Eugene Yang

Novel Role for the Potent Endogenous Inotrope Apelin in Human Cardiac Dysfunction

Background—Apelin is among the most potent stimulators of cardiac contractility known. However, no physiological or pathological role for apelin–angiotensin receptor-like 1 (APJ) signaling has ever been described. Methods and Results—We performed transcriptional profiling using a spotted cDNA microarray with 12 814 unique clones on paired samples of left ventricle obtained before and after placement of a left ventricular assist device in 11 patients. The significance analysis of microarrays and a novel rank consistency score designed to exploit the paired structure of the data confirmed that natriuretic peptides were among the most significantly downregulated genes after offloading. The most significantly upregulated gene was the G-protein–coupled receptor APJ, the specific receptor for apelin. We demonstrate here using immunoassay and immunohistochemical techniques that apelin is localized primarily in the endothelium of the coronary arteries and is found at a higher concentration in cardiac tissue after mechanical offloading. These findings imply an important paracrine signaling pathway in the heart. We additionally extend the clinical significance of this work by reporting for the first time circulating human apelin levels and demonstrating increases in the plasma level of apelin in patients with left ventricular dysfunction. Conclusions—The apelin-APJ signaling pathway emerges as an important novel mediator of cardiovascular control.

Targeted Disruption of Endothelial Cell-selective Adhesion Molecule Inhibits Angiogenic Processes in Vitro and in Vivo

Endothelial cell-selective adhesion molecule (ESAM) is a member of the immunoglobulin receptor family that mediates homophilic interactions between endothelial cells. To address potential in vivo angiogenic functions of this molecule, mice lacking ESAM (ESAM–/–) were generated by gene-targeted deletion. ESAM–/– mice did not show overt morphological defects in the vasculature. To evaluate the role of ESAM in pathological angiogenesis, wild type (WT) and ESAM–/– mice were injected with melanoma and Lewis lung carcinoma cells. By 14 days after injection, tumor volumes of B16F10 and LL/2 in ESAM–/– mice were 48 and 37% smaller, respectively, compared with WT mice. Vascular density of the tumors, as determined by CD31 staining, was also decreased in the ESAM null animals. Matrigel plug assays showed less neovascularization in ESAM–/– mice than in WT mice. ESAM–/– endothelial cells exhibited less in vitro tube formation and decreased migration in response to basic fibroblast growth factor when compared with WT cells, and endothelial-like yolk sac cells engineered to overexpress ESAM showed accelerated tube formation in vitro. These in vitro and in vivo studies suggest that ESAM has a redundant functional role in physiological angiogenesis but serves a unique and essential role in pathological angiogenic processes such as tumor growth.

Molecular cloning of nonsecreted endothelial cell-derived lipase isoforms

To expand our knowledge of factors involved in lipid metabolism in the blood vessel wall, we have cloned unique molecular isoforms of endothelial cell-derived lipase (EDL) (HGMW-approved symbol/LIPG). One isoform encoded a truncated protein (EDL2a) lacking the first 80 amino acid residues of the previously characterized EDL1a isoform, including the signal peptide. A similar second clone (EDL2b) was identified that lacked not only the first 80 amino acids, but also a 74-amino-acid region that encodes a portion of the lid domain. RT-PCR analysis confirmed expression of EDL2a/2b isoforms in several human tissues and cultured cells, including endothelial cells. Western blot and immunofluorescence studies using stable transfectants revealed that EDL2a and EDL2b were localized in the cytosol, while, EDL1a was secreted into the culture medium. Cell extracts of EDL2a/2b transfectants did not have triglyceride or phospholipase activity. Thus endothelial cells express three EDL isoforms, two of which remain intracellular and do not function as lipases.

Images in cardiovascular medicine. Cardiac magnetic resonance imaging for myocarditis: effective use in medical decision making.

A 19-year-old man presented with new onset fatigue and dyspnea. The results of the physical examination were unremarkable. ECG was unremarkable for any ischemic changes. Echocardiography demonstrated severe global hypokinesis with an ejection fraction of 15% to 25%. Laboratory workup was remarkable for a troponin I level of 1.56, brain natriuretic peptide of 2249, white blood cell count of 32 000, C-reactive protein of 13, and creatine kinase of 156. Cardiac catheterization demonstrated no significant coronary artery disease, a pulmonary capillary wedge pressure of 3 mm Hg, and cardiac index …A 19-year-old man presented with new onset fatigue and dyspnea. The results of the physical examination were unremarkable. ECG was unremarkable for any ischemic changes. Echocardiography demonstrated severe global hypokinesis with an ejection fraction of 15% to 25%. Laboratory workup was remarkable for a troponin I level of 1.56, brain natriuretic peptide of 2249, white blood cell count of 32 000, C-reactive protein of 13, and creatine kinase of 156. Cardiac catheterization demonstrated no significant coronary artery disease, a pulmonary capillary wedge pressure of 3 mm Hg, and cardiac index …

Cardiac Magnetic Resonance Imaging for Myocarditis Effective Use in Medical Decision Making

A 19-year-old man presented with new onset fatigue and dyspnea. The results of the physical examination were unremarkable. ECG was unremarkable for any ischemic changes. Echocardiography demonstrated severe global hypokinesis with an ejection fraction of 15% to 25%. Laboratory workup was remarkable for a troponin I level of 1.56, brain natriuretic peptide of 2249, white blood cell count of 32 000, C-reactive protein of 13, and creatine kinase of 156. Cardiac catheterization demonstrated no significant coronary artery disease, a pulmonary capillary wedge pressure of 3 mm Hg, and cardiac index …A 19-year-old man presented with new onset fatigue and dyspnea. The results of the physical examination were unremarkable. ECG was unremarkable for any ischemic changes. Echocardiography demonstrated severe global hypokinesis with an ejection fraction of 15% to 25%. Laboratory workup was remarkable for a troponin I level of 1.56, brain natriuretic peptide of 2249, white blood cell count of 32 000, C-reactive protein of 13, and creatine kinase of 156. Cardiac catheterization demonstrated no significant coronary artery disease, a pulmonary capillary wedge pressure of 3 mm Hg, and cardiac index …

Cardiac Magnetic Resonance Imaging for Myocarditis

A 19-year-old man presented with new onset fatigue and dyspnea. The results of the physical examination were unremarkable. ECG was unremarkable for any ischemic changes. Echocardiography demonstrated severe global hypokinesis with an ejection fraction of 15% to 25%. Laboratory workup was remarkable for a troponin I level of 1.56, brain natriuretic peptide of 2249, white blood cell count of 32 000, C-reactive protein of 13, and creatine kinase of 156. Cardiac catheterization demonstrated no significant coronary artery disease, a pulmonary capillary wedge pressure of 3 mm Hg, and cardiac index …A 19-year-old man presented with new onset fatigue and dyspnea. The results of the physical examination were unremarkable. ECG was unremarkable for any ischemic changes. Echocardiography demonstrated severe global hypokinesis with an ejection fraction of 15% to 25%. Laboratory workup was remarkable for a troponin I level of 1.56, brain natriuretic peptide of 2249, white blood cell count of 32 000, C-reactive protein of 13, and creatine kinase of 156. Cardiac catheterization demonstrated no significant coronary artery disease, a pulmonary capillary wedge pressure of 3 mm Hg, and cardiac index …

Molecular Biology Applications in Cardiovascular Medicine

Basic science research has made great contributions to the field of cardiovascular medicine. Scientific studies have had a major impact on clinical practices and outcomes. For example, the principles of cardiac contractile function and unique aspects of hemodynamic loading on the ventricles were defined in animal studies. These findings translated directly into pressure monitoring devices used for patients in the acute care setting. The rationale for drug therapies for treating cardiovascular diseases was based primarily on data derived from basic science investigations. For example, the treatment of heart failure and cardiac arrhythmias evolved from elegant pharmacologic and physiologic studies. A clear path has emerged from the basic science laboratory to the bedside.