Navigating the cardiovascular seas after allogeneic stem cell transplantation: charting a course for prevention

This editorial refers to ‘Predicting cardiovascular events in allogeneic haematopoietic stem cell transplant recipients’, by B. Sibilia et al., https://doi.org/10.1093/eurjpc/zwaf593. Allogeneic haematopoietic stem cell transplantation (alloHSCT) stands as a pivotal treatment modality for haematologic malignancies, offering durable remission and enhanced survival rates. Nevertheless, this potentially life-saving intervention is not without risks, most notably the heightened susceptibility of alloHSCT recipients to cardiovascular complications. These complications can significantly detract from patients’ quality of life and compromise their long-term survival. The growing incidence of cardiovascular events in this population has pursued researchers to further investigate about the underlying mechanisms and design preventive strategies. In this issue of the European Journal of Preventive Cardiology, Sibilia et al.1 and Itzhaki et al.2 present two compelling studies that illuminate the complex interplay of factors contributing to cardiovascular risk in alloHSCT recipients. These studies offer complementary insights into the complex landscape of cardiovascular risk following alloHSCT. Moreover, both studies are timely, as cardiovascular complications are a leading cause of late morbidity and mortality in alloHSCT survivors, significantly impacting their quality of life and long-term survival. Sibilia et al. conducted a retrospective monocentric study, encompassing 1027 patients who underwent alloHSCT between 2011 and 2020, and provided a comprehensive analysis of cardiovascular events and their predictive factors. The study’s findings underscore the substantial burden of cardiovascular disease in this population, with 30% of patients experiencing cardiotoxicity during a median follow-up of 4 years. Notably, the authors differentiated between early (≤100 days) and late (>100 days) cardiovascular events, revealing distinct risk profiles for each period. Early cardiotoxicity was associated with age, hypertension, pre-existing heart failure, cancer therapy-related cardiac dysfunction (CTRCD), and high-dose cyclophosphamide administration. In contrast, late cardiotoxicity was linked to age, hypertension, history of venous thromboembolism, atrial fibrillation/flutter, pre-existing heart failure, CTRCD, prior exposure to liposomal anthracyclines, and a high-risk haematopoietic cell transplantation-comorbidity index (HCT-CI) score. Complementing this work, Itzhaki et al. directly address the challenge of risk stratification in this vulnerable population by evaluating the performance of established cardiovascular risk prediction models (PCE and PREVENT ASCVD equations). Their finding that the PREVENT ASCVD model demonstrates reasonable discrimination and calibration for predicting ASCVD risk is a significant step forwards. This suggests the potential utility of this model in guiding risk-based interventions, such as statin therapy, to mitigate long-term cardiovascular risk in alloHSCT survivors. However, their study also underscores a critical unmet need: the poor performance of the PREVENT-HF model in predicting heart failure risk. Given the high incidence of heart failure post-alloHSCT and its strong association with adverse outcomes, including non-relapse mortality and overall survival, the development of improved, tailored Heart Failure (HF) risk prediction models is paramount. Both studies build upon a growing body of evidence highlighting the cardiovascular challenges faced by alloHSCT recipients. Several recent studies have further elucidated the nuances of these risks, providing complementary insights into the problem. A sub-analysis exploring cardiac toxicity after haploidentical haematopoietic cell transplantation conducted on behalf of GETH-TC (Grupo Español de Trasplante Hematopoyético y Terapia Celular) by Pinto et al. reinforces the importance of post-transplant cyclophosphamide (PTCy) in the development of early cardiac events.3 This finding aligns with Sibilia et al.’s observation regarding high-dose cyclophosphamide administration and early cardiotoxicity. Moreover, Salas et al. examined cardiac events occurring specifically after allogeneic haematopoietic cell transplantation with post-transplant cyclophosphamide, offering additional support for the impact of this conditioning regimen on cardiac outcomes.4 Their study, also conducted under the auspices of GETH-TC, provides a valuable European perspective on this issue. Fulcher et al. emphasize the importance of empowering both recipients and providers with knowledge on primary preventive care for HSCT survivors, highlighting the need for structured education programmes and guidelines.5 This call to action complements the risk stratification strategy shown by Sibilia et al. in better targeting preventive efforts. Lastly, Greenfield et al.’s European Society for Blood and Marrow Transplantation (EBMT) cross-sectional non-interventional study on metabolic syndrome and cardiovascular disease after HCT provides compelling evidence for the relevance of traditional cardiovascular risk factors in this specific patient population, supporting Sibilia et al.’s study.6 This study reinforces the need for vigilant screening and management of metabolic abnormalities to preserve long-term cardiovascular health. These two studies, taken together, highlight the multifactorial nature of cardiovascular risk in alloHSCT survivors. While Itzhaki et al. focus on the application of established risk prediction models, Sibilia et al. provide a detailed characterization of cardiovascular events and their associated risk factors in a large cohort of alloHSCT recipients. Several strengths enhance the impact of both studies. Itzhaki et al. rigorously evaluated the performance of established risk prediction models, while Sibilia et al. have provided with their large study a comprehensive assessment of cardiovascular outcomes. Nevertheless, limitations should be acknowledged. The retrospective design and single-centre nature of both studies, as well as the inclusion of patients transplanted over a specific time period, may limit the generalizability of the findings to contemporary transplant practices. Despite these limitations, the studies represent a significant step forwards in our understanding of cardiovascular risk in alloHSCT recipients. Future research should focus on validating these findings in larger, multi-centre cohorts, as well as exploring the underlying mechanisms linking risk factors to cardiovascular events. In addition, studies are needed to evaluate the effectiveness of targeted prevention strategies in reducing the incidence of cardiovascular complications in this population. These studies raise several important questions for future research. First, the development and validation of HF risk prediction models specifically tailored to alloHSCT survivors is crucial. These models should incorporate transplant-specific risk factors, such as exposure to cardiotoxic therapies, the presence of chronic graft-vs.-host disease, and the distinct risk profiles identified by Sibilia et al. Second, external validation of the PREVENT ASCVD model in larger, independent cohorts is warranted to confirm its generalizability. Finally, studies evaluating the impact of early, risk-based interventions on cardiovascular outcomes in alloHSCT survivors are needed to translate these findings into improved clinical practice. In conclusion, the manuscripts by Sibilia et al. and Itzhaki et al. significantly advance our understanding of cardiovascular risk in alloHSCT survivors. By highlighting the potential utility of existing risk prediction models and characterizing the distinct risk profiles associated with early and late cardiovascular events, these studies pave the way for more targeted and effective preventive strategies. Addressing these challenges will be essential to improving the long-term cardiovascular health and overall survival of alloHSCT survivors.7,8 Raul Cordoba (Writing—original draft [equal]) and Queralt Salas (Writing—original draft [equal])