Albert Jang

Cardiac Repair in a Porcine Model of Acute Myocardial Infarction with Human Induced Pluripotent Stem Cell-Derived Cardiovascular Cells

Human induced pluripotent stem cells (hiPSCs) hold promise for myocardial repair following injury, but preclinical studies in large animal models are required to determine optimal cell preparation and delivery strategies to maximize functional benefits and to evaluate safety. Here, we utilized a porcine model of acute myocardial infarction (MI) to investigate the functional impact of intramyocardial transplantation of hiPSC-derived cardiomyocytes, endothelial cells, and smooth muscle cells, in combination with a 3D fibrin patch loaded with insulin growth factor (IGF)-encapsulated microspheres. hiPSC-derived cardiomyocytes integrated into host myocardium and generated organized sarcomeric structures, and endothelial and smooth muscle cells contributed to host vasculature. Trilineage cell transplantation significantly improved left ventricular function, myocardial metabolism, and arteriole density, while reducing infarct size, ventricular wall stress, and apoptosis without inducing ventricular arrhythmias. These findings in a large animal MI model highlight the potential of utilizing hiPSC-derived cells for cardiac repair.

Myocardial ATP hydrolysis rates in vivo: a porcine model of pressure overload-induced hypertrophy

Left ventricular (LV) hypertrophy (LVH) and congestive heart failure are accompanied by changes in myocardial ATP metabolism. However, the rate of ATP hydrolysis cannot be measured in the in vivo heart with the conventional techniques. Here, we used a double-saturation phosphorous-31 magnetic resonance spectroscopy-magnetization saturation transfer protocol to monitor ATP hydrolysis rate in swine hearts as the hearts became hypertrophic in response to aortic banding (AOB). Animals that underwent AOB (n = 22) were compared with animals that underwent sham surgery (n = 8). AOB induced severe LVH (cardiac MRI). LV function (ejection fraction and systolic thickening fraction) declined significantly, accompanied by deferent levels of pericardial effusion, and wall stress increased in aorta banded animals at week 1 after AOB, suggesting acute heart failure, which recovered by week 8 when concentric LVH restored LV wall stresses. Severe LV dysfunction was accompanied by corresponding declines in myocardial bioenergetics (phosphocreatine-to-ATP ratio) and in the rate of ATP production via creatine kinase at week 1. For the first time, the same linear relationships of the rate increase of the constants of the ATP hydrolysis rate (kATP→Pi) vs. the LV rate-pressure product increase during catecholamine stimulation were observed in vivo in both normal and LVH hearts. Collectively, these observations demonstrate that the double-saturation, phosphorous-31 magnetic resonance spectroscopy-magnetization saturation transfer protocol can accurately monitor myocardial ATP hydrolysis rate in the hearts of living animals. The severe reduction of LV chamber function during the acute phase of AOB is accompanied by the decrease of myocardial bioenergetic efficiency, which recovers as the compensated LVH restores the LV wall stresses.

Early Detection of Myocardial Bioenergetic Deficits: A 9.4 Tesla Complete Non Invasive 31P MR Spectroscopy Study in Mice with Muscular Dystrophy

Background Duchenne muscular dystrophy (DMD) is the most common fatal form of muscular dystrophy characterized by striated muscle wasting and dysfunction. Patients with DMD have a very high incidence of heart failure, which is increasingly the cause of death in DMD patients. We hypothesize that in the in vivo system, the dystrophic cardiac muscle displays bioenergetic deficits prior to any functional or structural deficits. To address this we developed a complete non invasive 31P magnetic resonance spectroscopy (31P MRS) approach to measure myocardial bioenergetics in the heart in vivo. Methods and Results Six control and nine mdx mice at 5 months of age were used for the study. A standard 3D -Image Selected In vivo Spectroscopy (3D-ISIS) sequence was used to provide complete gradient controlled three-dimensional localization for heart 31P MRS. These studies demonstrated dystrophic hearts have a significant reduction in PCr/ATP ratio compare to normal (1.59±0.13 vs 2.37±0.25, p<0.05). Conclusion Our present study provides the direct evidence of significant cardiac bioenergetic deficits in the in vivo dystrophic mouse. These data suggest that energetic defects precede the development of significant hemodynamic or structural changes. The methods provide a clinically relevant approach to use myocardial energetics as an early marker of disease in the dystrophic heart. The new method in detecting the in vivo bioenergetics abnormality as an early non-invasive marker of emerging dystrophic cardiomyopathy is critical in management of patients with DMD, and optimized therapies aimed at slowing or reversing the cardiomyopathy.

Designing 3D selective adiabatic radiofrequency pulses with single and parallel transmission

To introduce a method of designing single and parallel transmit (pTx) 3D adiabatic π pulses for inverting and refocusing spins that are insensitive to transmit B1 ( B1+ ) inhomogeneity.

2D Pulses using spatially dependent frequency sweeping.

To introduce a method of designing two‐dimensional (2D) frequency‐modulated pulses that produce phase coherence in a spatiotemporal manner. Uniquely, this class of pulses provides the ability to compensate for field inhomogeneity using a spatiotemporally dependent trajectory of maximum coherence in a single‐shot.

Transmurally differentiated measurement of ATP hydrolysis rates in the in vivo porcine hearts.

Compare the transmural distribution of forward creatine kinase reaction (kf,CK) and ATP hydrolysis rate (kr,ATPase) in the myocardium of normal porcine heart. Rate constants were extracted from partially relaxed spectra by applying the T1nom method, effectively reducing data acquisition time by up to an order of magnitude.

Gradient rotating outer volume excitation (GROOVE): A novel method for single-shot two-dimensional outer volume suppression

To introduce a new outer volume suppression (OVS) technique that uses a single pulse and rotating gradients to accomplish frequency‐swept excitation. This new technique, which is called gradient rotating outer volume excitation (GROOVE), produces a circular or elliptical suppression band rather than suppressing the entire outer volume.

31P NMR 2D Mapping of Creatine Kinase Forward Flux Rate in Hearts with Postinfarction Left Ventricular Remodeling in Response to Cell Therapy

Utilizing a fast 31P magnetic resonance spectroscopy (MRS) 2-dimensional chemical shift imaging (2D-CSI) method, this study examined the heterogeneity of creatine kinase (CK) forward flux rate of hearts with postinfarction left ventricular (LV) remodeling. Immunosuppressed Yorkshire pigs were assigned to 4 groups: 1) A sham-operated normal group (SHAM, n = 6); 2) A 60 minutes distal left anterior descending coronary artery ligation and reperfusion (MI, n = 6); 3) Open patch group; ligation injury plus open fibrin patch over the site of injury (Patch, n = 6); and 4) Cell group, hiPSCs-cardiomyocytes, -endothelial cells, and -smooth muscle cells (2 million, each) were injected into the injured myocardium pass through a fibrin patch (Cell+Patch, n = 5). At 4 weeks, the creatine phosphate (PCr)/ATP ratio, CK forward flux rate (Flux PCr→ATP), and k constant of CK forward flux rate (kPCr→ATP) were severely decreased at border zone myocardium (BZ) adjacent to MI. Cell treatment results in significantly increase of PCr/ATP ratio and improve the value of kPCr→ATP and Flux PCr→ATP in BZ myocardium. Moreover, the BZ myocardial CK total activity and protein expression of CK mitochondria isozyme and CK myocardial isozyme were significantly reduced, but recovered in response to cell treatment. Thus, cell therapy results in improvement of BZ bioenergetic abnormality in hearts with postinfarction LV remodeling, which is accompanied by significantly improvements in BZ CK activity and CK isozyme expression. The fast 2D 31P MR CSI mapping can reliably measure the heterogeneity of bioenergetics in hearts with post infarction LV remodeling.

Gradient rotating outer volume excitation (GROOVE): A novel method for single-shot two-dimensional outer volume suppression: Single-Shot 2D Outer Volume Suppression

To introduce a new outer volume suppression (OVS) technique that uses a single pulse and rotating gradients to accomplish frequency‐swept excitation. This new technique, which is called gradient rotating outer volume excitation (GROOVE), produces a circular or elliptical suppression band rather than suppressing the entire outer volume.

Gradient ROtating Outer Volume Excitation (GROOVE): A Novel Method for Single-Shot 2-D OVS

To introduce a new outer volume suppression (OVS) technique that uses a single pulse and rotating gradients to accomplish frequency‐swept excitation. This new technique, which is called gradient rotating outer volume excitation (GROOVE), produces a circular or elliptical suppression band rather than suppressing the entire outer volume.