Right ventricular dysfunction in type 1 diabetic cardiomyopathy: An overlooked component?

Abstract

While left ventricular (LV) impairment in diabetic cardiomyopathy is well recognized, the contribution of right ventricular (RV) dysfunction has received far less attention. In their longitudinal investigation, Yu et al systematically examined RV and LV performance in a type 1 diabetic mouse model and demonstrated that RV diastolic dysfunction develops later than LV abnormalities, coinciding with structural remodeling marked by fibrosis, hypertrophy, and mild pulmonary hypertension. These observations underscore the progressive yet distinct trajectory of RV pathology in diabetes and point to the importance of incorporating RV assessment into the overall cardiac evaluation of diabetic patients. This letter explores the broader significance of these findings and highlights the urgent need for studies focused on RV-specific mechanisms and targeted therapies aimed at preventing or attenuating biventricular injury in diabetic cardiomyopathy.

Core Tip: In type 1 diabetic cardiomyopathy, right ventricular (RV) function is a key determinant of patient prognosis and must not be neglected. RV performance should be incorporated into the inclusion criteria and endpoint selection of clinical trials. There is a critical need for more robust surrogate markers to evaluate RV-pulmonary arterial coupling. Additionally, the development of therapies that directly improve RV systolic and diastolic function is urgently required.

TO THE EDITOR

Diabetes is a multifaceted metabolic disease that is clinically defined by elevated circulating glucose levels[1]. In type 1 diabetes mellitus (T1DM), disturbances in glucose regulation arise primarily from impaired insulin secretion and dysregulated immune responses[2]. Diabetic cardiomyopathy (DCM), a major chronic complication of diabetes, is characterized by cardiac hypertrophy, interstitial fibrosis, cardiomyocyte apoptosis, and ensuing diastolic and/or systolic dysfunction that can ultimately lead to heart failure (HF)[3]. Although most previous research has centered on left ventricular (LV) abnormalities, Yu et al[4] innovatively delineated the landscape of biventricular injury in a T1DM mouse model. Building on these findings, this letter underscores the importance of recognizing right ventricular (RV) involvement as an integral component of T1DM-induced cardiomyopathy, rather than a secondary or incidental feature. A deeper understanding of RV pathophysiology in diabetes is crucial for refining diagnostic strategies, improving risk stratification, and ultimately developing targeted interventions that address the full spectrum of biventricular dysfunction in diabetic patients.

RV in HF

During embryogenesis, the RV originates from the secondary heart field and develops as a crescent-shaped, thin-walled chamber[5]. Anatomically and functionally, it remains tightly integrated with the left ventricle via the interventricular septum[6]. In 1943, studies by Starr et al[7] suggested that the RV contributed minimally to the clinical picture of HF. However, accumulating evidence over subsequent decades has firmly established the RV as a key determinant of cardiovascular pathophysiology and patient outcomes across a wide range of conditions. For instance, Obokata et al[8] reported that among 271 patients with HF with preserved ejection fraction (HFpEF), those who developed new-onset RV dysfunction during a median 4-year follow-up nearly doubled their risk of mortality (adjusted hazard ratio = 1.89, 95% confidence interval: 1.01-3.44; P = 0.04). Frea et al[9] further demonstrated that estimated right atrial pressure and the RV contractile pressure index serve as strong predictors of in-hospital and short-term outcomes in individuals with advanced acute decompensated chronic HF. Complementing these findings, a meta-analysis of 108 studies by Kitano et al[10] showed that RV ejection fraction remains significantly associated with prognosis in both dilated and hypertrophic cardiomyopathy even after correcting for bias. Similarly, Sayour et al[11], through a meta-analysis of 10 studies, found that RV ejection fraction exhibits a stronger prognostic association than other commonly used RV parameters, including tricuspid annular plane systolic excursion, fractional area change, and free-wall longitudinal strain in cardiopulmonary disorders.

Although much of the existing research on DCM focuses on LV systolic and diastolic impairment, emerging evidence indicates that RV remodeling can also develop in patients with diabetes or even prediabetes, independent of other comorbid conditions[12,13]. Several mechanisms are thought to contribute to this process, including enhanced myocardial fibrosis, activation of inflammatory pathways, microvascular ischemia, and lipotoxicity[14]. Assessment of RV function typically depends on imaging modalities and invasive hemodynamic assessments; however, accurately characterizing RV-pulmonary arterial (RV-PA) coupling remains difficult. Commonly used indices such as the elastance ratio (end-systolic elastance to arterial elastance)[15], ratio of tricuspid annular plane systolic excursion to pulmonary-artery systolic pressure[16], and stroke volume/end-systolic volume[17] provide useful insights but have notable limitations in sensitivity and reproducibility. Consequently, more robust and precise surrogate markers are needed to better quantify RV-PA coupling and to identify patients at increased risk for RV dysfunction. Importantly, emerging applications of artificial intelligence hold promise for improving the automation, standardization, and prognostic value of RV functional assessments[18,19].

T1DM and HF

The mechanisms linking T1DM to HF are multifactorial and remain incompletely understood. Julián et al[20] outlined several major pathogenic pathways through which T1DM contributes to HF development, including chronic hyperglycemia and the accumulation of advanced glycation end products, heightened oxidative stress and mitochondrial dysfunction, persistent inflammation, lipotoxicity, endothelial and microvascular impairment, neurohormonal imbalance and autonomic neuropathy, cardiac autoimmunity, and defective autophagy. Luo et al[21] delineated extensive metabolic reprogramming and inter-organ communication networks such as the liver-heart, gut-heart, hematopoietic system-heart, and adipose tissue-heart axes that shape diabetic HFpEF, an early and increasingly recognized phenotype of DCM that reflects contemporary epidemiological patterns.

RV in T1DM

Regarding RV involvement in T1DM, early evidence dates back to 2007 when Karamitsos et al[22] evaluated echocardiograms from 66 patients with T1DM and 66 age- and sex-matched healthy controls, showing that biventricular diastolic dysfunction, particularly impaired myocardial relaxation appears before overt systolic impairment develops in T1DM. These changes were attributed to ventricular interdependence and the global impact of diabetes on myocardial performance[22]. Supporting this, Khokhlova et al[23], using an alloxan-induced T1DM rat model, demonstrated reduced contractility in cardiomyocytes from both ventricles, including diminished auxotonic tension amplitude and a blunted active tension–length relationship, although contractile function of interventricular septal myocytes remained relatively preserved. In a complementary large-animal study, Polson et al[24] reported that streptozotocin-induced T1DM in pigs led to RV hypertrophy and early upregulation of HF biomarkers within six weeks. Additionally, therapeutic studies have shown that angiotensin-(1-7) can ameliorate RV fibrosis and dysfunction in diabetic rat models[25]. Figure 1 provides an overview of the emerging role of RV abnormalities in T1DM-induced DCM.

Figure 1.

The role of right ventricle in diabetic cardiomyopathy induced by type 1 diabetes mellitus. Type 1 diabetes mellitus drives diabetic cardiomyopathy via pathways such as advanced glycation end products production, oxidative stress, and mitochondrial dysfunction. Pathological changes involve fibrosis, cardiac hypertrophy, and myocardial dysfunction. In diabetic cardiomyopathy: Left ventricle diastolic function deteriorates earliest (a potential early marker), while systolic function is most heavily studied (with left ventricular ejection fraction, as the most common assessment metric). Right ventricle (RV) is prognosis-relevant but often overlooked, and RV-pulmonary artery coupling requires functional evaluation. We emphasize three points: RV function’s critical role in prognosis (and need for inclusion in trial criteria/endpoints), the necessity for improved RV-pulmonary artery coupling markers, and the lack of drugs specifically targeting RV systolic/diastolic function. RV: Right ventricle; PA: Pulmonary artery; T1DM: Type 1 diabetes mellitus; AGEs: Advanced glycation end products; DCM: Diabetic cardiomyopathy; LV: Left ventricle; LVEF: Left ventricular ejection fraction; PAH: Pulmonary arterial hypertension.

Treatment of RV failure

Currently, there are no pharmacological agents specifically designed to improve RV systolic or diastolic function. Current clinical approaches to managing RV remodeling rely on three main strategies. The first is reducing RV load, which includes preload reduction with diuretics and afterload reduction using calcium channel blockers, inhaled vasodilators, endothelin receptor antagonists, prostacyclin analogs, phosphodiesterase-5 inhibitors, and soluble guanylate cyclase stimulators[26,27]. The second strategy focuses on augmenting RV contractility, employing β1-adrenergic agonists, phosphodiesterase-3 inhibitors, vasopressors, or mechanical circulatory support when necessary[28,29]. The third cornerstone of therapy is addressing the underlying disease process to halt or reverse continued RV deterioration.

The cardiovascular benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RA) are increasingly recognized. The STEP-HFpEF trial showed that semaglutide, a GLP1-RA, reduced RV enlargement in patients with obesity- or diabetes-related HFpEF[30]. In contrast, the EMPA-HEART CardioLink-6 study found no effect of empagliflozin, an SGLT2i, on RV structure, including RV mass, in individuals with diabetes and coronary artery disease[31]. A meta-analysis of 23 studies similarly concluded that SGLT2i do not meaningfully improve RV structure or function[32]. Collectively, these findings suggest that GLP1-RA may offer greater promise than SGLT2i for modulating RV remodeling in DCM.

Significance and outlook

In summary, RV diastolic dysfunction can emerge early during T1DM-induced DCM, underscoring the importance of recognizing RV involvement rather than focusing solely on LV abnormalities. RV structural and functional remodeling has strong prognostic implications in DCM, yet the current tools and biomarkers used to evaluate RV performance remain limited in accuracy and sensitivity. This highlights an urgent need for more refined and reliable surrogate markers, particularly those capable of assessing RV-PA coupling in both clinical practice and experimental research. Therefore, advancing these assessment methods will not only improve risk stratification but may also uncover specific mechanistic pathways driving RV vulnerability in diabetes. Furthermore, equally important is the development of therapeutic strategies that directly target RV systolic and diastolic dysfunction. Overall, such interventions could meaningfully alter disease progression and ultimately enhance outcomes for patients with DCM.