OUP user menu

Cardiac function and cytotoxic aldehyde production in a murine model of chronic iron-overload

Wally J. Bartfay, Fayez Dawood, Wen H. Wen, Denis C. Lehotay, David Hou, Emma Bartfay, Xiaoping Luo, Peter H. Backx, Peter P. Liu
DOI: http://dx.doi.org/10.1016/S0008-6363(99)00040-1 892-900 First published online: 1 September 1999

Abstract

Objectives: To determine the relationship between the total chronic dose of iron administered, ex-vivo cardiac function and the concentrations of cytotoxic aldehydes in heart tissue of a murine model. Methods: In the first experiment, 34 male B6D2F1 mice were randomized to receive intraperitoneal injections of 5, 10 or 20 mg of iron dextran for three weeks, or a placebo control. The mice were subsequently randomized to undergo ex-vivo assessment of cardiac function. In the second experiment, free radical generation, quantified by the presence of 20 separate cytotoxic aldehydes, was assessed in heart tissue of 40 mice that were randomized to receive chronic treatment with various concentrations of iron dextran (100 mg to 300 mg total chronic dose administered), placebo treatment with saline, or no treatment at all (baseline). Results: Iron-loaded groups displayed dose-dependent depressions of heart rate, systolic pressure, developed pressure, coronary pressure, −dP/dt and +dP/dt, and increases in diastolic pressure. Monotonic dose-dependent increases in total heart aldehydes were observed in the iron-treated groups (r=0.97, p<0.0001), whereas no significant differences were observed between baseline or time-placebo control groups. Conclusions: While no single mechanism is likely to account for the complex pathophysiology of iron-induced heart failure, our findings show that chronic iron-loading in a murine model results in dose-dependent alterations to cardiac function; and results in free radical mediated damage to the heart, as measured by excess concentrations of cytotoxic aldehyde-derived peroxidation products. This is the first description of the effects of excess iron on cardiac function assessed by an ex-vivo Langendorff technique in a murine model of chronic iron-overload.

Keywords
  • Iron-overload
  • Heart failure
  • Cardiac function
  • Free radicals
  • Aldehydes
  • Mice

Time for Primary review 21 days.

1 Introduction

Iron-overload cardiomyopathy, defined as the presence of systolic or diastolic cardiac dysfunction secondary to increased deposition of iron, is emerging as an important cause of heart failure due to both improved clinical recognition and a factual increase in the incidence of the disorder [1,2]. Clinical iron-overload leads to a classical cardiomyopathy of restrictive physiology with severe diastolic dysfunction, but preserved systolic function in the early stages of the disorder that correspond with lower concentrations of iron [1,3]. Conversely, in the later stages with high levels of iron, heart failure progresses quickly with severe systolic dysfunction, and ventricular dilation in these patients [1,3]. Death ensues promptly in the later stages due to cardiac failure and/or severe arrhythmias [1,4]. In fact, iron-induced heart failure is the leading cause of cardiovascular mortality in the second and third decades of life worldwide [1,2].

Although no single mechanism is likely to account for the complex pathophysiology of iron-induced heart failure, low molecular weight iron is conjectured to play a role because of its ability to catalyze the production of free radicals through Fenton-type reactions, which can damage compounds of all biochemical classes [5–7]. In fact, direct evidence for in-vivo hydroxyl radical generation in experimental iron-overload has now been demonstrated via spin-trapping electron spin resonance [8,9]. Furthermore, potentially toxic non-transferrin bound ‘free iron’ have been reported to be increased in the serum of patients with chronic iron-overload and fully saturated transferrin levels [10–13]. Indeed, increased concentrations of aldehyde-derived peroxidation products have been reported in patients with iron-overload disorders [12, 14,15], and in iron-loaded animals [16–18]. Nevertheless, the exact mechanism by which chronic iron-overload leads to heart failure remains to be elucidated [1]. Accordingly, we hypothesized that chronic iron-loading in a murine model would (1) result in alterations to cardiac function; and (2) lead to excess concentrations of cytotoxic aldehyde-derived peroxidation products in the heart, with corresponding increases in the total dose of iron administered.

2 Methods

Male B6D2F1 mice (Jackson Laboratory, Bar Harbor, ME) of three to five weeks of age, were employed for both of the experiments described below. The investigations had institutional approval and conformed to the standards of the Canadian Council on Animal Care [19]. We have previously shown that parenteral iron-loading of these mice produces iron-overload in the major organs, including the heart [20–22]. The mice were housed in stainless steel cages (five per cage) in a temperature-and-humidity controlled room with 12 hour light–dark cycles. The mice were adapted to their surroundings for a minimum of three days before commencing treatments, and were given access to food pellets and drinking water ad libitum. The rodent diet (Laboratory Autoclavable Rodent Diet 5012Ô, PMI Nutrition International, St. Louis, MO) consisted of 184 parts per million of iron. Unless otherwise stated, all chemicals used were reagent grade and were obtained from the Sigma Chemical, St. Louis, MO).

2.1 Cardiac function study

The objective of the first experiment was to assess the relationship between the total chronic dose of iron administered and cardiac function in our murine model. Thirty-four mice were randomized to receive the following treatments on 5 of 7 days per week, for a total period of three weeks: (1) placebo control (0.5 ml of normal saline, intraperitonal {i.p.} per day per mouse, n=6); (2) 5 mg of iron dextran (Imferon) i.p. per day per mouse (75 mg total iron dose, n=8); (3) 10 mg of iron dextran i.p. per day per mouse (150 mg total iron dose, n=8), or (4) 20 mg of iron dextran i.p. per day per mouse (300 mg total iron dose, n=12). Subsequently, the treated mice were also randomized to undergo ex-vivo Langendorff assessment of cardiac function based on modifications of previously described methods [23–26].

All mice were anesthetized prior to evaluation of cardiac function with ketamine hydrochloride (90 mg/kg i.p.) and rompun (xylazine, 10 mg/kg i.p.). Subsequently, the beating hearts with their ascending aortas were carefully removed through a rapid mid-sternal thoracotomy, and promptly placed in a Krebs–Henseleit buffer solution at 4° C. The isolated hearts were carefully cleared of excess tissue under a dissecting microscope (Nikon, model SM2-2T, Japan), and were subsequently connected through the aorta by a 20-gauge metal needle to the Langendorff perfusion apparatus. The Krebs–Henseleit buffer solution consisted of (in mmol/l): 1.2 KH2PO4; 1.2 MgSO4; 1.75 CaCl2; 4.7 KCl; 0.5 EDTA; 118.0 NaCl; 25.0 NaHCO3, and 11.0 dextrose. The Krebs–Henseleit solution was bubbled continuously with 95% O2: 5% CO2, at a rate of 2 l/min and a pressure of 40 kPa to maintain a pH of 7.40±0.05. The buffer solution was infused at a constant flow-rate of 5 ml/min via a digital roller pump (Masterflex 7518-10; Parmer Instruments, Burlington, VT), and the effluent volume was assessed at regular intervals to ensure proper pH and flow-rates. A constant temperature of 37° C was achieved by a coil condenser heat-exchanger circulator connected to an MGW 20 water bath (Lauda, Westbury, NY). Coronary perfusion pressure was assessed via a ‘Y’ shaped connector attached to the aortic perfusion cannula. Immediately after initiation of the retrograde perfusion, the left ventricle was decompressed, allowing free venting of Thebesian drainage through the insertion of a short drain into the left ventricle below the left atrium.

A custom-made, oversized, intraventricular latex balloon, was inserted while collapsed through the left atrial appendage into the cavity of the left ventricle and attached to a ‘Y’ connector. The balloon was fixed in position in the left ventricle by tying the connecting catheter to the perfusion apparatus, while the left atrial incision was not ligated. The balloon was attached to a PE50 connecting catheter that was 10 cm in length with a total volume of 20 ml of normal saline. One arm of the ‘Y’ connector from the balloon was connected to a transducer (model P231D; Gould, Cleveland, OH) to continuously record left ventricular pressure on an eight channel Gould physiological recorder (model 2800S; Gould). The second arm of the ‘Y’ connector was attached to a high fidelity microtip catheter (Millar 5F, Houston, TX) which joined a differentiator (Gould), and simultaneously recorded positive and negative dP/dt on the Gould physiological recorder. This high fidelity catheter was calibrated with 100 mmHg, and each left ventricular pressure recording was matched with pressure recordings from the fluid-filled system both before and after each record, as previously described [27].

The same custom-made balloon and set-up as described above were employed throughout the investigation. The balloon was slightly larger than the expected largest left ventricular chamber size, and its compliance was such that a pressure of less than 1.0 mmHg was generated by the balloon itself when inflated up to 80 ml (four times the largest volume used for the study). Furthermore, to take into account the differences in left ventricular chamber size between the various treatment groups, the volume in the balloon was initially adjusted to obtain a steady baseline end diastolic filling pressure (LVEDP) of 5 mmHg in all isolated hearts before measurements were undertaken. This baseline LVEDP was accomplished via a microinjector syringe (Microliter 702, Hamilton., Reno, NV) containing warmed normal saline, in increments of 5-μl initially and subsequent fine adjustments of 1 μl. The total volume of saline in the balloon ranged from 10 μl to 20 μl between the various treatment groups. In addition, left ventricular pressure was simultaneously recorded for the different LVEDP’s attained.

2.2 Cytotoxic aldehyde study

The objective of the second experiment was to determine the relationship between the total chronic dose of iron administered and the concentration of cytotoxic aldehydes in heart tissue of mice. Forty mice were randomized to receive chronic treatment with iron, placebo treatment with saline, or no treatment at all (baseline). Iron-loading was achieved by i.p. injections of iron dextran (Imferon, 20 mg/day/mouse), on five of seven days per week, for a duration of either one week (100 mg total iron dose, n=10), two weeks (200 mg total iron dose, n=10), or three weeks (300 mg total iron dose, n=10). Control mice received placebo treatment for three weeks with normal saline (0.5 ml, i.p. per mouse per day, n=5). Baseline measurements were also performed at the start of the investigation in non-treated mice (n=5). Following their designated treatment periods, the mice were sacrificed via cervical dislocation. The hearts were subsequently removed through a rapid mid-sternal thoracotomy and carefully cleared of excess tissue, promptly dipped into liquid nitrogen, and stored at −70° C until analysis.

The concentrations of 20 separate saturated and unsaturated aldehydes (C2–C12) in heart tissue (five per treatment group) were measured by capillary column gas chromatography–negative ionization mass spectrometry (GC–NICIMS, VG-Trio 2A), as previously described [28,29]. Briefly, the method utilizes O-hydroxylamine hydrochloride 2,3,4,5,6-pentafluorobenzyl to form a O-pentafluorobenzyl-oxime derivative (PFB-oxime) with subsequent trimethylsilylation of the hydroxyl group to trimethylsilyl (TMS) ethers. The PFB-oxime-TMS derivatives were analyzed by a high-sensitivity, research grade quadrupole mass spectrometer (VG-Trio 2A) with ammonia as reagent gas, and interfaced to a Hewlett Packard 5890 Series II gas chromatograph fitted with a 30-m, 0.32-μm, DB-5 capillary column. Total heart cytotoxic aldehyde concentrations were calculated by summing the values obtained for the 20 individual aldehydes measured for each mouse separately, and then mean values were subsequently calculated for each treatment group.

2.3 Statistical analysis

The Statistical Analysis System (SAS® Institute, Cary, North Carolina) was the principal software employed for data analysis. Descriptive statistics for the key variables are presented as mean±standard deviation. Pearson’s product moment correlational analysis was performed to determine the relationship between the key variables. Data analysis for treatment comparison followed a two-step procedure. One-way analysis of variance was first performed to compare overall treatment effect, and a p-value of 0.05 was deemed significant a priori. Secondly, when a statistically significant difference was detected between the treatment groups, post-hoc multiple pair-wise comparisons were performed using Duncan’s multiple range test.

3 Results

3.1 Cardiac function study

Iron-treated mice had coarse fur with loss of color, appeared progressively lethargic with increasing total chronic dose of iron administered, and had retarded growths rates in comparison to control mice (Table 1). Furthermore, 58% (n=7) of the mice in the 20-mg iron-treated group developed abdominal ascities. Upon sacrifice, the major organs (e.g., heart, liver, spleen) of iron-treated mice had bronze discoloration and were enlarged in appearance, although no statistically significant differences for heart weights were observed between control and iron-treated mice (Table 1). It was also observed that the heart tissue and aorta became increasing more fragile, inelastic, and difficult to manipulate with increasing total chronic dose of iron administered. The mortality was 0%, 0%, 12% and 17% for 0 mg (control), 5 mg, 10 mg, and 20 mg iron-loaded groups, respectively.

View this table:
Table 1

Initial body weights, body weights at sacrifice, and heart weights with assigned treatment (grams)a

Treatment groupsInitial body weightBody weight at sacrificeHeart wet weight
Control (0 mg total iron dose)17±122±1b0.13±0.02
5 mg iron-treated (75 mg total iron dose)17±119±2c0.11±0.01
10 mg iron-treated (150 mg total iron dose)17±118±10.12±0.004d
20 mg iron-treated (300 mg total iron dose)18±119±10.13±0.02
  • a Note: values are mean±standard deviation.

  • b =p<0.001 compared to initial body weight.

  • c =p<0.01 compared to initial body weight.

  • d =p<0.05 compared to 5 mg iron-treated heart weights.

The results of the ex-vivo cardiac function study for the saline control group and the various chronically iron-treated groups are shown in Table 2. Iron-treated mice displayed dose-dependent decreases in heart rate, systolic pressure, developed pressure, coronary pressure, −dP/dt and +dP/dt, in comparison to control mice (Table 2). Furthermore, a dose-dependent increase in diastolic pressure was observed (Table 2). Correlational analysis of the data summarized in Table 2 revealed significant negative associations between the total chronic dose of iron administered and heart rate (r=−0.7, p<0.001), and between the total chronic dose of iron administered and coronary pressure (r=−0.65, p<0.001).

View this table:
Table 2

Measures of cardiac function with total chronic dose of iron administereda

ParametersTotal dose of iron dextran administered
0 mg (Control)75 mg150 mg300 mg
Heart rate (beats per min)367±83c349±21ce240±37b224±40b
Systolic pressure (mmHg)105±3379±8f79±23g74±12f
Diastolic pressure (mmHg)8±411±611±713±7f
Developed pressure (mmHg)97±3368±6f68±17f62±15f
Coronary pressure (mmHg)90±12c57±19b65±12bd52±7b
−dP/dt (mmHg)908±338c511±93b689±271g578±97b
+dP/dt (mmHg)908±204489±33d444±174d431±91d
  • a Note: values are mean±standard deviation.

  • b =p<0.001 compared to control.

  • c =p<0.001 compared to 300 mg total dose of iron.

  • d =p<0.01 compared to 300 mg total dose of iron.

  • e =p<0.001 compared to 150 mg total dose of iron.

  • f =p<0.02 compared to control.

  • g =p <0.05 compared to control.

3.2 Cytotoxic aldehydes

Fig. 1 shows the total heart aldehyde concentrations for the various treatment groups. Monotonic dose-dependent increases in total heart aldehydes are observed in the iron-treated groups, whereas no significant differences are detected between baseline or time-placebo control groups. Correlational analysis revealed a highly significant positive association between the total chronic dose of iron administered and total heart aldehydes (r=0.97, p<0.0001). The individual cytotoxic aldehyde profiles for the various treatment groups are detailed in Table 3. Overall, we observe dose-dependent increases in the concentrations of individual aldehydes with the total chronic dose of iron administered, whereas no significant differences are observed between baseline or timed-placebo control groups (Table 3). The mortality was 0%, 0%, 10%, 10%, and 20% for baseline, timed-placebo control, 100 mg total iron dose (1 week), 200 mg total iron dose (2 weeks), and 300 mg total iron dose (3 weeks) groups, respectively.

Fig. 1

Total heart aldehydes with total dose of iron administered. Note: values are mean±standard deviation; a=p<0.001 compared to 0 mg (baseline or 3 weeks control); b=p<0.01 compared to 300 mg (week 3) total iron dose administered, and c=p<0.05 compared to 200 mg (week 2) total iron dose administered.

View this table:
Table 3

Heart cytotoxic aldehyde profiles with assigned treatmenta

Specific aldehydes0 mg Iron (Baseline)100 mg Iron (Week 1)200 mg Iron (Week 2)300 mg Iron (Week 3)0 mg Iron (Week 3)
Propanal9±113±2df16±2d19±4d9±2
Butanal2±14±1def8±2d8±2d4±1
Pentanal5±15±17±1d13±4d7±1
Furfural149±18198±3d174±23d219±55d104±16
Hexanal139±13168±12d177±27d210±36d150±30
Trans-2-hexenal3±18±2cd10±1bf14±1be3±1
Heptanal79±5161±23d171±43d172±21b97±11
Trans-2-heptenal68±594±18d108±7b124±7b62±12
Trans, trans-2, 4-heptadienal5±17±1def10±1b11±3d7±1
Octanal7±110±2def15±3df17±2b6±2
Trans-2-octenal7±110±1ce15±1b20±4d10±3
Nonanal27±335±4d42±1539±1227±6
trans-2-nonenal36±344±753±9d52±6d27±5
trans-2, cis-6-nonadienal5±16±1ef10±2d13±4d5±1
trans, trans-2, 4-nonadienal5±15±17±17±16±1
4-hydroxy-non-2-enal59±1290±3df97±12d109±12d58±19
Decanal37±2173±11df89±9df107±7de52±12
trans-4, cis-4-decenal150±23178±10174±9f205±10de140±37
Dodecanal436±10506±43ce603 ±56d650±11b402±38
Malondialdehyde1807±8821862±59ce2477±313f3794± 462be1071±68
  • a Note: values are mean±standard deviation.

  • b =p<0.001 compared to 0 mg control.

  • c =p<0.001 compared to 300 mg iron.

  • d =p<0.05 compared to 0 mg controls.

  • e =p<0.05 compared to 200 mg iron.

  • f =p <0.05 compared to 300 mg iron.

4 Discussion

In support of our first hypothesis, the results show that chronic iron-loading in a murine model adversely affects, in a dose-dependent manner, all measured parameters of cardiac function. To our knowledge, this is the first description of the effects of excess iron on cardiac function assessed by an ex-vivo Langendorff technique in a murine model [23–25]. Nevertheless, a decreased response to beta-adrenergic stimulation has been reported in iron-loaded cardiomyocytes in culture [30], and alterations to cardiac function have been reported in acutely iron-loaded dogs [31] and rabbits [32], and rats administered chronic intramuscular doses of iron dextran [33]. Given the small size of the left ventricle in the mouse, additional evaluations of ex-vivo cardiac function across a range of balloon volumes and dosages of iron are warranted for subsequent model development and validation, and to further elucidate the mechanism(s) of chronic iron-induced heart failure.

Iron has been shown to accumulate in cultured rat cardiac myocytes [30,34], and in the hearts of chronically iron-loaded animals [20–22]. Furthermore, nontransferrin-bound iron (NTBI) transport has been shown to be enhanced by prior iron-loading of the cell [35,36], and the uptake of NTBI has been demonstrated in cardiac myocytes [30,37]. Pathologically, iron is deposited initially in the epicardium, and only later involves the transmural wall thickness [1,22,38]. These observations may help to account in part for the preservation of systolic ventricular function for significant periods of time despite increased iron burden [22]. Moreover, reduced cellular ATP levels and damage to DNA may also contribute to injury and organ dysfunction with chronic iron-loading [39,40].

Even at low concentrations, it has been suggested that iron can actively interfere with the contractile apparatus and manifest as altered cardiac function [1,41]. Although the mechanism of this process is not clear, elevated resting levels of calcium have been implicated, which may lead to inadequate relaxation, spontaneous early depolarizations, and subsequent failure of contraction [1,41]. The heart has a high density of L-type Ca2+ channels, and single patch-clamp recordings have shown that Fe2+ is able to block Ca2+ currents and permeate L-type Ca2+ channels [42]. Indeed, excess iron has been implicated in the disruption of intracellular calcium homeostasis [43,44]. Similarly, various metals (e.g., mercury, lead) have been shown to result in a sustained elevation of calcium with resulting cell death [45,46]. Based on these preliminary observations, we further hypothesise that excess iron entry into cardiac myocytes leads to calcium-overload and subsequent diastolic dysfunction in chronic states of iron-overload. Additional investigations are required to verify the proposed relationship between the concentration of iron in the heart, calcium homeostasis, and altered diastolic function in chronic states of iron-overload.

In support of our second hypothesis, the findings show that the concentration of aldehydes in heart tissue increase parallel with the total chronic dose of iron administered in a murine model. Aldehydes are biologically stable and relatively active breakdown products of lipid hydroperoxides that originate by the reaction of superoxide or hydroxyl radicals with cellular membranes, and are therefore employed as both markers and evidence for recent free radical-mediated reactions in-vivo [28,29,47]. Therefore, an increase in the concentration of aldehydes in heart tissue of our murine model implies that greater levels of free radical-mediated reactions have recently taken place. Interestingly, the concentration of aldehydes detected in baseline and timed-placebo control groups suggests the presence of an intrinsically occurring basal level of lipid peroxidation in the heart, and this evidently reflects the balance between production and removal of free radicals by the antioxidant defenses of the normal heart. Indeed, preliminary evidence suggests that low subtoxic concentrations of aldehydes are physiologically important for normal cell function and cell proliferation [47,48]. Conversely, at increased concentrations they are known to be highly cytotoxic [28,49,50].

Increased levels of free radical mediated reactions, as measured by aldehyde-derived peroxidation products, have been reported in iron-loaded rat heart cells in culture [34], chronically iron-loaded animals [16–18], and in patients with iron-overload disorders [12,14,15]. Excess free radical generation has also been implicated in the disruption of intracellular calcium homeostasis [51–53], which can cause the degradation of phospholipids, proteins, and nucleotides with subsequent cell death [54,55]. Moreover, free radicals have been reported to alter cell membrane communication, reduce membrane potentials, increase permeability to ions, and result in the eventual rupture and release of its cellular contents [54–56]. In fact, excess iron-catalyzed free radical production has been linked to damage in various cell constituents, including mitochondria, lysosomes, and sarcolemmal membranes [6,33,51,56].

Due to experimental limitations, the simultaneous assessment of free radical generation and cardiac function could not be determined in our murine model. Additional investigations are warranted to assess the effects of iron-loading on free radical generation in-vivo [8,9] with simultaneous appraisal of cardiac function. Nonetheless, exposure of the myocardium to various free radical-generating systems has been shown to result in abnormalities in the contractile, electrophysiological, and biochemical properties of the myocardium with corresponding ultrastructural changes [57,58], whereas the administration of iron chelators have been shown to prevent damage in these systems [59–61]. The sensitivity of the heart to even trace amounts of iron may be partly explained by its relatively poor inherent defense mechanisms against free radicals, marked by low cardiac activities of catalase, superoxide dismutase and glutathione peroxidase [62,63]. Low molecular weight iron has been shown to increase 30% during ischemia in normal non-iron-loaded rat hearts [64]. Hence, patients with iron-overload disorders may be particularly vulnerable to iron-catalyzed free radical generation if there is any component of ischemia, since the resultant intracellular acidosis may result in the release of massive amounts of catalytic iron from ferritin and haemosiderin stores [64,65]. Although ferritin and haemosiderin have traditionally been regarded as ‘safe’ storage forms of iron, iron-loading of these storage forms have been shown to result in hydroxyl radical generation [66]. Several lines of evidence demonstrate that the superoxide radical is capable of mobilizing iron from ferritin, resulting in the production of iron-catalyzed hydroxyl radicals [67–69]. There is also disturbing evidence to show that catalytic iron may combine with the endogenous intracellular free radical scavenger superoxide dismutase, and paradoxically turn it into a free radical producer [70]. Hence, given that the heart possesses inherently poor defense mechanisms against free radicals [62,63], autocatalytic processes for free radical generation may become accelerated towards the end of myopathy development in chronic states of iron-overload, and this may help to partly account for the observed systolic dysfunction that fails to respond to traditional antifailure regimens [1]. Taken together, these observations suggest that excess free radical generation plays a role in damaging the heart in chronic iron-overload disorders.

While no single mechanism is likely to account for the complex pathophysiology of iron-induced heart failure, our results show that chronic iron-loading in a murine model can result in dose-dependent alterations to cardiac function; and result in free radical mediated damage to the heart, as measured by excess concentrations of cytotoxic aldehyde-derived peroxidation products. The precise mechanisms of how iron interferes with heart action are only beginning to unravel, and there are only a small number of studies in the existing literature addressing this serious clinical problem. It remains to be clarified whether chronic iron-overload produces cardiomyopathy through purely free radical mechanisms, interferes with the contractile apparatus via calcium fluxes, or results from a combination of both processes [1,41]. In addition, the determination of cytotoxic aldehyde profiles and concurrent assessment of cardiac function in patients with iron-overload and with different degrees of cardiac iron burden, may provide critical information regarding the time course and nature of compensatory mechanisms involved. Recent clinical evidence suggests that iron-overload cardiomyopathy may be reversible with effective removal of iron, since iron is loaded directly into the myocytes without excessive fibrosis [71–73]. Hence, our murine model may help to provide important insight into the mechanism(s) of chronic iron-induced heart failure, and serve as a vehicle for the evaluation of potential treatment modalities that seek to both prevent and eliminate iron deposits in the heart [20–22].

Acknowledgements

Wally Bartfay was supported in part by a graduate fellowship from the Centre for Cardiovascular Research, The Toronto Hospital, Toronto, Ontario, Canada. This research is supported in part by a grant from the Heart and Stroke Foundation of Ontario, Canada Peter Liu is a recipient of a Research Chair of the Heart and Stroke Foundation of Ontario, Canada.

References

  1. [1]
  2. [2]
  3. [3]
  4. [4]
  5. [5]
  6. [6]
  7. [7]
  8. [8]
  9. [9]
  10. [10]
  11. [11]
  12. [12]
  13. [13]
  14. [14]
  15. [15]
  16. [16]
  17. [17]
  18. [18]
  19. [19]
  20. [20]
  21. [21]
  22. [22]
  23. [23]
  24. [24]
  25. [25]
  26. [26]
  27. [27]
  28. [28]
  29. [29]
  30. [30]
  31. [31]
  32. [32]
  33. [33]
  34. [34]
  35. [35]
  36. [36]
  37. [37]
  38. [38]
  39. [39]
  40. [40]
  41. [41]
  42. [42]
  43. [43]
  44. [44]
  45. [45]
  46. [46]
  47. [47]
  48. [48]
  49. [49]
  50. [50]
  51. [51]
  52. [52]
  53. [53]
  54. [54]
  55. [55]
  56. [56]
  57. [57]
  58. [58]
  59. [59]
  60. [60]
  61. [61]
  62. [62]
  63. [63]
  64. [64]
  65. [65]
  66. [66]
  67. [67]
  68. [68]
  69. [69]
  70. [70]
  71. [71]
  72. [72]
  73. [73]
View Abstract