An echo-dense mass known as left ventricular thrombus (LVT) that has borders distinct from the endocardium and is usually found close to a segment that is contracting abnormally [1, 2]. LVT is found in 10%–33% of acute myocardial infarction (AMI) patients [2]. Previous research suggested that patients with LVT had poor clinical outcomes and were at an elevated risk of developing major adverse cardiac and cerebrovascular events (MACCE) [3, 4, 5, 6, 7]. Studies linking LVT to heart failure have also been published, indicating that LVT is a sign of left ventricular dysfunction [2, 3, 7, 8].

Like coronary artery disease and heart failure [9], diabetes and LVT often co-exist. According to previous research, the prevalence of diabetes mellitus (DM) in LVT patients ranged from 23.9% [10] to 46.0% [4]. Diabetes is one of the independent risk factors for the emergence of heart failure [9, 11, 12]. Concentric left ventricular remodeling is typically seen in people with type 2 diabetes mellitus (T2DM) and is linked to poor cardiovascular prognosis [13]. However, no research has been done on how DM affects LVT. There is yet no information on the differences between LVT patients with T2DM and those without diabetes.

In particular, the changes in LVT features, long-term clinical outcomes, and differential effects of direct oral anticoagulants (DOAC) between individuals with T2DM and without diabetes were the focus of this study’s investigation into the impact of T2DM on LVT.

As far as we know, no previous article has compared the variations between LVT both with and without T2DM. This is the first study to assess the differences between T2DM and non-diabetic patients in a large cohort of LVT patients. Additionally, this is the first investigation into the relationship between DOAC and diabetes in LVT patients. In this cohort analysis of 1068 LVT patients, we established (1) the location and morphology of LVT are similar in T2DM and non-diabetic patients; (2) people with T2DM have a worse cardiovascular prognosis; (3) DOAC treatment may increase the risk of MACCE in patients with LVT and T2DM.

Patients in the T2DM group tended to be much older, have lower LVEF, more hypertension, have a history of stroke, have atrial fibrillation, and have worse eGFR. Additionally, the T2DM group had greater proportions of prior MI and were paired with more coronary artery disease, which suggests a higher atherosclerotic burden. This was not surprising because metabolic syndrome includes T2DM [20], as well as complications in other systems [21]. Similar morphology was found in the T2DM group using imaging, including ultrasound. Survival curves, univariable, and multivariable analyses showed that diabetes increased MACCE in patients with LVT. However, the difference in risk between the two groups after matching and weighting was not statistically significant. This may be due to the insufficient sample size, although our cohort is the largest cohort of LVT to date. More than half of the patients in our LVT cohort had an LVEF 40%. The main cause of death was heart failure.

No prior studies compare the differences in LVT patients with T2DM and without diabetes. The coexistence of heart failure and T2DM is common and strongly impacts clinical management and prognosis. In individuals with heart failure and reduced or preserved ejection fraction, T2DM is linked to a worse clinical state and increased all-cause and cardiovascular mortality than in people without T2DM [9, 22, 23]. T2DM and heart failure patients in the CHARM trial had higher mortality rates across all subtypes of cardiovascular death [24]. According to the PARADIGM-HF trial, those with heart failure and diabetes were more likely to die from cardiovascular and other causes than people without diabetes [25].

It is important to note that various alterations can cause cardiovascular damage including those that affect the metabolism, the kidneys, the myocardium, the endothelium, and the inflammatory systems [23]. According to a widely accepted model, the interaction of three factors—stasis caused by diminished ventricular function, endocardial damage, and hypercoagulability—leads to the etiology of LVT [26]. The diabetic prothrombotic condition is caused by a number of processes, such as platelet hyperactivity, coagulative activation, and endothelial dysfunction [27, 28]. First, hyperactivity of platelets, or enhanced responsiveness of platelets, has been proposed as a key factor in the development of cardiovascular problems in diabetes. The finding of elevated levels of thromboxane B2 in the urine of T2DM patients suggests platelet hyperactivity [29, 30]. In T2DM, there is a decrease in the expression of the receptor for the negative platelet regulator prostacyclin, which improves platelet responsiveness [31]. Second, patients with T2DM are more likely to have hypercoagulable states due to altered plasma levels of coagulation factors [32]. At the same time, T2DM results in less fibrinolysis, the process by which clots dissolve [33]. The over-coagulative status could be caused by DM in patients with the lowest thrombotic risk score and atrial fibrillation [34] and those with acute coronary syndrome [35, 36]. In both cases, the over-thrombosis could be caused by endothelial dysfunction, increased platelet aggregation, and over-activation of the inflammatory cascade and prothrombotic pathways. Diabetes play an important role on the alteration of microbiota, and the microbiota thrombus colonization, then influencing the athero-thrombosis and leading to worse clinical outcomes [37]. However, no difference in LVT size was observed between our two groups of patients. Third, the increase in platelet adhesion and clot formation is the overall result of T2DM-dependent endothelial cell injury. The increased thrombotic risk for T2DM patients is a result of the endothelial cell-dependent modulation of platelets and fibrinolysis [38].

DOAC treatment has been widely used in the whole population with LVT [8, 39, 40, 41]. Moreover, our study suggests that DOAC can increase MACCE in patients with LVT and diabetes. Given the relatively small number of patients with LVT, no one has compared DOAC treatment with vitamin-K antagonists (VKA) in a diabetic subgroup and investigated the interaction of them. Previous studies focused on the LVT patients’ anticoagulation with DOAC and VKA [42, 43]. Rivaroxaban was shown to be comparable to warfarin in the NO-LVT Trial, and to have a faster rate of thrombus clearance, in patients from Egypt and Bulgaria [44]. According to an Israeli study, there is a 20% non-inferiority margin between apixaban and warfarin for treating patients with LVT after an acute MI [45]. However, the sample size of these two RCTs was small, the follow-up time was short, and the primary endpoint was not a hard endpoint. A newly published meta-analysis comprising 21 studies (n = 3172, 3 RCTs, 18 observational studies) found that compared with VKA, DOAC dramatically reduce the risk of bleeding events and stroke in LVT patients. Still, mortality was comparable in the two groups [42].

In patients with atrial fibrillation and T2DM, non-vitamin K antagonist oral anticoagulants produced reduced diabetes complications and mortality risk than did warfarin [46, 47]. Our study suggests that the efficacy of DOAC is different in patients with LVT and T2DM than in patients with atrial fibrillation and T2DM. Some potential mechanisms could explain why DOAC is inferior to warfarin in T2DM patients with LVT. First, unlike the treatment of atrial fibrillation, DOAC treatment has no specific dose recommendation in the treatment of LVT, which was confirmed in our study. In patients with atrial fibrillation, non-recommended DOAC doses were associated with an increased risk of death [48, 49]. Second, confounding problems with different DOAC may lead to reduced efficacy. No randomized clinical trials have compared different DOAC head-to-head. In a retrospective cohort analysis, Ray and associates compared the effectiveness of rivaroxaban with that of apixaban in treating atrial fibrillation [50]. They concluded that patients who received rivaroxaban had 2.7 additional adverse outcomes (95% CI 1.9–3.5) and 21.1 other nonfatal bleeding events (95% CI 20.0–22.3) over 1000 patient-years of treatment, than did those who received apixaban. Correspondingly, the application of rivaroxaban in our study was dominant in DOAC treatment. Third, like the INVICTUS trial [51], the lower MACCE in the VKA group is speculated to be related to the monthly INR monitoring and frequent contact and interaction with doctors to get better whole-course care. Future RCT studies, especially in diabetic samples, are needed. Given the small sample size in certain subgroups, our result needs to be interpreted with caution.

This study has several limitations. First, it is important to acknowledge the limitations of an observational cohort study conducted in a single center. The key limitations relate to the retrospective nature of our research, which was not a head-to-head comparison of anticoagulants. This may limit the potential generalizability to other populations. Therefore, our findings should be considered hypothesis-generating. Second, despite efforts to correct confounding variables, there are likely to be residual confounders that we have been unable to fix, such as the anticoagulation adherence and duration, treatment switching between DOAC and VKA, and time in therapeutic range during the follow-up. Third, major bleeding events and the resolution of LVT between groups were not analyzed. Finally, we enrolled patients over ten years. Hence, the cohort of patients enrolled in the later part of the study will have shorter follow-ups and less time to report events.

This is the first study to investigate differences in LVT characteristics, clinical outcomes, and differential effects of DOAC treatment among patients with T2DM and without diabetes. The location and morphology of LVT are similar between diabetic and non-diabetic patients. A higher risk of MACCE was found among patients with type 2 diabetes. The off-label use of DOAC, the main rivaroxaban, is popular in diabetic patients. However, DOAC may increase the risk of MACCE in patients with LVT and type 2 diabetes.

LVT, left ventricular thrombus; MACCE, major adverse cardiac and cerebrovascular events; DM, diabetes mellitus; T2DM, type 2 diabetes mellitus; DOAC, direct oral anticoagulants; MI, myocardial infarction; SE, systemic embolism; LVEF, left ventricular ejection fraction; VKA, vitamin-K antagonists.

Due to privacy and ethical concerns, the datasets used in the current work cannot be made publicly available. However, the corresponding author can provide them upon reasonable request.

BS, K-FD, and WS—study design and interpretation of results. BS—data collection. BS, RZ, KC, CS, DZ—data analysis. BS, LJ, DY, and HW—manuscript preparation. BS, WS, and K-FD—manuscript revision. The final manuscript was read and approved by all authors.

The institutional review board central committee approved this study at Fuwai hospital (2021-1644). The study was performed following the Declaration of Helsinki. Because there was little patient risk, written consent was waived. During the telephone interview, verbal consent was gained.

Not applicable.

This research was funded by the Chinese Academy of Medical Sciences Innovation Found for Medical Sciences (CIFMS), Grant Numbers: 2021-I2M-1-008 and 2020-I2M-C&T-B-056. It was also financed by Prevention and Control Projects of the Major Chronic Noninfectious Disease [2018YFC1315600].

The authors declare no conflict of interest.