P=0.0032). Clinically, these methods consistently exhibited a notable underestimation that varied with the reference EROA. This systematic underestimation was mitigated by both algorithms when either the VCA (biases of 19.6, 15.1, and 11.8 mm2 for uncorrected EROA, EROAVo-Va, and EROA0.7, respectively) or the volumetric EROA (biases of 10.1, 5.6, and 2.3 mm2 for uncorrected EROA, EROAVo-Va, and EROA0.7, respectively) served as the reference. Their ability to distinguish severe TR was similar, with area under the curve values of 0.905, 0.903, and 0.893 for uncorrected EROA, EROAVo-Va, and EROA0.7, respectively. No statistically significant differences were observed for diagnostic accuracy (all P values >0.05). Using a correction factor of 0.7 in quantifying TR provides similar accuracy when compared to other techniques. This represents a valuable clinical tool for quickly correcting the underestimation of the 2D PISA method in TR. This simple method may increase the frequency of applying the correction and earlier recognition of patients with severe TR.

Longitudinal Worsening of Left and Right Sided Cardiac Function in Patients with Sickle Cell Disease

Rationale: Sickle cell disease (SCD) is a genetic hemoglobinopathy characterized by hypercoagulability and accelerated mortality. Venous thromboembolism (VTE) occurs in 11-12% of SCD patients by age of 40 and increases mortality risk two to three-fold. Transthoracic echocardiography (TTE) can identify mortality risk factors in SCD including an elevated tricuspid regurgitant jet velocity (TRV) and diastolic dysfunction. We sought to characterize longitudinal changes in left and right sided cardiac function and to identify the impact of VTE in this process. Methods: We conducted a retrospective review of 402 consecutive SCD adults, 18 years of age and older, treated at our institution between 2003 and 2021. Deep venous thrombosis and/or pulmonary embolism with confirmatory diagnostic imaging defined VTE. Demographics, clinical history, laboratory data, and diagnostic evaluation were abstracted from the medical record. For echocardiographic data, clinical echocardiograms were individually re-analyzed with extensive coding of left ventricular (LV) and right ventricular (RV) systolic and diastolic function. Data were recorded at time of first contact or prior to VTE if applicable and were repeated at five years post-VTE. In the non-VTE group, baseline and five-year longitudinal data were obtained. Results: Within our cohort, 62% were HbSS/HbSβ 0, 56% were female, and 19% had a prior VTE. Prior history of acute chest syndrome, stroke, surgical splenectomy, and avascular necrosis was more common in the VTE group (p&amp;lt;0.01 for each comparison). Mortality was significantly higher in the VTE group compared to the non-VTE group (13% v 6%, p=0.04). In our cohort, 146 patients had initial and 5-year follow-up echocardiography (107/329 of non-VTE group, 39/75 of VTE group). Longitudinally, there were significant declines in both medial e ‘ and lateral e’ velocity and the E/A ratio, reflective of worsening left ventricular diastolic dysfunction. Right-sided cardiac function also worsened with a significantly increased TRV and right ventricular base dimension in follow-up echocardiograms. Of note, the baseline TRV was higher in the VTE group compared to the non-VTE group. In the VTE group, E/A ratio significantly decreased and RV base dimension significantly increased on follow-up study. In the non-VTE group, significant increases in TRV and RV base dimension were observed along decreases in left atrial ejection fraction, medial and lateral e', and E/A ratio on follow-up study (Table 1). Conclusions: Patients with SCD and VTE have increased mortality compared to those without VTE. Echocardiography demonstrates longitudinal worsening of left ventricular diastolic and right-sided cardiac function. These changes were more pronounced in the non-VTE group, and the lack of changes in the VTE group may reflect missing data. Our findings need to be confirmed prospectively but suggest the importance of a deeper evaluation of echocardiography to better understand the progression of SCD related cardiac dysfunction and pulmonary hypertension.

Long-Term Erythrocytapheresis Did Not Prevent Development of Severe Pulmonary Hypertension in Sickle Cell Disease

Background The WHO classifies pulmonary hypertension into five different groups based on pathophysiology, clinical presentation, and therapeutic options. The development of pulmonary hypertension (PH) in sickle cell disease (SCD) is multifactorial and can cause devastating complications. Erythrocytapheresis is utilized in patients with SCD who have multiple comorbidities or are unresponsive to first-line treatments like hydroxyurea. It is hypothesized that treatment with long-term erythrocytapheresis (LTE) could slow the progression to pulmonary hypertension by modifying the pathophysiology of the disease process. However, limited clinical data supports this transfusion modality [1]. Case Description The patient is a 17-year-old female with a history of SCD, obstructive sleep apnea (OSA), nocturnal hypoxemia, and recurrent pain crises maintained on LTE every four weeks for the past seven years. She had previously failed hydroxyurea therapy. She underwent a tonsillectomy and adenoidectomy seven years ago to treat OSA. The patient had an echocardiogram five years ago, which showed normal biventricular function and tricuspid regurgitation jet velocity. Recently she presented to the emergency department with cough, shortness of breath, fever, diarrhea, and nausea lasting for three days. Initial assessment revealed elevated liver enzymes, elevated BNP, hyperbilirubinemia, hemoglobin of 9.5 g/dL, and oxygen saturations in the 80's. Echo revealed right ventricular dysfunction and right atrial and ventricular enlargement with a tricuspid regurgitation jet velocity of 4.29 m/s and estimated right ventricular systolic pressure 90% systemic, as seen in figure 1. The patient was admitted to the PICU under concern of pulmonary hypertension crisis. She underwent a right cardiac catheterization three days into her admission and was diagnosed with severe pulmonary hypertension with a mean pulmonary artery pressure of 49 mmHg. Pulmonary capillary wedge pressure was 11 mmHg, and pulmonary vascular resistance was calculated to be 18 wood units x m 2 with 20 PPM of nitric oxide and 80% FiO2 the PVR decreased to 11 woods units x m 2 (figure 2). CTA showed subsegmental thrombosis and vascular surgery was consulted for evaluation for endarterectomy, but they decided she was not a surgical candidate. She was initiated on anticoagulation therapy with enoxaparin, sildenafil, and bosentan. Conclusions The cause of PH in this patient appears to be multifactorial. Possible etiologies include SCD-related, primary pulmonary hypertension, or subsegmental pulmonary embolism. Although LTE is increasingly used in the management of SCD, providers should not assume that a patient receiving this treatment will not progress to develop complications. Some patients on LTE may also develop progressive CNS vasculopathy and are still at risk for developing hypertension. Patients with SCD should be screened for PH if they are symptomatic or have comorbid conditions. This patient had a history of nocturnal hypoxemia and OSA, which some studies indicate are associated with pulmonary hypertension in adolescents with SCD. Screening for nocturnal hypoxemia and OSA is recommended in SCD to identify patients at high risk of PH development [2].

Improvement in Cardiac Morphology Demonstrated by Cardiac Magnetic Resonance Imaging and Echocardiography after Haploidentical Hematopoietic Cell Transplantation in Adults with Sickle Cell Disease

Cardiopulmonary complications account for approximately 40% of deaths in patients with sickle cell disease (SCD). Diffuse myocardial fibrosis, elevated tricuspid regurgitant jet velocity (TRV) and iron overload are all associated with early mortality. While HLA-matched sibling hematopoietic cell transplant (HCT) offers a potential cure, fewer than 20% of patients have a suitable donor. Haploidentical HCT allows for an increased donor pool and has recently demonstrated improved safety and efficacy. Our group has reported improved cardiac morphology via echocardiography at one year after HCT. Herein, we describe the first use of cardiac magnetic resonance imaging (CMR), the gold standard for measuring volume, mass, and ventricular function, to evaluate changes in cardiac morphology post-HCT in adults with SCD. We analyzed baseline and 1-year data from 12 adults with SCD who received nonmyeloablative haploidentical peripheral blood HCT at the NIH. Patients underwent non-contrast CMR at 3T, echocardiography, and laboratory studies. One year after HCT, patients showed marked improvement in cardiac chamber morphology by CMR, including left ventricular (LV) mass and volume (70.2 to 60.1 g/m2, p = 0.02; 114.5 to 90.6 mL/m2, p = 0.001). Furthermore, mean TRV normalized by 1 year, suggesting that HCT may offer a survival benefit. Fewer patients had pathologically prolonged native myocardial T1 times, an indirect marker of myocardial fibrosis at 1 year; these data showed a trend toward significance. In this small sample, CMR was very sensitive in detecting cardiac mass and volume changes after HCT and provided complementary information to echocardiography. Notably, post-HCT improvement in cardiac parameters can be attributed only in part to the resolution of anemia; further studies are required to determine the role of myocardial fibrosis reversal, improved blood flow, and survival impact after HCT for SCD.

The Prevalence of Pulmonary Hypertension in Beta-Thalassemia Patients in Hormozgan Province: A Cross-sectional Study

Background: Pulmonary hypertension (PH) is associated with an increased risk of cardiac failure among asymptomatic patients with beta-thalassemia. This study aimed to determine the prevalence of PH and associated risk factors in patients with beta-thalassemia major (TM) and beta-thalassemia intermedia (TI) in Hormozgan province, Iran. Materials and Methods: Eighty-nine patients, including 65 TM and 24 TI, were enrolled in this cross-sectional study. The data regarding the gender, age, history of splenectomy, and type of chelating therapy were collected, and then hematocrit, hemoglobin (Hb), and serum ferritin levels were determined. Doppler echocardiography was performed for patients, and tricuspid regurgitation jet velocity (TRV)≥2.5 m/s was used to screen PH. Eventually, the data were analyzed using SPSS. Results: The prevalence of TRV≥2.5 m/s was 21.3% in all patients, indicating that it was not significantly different between patients with TM (21.8%) and TI (20.8%). There was a significant association between the prevalence of PH and the male gender. Based on the results, TRV≥2.5 m/s was observed in both children and adults. No significant association was detected between Hb, serum ferritin levels, and splenectomy with PH prevalence. Conclusion: The findings revealed that PH is common in both children and adult patients with TM and TI in our population and should be considered to choose the optimal treatment of patients with TM and TI.

Dual-energy computed tomography to detect early pulmonary vascular changes in children with sickle cell disease: a pilot study.

Pulmonary hypertension (PH) is a rare but fatal complication of sickle cell disease (SCD) that is possibly reversible if treated early. Dual-energy computed tomography (DECT) is a valuable tool for diagnosing PH. We attempted to determine if DECT can detect early signs of PH in children with SCD. This prospective observational pilot study was conducted at the Geneva University Hospitals and was approved by the local human ethics committee (CCER 2019-01975). A written informed consent was obtained from the patients and/or their legal guardian. Eight children (consisting of five girls and three boys) with homozygous SCD were included in the study. They underwent full cardiological workup using transthoracic echocardiography (TTE) and cardiopulmonary exercise test (CPET), as well as DECT. The median age of the children was 11 years old (range 8-12). All patients exhibited a normal biventricular systo-diastolic function using the TTE. The median tricuspid regurgitant jet velocity value was 2.24 m/s (range 1.96-2.98). Four children were found to have signs of vasculopathy detected on DECT. Of them, two had abnormal screening test results. They both had an increased VE/VCO2 slope during CPET and an increased TVR of >2.5 m/s on TTE. DECT is capable of identifying early signs of pulmonary vascular disease in children with SCD. Further studies are needed to understand the correlation between DECT abnormalities and hemodynamic pulmonary circulation better.

Association of haemolysis markers, blood viscosity and microcirculation function with organ damage in sickle cell disease in sub-Saharan Africa (the BIOCADRE study).

Sickle cell anaemia (SCA) is a monogenic disease with a highly variable clinical course. We aimed to investigate associations between microvascular function, haemolysis markers, blood viscosity and various types of SCA-related organ damage in a multicentric sub-Saharan African cohort of patients with SCA. In a cross-sectional study, we selected seven groups of adult patients with SS phenotype in Dakar and Bamako based on the following complications: leg ulcer, priapism, osteonecrosis, retinopathy, high tricuspid regurgitant jet velocity (TRV), macro-albuminuria or none. Clinical assessment, echocardiography, peripheral arterial tonometry, laboratory tests and blood viscosity measurement were performed. We explored statistical associations between the biological parameters and the six studied complications. Among 235 patients, 58 had high TRV, 46 osteonecrosis, 43 priapism, 33 leg ulcers, 31 retinopathy and 22 macroalbuminuria, whereas 36 had none of these complications. Multiple correspondence analysis revealed no cluster of complications. Lactate dehydrogenase levels were associated with high TRV, and blood viscosity was associated with retinopathy and the absence of macroalbuminuria. Despite extensive phenotyping of patients, no specific pattern of SCA-related complications was identified. New biomarkers are needed to predict SCA clinical expression to adapt patient management, especially in Africa, where healthcare resources are scarce.

#4358 INCREASED RV PRESSURE AS A PREDICTOR OF ACUTE DECOMPENSATED HF IN ESRD PATIENTS ON MAINTENANCE HD

Abstract Background and Aims Many patients with end-stage renal disease (ESRD) on hemodialysis (HD) have reduced vascular compliance and are likely to develop heart failure (HF). This study aimed to determine the factors associated with acute decompensation events among ESRD patients undergoing HD. Methods We retrospectively investigated ESRD patients on HD using a medical record review. We divided the patients into those admitted to hospital due to acute decompensated heart failure (ADHF) and those who were not. We compared the medical histories, electrocardiograms, and echocardiographic and laboratory data between the two groups. The cut-off value of the TR jet velocity for predicting an ADHF with corresponding sensitivity and specificity was estimated using a receiving operator characteristic (ROC) curve analysis. A p value &amp;lt; 0.05 was considered to indicate statistical significance. Results Of the 188 ESRD patients on HD, 87 were excluded, and 101 were enrolled (mean age: 63.7 years; 52.1% male). Thirty patients (29.7%) were admitted due to ADHF. These patients exhibited similar left ventricular ejection fraction (LVEF), left ventricular (LV) mass index, and E/E′ values compared to the non-ADHF group. However, the ADHF group exhibited significantly higher tricuspid regurgitation (TR) jet velocity (2.9±0.6 vs. 2.5±0.4 m/s; p = 0.004) and right ventricular systolic pressure (RVSP) (43.5±17.2 vs. 34.2±9.9 mmHg; p = 0.009) than the non-ADHF group, respectively. A multivariate logistic regression analysis demonstrated that the TR jet velocity (odds ratio, 8.356; 95% confidence interval, 1.806–38.658; p = 0.007) was an independent predictor of ADHF after adjusting for age and sex, while the LVEF and E/E′ were not. Conclusions Our data showed that an increased TR jet velocity was an independent predictor of ADHF events in ESRD patients on HD, but the LVEF and E/E′ were not.

0488 The Relationship between Myocardial Blood Flow and Diastolic Function in a Clinical Population with Obstructive Sleep Apnea

Abstract Introduction Emerging evidence links abnormal myocardial blood flow reserve (MBFR), a marker of coronary microvascular dysfunction (CMD), and heart failure with preserved ejection fraction (HFpEF). However, the relationship between CMD and diastolic dysfunction (DD) in patients with OSA remains unclear. We analyzed the relationship between OSA, abnormal MBFR and markers of DD in a patient cohort. Methods Using healthcare records, we generated a cross-sectional database of 231 individuals who had sleep testing, echocardiogram(s), and cardiac PET stress test. Abnormal MBFR was defined as the stress-to-rest ratio of myocardial blood flow &amp;lt; 2.0. We created DD score with a point each given to a) left atrial volume index (LAVI) ≥34, b)average E/e’ ratio&amp;gt;14/lateral e’&amp;gt;10/medial e’&amp;gt;7, and in a subgroup of 122 individuals with available data we added c)tricuspid regurgitation jet (TR) velocity &amp;gt; 2.7m/s. Higher scores suggest greater likelihood of DD. Models were adjusted for demographics and cardiometabolic risk factors. Results The mean (SD) age and BMI was 60(11) years and 39.5(8.7) kg/m2; 61% were female. Eighty-four participants had severe OSA (apnea-hypopnea index ≥ 30/hr). Compared to non-severe OSA, severe OSA was associated with 2-fold odds of abnormal MBFR (adjusted OR [aOR) 2.1, 95%CI:1.1–4.0). However, there was no association with abnormal LAVI, abnormal E/e’ (average E/e’&amp;gt;14 vs. &amp;lt; 9), or elevated TR velocity. In the adjusted model, abnormal MBFR was associated with abnormal E/e’ (aOR 4.4 [95% CI: 1.6-11.8]) and elevated TR velocity (aOR: 3.7 [95%CI: 1.3-10.9]). Abnormal MBFR was associated with increase in DD score (range 0–2; aOR per-unit increase = 1.7 [95% CI: 1.0-3.0]. In the subset with data on TR velocity, abnormal MBFR was associated with a three-fold increase in the odds of a unit increase in DD score (range 0–3; aOR 3.3 [95% CI: 1.5,7.4]). The association between abnormal MBFR and DD was present regardless of OSA severity. Severe OSA was not associated with DD. Conclusion Abnormal MBFR/CMD may be implicated in the development of DD and HFpEF in patients with OSA. MBFR assessment may be useful in HFpEF risk stratification in non-severe OSA. Larger studies are required to determine the role of CMD in the development of DD/HFpEF in OSA. Support (if any)  

Prognostic significance of incorporating exercise tissue doppler mitral annular early diastolic velocity in exercise diastolic dysfunction assessment.

The existing algorithm for defining exercise-induced diastolic dysfunction incorporates resting e' velocity as a surrogate of myocardial relaxation. The additive prognostic value of incorporating post-exercise e' velocity in definition of exercise-induced diastolic dysfunction is poorly studied. To define the additive prognostic value of post-exercise e' septal velocity in the assessment of exercise-induced diastolic dysfunction compared to the traditional approach. This retrospective study included 1409 patients undergoing exercise treadmill echocardiography with available full set of diastolic variables. Doppler measures of diastolic function included resting septal e' velocity, post-exercise septal e' velocity, post-exercise E/e' ratio, and post-exercise tricuspid regurgitant jet velocity. Approaches incorporating resting septal e' velocity and post-exercise septal e' velocity were compared in defining exercise-induced diastolic dysfunction, and for association with adverse cardiovascular outcomes. The mean age of study subjects was 56.3 ± 16.5 years and 791 (56%) patients were women. A total of 524 patients had disagreement between resting and post exercise septal e' velocities, and these values showed only weak agreement (kappa statistics: .28, P = .02). All categories of the traditional exercise-induced DD approach incorporating resting septal e' velocity witnessed reclassification when exercise septal e' velocity was used. When both approaches were compared, increased event rates were only evident when both approaches agreed on exercise-induced diastolic dysfunction (HR: 1.92, P < .001, 95% CI: 1.37-2.69). This association persisted after multivariable adjustment and propensity score matching for covariates. Incorporation of post-exercise e' velocity into the set of variables defining exercise-induced diastolic dysfunction can improve the prognostic utility of diastolic function assessment.

5612539 TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2A CROSSWALK-C TRIAL EVALUATING THE EFFICACY OF CROVALIMAB AS ADJUNCT TREATMENT IN THE PREVENTION OF VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, with either homozygous inheritance or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. Hemoglobin S, produced as a result of this point mutation, polymerizes within RBCs under certain conditions, distorting them and generating dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute painful episodes called VOEs. Pts with SCD may also have severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. Current therapies for SCD include hydroxyurea, as well as newer treatments such as L-glutamine, crizanlizumab, and voxelotor. Despite these treatments, considerable morbidity and mortality among pts with SCD represents a significant unmet medical need. Complement pathway activation has been reported in pts with SCD at baseline, in acute pain crises, and in delayed hemolytic transfusion reaction. Accumulating nonclinical data suggest the potential multimodal role for complement dysregulation in the pathophysiology of SCD, including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.1 The complement pathway can be targeted with crovalimab, a novel anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. In a Phase 1/2 paroxysmal nocturnal hemoglobinuria (a complement-mediated disorder) study, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety.2 Aim: CROSSWALK-c (NCT05075824) is a randomized, double-blind, placebo-controlled, Phase 2a study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β0 thalassemia (HbSβ0), and presenting with 2 to 10 VOEs are eligible, including pts on concurrent SCD-directed therapies. Vaccinations against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumoniae are required. Pts with a history of hematopoietic stem cell transplant will be excluded. Eligible pts will be randomized 1:1 to the crovalimab or placebo arms (Figure). An initial intravenous loading dose of crovalimab or placebo will be given on Week 1, Day 1, followed by SC dose on Week 1, Day 2, and then weekly SC doses on Weeks 2–4. Starting Week 5, a maintenance dose will be given every 4 weeks for 48 weeks. All study treatment will be given according to a weight-based tiered dosing schedule (pts weighing ≥ 40 kg to < 100 kg and pts ≥ 100 kg). The primary objective is to evaluate the efficacy of crovalimab vs placebo based on the annualized rate of medical facility VOEs. Key secondary efficacy objectives are the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin–creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetic, immunogenicity, and exploratory biomarker objectives will also be evaluated. Protocol updates are in progress. Results: Primary results are expected in July 2024. Summary: CROSSWALK-c is enrolling pts with SCD and chronic VOEs in six countries.

RASA3 is a candidate gene in sickle cell disease-associated pulmonary hypertension and pulmonary arterial hypertension.

Pulmonary hypertension (PH)is associated with significant morbidity and mortality. RASA3 is a GTPase activatingprotein integral to angiogenesis and endothelial barrier function. In this study, we explore the association of RASA3 genetic variation with PH risk in patients with sickle cell disease (SCD)-associatedPH and pulmonary arterial hypertension (PAH).Cis-expression quantitative trait loci (eQTL)were queried for RASA3 using whole genome genotype arrays and gene expression profiles derived from peripheral blood mononuclear cells (PBMC)of three SCD cohorts. Genome-wide single nucleotide polymorphisms (SNPs)near or in the RASA3 gene that may associate with lung RASA3 expression were identified, reduced to 9 tagging SNPs for RASA3 and associated with markers of PH. Associations between the top RASA3 SNP and PAH severity were corroborated using data from the PAH Biobank and analyzed based on European or African ancestry (EA,AA).We found that PBMC RASA3 expression was lower in patients with SCD-associated PH as defined by echocardiography and right heart catheterization and was associated with higher mortality. One eQTL for RASA3 (rs9525228) was identified, with the risk allele correlating with PH risk, higher tricuspid regurgitant jet velocity and higher pulmonary vascular resistance in patients with SCD-associated PH. rs9525228 associated with markers of precapillary PH and decreased survival in individuals of EA but not AA. In conclusion, RASA3 is a novel candidate gene in SCD-associated PH and PAH, with RASA3 expression appearing to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.

111 POST-OPERATIVE OUTCOME OF ADULT PATIENTS WITH PRE-TRICUSPID SHUNT UNDERGOING DEFECT CLOSURE

Abstract Background patients with pulmonary arterial hypertension (PAH) associated with corrected congenital heart disease (CHD) have a worse prognosis than other 3 groups of patients with PAH associated with CHD (Eisenmenger, small defect, prevalent systemic-to-pulmonary shunt). For this reason, in CHD the indication and timing of defect repair should be evaluated carefully. Current recommendations rely essentially on pulmonary vascular resistance (PVR) when deciding about defect closure, but this may be insufficient as PAH may develop even in cases of normal pre-operative PVR. In particular, patients with PVR below 3 WU are usually deemed operable and patients between 3 and 5 WU (gray zone) are deemed operable in case of significant persistence of left-to-right shunt. Detecting preoperative characteristics of patients who developed PAH after pre-tricuspid shunt repair can be helpful when deciding about CHD correction. Methods we enrolled adult patients referred to our centre for the suspicious of PAH after pre-tricuspid shunt correction from 2006 to 2021. We evaluated clinical, echocardiographic and hemodynamic parameters before and after defect repair (a post-correction hemodynamic evaluation was performed only in case of non-invasive signs of PAH) and PAH after defect closure was defined by the concomitant occurrence of a mean pulmonary artery pressure (mPAP) &amp;gt;25 mmHg and PVR &amp;gt;3 WU. Continuous variables were summarized using mean and standard deviation and Student's t-test was used for comparisons. Results sixty patients were included in the final analysis. After shunt repair, 10 patients (16.6%) were diagnosed with PAH during the long-term follow-up, with no differences given by the type of defect or type of correction. As expected, these patients already had an abnormal baseline hemodynamic profile: 7 had a clear PAH diagnosis before the correction [mPAP &amp;gt;25 mmHg with PVR between 3 and 5 WU and with a pulmonary/systemic cardiac output ratio of at least 1.5] while 3 had pulmonary hypertension related to high pulmonary blood flow (mPAP &amp;gt;25 mmHg and PVR &amp;lt;3 WU). At the baseline hemodynamic evaluation, patients with PAH after shunt repair had higher mPAP (39±6 vs 24±10 mmHg, p &amp;lt;0.001) and PVR (3.7±1.2 vs 1.5±0.9, p &amp;lt;0.001) and lower mixed venous oxygen saturation (81±3 vs 87±3, p &amp;lt;0.001). At the baseline echocardiographic evaluation, patients with PAH after shunt repair had a greater right ventricular hypertrophy (RV wall thickness 0.7±0.1 vs 0.5±0.2 cm, p= 0.011), tricuspid regurgitation jet velocity (424±63 vs 319±62 cm/s, p &amp;lt;0.001) and a significant lower RV fractional area change (34±8 vs 43±9%, p= 0.009). Conclusions currently there are no established evidence-based algorithms to predict the development of PAH after defect correction. Our study shows that this condition may persist or develop even when PVR values are lower than 5 WU despite a significant left-to-right shunt before defect closure. Patients with grey zone PVR values require a global clinical, instrumental and hemodynamic assessment that takes into account more than bare calculated PVR that, especially in patients with a high pulmonary blood flow, can be less reliable.

Venous Thromboembolism Is Associated with Right-Sided Cardiac Dysfunction and Increased Mortality in Patients with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a hypercoagulable state. Approximately 11-12% of patients with SCD have a venous thromboembolism (VTE) by age 40 which portends a nearly three-fold increased mortality risk compared to those without VTE. Additionally, echocardiographic findings of right-sided cardiac dysfunction and pulmonary hypertension (PH) are also independent mortality predictors in SCD. In the general population, VTE is a risk factor for PH; however, the association in SCD is uncertain. We hypothesized that patients with SCD and VTE have a greater frequency of right-sided cardiac dysfunction by transthoracic echocardiogram (TTE) and associated mortality risk compared to those without VTE. Methods: We performed a retrospective chart review of 402 consecutive SCD patients who received care at our institution between 2003 and 2021. VTE was defined as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) by diagnostic imaging. Demographics, clinical and laboratory data, VTE diagnostic imaging, and TTE results were obtained from each subject. For those with VTE, we recorded data pre-VTE and 5 years post-VTE. For those without VTE, we recorded data at entry into the database and 5 years later. The atrial and ventricular size, right and left ventricular function, valvular function, and tricuspid regurgitant jet velocity (TRV) were collected from each echocardiogram. Data were analyzed using Fisher's exact, Sign-ranked and McNemar's tests. Results: In our cohort, 251 subjects (62%) were HbSS/HbSβ0 and 227 (56%) were female. VTE occurred in 75 individuals (19%) with deep vein thrombosis in 35 (47%), pulmonary embolism in 50 (67%), and both observed in 9 (12%). Prior history of acute chest syndrome, avascular necrosis, stroke, and surgical splenectomy was associated with VTE (p<0.01 for all). History of VTE was associated with an increased mortality rate during our study period compared to those without VTE (13% vs 6%, p=0.04). Within our cohort, 183 patients had initial and follow-up echocardiography (77% of VTE group, 38% of non-VTE group). In the VTE group, there was a higher frequency of right atrial enlargement five years post-VTE compared to pre-VTE (p=0.03). There was a non-significant trend towards decreased right ventricular function over five years in the VTE group (p=0.08) Neither of these findings occurred in the non-VTE group. There was no significant change in TRV after five years of follow-up in either group; however, only 45% of echocardiograms had TRV ascertained. Conclusions: Sickle cell disease patients who sustained a VTE had an increased risk of prior complications and subsequent mortality compared to those without a VTE. The presence of increased right atrial size and a trend towards right ventricular dysfunction five years post-VTE suggest development of pulmonary hypertension despite lack of change in the TRV. These findings need to be explored by a deeper analysis of the echocardiography, and in the future, a prospective study.

Individual Red Blood Cell Fetal Hemoglobin Concentrations Determined By Imaging Flow Cytometry and the Number of F Cells Are Very Good Predictors of Clinical Response to Increased Level of HbF and Are Associated with Hemolysis, Tricuspid Regurgitant Jet Velocity, and Sickle Retinopathy in Adult Sickle Cell Disease Patients

Sickle cell disease (SCD) patients with similar total fetal hemoglobin (HbF) levels may present with different severity, which is attributed to the heterogeneous distribution of HbF among red blood cells (RBCs) with varying percentages of circulating HbF-containing RBCs (% F cells). Steinberg et al. (2014) proposed that an individual HbF concentration per cell (iHbF) above 10pg inhibits the polymerization of HbS, so the development of precise methods to quantify iHbF and the percentage of F cells may allow clinicians to use those parameters as targets to monitor patient treatment. We devised a novel procedure to very accurately measure and quantify iHbF using imaging flow cytometry (Amnis Imagestream) and investigated its correlations with clinical manifestations. Samples from 54 adult SCD patients (22 [41%] female, 39 [72%] on hydroxyurea) were used to acquire images from RBCs labeled with fluorescent anti-HbF antibody and were analyzed using IDEAS software v 6.2. Along with the hematimetric data and HPLC quantification of total HbF of each sample, we modified the formulas by Maier-Redelsperger et al. (1994) and Horiuchi et al. (1995), with minimization of interference from autofluorescence of non-F cells, correction for area and fluorescence intensity, and analyzed RBC subpopulations with varying levels of HbF expression. Statistical analysis was performed using R considering a p value <0.05 to be statistically significant. We did not find associations of iHbF with alpha thalassemia carrier state or beta globin cluster haplotypes Benin or Bantu, the most common in our population. Perpendicular cutoff correlation studies defined two patient populations: one group with lower mean iHbF (9.9pg) and lower % F cells (28.2%) and another group with a higher mean iHbF (15.8pg) and higher mean % F cells (72.5%). The latter group had a lower frequency of vaso-occlusive crises (p=0.011). That was further validated with our finding that the cutoffs of % F cells>30% and iHbF>10pg were strongly associated with lower absolute reticulocyte counts (p<0.001), LDH (p=0.002), and indirect bilirubin (p<0.001). The association between hemolysis and iHbF was further explored regarding pulmonary hypertension, showing that a value of iHbF>10pg was associated with a lower median tricuspid regurgitant jet velocity than in patients with iHbF<10pg (2.72m/s vs. 2.29m/s, p=0.046). We also found an association of a mean iHbF<8pg with the presence of sickle retinopathy (p=0.002). Patients with retinopathy had a lower mean iHbF and % F cells than those without it (7.08pg vs. 8.75pg, p=0.032; 48.5% vs. 71.0%, p=0.043, respectively), suggesting increments in iHbF and % F cells may be protective against sickle retinopathy, a complication not usually associated with high hemolytic rates. Our results suggest that a percentage of F cells above 30% along with individual RBC HbF concentration of 10pg may be protective against complications in SCD patients and, therefore, should be explored as goals for hydroxyurea therapy in this population. In addition, the data presented here suggest further studies on the efficacy of HbF induction therapy against the development of sickle retinopathy may be performed in a large population of sickle cell disease patients.

Abstract 14839: Clinical, Polysomnographic and Echocardiographic Correlates of Excessive Daytime Sleepiness

Introduction: Excessive Daytime Sleepiness (EDS) has been associated with adverse CVD outcomes. However, the mechanisms of elevated CVD risk in persons with EDS remains uncertain. In this study, we examined polysomnographic and echocardiographic correlates of EDS in a population of adults who underwent both sleep and cardiac stress tests. Methods: We analyzed data from 264 participants who had an in-lab polysomnogram (PSG) and a cardiac stress test between 2016 and 2019. All patients completed the Epworth Sleepiness Scale (ESS) questionnaire. EDS was categorized into 3 groups no EDS (ESS&lt;10), non-severe EDS (ESS 10-14), and severe EDS (ESS ≥15). T90%, the percentage of sleep time spent with oxygen desaturation &lt; 90%, was categorized into severe (≥ 20%) and non-severe nocturnal hypoxemia (&lt;20%). We assessed the relationship between EDS and CV risk factors, and EDS and echocardiographic parameters of diastolic dysfunction such as the E/e’, E/A ratio, left atrial volume index, tricuspid regurgitation jet velocity, and systolic function (ejection fraction, EF). Results: The mean age (SD) of the participants was 59 (11) years, and 59% were female. In logistic regression analysis severe EDS was associated with &gt;3-fold odds of a history of stroke or TIA [a OR 3.2 (95%CI:1.2-8.2), P=0.017] and nearly 4 times the odds of severe nocturnal hypoxemia [aOR 3.8 (95%CI: 1.7-8.6, P=0.002] compared to those with no EDS. We found no other association between EDS and demographic or CV characteristics or PSG variables. In the subset of patients with available echocardiogram data (n=199 - 213), there was no association between EDS and EF or echocardiographic parameters of diastolic dysfunction. Conclusions: EDS is strongly associated with severe nocturnal hypoxia and a history of stroke or TIA in adults with OSA. Further studies are needed to characterize the relationship between EDS and CVD.