Cardiovascular disease following hematopoietic stem cell transplantation: Pathogenesis, detection, and the cardioprotective role of aerobic training

Abstract

Advances in hematopoietic cell transplantation (HCT) techniques and supportive care strategies have led to dramatic improvements in relapse mortality in patients with high-risk hematological malignancies. These improvements, however, conversely increase the risk of late-occurring non-cancer competing causes, mostly cardiovascular disease (CVD). HCT recipients have a significantly increased risk of CVD-specific mortality, including elevated incidence of coronary artery disease (CAD), cerebrovascular disease, and heart failure (HF) compared to age-matched counterparts. Accordingly, there is an urgent need to identify techniques for the detection of early CVD in HCT patients to inform early prevention strategies. Aerobic training (AT) is established as the cornerstone of primary and secondary disease prevention in multiple clinical settings, and may confer similar benefits in HCT patients at high-risk of CVD. The potential benefits of AT either before, immediately after, or in the months/years following HCT have received limited attention. Here, we discuss the risk and extent of CVD in adult HCT patients, highlight novel tools for early detection of CVD, and review existing evidence in oncology and non-oncology populations supporting the efficacy of AT to attenuate HCT-induced CVD. This knowledge can be utilized to optimize treatment, while minimizing CVD risk in individuals with hematological malignancies undergoing HCT.

Keywords: Cardiovascular disease; Detection; Exercise; Hematopoietic stem cell transplantation.

Figure 1. Mechanisms underlying ‘direct’ cardiovascular hits

A) Anthracycline-induced generation of ROS is a central mediator of: 1) accelerated myofilament apoptosis via upregulation of p53 pathway, 2) suppression of myofilament protein synthesis via inhibition of CPCs and GATA-4, 3) alterations in cardiac energy metabolism via downregulation of AMPK, 4) ultrastructural changes to myocytes via calcium overload. These changes lead to myocardial and vascular dysfunction. B) Radiation-induced vascular injury occurs via downregulation of endothelial cell-specific p53/activation of nuclear transcription factor NF-κB, which ultimately up-regulates matrix metalloproteinases, adhesion molecules, pro-inflammatory cytokines, while inactivating vasculoprotective nitric oxide. Eventually, coronary vascular injury characterized by endothelial cell proliferation, intimal thickening, medial scarring, lipid deposits and adventitial fibrosis may occur. ROS, reactive oxygen species; mitogen activated protein kinases, MAPK; cardiac progenitor cells, CPCs; AMP-activated protein kinase, AMPK.

Figure 1. Mechanisms underlying ‘direct’ cardiovascular hits

A) Anthracycline-induced generation of ROS is a central mediator of: 1) accelerated myofilament apoptosis via upregulation of p53 pathway, 2) suppression of myofilament protein synthesis via inhibition of CPCs and GATA-4, 3) alterations in cardiac energy metabolism via downregulation of AMPK, 4) ultrastructural changes to myocytes via calcium overload. These changes lead to myocardial and vascular dysfunction. B) Radiation-induced vascular injury occurs via downregulation of endothelial cell-specific p53/activation of nuclear transcription factor NF-κB, which ultimately up-regulates matrix metalloproteinases, adhesion molecules, pro-inflammatory cytokines, while inactivating vasculoprotective nitric oxide. Eventually, coronary vascular injury characterized by endothelial cell proliferation, intimal thickening, medial scarring, lipid deposits and adventitial fibrosis may occur. ROS, reactive oxygen species; mitogen activated protein kinases, MAPK; cardiac progenitor cells, CPCs; AMP-activated protein kinase, AMPK.

Figure 2. Model of accelerated CVD phenotype

At diagnosis, a significant proportion of HCT patients present with pre-existing or heightened CVD risk factors, which increase the risk of therapy-associated cardiovascular injury. Independently, total-body irradiation and/or high dose chemotherapy are associated with direct adverse effects on the cardiovascular system. These direct effects occur in the context of concomitant lifestyle perturbations (indirect effects: deconditioning, GVHD). Collectively, these direct and indirect insults enhance susceptibility to CVD risk factors, CVD, and premature CVD mortality. CVD, cardiovascular disease; HCT, hematopoietic cell transplantation; GVHD, graft versus host disease.