Dispersion of repolarization and beta-thalassemia major: the prognostic role of QT and JT dispersion for identifying the high-risk patients for sudden death

Russo, Vincenzo; Rago, Anna; Pannone, Bruno; Papa, Andrea Antonio; Meo, Francesco; Mayer, Maria Carolina; Spasiano, Anna; Russo, Maria Giovanna; Golino, Paolo; Calabrò, Raffaele; Nigro, Gerardo

doi:10.1111/j.1600-0609.2011.01579.x

Cited by 43 publications

(44 citation statements)

References 29 publications

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“…The most important clinical manifestation of β-thalassemia is microcytic, suggesting a dominant negative effect of an erythroid regulator (69).The anemia in β-thalassemia is attributed to intramedullary hemolysis, increased destruction of existing rbcs, and shortened rbc survival. However, the major cause of morbidity and mortality in β-thalassemias is iron overload, with iron-induced cardiomyopathy being the leading cause of death in transfusion-dependent thalassemia (70).…”

Section: Hepcidin and Iron Regulation In β-Thalassemiamentioning

confidence: 99%

Iron regulation by hepcidin

Zhao

Zhang²,

Enns³

2013

J. Clin. Invest.

195

158

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Discovery and function of hepcidin in iron homeostasisHepcidin is a key peptide hormone that regulates iron homeostasis in chordates. Hepcidin was initially characterized as an antimicrobial peptide in a mass spectrometry-based search for cysteine-rich defensin-like peptides in blood (1) and in urine (2). However, both groups showed that hepcidin displays only a weak antimicrobial activity. Further, unlike defensins, which vary in sequence among species, hepcidin is highly conserved from zebrafish to humans. Shortly after hepcidin was described, subtractive hybridization studies comparing the livers of normal and iron overloaded mice established a connection between iron loading and increased hepcidin mRNA (3, 4). The fundamental insight into hepcidin's role in iron homeostasis came in 2004 with the discovery that hepcidin acts to lower iron in the blood by binding to and downregulating the iron transporter, ferroportin (FPN1) (5). FPN1 is the only known transporter that is responsible for the efflux of iron from cells. Downregulation of FPN1 by hepcidin in splenic and hepatic macrophages decreases the ability of macrophages to export recycled iron from senescent rbcs, which constitute the primary source of iron in the plasma. In addition, a high concentration of hepcidin in the blood decreases the transport of iron out of intestinal epithelial cells, further limiting iron in the blood. Control of hepcidin expressionHepcidin is synthesized, processed to an active form, and secreted predominantly by hepatocytes (6, 7). The expression of hepcidin is mediated through the bone morphogenetic protein (BMP) and JAK2/STAT3 signaling pathways (Figure 1). Under nonpathological conditions, iron levels in the body upregulate hepcidin expression. Although the underlying mechanisms are poorly understood, recent studies have documented the essential roles of hemojuvelin (HJV), hereditary hemochromatosis protein (HFE), transferrin receptor 2 (TfR2), and matriptase-2 (MT2, encoded by the gene TMPRSS6) in the process of hepcidin regulation in humans and animal models as well as of BMP6, neogenin, and BMP receptors (ActRIIA/ALK2/ALK3) in animal models (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).Intact BMP signaling is essential for hepcidin expression. The canonical BMP-signaling pathway is initiated upon BMP binding to a BMP receptor complex on the cell surface, which activates the receptor kinase to phosphorylate the cytoplasmic proteins SMAD1, SMAD5, and SMAD8. These phosphorylated, receptor-regulated SMADs then form transcription factor complexes with SMAD4, consisting of receptor-regulated SMADs and SMAD4, that translocate into the nucleus to induce the transcription of target genes such as hepcidin (18). In mice, liver-specific disruption of SMAD4 or the BMP receptors ALK2 or ALK3 markedly decreased hepcidin expression, resulting in iron overload (15,19).BMP6. At least 20 BMPs are expressed in mammals. In vitro studies reveal that BMP2, -4, -5, -6, -7, and -9 can robustly induce BMP signaling and markedly increase hepcidin expres...

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Section: Hepcidin and Iron Regulation In β-Thalassemiamentioning

confidence: 99%

Iron regulation by hepcidin

Zhao

Zhang²,

Enns³

2013

J. Clin. Invest.

195

158

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“…Historically, sudden death accounts for ≈5% of cardiac deaths in TM and is associated with severe iron overload and increased QT dispersion, which suggests iron-mediated repolarization abnormalities and torsade de pointes as a causative mechanism. 46,216 Ventricular late potentials have also been described in thalassemia and are correlated with serum ferritin levels. 217 Treatment of potentially life-threatening ventricular arrhythmias in patients with severe cardiac iron burdens is problematic, because the physiological substrate is potentially reversible, and device therapy should be avoided if possible because it precludes further monitoring of cardiac iron stores by CMR.…”

Section: Unique Electrophysiologymentioning

confidence: 99%

“…As noted above, the role of other preclinical markers of cardiac iron toxicity, including arrhythmias, QT prolongation, and exercise capacity, in guiding chelation therapy is currently unknown. 6,155,216 Longitudinal trends in cardiac T2* values are also important. 148 Cardiac iron clears slowly, with a half-life of ≈13.5 months (5% per month) during continuous intravenous deferoxamine, 47 and a third as fast with intermittent deferoxamine therapy.…”

Section: Level Of Urgencymentioning

confidence: 99%

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Cardiovascular Function and Treatment in β-Thalassemia Major

Pennell¹,

Udelson²,

Arai³

et al. 2013

Circulation

331

172

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This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non–cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM. The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.

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“…Beta-thalassemia, the impaired production of the beta hemoglobin chain, is associated with significant changes in heterogeneity of cardiac ventricular repolarization and SCD (Russo et al, 2011). In the late stages, frequent premature ventricular contractions and sustained ventricular tachycardia have been mentioned, related to cardiac death.…”

Section: Thalassemiamentioning

confidence: 99%