The heart in sickle cell disease, a model for heart failure with preserved ejection fraction

Wood, John C.

doi:10.1073/pnas.1611899113

Cited by 19 publications

(9 citation statements)

References 21 publications

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“…Several groups have shown that elevated TRV in at least half of patients with HbSS can be largely explained by left heart disease, which produces secondary, post‐capillary pulmonary hypertension, rather than primary pulmonary vascular disease . We have confirmed this finding in a meta‐analysis and also demonstrated that a cardiomyopathy with restrictive physiology is at least one cause of this left heart disease in both humans with HbSS and sickle mice . In contrast, intravascular hemolysis could predispose to precapillary pulmonary hypertension, but even precapillary pulmonary hypertension can be a secondary complication of left heart disease .…”

Section: Discussionsupporting

confidence: 76%

Biochemical surrogate markers of hemolysis do not correlate with directly measured erythrocyte survival in sickle cell anemia

et al. 2016

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Hemolysis is a key feature of sickle cell anemia (HbSS). Direct quantitation of hemolysis could be used as an objective outcome in clinical trials of new therapeutics for HbSS and would also enable better human studies of the pathogenesis of complications of HbSS that are ostensibly hemolysis-related, such as pulmonary hypertension. However, contemporary human studies in HbSS have used only surrogate markers of hemolysis rather than direct measurements of RBC survival. We directly quantified hemolysis in HbSS by measuring survival of an age cohort of RBCs labeled with a stable isotope, administered orally as 15N-glycine, a metabolic precursor of heme. The atomic excess of 15N in heme extracted from blood was monitored by mass spectrometry over time. We performed 13 labeling experiments in 11 individuals with HbSS. Mean RBC survival was 31.9 days (range 14.1 – 53.6). Both HbF level, a known determinant of hemolysis, and absolute reticulocyte count (ARC), an index of the marrow’s response to hemolysis, correlated with directly measured RBC survival (r=0.61, P<0.002; r=−0.84, P<0.001). However, commonly used biochemical surrogates of hemolysis (LDH, AST, bilirubin and plasma free hemoglobin) did not correlate with directly measured RBC survival. These biochemical surrogates should be interpreted cautiously, at best, in clinical trials and human physiologic studies in HbSS. ARC was the best correlate of total hemolysis, but only 70% of the variation in RBC survival was reflected in this marker. If greater accuracy is required in human studies, 15N-glycine RBC labeling can directly and accurately quantify hemolysis.

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Section: Discussionsupporting

confidence: 76%

Biochemical surrogate markers of hemolysis do not correlate with directly measured erythrocyte survival in sickle cell anemia

et al. 2016

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“…The interaction between anemia and many cardiac complications in SCA is intricate and incompletely understood, and isolating the effects of anemia from other concurrent pathologic processes of SCA in the heart, such as vaso-occlusion and inflammation, is challenging. 40 Many processes, including ischemia, inflammation, and microvascular disease, may predispose to myocardial fibrosis. 41 Ischemia-reperfusion injury, increased reactive oxygen species, and dysregulated transforming growth factor b have all been described in SCA [42][43][44] and could also be implicated in the development of myocardial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Association between diffuse myocardial fibrosis and diastolic dysfunction in sickle cell anemia

Niss¹,

Fleck²,

Makue

et al. 2017

Blood

116

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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, < .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, = .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; 191 ± 261 vs 33 ± 33 pg/mL, = .04) but lower hemoglobin (8.4 ± 0.3 vs 10.9 ± 1.4 g/dL, = .004) compared with participants with normal diastolic function. Participants with the highest ECV values (≥0.40) were more likely to have diastolic dysfunction ( = .003) and increased left atrial volume (57 ± 11 vs 46 ± 12 mL/m, = .04) compared with those with ECV<0.4. ECV correlated with hemoglobin ( = -0.46, = .03) and NT-proBNP ( = 0.62, = .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.

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“…Small vessel damage causes silent strokes in the brain, pulmonary hypertension in the lungs, and focal glomerular sclerosis in the kidney . Recently, a cardiac phenotype of diffuse myocardial fibrosis and heart failure with preserved ejection fraction has been identified and linked to microangiopathy as well . In normal subjects, vital organs tolerate intermittent interruptions in oxygen delivery by increasing oxygen extraction and blood flow as well as redirecting flow from non‐vital tissues.…”

Section: Discussionmentioning

confidence: 99%

Sickle cell microvascular paradox—oxygen supply‐demand mismatch

et al. 2019

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We have previously demonstrated that sickle cell disease (SCD) patients maintain normal global systemic and cerebral oxygen delivery by increasing cardiac output. However, ischemic end‐organ injury remains common suggesting that tissue oxygen delivery may be impaired by microvascular dysregulation or damage. To test this hypothesis, we performed fingertip laser Doppler flowmetry measurements at the base of the nailbed and regional oxygen saturation (rSO2) on the dorsal surface of the same hand. This was done during flow mediated dilation (FMD) studies in 26 chronically transfused SCD, 75 non‐transfused SCD, and 18 control subjects. Chronically transfused SCD patients were studied prior to and following a single transfusion and there was no acute change in rSO2 or perfusion. Laser Doppler estimates of resting perfusion were 76% higher in non‐transfused and 110% higher in transfused SCD patients, compared to control subjects. In contrast, rSO2 was 12 saturation points lower in non‐transfused SCD patients, but normal in the transfused SCD patients. During cuff occlusion, rSO2 declined at the same rate in all subjects suggesting similar intrinsic oxygen consumption rates. Upon cuff release, laser doppler post occlusive hyperemia was blunted in SCD patients in proportion to their resting perfusion values. Transfusion therapy did not improve the hyperemia response. FMD was impaired in SCD subjects but partially ameliorated in transfused SCD subjects. Taken together, non‐transfused SCD subjects demonstrate impaired conduit artery FMD, impaired microcirculatory post‐occlusive hyperemia, and resting hypoxia in the hand despite compensated oxygen delivery, suggesting impaired oxygen supply‐demand matching. Transfusion improves FMD and oxygen supply‐demand matching but not microcirculation hyperemic response.

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The heart in sickle cell disease, a model for heart failure with preserved ejection fraction

Cited by 19 publications

References 21 publications

Biochemical surrogate markers of hemolysis do not correlate with directly measured erythrocyte survival in sickle cell anemia

Biochemical surrogate markers of hemolysis do not correlate with directly measured erythrocyte survival in sickle cell anemia

Association between diffuse myocardial fibrosis and diastolic dysfunction in sickle cell anemia

Sickle cell microvascular paradox—oxygen supply‐demand mismatch

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