Heart disease and cancer are the two leading causes of global mortality (1). Worldwide, 17.9 million deaths were due to cardiovascular diseases (CVDs) in 2019, accounting for 32% of global deaths (2). Nearly 10 million deaths were due to cancer in 2020 globally, and approximately 70% occurred in low- and middle-income countries (3). Leukemia is a life-threatening malignant clonal disease of the hematopoietic system and plays an important part in the global cancer burden (4). According to the 2017 Global Burden of Disease study data, the number of newly diagnosed leukemia cases increased from 354,500 in 1990 to 518,500 in 2017. Globally, the number of acute myelocytic leukemia (AML) deaths rose to 92.98% from 1990 to 2017, while acute lymphoblastic leukemia (ALL) deaths increased by 40.12% (5).

In recent years, researchers have paid increasing attention to the new field of cardio-oncology (6, 7). Studies have found that cancer survivors have an increased risk of CVDs, mostly due to the cardiotoxicity of anti-cancer agents (8–10) or shared common lifestyle risk factors (11, 12). In addition, cancer and CVDs share common systemic pathogenic pathways and mechanisms: inflammation, metabolic modification, clonal hematopoiesis, and altered angiogenesis, as well as extracellular matrix (ECM) and stroboscopic cells (13). Therefore, cancer often coexists with cardiac-related lesions. Studies have found that secondary cardiac tumors (often malignant) with a high incidence most often metastasize from the respiratory system, followed by the hematopoietic system (leukemia/multiple myeloma) (14). The clinical manifestations of leukemic infiltration of the heart include congestive heart failure, pericardial effusion, infiltrative cardiac disease, and constrictive pericarditis (15, 16). Due to high cytokine release or direct leukemic myocardial infiltration, patients with AL may present cardiac dysfunction before starting anthracycline chemotherapy (17). Moreover, hyperleukocytic leukemia, associated with increased white blood cells, greatly increases the incidence of acute myocardial infarction (AMI) and stroke (18).

This study aimed to investigate baseline cardiac function and risk of CVDs in patients with new-onset AL, explore CVD risk factors present before treatment and their association with prognostic survival, and provide data on cardiac management strategies for patients with AL.

This study examined the correlation between clinical characteristics, cardiac biomarkers, and cardiac imaging parameters in newly diagnosed AL patients. The results showed that compared with the control group, AL patients had already experienced some heart-related injuries, accompanied by a significant increase in CK-MB, LDH, hs-cTnI, BNP, and LVID, and a decrease in EF. However, the degree of cardiac damage was less than that of the CAD group. PSM analysis showed that cardiac damage in AL patients was significantly manifested in BNP, HBDH, and LVID. Subgroup analysis showed that cardiac damage was more severe in the HAL than NHAL subgroup. Furthermore, the best predictor of cardiac damage in AL patients was LVID, while age and EF were independent prognostic risk factors. The ratio of bone marrow blasts was positively correlated with the index of cardiac damage.

In recent years, cardiac tumors have been recognized as an important aspect of cardio-oncology practice where diagnosis and management are critical (23, 24). However, most scholars only focus on heart damage caused by anti-tumor therapy (25, 26). Cardiotoxicity during the treatment of AL patients has been extensively reported (27), including radiotherapy (28, 29), conventional chemotherapies (e.g., anthracyclines, antimetabolites, and cyclophosphamide) (30–32), immune checkpoint inhibitors (programmed cell death 1, programmed death ligand 1, or CTL-associated protein 4) (33, 34), and many targeted therapies, particularly monoclonal antibodies and tyrosine kinase inhibitors (35, 36), CART therapy (37–39), natural killer cell immunotherapy (40), and hematopoietic stem cell transplantation (41–43). Possible mechanisms are mediated by reactive oxygen species generated in iron-dependent chemical reactions (44), mitochondrial dysfunction (45), increased calcium flux in cardiomyocytes (46), and disorders of DNA topoisomerase 2-beta metabolism (47). However, only a small amount of research has been done on cardiac lesions directly attributed to leukemia in AL patients.

Patients with leukemia can have secondary cardiac tumors. It has been reported that cardiac tumors metastasize most frequently from the respiratory system, followed by the hematopoietic system (leukemia/multiple myeloma), and most commonly involve the pericardium, followed by myocardium, epicardium, and endocardium (14, 47, 48). Cardiac infiltration is frequently observed in leukemia patients at autopsy, with an incidence of 11–44% (48–52). However, most patients with cardiac infiltrates are clinically asymptomatic, and only a small number of cases presented pericardial effusion, hypertrophic cardiomyopathy, or AMI (15, 49, 53–59) as the first sign. There appears to be no significant difference in these microanatomical or clinical features between AML and ALL patients. Therefore, we have reason to speculate that AL itself will cause the heart lesions, and anti-cancer treatment may be an aggravating factor for cardiotoxicity. However, due to the concealment of clinical symptoms in patients with newly diagnosed AL, the incidence of cardiac dysfunction reported in the current study may only be the tip of the iceberg. Furthermore, as these cases occur more frequently in older patients with cardiac risk factors, the role of AL itself on heart disease may be overlooked.

Our analysis of cardiac-related parameters in newly diagnosed AL patients showed that compared with controls, AL patients did experience some cardiac-related lesions, both in myocardial enzymes and echocardiographic parameters. These clinical manifestations are similar to existing reports and recommendations for cardiac management monitoring in cancer patients (60–62). However, at the time of diagnosis, AL patients often present with anemia and increased WBC count that can cause a certain degree of myocardial damage, which introduces confounding factors to our research results. However, it should be noted that the WBCs of AL patients contain many leukemia cells, which differs from the WBCs of other diseases. Therefore, we matched the AL with the control group and tried to adjust for possible confounding factors, including age, sex, cardiovascular risk factors (hypertension, smoking), and hemoglobin, and found that cardiac injury in the AL group remained. In a subgroup comparison of HAL and NHAL, we found that HAL caused more severe myocardial enzymatic changes. This may be related to the stagnation and accumulation of leukemia cells (58, 63, 64). In addition, correlation analysis showed that the proportion of blast cells was positively correlated with heart damage. Although the correlation coefficient was not particularly high, it still suggested that leukemia itself may cause direct damage to the heart.

Acute leukemia disease itself may be associated with cardiac damage because it shares systemic pathogenic pathways and mechanisms with CVDs: inflammation, metabolic alterations, clonal hematopoiesis, angiogenesis alterations, and extracellular matrix and stroboscopic cells (13, 65). Cancer metabolic byproducts can also impair cardiac function. An increased amount of d-2-hydroxyglutaric acid produced by IDH2-mutant leukemia cells directly contributes to cardiac insufficiency by inhibiting α-KGDH (66). Furthermore, cancer cells can directly secrete factors that induce cardiomyocyte atrophy and metabolic changes, but the exact signaling pathways in cardiomyocytes remain poorly understood (67).

For the reasons described above, clinicians should comprehensively evaluate patients’ cardiac function before chemotherapy. Echocardiography can be used to observe changes in LVEF (68). Conditioned individuals can examine peak systolic global longitudinal strain by speckle-tracking echocardiography (69), which can detect cardiotoxicity at an early stage. In addition, cardiac biomarkers (26) such as troponin, high-sensitivity troponin, BNP, cardiac enzymes, and other potential biomarkers such as those for endothelial dysfunction, myocardial ischemia, oxidative stress and inflammation should be evaluated for a comprehensive assessment to achieve early real-time identification, assessment, and monitoring of cardiotoxicity, and timely targeted treatment. In addition, some studies (26, 70) suggest that early application of cardioprotective therapy to cancer patients may be considered, but its role has not been proven or recommended.

There were several limitations in this study. First, in order to eliminate confounding factors, we used PSM analysis, but the sample size after PSM analysis was small, which may cause some data bias and be different from the real-world situation. Second, we focused on the systolic function of the ventricle, and did not collect related indicators of ventricular diastolic function, thus possibly missing some correlations. Finally, this was a single-center observational study and the sample size was small. Larger sample size validation and prospective studies are needed to confirm the degree of cardiac damage in patients with leukemia. Nonetheless, our study provides important information about the relationship between cardiac damage and leukemia.

In summary, we identified significant differences in cardiac function between patients with primary AL and control patients, and these differences could have an impact on patient prognosis. Our findings provide new insights into the complex etiology and molecular events leading to cardiac injury in patients with AL, and how they can alert clinicians to the presence of cardiac injury in AL patients. In addition, more research is still needed to confirm and explore the specific mechanism between leukemia and cardiac lesions.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Research Committee of Wuhan University in Wuhan, China. The patients/participants provided their written informed consent to participate in this study.

WX, LM, YT, and FZ conceived and designed this research. LM, FY, GC, and JW were responsible for collecting the clinical outcome data of the patients included in the study. YL and TR re-checked the data. WX, YS, QW, and NZ performed the statistical analysis. WX, LM, and FZ wrote the manuscripts and created figures and tables. All authors strictly reviewed the manuscript and approved the final submitted manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.