Impact of Mechanical Unloading on Microvasculature and Associated Central Remodeling Features of the Failing Human Heart
Stavros G. Drakos, MD*,,,¶,#,*, Abdallah G. Kfoury, MD*,,¶, Elizabeth H. Hammond, MD,¶, Bruce B. Reid, MD*,||,¶, Monica P. Revelo, MD, PhD,¶, Brad Y. Rasmusson, MD*,¶, Kevin J. Whitehead, MD,, Mohamed E. Salama, MD, Craig H. Selzman, MD||,¶, Josef Stehlik, MD,¶, Stephen E. Clayson, MD*, Michael R. Bristow, MD, PhD**, Dale G. Renlund, MD*,,¶,* and Dean Y. Li, MD, PhD,,*
* Cardiovascular Department and Utah Artificial Heart Program, Intermountain Medical Center, Salt Lake City, Utah
Molecular Medicine Program, University of Utah, Salt Lake City, Utah
Division of Cardiology, University of Utah, Salt Lake City, Utah
Department of Pathology/ARUP Reference Laboratory, University of Utah, Salt Lake City, Utah
|| Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, Utah
¶ Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah
# 3rd Division of Cardiology, University of Athens, Athens, Greece
** Division of Cardiology, University of Colorado, Denver, Colorado
* Reprint requests and correspondence: Drs. Dean Y. Li, Dale G. Renlund, and Stavros G. Drakos, Eccles Institute of Human Genetics, University of Utah, 15N, 2030E, Salt Lake City, Utah 84112 (Email: stavros.drakos@u2m2.utah.edu).
Objectives: This study investigates alterations in myocardial microvasculature, fibrosis, and hypertrophy before and after mechanical unloading of the failing human heart.
Background: Recent studies demonstrated the pathophysiologic importance and significant mechanistic links among microvasculature, fibrosis, and hypertrophy during the cardiac remodeling process. The effect of left ventricular assist device (LVAD) unloading on cardiac endothelium and microvasculature is unknown, and its influence on fibrosis and hypertrophy regression to the point of atrophy is controversial.
Methods: Hemodynamic data and left ventricular tissue were collected from patients with chronic heart failure at LVAD implant and explant (n = 15) and from normal donors (n = 8). New advances in digital microscopy provided a unique opportunity for comprehensive whole-field, endocardium-to-epicardium evaluation for microvascular density, fibrosis, cardiomyocyte size, and glycogen content. Ultrastructural assessment was done with electron microscopy.
Results: Hemodynamic data revealed significant pressure unloading with LVAD. This was accompanied by a 33% increase in microvascular density (p = 0.001) and a 36% decrease in microvascular lumen area (p = 0.028). We also identified, in agreement with these findings, ultrastructural and immunohistochemical evidence of endothelial cell activation. In addition, LVAD unloading significantly increased interstitial and total collagen content without any associated structural, ultrastructural, or metabolic cardiomyocyte changes suggestive of hypertrophy regression to the point of atrophy and degeneration.
Conclusions: The LVAD unloading resulted in increased microvascular density accompanied by increased fibrosis and no evidence of cardiomyocyte atrophy. These new insights into the effects of LVAD unloading on microvasculature and associated key remodeling features might guide future studies of unloading-induced reverse remodeling of the failing human heart.
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