Quarterly Focus Issue: Heart Failure
Clinical Research
Impact of Mechanical Unloading on Microvasculature and Associated Central Remodeling Features of the Failing Human Heart

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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.

Key Words

heart failure
left ventricular assist device
microvasculature
remodeling
unloading

Abbreviations and Acronyms

HF
heart failure
LV
left ventricular
LVAD
left ventricular assist device
PAS
periodic acid Schiff
PASD
periodic acid Schiff with diastase

Cited by (0)

This work was funded by grants from the National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; Juvenile Diabetes Research Foundation; HA and Edna Benning Foundation; National Center for Research Resources Public Health Services ResearchGrant UL1-RR025764; and the Department of Defense(to Dr. Li). Dr. Li is a Burroughs Wellcome Foundation Clinical Scientist in Translational Research and an Established Investigator of the American Heart Association (AHA). A National Institutes of Health National Center for Research ResourcesGrant supports the Center for Clinical and Translational Science (UL1-RR025764and C06-RR11234to Drs. Kfoury and Drakos). Dr. Drakos was supported by a Hellenic Cardiological SocietyGrant 11.2006for Molecular Cardiology Research. Dr Stehlik is supported by an AHAGrant #09CRP2050127. Drs. Kfoury and Drakos are supported by a Deseret Foundation, Utah, Grant #571.