TO THE EDITOR
Cardiovascular complications are the leading cause of morbidity and mortality in type 1 diabetes (T1D)[1]. In this context, diabetic cardiomyopathy (DCM), a cardiac disease characterized by left ventricular (LV) structural and functional disorders independent of hypertension or coronary artery disease, is a traditional disorder seen in T1D[2]. The classical DCM progression consists of the early diastolic dysfunction and the increasing myocardial stiffness, which later progresses to systolic failure[3]. Compared to the LV, the right ventricle (RV), which is also vital for the maintenance of pulmonary circulation and hemodynamic balance, is considered a more "silent" ventricle and has not received sufficient attention in previous research. However, accumulating evidence has shown that RV function is more frequently compromised in T1D than previously recognized. This RV impairment is associated with a worse clinical status, including reduced exercise capacity, diminished quality of life, and an increased risk of death[4-6]. In a valuable longitudinal evaluation, Yu et al[7] reported early LV diastolic impairment preceding systolic dysfunction in the OVE26 diabetic mouse model, and further tracked cardiac alterations from the onset of hyperglycemia. They found a progressive early decline of LV diastolic function, followed by a gradual deterioration in LV systolic performance. With disease progression, RV diastolic dysfunction also emerged, concomitant with developing fibrosis and pulmonary arterial hypertension (PAH). Their investigation may help understand the overlooked role of biventricular interplay in the occurrence and development of DCM.
Right ventricular dysfunction: The overlooked dimension in DCM
For decades, DCM has been explored using the LV as the main paradigm in translational and clinical studies. Cardiac echocardiography and magnetic resonance imaging (MRI) have demonstrated that both type 1 and type 2 diabetics—including those who are normotensive—exhibit significant diastolic dysfunction[3,8]. This focus on the LV neglects the possibility that the RV may in fact be more vulnerable. Yu et al[7] supported this view by demonstrating that a decline in LV functions occurs first, followed by the subsequent development of RV functional impairment, as measured in their longitudinal study. As well, recent evidence has highlighted that RV dysfunction is a common yet underrecognized feature of diabetes[9]. Widya et al[4], using MRI, observed reduced RV strain early in patients with T2D. Speckle-tracking echocardiography now enables a more detailed assessment of myocardial function beyond traditional echocardiographic parameters. Several studies have identified latent ventricular dyssynchrony even in asymptomatic young individuals with T1D[10]. Data from DCM registries further indicate that progressive RV impairment in patients with heart failure due to DCM predicts exercise intolerance and mortality[11]. Despite these compelling findings, endpoints related to right ventricular ejection fraction remain seldom incorporated into most preclinical as well as clinical trials for DCM.
Sequential remodeling in T1D: Lessons from longitudinal models
A key contribution of Yu et al[7] was the establishment of a clear timeline of cardiac dysfunction. Their results showed that LV diastolic impairment was already present at week 12, followed by the emergence of LV systolic dysfunction around week 18, while RV diastolic function began to decline only at week 30. This sequence suggests a physiological interdependence between ventricular responses, influenced by contractile mechanisms, hemodynamic interpaly, shared myocardial fibers, septal mechanics, and pulmonary vascular load[12]. A similar progression has been observed in human patients, who often exhibit significant LV dysfunction early in the disease course, with RV involvement manifesting later in the progression of DCM[11,13]. Thus, the timeline delineated in this T1D model provides an experimental framework that parallels human disease, supporting the need for early detection and targeted therapeutic strategies.
Pulmonary vascular injury and biventricular crosstalk
The most novel finding reported by Yu et al[7] was the induction of PAH at 30 weeks, concomitant with RV structural remodeling. The observed increase in RV systolic pressure and shortened pulmonary acceleration time indicate that the disease course severely influences the myocardium and leads to progressive RV functional deterioration. This perspective aligns well with accumulating observations suggesting that diabetes induces a range of alterations in vascular endothelial functions, rigidity, and vasodilation[14,15]. Chronic hyperglycemia and oxidative stress induce vessel wall remodeling and then increase the afterload on the RV. In addition, a combination of LV diastolic dysfunction, LA hypertension, and pulmonary vascular backpressure would induce PAH and promote subsequent RV remodeling[16]. Therefore, RV insufficiency or dysfunction in diabetes should not be viewed merely as a myocardial pathology but rather as a one component within a broader ventricular-vascular axis, where hyperglycemia and inflammatory processes jointly promote myocardial fibrosis and vascular remodeling.
Mechanistic underpinnings: Fibrosis, inflammation, and oxidative stress
Yu et al[7] demonstrated that perivascular fibrosis and mitochondrial injury appear earlier in the RV than in the LV, suggesting a heightened vulnerability of the RV to oxidative and metabolic stress. Given the RV’s thinner myocardium, lower coronary reserve, and distinct loading conditions, these findings provide a mechanistic rationale for its early diastolic impairment and gradual decline in contractile performance under chronic diabetic stress[17-19]. While these pathophysiological principles have been largely established in the context of LV pathologies, data from Yu et al[7] confirm their relevance to RV pathology, albeit with a distinct temporal progression. Specifically, the RV's structural thinness and its reliance on longitudinal contraction make it particularly vulnerable to increases in afterload[20], which may account for its differential response in DCM.
Translational implications and future directions
Early detection: The earliest detectable abnormality is LV diastolic dysfunction, emphasizing the value of tissue Doppler and speckle-tracking echocardiography identifying subclinical alterations, even among young patients with T1D[3,10].
RV as a prognostic marker: RV dysfunction has been shown in clinical investigations to forecast negative outcomes independently of LV function[9-11]. Adding RV analysis to preclinical and clinical trial protocols may optimize the assessment of patient risk.
Pulmonary vascular targets: With PAH being evident, strategies that preserve endothelial function, for example SGLT2 inhibition, endothelin antagonism, or antioxidant therapy, could slow the progression of RV dysfunction.
The OVE 26 mouse model: Although the OVE26 mouse provides a robust model for investigating early-onset T1D and progressive cardiac remodeling, it does not fully capture the multifactorial nature of human DCM, which involves comorbid factors such as hypertension, dyslipidemia, and aging. Therefore, extrapolation of these findings to clinical settings must be cautious. Also, the model does not fully reproduce the complex metabolic, hormonal, and hemodynamic interactions observed in human disease. Therefore, conclusions drawn from these models should be interpreted with caution, and validation in well-characterized patient cohorts will be necessary to confirm translational relevance.
Timing of therapy: The sequential trajectory suggests a therapeutic window: Interventions targeting fibrosis and oxidative stress should be initiated prior to the onset of irreversible RV damage. Validation of these findings in well-defined clinical cohorts, particularly in adolescents and young adults with T1D, is essential. The application of multimodal imaging techniques such as cardiac MRI and right heart catheterization may help identify early RV abnormalities[8,13,21].
Systems biology approaches: Multi-omics profiling of diabetic myocardium could unravel molecular networks that link hyperglycemia to ventricular and vascular remodeling[22].
Future studies should aim to elucidate the molecular and hemodynamic mechanisms underlying RV remodeling in DCM, including how hyperglycemia, oxidative stress, and pulmonary vascular changes interact to impair RV function. Longitudinal imaging and molecular profiling in both type 1 and type 2 diabetes models could help clarify whether RV dysfunction represents a primary pathogenic event or a secondary consequence of pulmonary vascular injury. Furthermore, identifying circulating biomarkers or imaging signatures predictive of early RV involvement could facilitate earlier diagnosis and intervention.
CONCLUSION
The study of Yu et al[7] broadens our appreciation of diabetes-induced cardiomyopathy by highlighting a previously unrecognized temporal delay between pathological cardiac growth and functional impairment. It underscores that DCM is not solely an LV disease, but rather—from its earliest stages—a biventricular and vascular pathology driven by fibrosis, inflammation, and even pulmonary vascular injury. Future efforts should consider RV function in disease diagnosis, prognosis, and treatment development. Acknowledging the interdependence between both ventricles and the pulmonary circulation is essential to fully grasp the spectrum of diabetic heart disease and to improve patient outcomes. While targeting mechanisms such as ferroptosis, oxidative stress, or metabolic signaling shows therapeutic potential, translating these mechanisms into clinical interventions remains challenging. Potential obstacles include the lack of specific pharmacologic agents targeting early RV remodeling, interindividual variability in DCM progression, and the difficulty of monitoring ventricular tissue responses noninvasively. Future studies integrating advanced imaging and biomarker approaches will be critical to bridge this translational gap. Although the OVE26 mouse model reflects early hyperglycemia and progressive cardiac remodeling, it fails to encompass the complex comorbidities specific to human DCM, including hypertension, dyslipidemia, obesity, and age-related vascular remodeling. These factors exacerbate myocardial oxidative stress, fibrosis, and pulmonary vascular load in patients, while the absence of these factors in OVE26 mice limits direct translational extrapolation. Therefore, validation through other preclinical models and human cohort studies is required to confirm the broad applicability of the findings related to RV dysfunction.
