Early initiation of disease-modifying therapy can impede or prevent diffuse myocardial fibrosis in sickle cell anemia.
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ABSTRACT:
SUBMITTER: Niss O
PROVIDER: S-EPMC9479038 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Early initiation of disease-modifying therapy can impede or prevent diffuse myocardial fibrosis in sickle cell anemia.
Niss Omar O Detterich Jon J Wood John C JC Coates Thomas D TD Malik Punam P Taylor Michael D MD Quinn Charles T CT
Blood 20220901 11
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Project description:Sickle cell anemia (SCA)-related cardiomyopathy is characterized by diastolic dysfunction and hyperdynamic features. Diastolic dysfunction portends early mortality in SCA. Diastolic dysfunction is associated with microscopic myocardial fibrosis in SCA mice, but the cause of diastolic dysfunction in humans with SCA is unknown. We used cardiac magnetic resonance measurements of extracellular volume fraction (ECV) to discover and quantify diffuse myocardial fibrosis in 25 individuals with SCA (mean age, 23 ± 13 years) and determine the association between diffuse myocardial fibrosis and diastolic dysfunction. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium, and diastolic function was assessed by echocardiography. ECV was markedly increased in all participants compared with controls (0.44 ± 0.08 vs 0.26 ± 0.02, P < .0001), indicating the presence of diffuse myocardial fibrosis. Seventeen patients (71%) had diastolic abnormalities, and 7 patients (29%) met the definition of diastolic dysfunction. Participants with diastolic dysfunction had higher ECV (0.49 ± 0.07 vs 0.37 ± 0.04, P = .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; 191 ± 261 vs 33 ± 33 pg/mL, P = .04) but lower hemoglobin (8.4 ± 0.3 vs 10.9 ± 1.4 g/dL, P = .004) compared with participants with normal diastolic function. Participants with the highest ECV values (≥0.40) were more likely to have diastolic dysfunction (P = .003) and increased left atrial volume (57 ± 11 vs 46 ± 12 mL/m2, P = .04) compared with those with ECV <0.4. ECV correlated with hemoglobin (r = -0.46, P = .03) and NT-proBNP (r = 0.62, P = .001). In conclusion, diffuse myocardial fibrosis, determined by ECV, is a common and previously underappreciated feature of SCA that is associated with diastolic dysfunction, anemia, and high NT-proBNP. Diffuse myocardial fibrosis is a novel mechanism that appears to underlie diastolic dysfunction in SCA.
| S-EPMC5510791 | biostudies-literature
Project description:Elevated tricuspid regurgitant velocity (TRV) ≥2.5 m/s is a predictor of disease severity in adults and children with sickle cell anemia (SCA), but how disease-modifying therapies (DMTs) affect this biomarker is incompletely understood. We investigated the effect of DMTs on TRV elevation in children. In a prospective single-center study, 204 subjects with HbSS or HbSβ0 thalassemia (mean age, 10.6 years; range, 5-18) had echocardiograms with assessment of TRV, with repeat evaluations after 2 years of observation. One-hundred and twelve participants received DMTs (hydroxyurea, n = 72; monthly erythrocyte transfusions, n = 40), 58 did not receive any DMT, and 34 were begun on hydroxyurea during this observation period. In the entire cohort, an increase in hemoglobin of 1.0 g/dL was associated with a 0.03-m/s decrease in TRV (P = .024), and a decrease in absolute reticulocyte count of 1.0 × 106/mL was associated with a 0.34-m/s decrease in TRV (P = .034). Compared with baseline, hydroxyurea exposure (continuous or newly started) was associated with an average 5% decline in mean TRV at the 2-year evaluation. Among participants newly started on hydroxyurea (mean treatment duration 1.2 ± 0.6 years), an increase in hemoglobin of 1.0 g/dL was associated with a 0.06-m/s decrease in TRV (P = .05). We conclude that hydroxyurea therapy may mitigate TRV elevation in children with SCA, possibly as a result of a reduction in hemolysis and improvement in anemia.
| S-EPMC7805333 | biostudies-literature
Project description:The Food and Drug Administration requires contemporaneous controls to compare clinical outcomes for participants receiving experimental gene therapy or gene editing clinical trials. However, developing a contemporaneous cohort of rare diseases requires multiple person-hours. In a single referral center for sickle cell disease, we tested the hypothesis that we could create an automated contemporaneous cohort of children and adults with sickle cell anemia (SCA) to predict mortality. Data were obtained between 1 January 2004 and 30 April 2021. We identified 419 individuals with SCA with consistent medical care defined as followed continuously for >0.5 years with no visit gaps >3.0 years. The median age was 10.2 years (IQR, 1-24 years), with a median follow-up of 7.4 years (IQR, 3.6-13.5 years) and 47 deaths. A total of 98% (274 of 277) of the children remained alive at 18 years of age, and 34.3% (94 of 274) of those children were followed into adulthood. For adults, the median age of survival was 49.3 years. Treatment groups were mutually exclusive and in a hierarchical order: hematopoietic stem cell transplant (n = 22)>regular blood transfusion for at least 2 years (n = 56)>hydroxyurea for at least 1 year (n = 243)>no disease-modifying therapy (n = 98). Compared to those receiving no disease-modifying treatment, those treated with hydroxyurea therapy had a significantly lower hazard of mortality (hazard ratio = 0.38; P = 0.016), but no statistical difference for those receiving regular blood transfusions compared to no disease-modifying therapy (hazard ratio = 0.71; P = 0.440). An automated contemporaneous SCA cohort can be generated to estimate mortality in children and adults with SCA.
| S-EPMC10393740 | biostudies-literature
Project description: Not available
| S-EPMC6963249 | biostudies-literature
Project description:BackgroundBreast radiotherapy (RT) induces diffuse myocardial changes, which may increase the incidence of heart failure with preserved ejection fraction. This study aimed to evaluate the early signs of diffuse fibrosis after RT and their evolution during a six-year follow-up.MethodsThirty patients with early-stage left-sided breast cancer were studied with echocardiography and electrocardiography (ECG) at baseline, after RT, and at three-year and six-year follow-up visits. Echocardiography analysis included an off-line analysis of integrated backscatter (IBS). ECG was analysed for fragmented QRS (fQRS). In addition, cardiac magnetic resonance (CMR) imaging was performed at the six-year control. The left ventricle 16-segment model was used in cardiac imaging, and respective local radiation doses were analysed.ResultsRegional myocardial reflectivity in inferoseptal segments increased by 2.02 (4.53) dB (p = 0.026) and the percentage of leads with fQRS increased from 9.2 to 16.4% (p = 0.002) during the follow-up. In CMR imaging, abnormal extracellular volume (ECV) and T1 mapping values were found with anteroseptal and apical localization in a median of 3.5 (1.00-5.75) and 3 (1.25-4.00) segments, respectively. A higher left ventricle radiation dose was associated with an increased likelihood of having changes simultaneously in CMR and echocardiography (OR 1.26, 95% Cl. 1.00-1.59, p = 0.047).ConclusionsAfter radiotherapy, progressive changes in markers of diffuse myocardial fibrosis were observed in a multimodal manner in ECG and echocardiography. Changes in echocardiography and abnormal values in CMR were localized in the septal and apical regions, and multiple changes were associated with higher radiation doses.
| S-EPMC10373367 | biostudies-literature
Project description:BackgroundHydroxyurea improves laboratory parameters and prevents acute clinical complications of sickle cell anemia (SCA) in children and adults, but its effects on organ function remain incompletely defined.MethodsTo assess the safety and efficacy of hydroxyurea in young children with SCA and to prospectively assess kidney and brain function, 14 young children (mean age 35 months) received hydroxyurea at a mean maximum tolerated dose (MTD) of 28 mg/kg/day.ResultsAfter a mean of 25 months, expected laboratory effects included significant increases in hemoglobin, MCV and %HbF along with significant decreases in reticulocytes, absolute neutrophil count, and bilirubin. There was no significant increase in glomerular filtration rate by DTPA clearance or Schwartz estimate. Mean transcranial Doppler (TCD) velocity changes were -25.6 cm/sec (P < 0.01) and -26.8 cm/sec (P < 0.05) in the right and left MCA vessels, respectively. At study exit, no child had conditional or abnormal TCD values, and none developed brain ischemic lesions or vasculopathy progression by MRI/MRA. Growth and neurocognitive scores were preserved and Impact-on-Family scores improved.ConclusionsThese pilot data indicate hydroxyurea at MTD is well-tolerated by both children and families, and may prevent chronic organ damage in young children with SCA.
| S-EPMC5600482 | biostudies-literature
Project description: Not available
| S-EPMC7271570 | biostudies-literature
Project description:BackgroundCardiac failure from myocardial iron deposition is a severe complication in patients with transfusion-related iron overload. Progressive heart damage from iron overload can cause left ventricular systolic and diastolic dysfunction in patients with hematologic disorders. Since nontransfused patients with sickle cell anemia (SCA) have a high incidence of diastolic dysfunction, we investigated the relationships among transfusional iron burden, myocardial iron deposition, and diastolic ventricular dysfunction by T2*-MRI and tissue Doppler echocardiography in iron-overloaded children with SCA.ProcedureChildren (> or =7 years) with SCA and iron overload (serum ferritin >1,000 ng/ml or > or =18 lifetime transfusions) were eligible. Serum ferritin and hepatic iron content (HIC) were measured and participants underwent nonsedated T2*-MRI of the heart, echocardiogram, electrocardiogram, and multi-uptake gated acquisition (MUGA) scan. Age-matched normative echocardiographic data were used for comparison.ResultsAmong 30 children with SCA (median age, 13 years) and iron overload, mean (+/-SD) HIC and serum ferritin were 10.8 mg Fe/g (+/-5.9 mg Fe/g) and 3,089 ng/ml (+/-2,167 ng/ml), respectively. Mean T2*-MRI was 33 msec (+/-7 msec, range, 22-49). Echocardiography showed a high prevalence of diastolic dysfunction (77% and 45% abnormally low mean mitral annular velocity and mean tricuspid annular velocity, respectively); however, echocardiogram and MUGA scan findings were not significantly associated with HIC or T2*-MRI.ConclusionsDiastolic dysfunction is not associated with transfusional iron burden or myocardial iron deposition among children with SCA. Diastolic dysfunction likely results from disease pathophysiology and severity rather than iron overload.
| S-EPMC3075427 | biostudies-literature
Project description:BACKGROUND:Atrial fibrillation (AF) is associated with cardiac fibrosis, which can now be measured noninvasively using T1-mapping with cardiac magnetic resonance imaging (CMRI). This study aimed to assess the impact of AF on ventricular T1 at the time of CMRI. METHODS:Subjects with AF scheduled for AF ablation underwent CMRI with standard electrocardiography gating and breath-hold protocols on a 1.5 T scanner with post-contrast ventricular T1 recorded from 6 regions of interest at the mid-ventricle. Baseline demographic, clinical, and imaging characteristics were examined using univariate and multivariable linear regression modeling for an association with myocardial T1. RESULTS:One hundred fifty-seven patients were studied (32% women; median age, 61 years [interquartile range {IQR}, 55-67], 50% persistent AF [episodes>7 days or requiring electrical or pharmacologic cardioversion], 30% in AF at the time of the CMRI). The median global T1 was 404 ms (IQR, 381-428). AF at the time of CMRI was associated with a 4.4% shorter T1 (p=0.000) compared to sinus rhythm when adjusted for age, sex, persistent AF, body mass index, congestive heart failure, and renal dysfunction (estimated glomerular filtration rate<60). A post-hoc multivariate model adjusted for heart rate suggested that heart rate elevation (p=0.009) contributes to the reduction in T1 observed in patients with AF at the time of CMRI. No association between ventricular T1 and AF recurrence after ablation was demonstrated. CONCLUSION:AF at the time of CMRI was associated with lower post-contrast ventricular T1 compared with sinus rhythm. This effect was at least partly due to elevated heart rate. T1 was not associated with the recurrence of AF after ablation.
| S-EPMC4759117 | biostudies-literature
Project description: Not available
| S-EPMC5248934 | biostudies-literature