Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease manifested by progressive pulmonary vascular remodeling, compromised pulmonary blood flow and right heart failure. Most studies explore how pulmonary endothelial function modulates disease pathogenesis. We hypothesize that IPAH is a progressive panvasculopathy, affecting both pulmonary and systemic vascular beds, and that systemic endothelial dysfunction correlates with disease severity. Recent studies demonstrate systemic endothelial dysfunction in adults with pulmonary hypertension, however adults often have additional comorbidities affecting endothelial function. Systemic endothelial function has not been explored in children with IPAH.
This single-center, prospective, cross-sectional study examined brachial artery flow mediated dilation (FMD), a nitric oxide mediated, endothelial-dependent response, in children with IPAH and matched controls. FMD measurements were compared with clinical and echocardiographic measures of IPAH severity.
Thirteen patients and 13 controls were studied, ages 6–20 years old. FMD was decreased in IPAH subjects compared with controls (5.1 +/− 2.1% vs 9.7 +/− 2.0%; p<0.0001). In IPAH subjects, FMD correlated directly with cardiac index (R2=0.34, p=0.035), and inversely with tricuspid regurgitation velocity (R2=0.57, p=0.019) and right ventricular myocardial performance index (R2= 0.44, p=0.028).
The presence of systemic endothelial dysfunction in children with IPAH and its strong association with IPAH severity demonstrate that IPAH is a global vasculopathy. Although morbidity in IPAH is typically associated with pulmonary vascular disease, systemic vascular changes may also relate to disease pathogenesis and progression. Further study into shared mechanisms of systemic and pulmonary endothelial dysfunction may contribute to future therapies for IPAH.
Iron overload is a serious condition for patients with β-thalassemia, transfusion-dependent sickle cell anemia and inherited disorders of iron metabolism. MRI is becoming increasingly important in non-invasive quantification of tissue iron, overcoming the drawbacks of traditional techniques (liver biopsy). R2*(1/T2*) rises linearly with iron while R2(1/T2) has a curvilinear relationship in human liver. Although recent work has demonstrated clinically-valid estimates of human liver iron, the calibration varies with MRI sequence, field strength, iron chelation therapy and organ imaged, forcing recalibration in patients. To understand and correct these limitations, a thorough understanding of the underlying biophysics is of critical importance. Toward this end, a Monte Carlo based approach, using human liver as a ‘model’ tissue system, was employed to determine the contribution of particle size and distribution on MRI signal relaxation. Relaxivities were determined for hepatic iron concentrations (HIC) ranging from 0.5–40 mg iron/ g dry tissue weight. Model predictions captured the linear and curvilinear relationship of R2* and R2 with HIC respectively and were within in vivo confidence bounds; contact or chemical exchange mechanisms were not necessary. A validated and optimized model will aid understanding and quantification of iron-mediated relaxivity in tissues where biopsy is not feasible (heart, spleen).
iron overload; liver; Monte Carlo; relaxation; relaxivity
This study compared pulmonary function tests (PFTs) with cardiac, pancreatic and liver iron in 76 thalassemia major (TM) patients. Restrictive lung disease was observed in 16%, hyperinflation in 32%, and abnormal diffusing capacity in 3%. While no patients met Global Initiative for Chronic Lung Disease criteria for airways obstruction, there were indicators of small airways disease and air trapping. PFTs did not correlate with somatic iron burden, blood counts or haemolysis. Restrictive lung disease was associated with inflammation. We conclude that TM patients have pulmonary abnormalities consistent with small airways obstruction. Restrictive disease and impaired diffusion are less common.
Iron overload; pulmonary function; thalassaemia; magnetic resonance imaging; lung disease
Measurement of myocardial iron is key to the clinical management of patients at risk of siderotic cardiomyopathy. The cardiovascular magnetic resonance (CMR) relaxation parameter R2* (assessed clinically via its reciprocal T2*) measured in the ventricular septum is used to assess cardiac iron, but iron calibration and distribution data in humans is limited.
Methods and Results
Twelve human hearts were studied from transfusion dependent patients following either death (heart failure n=7, stroke n=1) or transplantation for end-stage heart failure (n=4). After CMR R2* measurement, tissue iron concentration was measured in multiple samples of each heart using inductively coupled plasma atomic emission spectroscopy. Iron distribution throughout the heart showed no systematic variation between segments, but epicardial iron concentration was higher than in the endocardium. The mean (±SD) global myocardial iron causing severe heart failure in 10 patients was 5.98 ±2.42mg/g dw (range 3.19–9.50), but in 1 outlier case of heart failure was 25.9mg/g dw. Myocardial ln[R2*] was strongly linearly correlated with ln[Fe] (R2=0.910, p<0.001) leading to [Fe]=45.0•(T2*)−1.22 for the clinical calibration equation with [Fe] in mg/g dw and T2* in ms. Mid-ventricular septal iron concentration and R2* were both highly representative of mean global myocardial iron.
These data detail the iron distribution throughout the heart in iron overload and provide calibration in humans for CMR R2* against myocardial iron concentration. The iron values are of considerable interest with regard to the level of cardiac iron associated with iron-related death and indicate that the heart is more sensitive to iron loading than the liver. The results also validate the current clinical practice of monitoring cardiac iron in-vivo by CMR of the mid septum.
Magnetic resonance imaging; heart; iron overload; siderosis; thalassemia
Rationale: Sickle cell disease is an inherited blood disorder characterized by vasoocclusive crises. Although hypoxia and pulmonary disease are known risk factors for these crises, the mechanisms that initiate vasoocclusive events are not well known.
Objectives: To study the relationship between transient hypoxia, respiration, and microvascular blood flow in patients with sickle cell.
Methods: We established a protocol that mimics nighttime hypoxic episodes and measured microvascular blood flow to determine if transient hypoxia causes a decrease in microvascular blood flow. Significant desaturations were induced safely by five breaths of 100% nitrogen.
Measurements and Main Results: Desaturation did not induce change in microvascular perfusion; however, it induced substantial transient parasympathetic activity withdrawal in patients with sickle cell disease, but not controls subjects. Marked periodic drops in peripheral microvascular perfusion, unrelated to hypoxia, were triggered by sighs in 11 of 11 patients with sickle cell and 8 of 11 control subjects. Although the sigh frequency was the same in both groups, the probability of a sigh inducing a perfusion drop was 78% in patients with sickle cell and 17% in control subjects (P < 0.001). Evidence for sigh-induced sympathetic nervous system dominance was seen in patients with sickle cell (P < 0.05), but was not significant in control subjects.
Conclusions: These data demonstrate significant disruption of autonomic nervous system balance, with marked parasympathetic withdrawal in response to transient hypoxia. They draw attention to an enhanced autonomic nervous system–mediated sigh–vasoconstrictor response in patients with sickle cell that could increase red cell retention in the microvasculature, promoting vasoocclusion.
hypoxia; autonomic nervous system; respiration; vasoconstriction; sickle cell disease
Deferasirox effectively controls liver iron concentration; however, little is known regarding its ability to remove stored cardiac iron. Deferiprone seems to have increased cardiac efficacy compared with traditional deferoxamine therapy. Therefore, the relative efficacy of deferasirox and deferiprone were compared in removing cardiac iron from iron-loaded gerbils.
Twenty-nine 8- to 10-week-old female gerbils underwent 10 weekly iron dextran injections of 200 mg/kg/week. Prechelation iron levels were assessed in 5 animals, and the remainder received deferasirox 100 mg/kg/D po QD (n = 8), deferiprone 375 mg/kg/D po divided TID (n = 8), or sham chelation (n = 8), 5 days/week for 12 weeks.
Deferasirox reduced cardiac iron content 20.5%. No changes occurred in cardiac weight, myocyte hypertrophy, fibrosis, or weight-to-dry weight ratio. Deferasirox treatment reduced liver iron content 51%. Deferiprone produced comparable reductions in cardiac iron content (18.6% reduction). Deferiprone-treated hearts had greater mass (16.5% increase) and increased myocyte hypertrophy. Deferiprone decreased liver iron content 24.9% but was associated with an increase in liver weight and water content.
Deferasirox and deferiprone were equally effective in removing stored cardiac iron in a gerbil animal model, but deferasirox removed more hepatic iron for a given cardiac iron burden.
Iron overload occurs in patients who require regular blood transfusions to correct genetic and acquired anaemias, such as β-thalassaemia major, sickle cell disease, and myelodysplastic syndromes. Although iron overload causes damage in many organs, accumulation of cardiac iron is a leading cause of death in transfused patients with β-thalassaemia major. The symptoms of cardiac iron overload will occur long after the first cardiac iron accumulation, at a point when treatment is more complex than primary prevention would have been. Direct measurement of cardiac iron using T2* magnetic resonance imaging, rather than indirect methods such as measuring serum ferritin levels or liver iron concentration have contributed to earlier recognition of myocardial iron loading and prevention of cardiac toxicity. Cardiac siderosis occurs in all transfusional anaemias, but the relative risk depends upon the underlying disease state, transfusional load, and chelation history. All three available iron chelators can be used to remove cardiac iron, but each has unique physical properties that influence their cardiac efficacy. More prospective trials are needed to assess the effects of single-agent or combination iron chelation therapy on the levels of cardiac iron and cardiac function. Ultimately, iron chelation therapies should be tailored to meet individual patient needs and lifestyle demands.
Cardiac iron; Iron chelation therapy; Myelodysplastic syndrome; Sickle cell disease; β-Thalassaemia major
We reviewed cardiac T2* assessments from 77 thalassemia major patients between the ages of 2.5 and 18 years to study optimal timing of cardiac iron screening by magnetic resonance imaging. No patient under 9.5 years of age showed detectable cardiac iron in contrast to 36% of patients between the ages of 15–18 years old, corresponding to an odds-ratio of 1.28 (28%) per year. All patients with cardiac iron had received at least 35 grams of transfusional iron. Liver iron and ferritin failed to predict cardiac iron loading. Initiation of cardiac magnetic resonance imaging assessment should be determined according to age and transfusional burden rather than indices of iron overload. When appropriate chelation therapy has been administered since birth, cardiac magnetic resonance imaging can be postponed until 8 years of age when anesthesia is not required. Patients with suboptimal chelation, increased transfusional requirements, or who have initiated transfusions later in life should be tested sooner.
thalassemia major; heart; MRI; iron overload; children
Close monitoring of liver iron content is necessary to prevent iron overload in transfusion-dependent anemias. Liver biopsy remains the gold standard; however, MRI potentially offers a noninvasive alternative. Iron metabolism and storage is complicated and tissue/disease-specific. This report demonstrates that iron distribution may be more important than iron speciation with respect to MRI signal changes. Simple synthetic analogs of hepatic lysosomes were constructed from noncovalent attachment of horse-spleen ferritin to 0.4 μm diameter phospholipid liposomes suspended in agarose. Graded iron loading was achieved by varying ferritin burden per liposome as well as liposomal volume fraction. T1 and T2 relaxation times were measured on a 60 MHz NMR spectrometer and compared to simple ferritin-gel combinations. Liposomal-ferritin had 6-fold stronger T2 relaxivity than unaggregated ferritin but identical T1 relaxivity. Liposomal-ferritin T2 relaxivity also more closely matched published results from hemosiderotic marmoset liver, suggesting a potential role as an iron-calibration phantom.
iron overload; MRI; liver; hemochromatosis; thalassemia; T2; T1; relaxometry; ferritin; microspheres
Purpose of review
To highlight recent advances in magnetic resonance imaging estimation of somatic iron overload. This review will discuss the need and principles of magnetic resonance imaging-based iron measurements, the validation of liver and cardiac iron measurements, and the key institutional requirements for implementation.
Magnetic resonance imaging assessment of liver and cardiac iron has achieved critical levels of availability, utility, and validity to serve as the primary endpoint of clinical trials. Calibration curves for the magnetic resonance imaging parameters R2 and R2* (or their reciprocals, T2 and T2*) have been developed for the liver and the heart. Interscanner variability for these techniques has proven to be on the order of 5–7%.
Magnetic resonance imaging assessment of tissue iron is becoming increasingly important in the management of transfusional iron load because it is noninvasive, relatively widely available and offers a window into presymptomatic organ dysfunction. The techniques are highly reproducible within and across machines and have been chemically validated in the liver and the heart. These techniques will become the standard of care as industry begins to support the acquisition and postprocessing software.
heart; iron overload; liver; magnetic resonance imaging; thalassemia
We measured left atrial size and function from biplane MRI data in 62 adults with thalassemia major. Age-adjusted left atrial ejection fraction was depressed in 7 out of 20 subjects having T2* < 10 ms. Left atrial size, left ventricular size and cardiac output fell with cardiac iron loading, representing increased cardiac or peripheral vascular stiffness.
thalassemia; diastolic function; systolic function; iron overload; MRI
Editorials; anemia; arrhythmia; heart failure; iron overload; magnetic resonance imaging
Patients with transfusion-dependent anemia develop cardiac and endocrine toxicity from iron overload. Classically, serum ferritin and liver biopsy have been used to monitor patient response to chelation therapy. Recently, magnetic resonance imaging (MRI) has proven effective in detecting and quantifying iron in the heart and liver. Tissue iron is paramagnetic and increases the MRI relaxation rates R2 and R2* in a quantifiable manner. This review outlines the principles and validation of non invasive iron estimation by MRI, as well as discussing some of the technical considerations necessary for accurate measurements. Specifically, the use of R2 or R2* methods, choice of echo times, appropriate model for data fitting, the use of a pixel-wise or region-based measurement, and the choice of field strength are discussed.
Iron Overload; Magnetic resonance imaging (MRI); Thalassemia; Sickle Cell Disease; Liver; Heart
Iron cardiomyopathy in β-thalassemia major patients is associated with vitamin D deficiency. Stores of 25-OH-D3 are markedly reduced, while the active metabolite, 1-25-(OH)-D3, is normal or increased. Interestingly, the ratio of 25-OH-D3 to 1-25-(OH)-D3 (a surrogate for parathyroid hormone (PTH)) is the strongest predictor of cardiac iron. Increased PTH and 1-25-OH-D3 levels have been shown to up-regulate L-type voltage-gated calcium channels (LVGCC), the putative channel for cardiac iron uptake. Therefore, we postulate that vitamin D deficiency increases cardiac iron by altering LVGCC regulation. Hemojuvelin knockout mice were calcitriol treated, PTH treated, vitamin D-depleted, or untreated. Half of the animals in each group received the Ca2+-channel blocker verapamil. Mn2+ was infused to determine LVGCC activity. Hearts and livers were harvested for iron, calcium, and manganese measurements as well as histology. Cardiac iron did not differ amongst the treatment groups; however, liver iron was increased in vitamin D-depleted animals (p<0.0003). Cardiac iron levels did not correlate with manganese uptake, but were proportional to cardiac calcium levels (r2 = 0.6, p < 0.0001). Verapamil treatment reduced both cardiac (p <0.02) and hepatic (p < 0.003) iron levels significantly by 34% and 28%. The association between cardiac iron and calcium levels was maintained after verapamil treatment (r2 = 0.3, p < 0.008). Vitamin D-depletion is associated with an increase in liver, but not cardiac, iron accumulation. Cardiac iron uptake was strongly correlated with cardiac calcium stores and was significantly attenuated by verapamil, suggesting that cardiac calcium and iron are related.
b-thalassemia; vitamin D; iron overload; hemojuvelin
To evaluate the magnetic properties of the spleen in chronically transfused, iron-overloaded patients with sickle cell disease (SCD) and thalassemia major (TM) and to compare splenic iron burdens to those in the liver, heart, pancreas, and kidneys.
Materials and Methods
A retrospective analysis of 63 TM and 46 SCD patients was performed. Spleen R2 and R2* values were calculated from spin-echo and gradient-echo images collected between April 2004 and September 2007.
The spleen showed a different R2–R2* relationship than that previously established for the liver. At high iron concentrations (R2* > 300 Hz), spleen R2 was lower than predicted for liver. The proportion of splenic to hepatic iron content was greater in SCD patients compared with TM patients (23.8% vs. 13.8%). A weak association was found between splenic and liver iron—this association was stronger in SCD patients. Little correlation was found between splenic iron and extrahepatic R2* values.
For spleen and liver tissue with the same R2* value, splenic R2 was significantly lower than hepatic R2, particularly for R2* > ≈300 Hz. Splenic iron levels have little predictive value for R2* values of heart, pancreas, and kidney.
spleen; sickle cell; thalassemia; MRI; iron
Thalassemia major is characterized by chronic ineffective erythropoiesis and anemia as its primary problems. These, in turn, produce physiologic adaptations in the cardiovascular system as well as pathologic/iatrogenic processes such as iron overload, splenectomy, nutritional deficiencies, chronic oxidative stress, and lung disease. This article discusses the pathophysiology of thalassemia as it relates to the cardiovascular system, the mechanisms and monitoring of iron cardiomyopathy, pulmonary hypertension, and vascular aging in thalassemia patients.
Thalassemia; Heart complications; Iron cardiomyopathy; Pulmonary hypertension
Transfusional therapy for thalassemia major and sickle cell disease can lead to iron deposition and damage to the heart, liver, and endocrine organs. Iron causes the MRI parameters T1, T2, and T2* to shorten in these organs, which creates a potential mechanism for iron quantification. However, because of the danger and variability of cardiac biopsy, tissue validation of cardiac iron estimates by MRI has not been performed. In this study, we demonstrate that iron produces similar T1, T2, and T2* changes in the heart and liver using a gerbil iron-overload model.
Methods and Results
Twelve gerbils underwent iron dextran loading (200 mg · kg−1 · wk−1) from 2 to 14 weeks; 5 age-matched controls were studied as well. Animals had in vivo assessment of cardiac T2* and hepatic T2 and T2* and postmortem assessment of cardiac and hepatic T1 and T2. Relaxation measurements were performed in a clinical 1.5-T magnet and a 60-MHz nuclear magnetic resonance relaxometer. Cardiac and liver iron concentrations rose linearly with administered dose. Cardiac 1/T2*, 1/T2, and 1/T1 rose linearly with cardiac iron concentration. Liver 1/T2*, 1/T2, and 1/T1 also rose linearly, proportional to hepatic iron concentration. Liver and heart calibrations were similar on a dry-weight basis.
MRI measurements of cardiac T2 and T2* can be used to quantify cardiac iron. The similarity of liver and cardiac iron calibration curves in the gerbil suggests that extrapolation of human liver calibration curves to heart may be a rational approximation in humans.
magnetic resonance imaging; anemia; iron overload; thalassemia; cardiomyopathy
Iron cardiomyopathy is a lethal complication of transfusion therapy in thalassemia major. Nutritional supplements decreasing cardiac iron uptake or toxicity would have clinical significance. Murine studies suggest taurine may prevent oxidative damage and inhibit Ca2+-channel-mediated iron transport. We hypothesized that taurine supplementation would decrease cardiac iron-overloaded toxicity by decreasing cardiac iron. Vitamin E and selenium served as antioxidant control.
Animals were divided into control, iron, taurine, and vitamin E/selenium groups. Following sacrifice, iron and selenium measurements, histology, and biochemical analyses were performed.
No significant differences were found in heart and liver iron content between treatment groups, except for higher hepatic dry-weight iron concentrations in taurine-treated animals (p < 0.03). Serum iron increased with iron loading (751 ± 66 vs. 251 ± 54 μg/dl, p < 0.001) and with taurine (903 ± 136 μg/dl, p = 0.03).
Consistent with oxidative stress, iron overload increased cardiac malondialdehyde levels, decreased heart glutathione peroxidase (GPx) activity, and increased serum aspartate aminotransferase. Taurine ameliorated these changes, but only significantly for liver GPx activity. Selenium and vitamin E supplementation did not improve oxidative markers and worsened cardiac GPx activity. These results suggest that taurine acts primarily as an antioxidant rather than inhibiting iron uptake. Future studies should illuminate the complexity of these results.
Iron overload; Taurine; Heart; Liver; Antioxidants
Iron cardiomyopathy remains the leading cause of death in patients with thalassemia major. Magnetic resonance imaging (MRI) is ideally suited for monitoring thalassemia patients because it can detect cardiac and liver iron burdens as well as accurately measure left ventricular dimensions and function. However, patients with thalassemia have unique physiology that alters their normative data. In this article, we review the physiology and pathophysiology of thalassemic heart disease as well as the use of MRI to monitor it. Despite regular transfusions, thalassemia major patients have larger ventricular volumes, higher cardiac outputs, and lower total vascular resistances than published data for healthy control subjects; these hemodynamic findings are consistent with chronic anemia. Cardiac iron overload increases the relative risk of further dilation, arrhythmias, and decreased systolic function. However, many patients are asymptomatic despite heavy cardiac burdens. We explore possible mechanisms behind cardiac iron-function relationships and relate these mechanisms to clinical observations.
iron; heart; MRI; ejection fraction; cardiac function; T2*
Vitamin D25-OH and D1-25OH levels were compared with cardiac R2★ (1/T2★), left ventricular ejection fraction (LVEF), age, ferritin and liver iron in 24 thalassaemia major patients. Vitamin D25-OH levels were reduced in 13/24 patients while vitamin D1-25OH levels were often elevated. Vitamin D25-OH levels decreased with age (r2 = 0·48) and with liver iron (r2 = 0·20). Cardiac R2★ was inversely related with the ratio of D25-OH to D1-25OH levels (r2 = 0·42). LVEF was also proportional to the D25-OH/D1-25OH ratio (r2 = 0·49). Vitamin D deficiency may be associated with cardiac iron uptake and ventricular dysfunction in thalassaemia major patients.
iron overload; thalassaemia major; magnetic resonance imaging; heart; vitamin D
The characterization of iron stores is important to prevent and treat iron overload. Serum markers such as ferritin, serum iron, iron binding capacity, transferrin saturation, and nontransferrin-bound iron can be used to follow trends in iron status; however, variability in these markers limits predictive power for any given individual. Liver iron represents the best single marker of total iron balance. Measures of liver iron include biopsy, superconducting quantum interference device, computer tomography, and magnetic resonance imaging (MRI). MRI is the most accurate and widely available noninvasive tool to assess liver iron. The main advantages of MRI include a low-rate of variability between measurements and the ability to assess iron loading in endocrine tissues, the heart and the liver. This manuscript describes the principles, validation, and clinical utility of MRI for tissue iron estimation.