Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome <i>c</i> release: involvement of nitric oxide synthase and protein tyrosine nitration

Dong, Feng; Zhang, Xiaochun; Culver, Bruce; Chew, Herbert G; Kelley, Robert O.; Ren, Jun

doi:10.1042/cs20040278

Cited by 150 publications

(137 citation statements)

References 37 publications

Supporting

Mentioning

130

Contrasting

Unclassified

Order By: Relevance

“…Increased oxidative stress likely further compounds this effect. Similar, albeit milder changes, have been described in IDA animal models (59,60,75,76). It may be that these changes are more severe in SCA because of the added disadvantage of sickling in the microvasculature and increased oxidative stress, both evident in our transcriptome analyses.…”

Section: Berk-ss Mice Develop Corrected Qt Prolongation and Widening supporting

confidence: 48%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.sickle cell anemia | cardiomyopathy | restrictive physiology | arrhythmias | sudden death S ickle cell anemia (SCA) results from a point mutation in the β-globin gene and affects millions world-wide. It is characterized by production of the mutant hemoglobin S (HbS), which polymerizes upon deoxygenation and distorts the shape of RBCs, increasing their propensity to hemolysis and microvascular occlusion. Recurrent cycles of HbS polymerization result in a host of acute and chronic complications, including vaso-occlusive pain crisis, chronic hemolytic anemia, and organ damage. SCA-associated mortality rates have improved because of early diagnosis with universal newborn screening, immunization, and penicillin prophylaxis, which has changed the natural history of SCA (1, 2) and the impact of SCA on organ pathologies is now becoming evident.Despite improved early survival, nearly one-third of young adults with SCA die suddenly (3-9). The sickle myocardium has been presumed to be relatively resistant to the effects of sickling (10), and studies/autopsies show little evidence of atherosclerosis or coronary disease (11)(12)(13)(14). Mildly increased systolic pulmonary arterial pressure (PAP) estimated by tricuspid regurgitant jet vel...

show abstract

Section: Berk-ss Mice Develop Corrected Qt Prolongation and Widening supporting

confidence: 48%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Experimental studies have shown that ID induced cardiac dysfunction13 and cardiac hypertrophy, characterized by aberrant mitochondrial and irregular sarcomere organization 14…”

Section: Discussionmentioning

confidence: 99%

“…Experimental studies have shown that iron deficiency (ID) led to structural and functional abnormalities of the heart 3. In humans, a small report showed a reduction in iron content of cardiomyocytes of patients with HFrEF compared with controls 4.…”

Section: Introductionmentioning

confidence: 99%

Left ventricular ejection fraction recovery in patients with heart failure treated with intravenous iron: a pilot study

et al. 2016

View full text Add to dashboard Cite

AimsIn patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency, treatment with intravenous iron has shown a clinical improvement regardless of anaemic status. Cardiac magnetic resonance (CMR) T2* sequence has shown a potential utility for evaluating myocardial iron deficiency. We aimed to evaluate whether T2* sequence significantly changes after ferric carboximaltose (FCM) administration, and if such changes correlate with changes in left ventricle ejection fraction (LVEF).Methods and resultsIn this pilot study, we included eight patients with chronic symptomatic (New York Heart Association II–III) HFrEF and iron deficiency. A CMR, including T2* analysis, was performed before and at a median of 43 days (interquartile range = 35–48) after intravenous FCM administration. Pearson or Spearman correlation coefficient (r) was used for bivariate contrast as appropriate. A partial correlation analysis was performed between ΔLVEF and ΔT2* while controlling for anaemia status at baseline. Anaemia was present in half of patients. After FCM administration, T2* decreased from a median of 39.5 (35.9–48) to 32 ms (32–34.5), P = 0.012. Simultaneously, a borderline increase in median of LVEF [40% (36–44.5) to 48.5% (38.5–53), P = 0.091] was registered. In a bivariate correlational analysis, ΔT2* was highly correlated with ΔLVEF (r = −0.747, P = 0.033). After controlling for anaemia at baseline, the association between ΔT2* and ΔLVEF persisted [r(partial): −0.865, R 2(partial): 0.748, P = 0.012]. A median regression analysis backed‐up these findings.ConclusionsIn a small sample of patients with HFrEF and iron deficiency, myocardial iron repletion assessed by CMR was associated to left ventricular remodelling. Further studies are warranted.

show abstract

“…Cardiac muscle examined by transmission electron microscopy showed mitochondrial swelling and abnormal sarcomere structure. 15 In another study, iron deficiency was associated with impairment of myocardial mitochondrial electron transport in rat heart. 16 …”

Section: Experimental Evidence With Iron and Muscle Functionmentioning

confidence: 99%

“…Two studies fed iron-deficient diets to rats and examined cardiac muscle. 15,16 Rats receiving iron-deficient diet were anemic. Cardiac muscle examined by transmission electron microscopy showed mitochondrial swelling and abnormal sarcomere structure.…”

Section: Experimental Evidence With Iron and Muscle Functionmentioning

confidence: 99%

Iron Deficiency and Heart Disease: Ironclad Evidence?

Carson

Adamson

2010

Hematology

View full text Add to dashboard Cite

Patients with heart failure have elevated levels of circulating inflammatory cytokines and commonly have iron deficiency anemia or anemia of chronic inflammation. Clinical trials in patients with congestive heart failure and iron deficiency have demonstrated that intravenous iron treatment appears to improve subjective and objective outcomes. Most patients in these trials were not anemic or only had mild anemia, and hemoglobin concentration rose only slightly after treatment with iron. Experimental evidence demonstrates that iron is a cofactor for muscle function, which could explain the improvement in clinical outcomes. Many questions remain to be answered to understand the role of iron therapy in patients with congestive heart failure.In a landmark randomized clinical trial, Anker and colleagues 1 found that intravenous iron improved symptoms and physical function in patients with chronic heart failure and anemia. This trial potentially has broad implications for the hematologist, cardiologist, and internist. In this paper, we review the essential background information on anemia and heart failure, including the frequency, causes, and consequences of anemia in heart failure. We summarize the results of this trial in detail and describe the strengths and weaknesses. We then describe potential pathophysiological explanation(s) for the results. We finish with a description of the many uncertainties and questions that this trial raises. Prevalence and Consequences of Anemia in Heart FailureThe prevalence of anemia varies by age and gender. In an analysis of a representative population of community-dwelling persons from the US (NHANES-III [Third National Health and Nutrition Examination Survey]), the prevalence of anemia in patients 65 years and older was 10.6% and rises to over 20% in 85-year-old individuals. 2 However, in patients with congestive heart failure, the prevalence may be much higher. In a large cohort of patients with congestive heart failure, 37.2% were anemic. 3 In contrast, the prevalence of anemia was 17% in a population-based cohort of patients with new-onset congestive heart failure (mean age 78) from Canada. 4 The patient with heart failure who has anemia has an increased risk of death. In a systematic review of 153,180 patients with heart failure, 48% of anemic patients died within 6 months, compared with 29.5% of nonanemic patients (adjusted hazard ratio 1.46; 95% CI 1.26 -1.69). 3 This experience is similar to the Canadian cohort in which the risk of death was 1.34 times higher in anemic than in nonanemic patients with heart failure. 4 It is unknown if the increased risk of death is from anemia or is just a marker for underlying severity of disease.

show abstract

Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: involvement of nitric oxide synthase and protein tyrosine nitration

Cited by 150 publications

References 37 publications

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Left ventricular ejection fraction recovery in patients with heart failure treated with intravenous iron: a pilot study

Iron Deficiency and Heart Disease: Ironclad Evidence?

Contact Info

Product

Resources

About