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Research Areas

Imaging-based interrogation of myocardial oxygenation

The most desirable approach for identifying the presence of ischemic heart disease would be through the demonstration of the existence of abnormal myocardial oxygenation. Currently however, in the clinical arena, ischemic heart disease is identified on the basis of surrogate parameters (wash-in and wash-out of exogenous contrast media, wall motion, etc.). MRI provides a unique opportunity to map the oxygenation changes in the heart muscle; however, the method has been limited by poor sensitivity and specificity.

Our group has made significant contributions to the field of oxygenation-sensitive imaging (BOLD MRI) in the heart. We have (i) developed and tested MRI-based approaches for examining myocardial oxygenation throughout the cardiac cycle; (ii) demonstrated that myocardial oxygenation changes can be identified with greater sensitivity at 3T over 1.5T; (iii) developed image processing algorithms to substantially improve the visualization and quantification of myocardial territories with oxygenation abnormalities; and (iv) developed novel methods to uniquely identify ischemic territories on the basis of unique variations in oxygenation and blood volume changes at rest.

Cardiac stress testing with inhalational CO2

We have developed the key elements of a truly noninvasive cardiac stress test for patients with decreased functional capacity who cannot complete conventional exercise stress tests. The exercise stress test uses a treadmill or stationary bicycle with electrocardiography (ECG) and blood pressure monitors to assess the probability and extent of coronary artery disease. Patients unable to exercise are given the drug adenosine, which makes the heart respond as if the patient were exercising. However, adenosine carries with it myriad side effects, including death.

Our approach uses a device to increase the arterial CO2 through the modulation of breathing gases to vasodilate the coronary arteries, much as adenosine does but without the significant side effects (Yang and Dharmakumar SCMR 2014). The CO2 approach may be combined with any imaging method to detect myocardial territories with poor blood supply due to coronary or microvascular disease.

Noninvasive characterization of myocardial infarction

Over the past decade, late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (CMR) has evolved into a robust noninvasive imaging technique for detecting myocardial infarctions with excellent diagnostic accuracy and prognostic significance. However, accurate infarct sizing using LGE imaging is dependent on the wash-in and wash-out kinetics of gadolinium contrast agent. Most important, contrast-enhanced imaging requires administration of a gadolinium chelate, which is contraindicated in patients with chronic kidney disease, which is a rising epidemic worldwide. In fact, according to the United States Renal Data System, the fraction of patients with cardiovascular disease who also have chronic kidney disease is >40%. We have developed and tested a new imaging approach for characterizing chronic myocardial infarction without requiring any contrast infusions (Kali and Dharmakumar SCMR 2014). The proposed approach is expected to provide an appealing alternative for viability imaging when LGE imaging is contraindicated.

Post-infarction iron and its relation to cardiac arrhythmias

Sudden cardiac death (SCD) is a major public health problem in the United States and the leading cause of death. Approximately 80% of patients dying of SCD have underlying coronary heart disease, and chronic myocardial infarctions (MI) are present in ≥50% of all victims. In the majority of cases, SCDs are triggered by the onset of malignant ventricular arrhythmias (mVA). Therefore, developing a reliable and, ideally, noninvasive approach for stratifying the chronic MI patients at risk for mVAs is of great importance. Currently there are no reliable methods for identifying vulnerable patients who may be at risk for SCD.
We have recently demonstrated that chronic iron deposition following myocardial infarction alters the electrical activity of the heart. Ongoing studies are exploring the mechanistic underpinning of how iron may mediate ventricular arrhythmias, and whether it is implicated in SCD patients.

Representative co-registered MRI and high-resolution electroanatomical maps showing the association between isolated late potentials (ILPs) and iron deposition in non-reperfused MI. Co-registered LGE CMR projected onto the blood pool surface (A) with MI territory (red color, 5SD above remove signal intensity), border zone (yellow and blue shades) and remote territories (purple) with the corresponding bipolar map (B, color-coded to indicate low voltage areas, <1mv) are shown. Note the close correspondence between scar regions identified by CMR and bipolar voltage threshold in B. For reference, an ILP deep within the scar tissue (white arrow) is shown. Note the presence of an isolated low-voltage sharp ILP in the bipolar and unipolar traces following the local ventricular activation (yellow arrow) in C. The activation map (D), a map of the ILPs (E), and iron containing regions (in red), (F) are also shown for reference. Note that iron-rich regions have a greater incidence of ILPs and slow activation regions. From Cokic and Dharmakumar et al (PLOS ONE, 2013)

Myocardial bleeding and risk of heart failure

Hemorrhagic infarctions have been shown to be associated with adverse left-ventricular (LV) remodeling and major adverse cardiovascular events. However, the long-term fate of acute reperfused myocardial hemorrhage and its effects on the heart remain largely unexplored.

We have been investigating the mechanistic underpinnings of why reperfusion hemorrhage leads to adverse remodeling. We recently demonstrated that chronic iron deposition could take place in humans and animals following acute hemorrhagic myocardial infarctions (Fig. B) and that such depositions are a source of prolonged and active inflammation in the chronic infarctions. Additional imaging and histological studies are under way to investigate the role of post-infarction iron on heart failure. The clinical component of this work is being performed through a multicenter clinical registry (MIRON) established through external collaboration sites across Europe, Asia and North America.

Long-term Effects of Intramyocardial Bleeding. ACUTE (5 days post MI), CHRONIC (8 weeks post MI), and EX-VIVO CMRshow the resolution of persistent MVO (ACUTE LGE, dark core, arrows) into iron depositions (low T2* in CHRONIC scans). Short- and long-axis images are shown at ACUTE and CHRONIC state. Note the resolution of MVO in chronic MI (LGE) but the persistence T2* loses. From Kali and Dharmakumar et al (Circulation: CV Imaging, 2013)

Magnetic targeting of therapeutic substrates

Retention of therapeutic cells within regions of interest following their delivery is a known obstacle in the field of regenerative medicine. Recent studies demonstrate that the magnetic field gradient of bar magnets, coupled with the dipole moment of the cells labeled with iron oxide, can be used to enhance retention and therapeutic regeneration. However, this approach typically requires invasive procedures to ensure that the magnetic field gradients of the bar magnets are sufficiently close to the labeled cells. Moreover, such an approach is not conducive to the immediate assessment of the effectiveness of gradient fields in retaining the cells once the magnetic force is removed. We are exploring novel approaches for delivering stem cells and other therapeutic substrates in a magnetic environment (Yang and Dharmakumar ISMRM 2014).

Integrated PET and MR imaging for ischemic heart disease

MRI has the unique capability to create images true to the biophysical and chemical environment of the myocardium. This permits us to generate images with exquisite image contrast; typically however, it is difficult to simultaneously examine the ongoing metabolic changes in the heart. PET imaging provides highly sensitive information on tissue metabolism. Using Siemens state-of-the art mMR technology, which enables simultaneous acquisition of MR and PET signal, we are examining tissue-specific changes in the heart in ways that have not been previously possible.

Contact the Dharmakumar Lab

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Los Angeles, CA 90048