Nilesh R. Ghugre

Improved R2* measurements in myocardial iron overload

To optimize R2*(1/T2*) measurements for cardiac iron detection in sickle cell and thalassemia patients.

Rapid multislice imaging of hyperpolarized 13C pyruvate and bicarbonate in the heart.

Hyperpolarization of spins via dynamic nuclear polarization (DNP) has been explored as a method to non‐invasively study real‐time metabolic rocesses occurring in vivo using 13C‐labeled substrates. Recently, hyperpolarized 13C pyruvate has been used to characterize in vivo cardiac metabolism in the rat and pig. Conventional 3D spectroscopic imaging methods require in excess of 100 excitations, making it challenging to acquire a full cardiac‐gated, breath‐held, whole‐heart volume. In this article, the development of a rapid multislice cardiac‐gated spiral 13C imaging pulse sequence consisting of a large flip‐angle spectral‐spatial excitation RF pulse combined with a single‐shot spiral k‐space trajectory for rapid imaging of cardiac metabolism is described. This sequence permits whole‐heart coverage (6 slices, 8.8‐mm in‐plane resolution) in any plane, allowing imaging of the metabolites of interest, [1‐ 13C] pyruvate, [1‐ 13C] lactate, and 13C bicarbonate, within a single breathhold. Pyruvate and bicarbonate cardiac volumes were acquired, while lactate images were not acquired due to low lactate levels in the animal model studied. The sequence was demonstrated with phantom experiments and in vivo testing in a pig model. Magn Reson Med, 2010.

MRI Detects Myocardial Iron in the Human Heart

Iron‐induced cardiac dysfunction is a leading cause of death in transfusion‐dependent anemia. MRI relaxation rates R2(1/T2) and R  2* (1/T  2* ) accurately predict liver iron concentration, but their ability to predict cardiac iron has been challenged by some investigators. Studies in animal models support similar R2 and R  2* behavior with heart and liver iron, but human studies are lacking. To determine the relationship between MRI relaxivities and cardiac iron, regional variations in R2 and R  2* were compared with iron distribution in one freshly deceased, unfixed, iron‐loaded heart. R2 and R  2* were proportionally related to regional iron concentrations and highly concordant with one another within the interventricular septum. A comparison of postmortem and in vitro measurements supports the notion that cardiac R  2* should be assessed in the septum rather than the whole heart. These data, along with measurements from controls, provide bounds on MRI‐iron calibration curves in human heart and further support the clinical use of cardiac MRI in iron‐overload syndromes. Magn Reson Med, 2006.

Physiology and Pathophysiology of Iron Cardiomyopathy in Thalassemia

Abstract: 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.

MAGNETIC RESONANCE IMAGING ASSESSMENT OF EXCESS IRON IN THALASSEMIA, SICKLE CELL DISEASE AND OTHER IRON OVERLOAD DISEASES

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.

Characterizing Myocardial Edema and Hemorrhage Using Quantitative T2 and T2* Mapping at Multiple Time Intervals Post ST-Segment Elevation Myocardial Infarction

Background—Accurate characterization of the longitudinal trends of myocardial edema and hemorrhage has been previously limited by subjective qualitative methods. We aimed to prospectively characterize the evolution of myocardial edema and hemorrhage post acute myocardial infarction using quantitative measures. Methods and Results—Sixty-two patients were enrolled post primary percutaneous coronary intervention and underwent cardiovascular magnetic resonance on a 1.5-T scanner at 48 hours, 3 weeks, and 6 months. Myocardial edema and hemorrhage were assessed by T2 and T2* mapping, respectively, in both infarct segment (IS) and remote segment (RS). At 48 hours, T2 is higher in IS compared with RS (56.7 ms versus 43.4 ms; P<0.01). At 3 weeks T2 remains higher in IS compared with RS (51.8 ms versus 39.5 ms; P<0.01), and subsequently equalizes by 6 months (39.8 ms versus 39.5 ms; P=nonsignificant). T2 is also increased in RS at day 2 versus 3 weeks (43.4 ms versus 39.5 ms; P<0.01). At 48 hours T2* was reduced in IS compared with RS (32.4 ms versus 37.4 ms; P<0.01). At 3 weeks (IS, 37.7 ms versus RS, 38.4 ms; P=nonsignificant) and 6 months (IS, 37.3 ms versus RS, 38.2 ms; P=nonsignificant), T2* values were equal in both segments. Conclusions—Quantification of myocardial edema and hemorrhage by T2 and T2* mapping is feasible post acute myocardial infarction and demonstrates that hemorrhage resolves faster than edema. Noninfarcted segments can also demonstrate edema in the acute phase possibly due to global hyperemia.

Quantitative tracking of edema, hemorrhage, and microvascular obstruction in subacute myocardial infarction in a porcine model by MRI.

Pathophysiological responses after acute myocardial infarction include edema, hemorrhage, and microvascular obstruction along with cellular damage. The in vivo evolution of these processes simultaneously throughout infarct healing has not been well characterized. The purpose of our study was to quantitatively monitor the time course of these mechanisms by MRI in a porcine model of myocardial infarction. Ten pigs underwent MRI before coronary occlusion with subgroups studied at day 2 and weeks 1, 2, 4, and 6 post‐infarction. Tissue characterization was performed using quantitative T2 and T2* maps to identify edema and hemorrhage, respectively. Contrast‐enhanced MRI was used for infarct/ microvascular obstruction delineation. Inflammation was reflected by T2 fluctuations, however at day 2, edema and hemorrhage had counter‐acting effects on T2. Hemorrhage (all forms) and mineralization (calcium) could be identified by T2* in the presence of edema. Simultaneous resolution of microvascular obstruction and T2* abnormality suggested that the two phenomenon were closely associated during the healing process. Our study demonstrates that quantitative T2 and T2* mapping techniques allow regional, longitudinal, and cross‐subject comparisons and give insights into histological and tissue remodeling processes. Such in vivo characterization will be important in grading severity and evaluating treatment strategies for myocardial infarction, potentially improving clinical outcomes. Magn Reson Med, 2011.

Mechanisms of tissue–iron relaxivity: Nuclear magnetic resonance studies of human liver biopsy specimens

MRI is becoming an increasingly important tool to assess iron overload disorders, but the complex nature of proton–iron interactions has troubled noninvasive iron quantification. Intersite and intersequence variability as well as methodological inaccuracies have been limiting factors to its widespread clinical use. It is important to understand the underlying proton relaxation mechanisms within the (human) tissue environment to address these differences. In this respect, NMR relaxometry was performed on 10 fresh human liver biopsy specimens taken from patients with transfusion‐dependent anemia. T1 (1/R1) inversion recovery, T2 (1/R2) single echo, and multiecho T2 CPMG measurements were performed on a 60‐MHz Bruker Minispectrometer. NMR parameters were compared to quantitative iron levels and tissue histology. Relaxivities R1 and R2 both increased linearly with hepatic iron content, with R2 being more sensitive to iron. CPMG data were well described by a chemical‐exchange model and predicted effective iron center dimensions consistent with hemosiderin‐filled lysosomes. Nonexponential relaxation was evident at short refocusing intervals with R2 and amplitude behavior suggestive of magnetic susceptibility‐based compartmentalization rather than anatomic subdivisions. NMR relaxometry of human liver biopsy specimens yields unique insights into the mechanisms of tissue–iron relaxivity. Magn Reson Med, 2005.

Relaxivity‐iron calibration in hepatic iron overload: Probing underlying biophysical mechanisms using a Monte Carlo model

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 noninvasive quantification of tissue iron, overcoming the drawbacks of traditional techniques (liver biopsy). Effective transverse relaxation rate (1/effective transverse relaxation time) rises linearly with iron while transverse relaxation rate (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 used to determine the contribution of particle size and distribution on MRI signal relaxation. Relaxivities were determined for hepatic iron concentrations ranging from 0.5 to 40 mg iron per gram dry tissue weight. Model predictions captured the linear and curvilinear relationship of effective transverse relaxation rate and transverse relaxation rate with hepatic iron concentrations, 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 and spleen). Magn Reson Med, 2011.

Quantitative magnetic resonance imaging can distinguish remodeling mechanisms after acute myocardial infarction based on the severity of ischemic insult

The type and extent of myocardial infarction encountered clinically is primarily determined by the severity of the initial ischemic insult. The purpose of the study was to differentiate longitudinal fluctuations in remodeling mechanisms in porcine myocardium following different ischemic insult durations. Animals (N = 8) were subjected to coronary balloon occlusion for either 90 or 45 min, followed by reperfusion. Imaging was performed on a 3 T MRI scanner between day‐2 and week‐6 postinfarction with edema quantified by T2, hemorrhage by T2*, vasodilatory function by blood‐oxygenation‐level‐dependent T2 alterations and infarction/microvascular obstruction by contrast‐enhanced imaging. The 90‐min model produced large transmural infarcts with hemorrhage and microvascular obstruction, while the 45 min produced small nontransmural and nonhemorrhagic infarction. In the 90‐min group, elevation of end‐diastolic‐volume, reduced cardiac function, persistence of edema, and prolonged vasodilatory dysfunction were all indicative of adverse remodeling; in contrast, the 45‐min group showed no signs of adverse remodeling. The 45‐ and 90‐min porcine models seem to be ideal for representing the low‐ and high‐risk patient groups, respectively, commonly encountered in the clinic. Such in vivo characterization will be a key in predicting functional recovery and may potentially allow evaluation of novel therapies targeted to alleviate ischemic injury and prevent microvascular obstruction/hemorrhage. Magn Reson Med, 70:1095–1105, 2013.