Impaired Endothelial Regeneration Through Human Parvovirus B19–Infected Circulating Angiogenic Cells in Patients With Cardiomyopathy

Abstract

Human parvovirus B19 (B19V) is a common pathogen in microvascular disease and cardiomyopathy, owing to infection of endothelial cells. B19V replication, however, is almost restricted to erythroid progenitor cells (ErPCs). Endothelial regeneration attributable to bone marrow-derived circulating angiogenic cells (CACs) is a prerequisite for organ function. Because of many similarities of ErPCs and CACs, we hypothesized that B19V is a perpetrator of impaired endogenous endothelial regeneration. B19V DNA and messenger RNA from endomyocardial biopsy specimens, bone marrow specimens, and circulating progenitor cells were quantified by polymerase chain reaction analysis. The highest B19V DNA concentrations were found in CD34(+)KDR(+) cells from 17 patients with chronic B19V-associated cardiomyopathy. B19V replication intermediates could be detected in nearly half of the patients. Furthermore, chronic B19V infection was associated with impaired endothelial regenerative capacity. B19V infection of CACs in vitro resulted in expression of transcripts encoding B19V proteins. The capsid protein VP1 was identified as a novel inducer of apoptosis, as were nonstructural proteins. Inhibition studies identified so-called death receptor signaling with activation of caspase-8 and caspase-10 to be responsible for apoptosis induction. B19V causally impaired endothelial regeneration with spreading of B19V in CACs in an animal model in vivo. We thus conclude that B19V infection and damage to CACs result in dysfunctional endogenous vascular repair, supporting the emergence of primary bone marrow disease with secondary end-organ damage.

Research update for articles published in EJCI in 2014

“…Since our paper has been published, interesting studies have explored the possible mechanisms involved in the tropism of Parvovirus (PV) B19 for different cell types , including endothelial cells , erythroid progenitor cells and T cells . Altered function of these cell types might be responsible for the occurrence of major adverse cardiac events (MACE) after coronary stenting in different ways, thus supporting the main observation of our paper.…”

Phosphorylated STAT5 directly facilitates parvovirus B19 DNA replication in human erythroid progenitors through interaction with the MCM complex

“…B19V also infects non-erythroid tissues [18–20], but the infection of these tissues is non-productive, as virus replication is not fully supported [19,21,22]. Erythropoietin (EPO), a hormone secreted by renal tissue in response to hypoxia, is essential for survival, differentiation, and development of EPCs during the late maturation stages [23].…”

Therapeutic implications of a combined diagnostic workup including endomyocardial biopsy in an all‐comer population of patients with heart failure: a retrospective analysis

“…On the basis of an animal model, in which B19V causally impaired endothelial regeneration with spreading of the virus in bone marrow-derived circulating angiogenic cells, Schmidt-Lucke et al support the theory of a primary bone marrow disease with secondary end-organ damage, caused by dysfunctional endogenous vascular repair. 34 This could explain why parvovirus infection often mimics acute myocardial infarction. 35 Interestingly, there was no correlation between active viral replication and the presence of inflammatory infiltrates in our patients' selection.…”