Evidence for a Novel Mechanism Independent of Myocardial Iron in β-Thalassemia Cardiac Pathogenesis

Abstract

Human β-thalassemia major is one of the most prevalent genetic diseases characterized by decrease/absence of β-globin chain production with reduction of erythrocyte number. The main cause of death of treated β-thalassemia major patients with chronic blood transfusion is early cardiac complications that have been attributed to secondary iron overload despite optimal chelation. Herein, we investigated pathophysiological mechanisms of cardiovascular dysfunction in a severe murine model of β-thalassemia from 6 to 15-months of age in the absence of confounding effects related to transfusion. Our longitudinal echocardiography analysis showed that β-thalassemic mice first display a significant increase of cardiac output in response to limited oxygen-carrying erythrocytes that progressed rapidly to left ventricular hypertrophy and structural remodeling. Following this compensated hypertrophy, β-thalassemic mice developed age-dependent deterioration of left ventricular contractility and dysfunction that led toward decompensated heart failure. Consistently, murine β-thalassemic hearts histopathology revealed cardiac remodeling with increased interstitial fibrosis but virtual absence of myocardial iron deposits. Importantly, development of thalassemic cardiac hypertrophy and dysfunction independently of iron overload has uncoupled these cardiopathogenic processes. Altogether our study on β-thalassemia major hemoglobinopathy points to two successive phases resulting from severe chronic anemia and from secondarily induced mechanisms as pathophysiologic contributors to thalassemic cardiopathy.

Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases

“…Consistent with our results on SCD mice, others have recently reported that even thalassemic mice developed cardiovascular dysfunction with aging, 34,45 thus suggesting that the deterioration of cardiovascular function may occur more slowly in these animals. This is consistent with our data showing milder endothelial damage in thalassemic compared with SCD mice and further strengthens the relationship between endothelial dysfunction and heart damage.…”

“…In agreement with liver heme uptake results, ALAS-1 mRNA, which is transcriptionally down-regulated by intracellular heme 34 , was decreased in the liver of heme-treated wild-type mice but not in that of Hx-null mice ( Figure S1a). …”

“…It has consistently been reported recently that 10-to 14-month-old thalassemic mice show left ventricular hypertrophy and decreased fractional shortening and ejection fraction. 34 Because our data on endothelium ( Figure 5) indicated that the damage was worse in SCD mice, we supposed that cardiac function might become altered earlier in these animals. Indeed, measurement of blood pressure and echocardiography analysis on 2-month-old SCD mice demonstrated that HbS mice were hypertensive compared with HbA controls, showing a 1.6-fold increase in mean arterial blood pressure (Figure VIIa in the online-only Data Supplement).…”

Cardiac complications in beta-thalassemia: From mice to men

“…37 Both in vitro and in vivo studies indicated that heterozygous (Hbb th-3 /Hbb þ ) b-thalassemic mice were anemic, had increased heart weight and cardiac iron accumulation when getting old, and had measurable cardiac dysfunction. [13][14][15][16][17][18][19]30,32,33,[37][38][39][40] Moreover, the homozygous (Hbb th1 / Hbb th1 ), (Hbb d3(th) /Hbb d3(th) ) and heterozygous b-thalassemic mice showed a greater severity of anemia and had higher levels of cardiac iron accumulation than the heterozygous (Hbb th-3 /Hbb þ ) b-thalassemic mice did, even though the mice were still young. [37][38][39] A summary of reports regarding cardiac iron accumulation, cardiac function, and mitochondrial function in b-thalassemic mice (in vivo models) is shown in Table 2.…”

Early detection of myocardial dysfunction in poorly treated pediatric thalassemia children and adolescents: Two Saudi centers experience

“…Despite improved survival after the use of iron chelators, the cardiac complications are still the primary leading cause of death for young adults with β-thalassemia major [7] . Cardiac dysfunctions in β-thalassemia major have traditionally been attributed to iron-overload [8] related to repeated transfusions and increased intestinal absorption rate combined with a sustained state of increased cardiac output [9] .…”