Barutta F, Andreis A, Bellettini M, Beccuti G, Ferro A, Bollati M, Bellini S, Gioiello G, Mengozzi G, De Ferrari GM, Alunni G, Broglio F, Gruden G. Albuminuria is independently associated with preclinical left ventricular systolic dysfunction: The TESEO study. World J Diabetes 2025; 16(9): 106914 [DOI: 10.4239/wjd.v16.i9.106914]
Corresponding Author of This Article
Federica Barutta, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, Turin 10126, Italy. federica.barutta@unito.it
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Prospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Federica Barutta, Alessandro Andreis, Matteo Bellettini, Guglielmo Beccuti, Arianna Ferro, Martina Bollati, Stefania Bellini, Giulia Gioiello, Giulio Mengozzi, Gaetano M De Ferrari, Gianluca Alunni, Fabio Broglio, Gabriella Gruden, Department of Medical Sciences, University of Turin, Turin 10126, Italy
Alessandro Andreis, Gaetano M De Ferrari, Division of Cardiology, Città della Salute e della Scienza di Torino, Turin 10126, Italy
Alessandro Andreis, Gianluca Alunni, Advanced Cardiovascular Echocardiography Unit, Department of Cardiovascular and Thoracic, Città della Salute e della Scienza di Torino, University Hospital, Turin 10126, Italy
Co-first authors: Federica Barutta and Alessandro Andreis.
Author contributions: Barutta F and Andreis A analyzed the data and wrote the manuscript, they contributed equally to this article, they are the co-first authors of this manuscript; Bellettini M, Beccuti G, Ferro A, Bellettini M, Bellini S, and Gioiello G performed research; Mengozzi G, De Ferrari GM, Alunni G, and Broglio F reviewed and edited the manuscript; Gruden G designed and directed the study, wrote the manuscript, had access to all data, and is responsible for the integrity of the data and the accuracy of the data analysis; and all authors have read and approved the final manuscript.
Supported by the Italian Ministry for Education, University and Research under the Programme “Dipartimenti di Eccellenza 2018-2022” Project, No. D15D18000410001; and Novo Nordisk “Gestione delle complicanze croniche del diabete: From bedside to bench?”, No. n1/2021.
Institutional review board statement: This study was approved by the Medical Ethics Committee of the City of Health and Science of Turin, approval No. D15D18000410001.
Clinical trial registration statement: The clinical trial statement is not applicable as this study is not a clinical trial.
Informed consent statement: All participants provided written informed consent.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Federica Barutta, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, Turin 10126, Italy. federica.barutta@unito.it
Received: March 11, 2025 Revised: May 7, 2025 Accepted: August 4, 2025 Published online: September 15, 2025 Processing time: 185 Days and 0.4 Hours
Abstract
BACKGROUND
Global longitudinal strain (GLS) of the left ventricular is a highly sensitive and reliable marker of systolic function and GLS outperforms ejection fraction (EF) in detecting preclinical left ventricular systolic dysfunction (LVSD). In patients with type 2 diabetes (DM2) albuminuria is a predictor of symptomatic heart failure, but data on the relationship between GLS and albuminuria are conflicting.
AIM
To explore the relationship between GLS and albuminuria in a contemporary cohort of DM2 patients.
METHODS
The study was performed on DM2 patients consecutively enrolled in the TESEO study. Patients with symptoms/signs of heart failure, EF < 50%, coronary artery, other cardiac diseases, or non-adequate acoustic window for GLS assessment were excluded. We collected clinical data, screened for complications, and measured GLS by speckle-tracking echocardiography. Univariate and multiple linear regression analyses were performed to identify independent explanatory variables associated with GLS. Logistic regression analysis was used to assess whether albuminuria was independently associated with GLS-diagnosed (GLS > -18%) LVSD.
RESULTS
Patients (n = 193, age: 60.6 ± 8.1, male: 57%) had a short DM2 duration (3.8 ± 4.9 years) and good metabolic control (glycated haemoglobin A1c: 6.5% ± 1.0). Preclinical GLS-LVSD was present in 21.8% of the patients. GLS values were significantly higher in patients with albuminuria (-19.88 ± 2.16 vs -18.29 ± 2.99, P < 0.001) and in multivariate analysis natural logarithm of albumin-creatinine ratio and uric acid were independent predictors of GLS. In logistic regression analysis, albuminuria was associated with a 6.01 (95% confidence interval: 1.874-19.286) increased odds ratio of GLS-LVSD, independent of age, sex, diastolic blood pressure, chronic kidney disease, EF, mitral annulus velocity lateral, uric acid, and treatments.
CONCLUSION
Albuminuria was independently associated with subclinical LVSD in our contemporary cohort of DM2 patients.
Core Tip: This study provides evidence that the prevalence of preclinical global longitudinal strain-left ventricular systolic dysfunction was elevated in type 2 diabetic patients despite the short duration of the disease and that albuminuria was independently associated with a 6-fold increased risk of preclinical global longitudinal strain-left ventricular systolic dysfunction. Our results suggest that albuminuria may help identify individuals with pre-heart failure who might benefit from an early intervention to prevent/delay heart failure development.
Citation: Barutta F, Andreis A, Bellettini M, Beccuti G, Ferro A, Bollati M, Bellini S, Gioiello G, Mengozzi G, De Ferrari GM, Alunni G, Broglio F, Gruden G. Albuminuria is independently associated with preclinical left ventricular systolic dysfunction: The TESEO study. World J Diabetes 2025; 16(9): 106914
Heart failure (HF) is one of the most prevalent and severe complications of type 2 diabetes (DM2). Patients with DM2 have a 2- to 5-fold increased risk of HF[1,2], and DM2 is an independent risk factor for HF development. Moreover, outcomes are significantly worse in patients who suffer from both DM2 and HF.
Symptomatic HF is preceded by an asymptomatic stage, referred to as pre-HF, which is diagnosed based on the detection of structural abnormalities, systolic or diastolic dysfunction, or elevated cardiac biomarkers[3-5]. Systolic and diastolic dysfunction are traditionally defined by reduced ejection fraction (EF) and elevated filling pressures, respectively. However, global longitudinal strain (GLS) of the left ventricle (LV), assessed using speckle-tracking echocardiography (STE), is more sensitive than EF in diagnosing LV systolic dysfunction (LVSD)[6]. Notably, incorporating GLS into the diagnostic criteria for pre-HF provides independent and incremental prognostic value in predicting the onset of HF[7]. This highlights the potential for early intervention to prevent or delay the development of HF in high-risk populations.
GLS values are significantly worse in patients with DM2[8] and GLS is associated with glycated haemoglobin A1c (HbA1c) levels, obesity, arterial hypertension, and uric acid in either DM2 patients or the general population[9-12]. Prospective studies on DM2 patients with normal EF (≥ 50%) and no evidence of coronary artery disease (CAD) have demonstrated a high prevalence of GLS-LVSD (GLS ≥ -18.9%) at baseline[13,14]. GLS-LVSD was independently associated with subsequent hospitalizations and all-cause mortality[13]. Furthermore, GLS-LVSD (GLS ≥ -18%) also emerged as a predictor of future cardiovascular events[15].
Albuminuria, a well-established marker of kidney damage, is recognized as a significant risk factor for both the development and progression of symptomatic HF[16]. However, the relationship between albuminuria and GLS in patients with DM2 remains unclear, with existing data yielding conflicting results. Jørgensen et al[17] reported an independent association between GLS and macroalbuminuria in DM2 patients without coronary heart disease, while no association was found with microalbuminuria. In contrast, Pararajasingam et al[18], in a cohort of 222 asymptomatic diabetic patients (77% with DM2) without coronary heart disease, found that microalbuminuria - but not macroalbuminuria - was significantly associated with reduced GLS. Conversely, a small study by Abdellatif et al[19] involving asymptomatic, normotensive individuals found no difference in GLS values between diabetic patients with and without albuminuria. Similarly, in a recent study by Silverii et al[20] including 206 DM2 patients without cardiovascular disease, valvular heart disease, or significant arrhythmias, no significant difference in GLS was observed between patients with and without microalbuminuria. Additionally, whether albuminuria is associated with preclinical GLS-LVSD has yet to be explored. This study aimed to investigate whether albuminuria is independently associated with subclinical GLS-LVSD in a contemporary prospective cohort of DM2 patients with preserved EF and no evidence of heart disease.
MATERIALS AND METHODS
Study population
The study was performed on DM2 patients consecutively recruited between July 2019 and October 2024 as part of the prospective TESEO cohort study, investigating chronic DM2 complications. Patients were included in the study if they met the following criteria: Age 18-80 years, first referral to the Unified Diabetes Center at San Giovanni Antica Sede Hospital Turin, and availability of speckle-tracking echocardiographic data. Exclusion criteria were the presence of symptoms/signs of HF, EF < 50%, CAD, moderate-to-severe valvular heart disease, biological or mechanical valve prostheses, significant rhythm disturbances, cardiomyopathies, congenital heart disease, inadequate acoustic window for GLS assessment, and/or current malignancy.
At recruitment, data were collected on demographic and clinical characteristics, including age, sex, educational level, occupation, marital status, ethnicity, dietary habits, physical activity, alcohol consumption, smoking status, cardiovascular risk factors, family history of diabetes, DM2 duration, comorbidities, chronic complications, and current therapy. All participants underwent a comprehensive physical examination and fasting blood samples were taken for biochemical analyses. Additionally, morning urine samples were collected. Fundus oculi examination, a 12-lead electrocardiogram, and transthoracic echocardiography with STE were also performed.
Biochemistry
HbA1c was measured using an immunoenzymatic assay with values standardized according to the DCTT method. Blood glucose, total cholesterol, triglycerides, high-density lipoproteins (HDL)-cholesterol, and serum creatinine were analyzed using standardized enzymatic methods on a Cobas-Bio Analyzer. Urinary albumin and creatinine levels were determined using an immunoturbidimetric assay. Serum N-terminal pro b-type natriuretic peptide levels were measured using a two-site sandwich electrochemiluminescence immunoassay (Elecsys proBNP II, Roche Diagnostic, Mannheim, Germany) on a Modular Analytics Evo analyzer equipped with an E170 module (Roche).
Definitions and calculations
Body mass index (BMI) was calculated using the formula: Weight (kg)/height (m²). Waist circumference (WC) was measured in the horizontal plane at the superior border of the right iliac crest at the end of a normal exhalation. Obesity was defined as a BMI ≥ 30 kg/m², while overweight was defined as a BMI between 24.9 kg/m² and 29.9 kg/m². Body surface area (BSA) was estimated using the Du Bois formula. Systolic and diastolic blood pressure (BP) levels were measured with a standard sphygmomanometer (Hawksley, Lancing, United Kingdom). Hypertension was defined as systolic BP values ≥ 130 mmHg and/or diastolic BP values ≥ 80 mmHg, confirmed on two separate occasions, or the use of antihypertensive therapy[21]. Low-density lipoprotein-cholesterol was calculated using the Friedewald formula. According to current guideline[22], the presence of albuminuria was assessed by measuring the urine albumin-to-creatinine ratio (ACR) in first morning urine samples. Albuminuria is classified as normoalbuminuria (ACR < 3 mg/mmol); microalbuminuria (ACR: 3-30 mg/mmol); and macroalbuminuria (ACR > 30 mg/mmol). In the present analysis, subjects with either micro- or macro-albuminuria were grouped together and albuminuria defined as ACR values ≥ 3 mg/mmol in at least 2 out of 3 determinations performed over a 6-month period. The estimated glomerular filtration rate was calculated based on serum creatinine levels using the chronic kidney disease (CKD)-epidemiology collaboration equation. Patients with an estimated glomerular filtration rate ≤ 60 mL/minute/1.73 m² were classified as having CKD.
Retinopathy was assessed by a specialized ophthalmologist through the analysis of retinal images (Optomed Aurora, Midimedical) and categorized as either absent or present (non-proliferative or proliferative). Non-proliferative retinopathy was diagnosed based on the presence of at least one of the following pathological findings: Microaneurysms, haemorrhages, or hard exudates. Proliferative retinopathy was diagnosed in the presence of neovascularization, fibrotic scar tissue, or preretinal/intravitreal haemorrhages. The eye with the more severe clinical presentation was considered for the assessment. CAD was defined as a history of myocardial infarction, angina pectoris, percutaneous coronary intervention, or coronary artery bypass graft surgery. Patients with electrocardiographic or echocardiography abnormalities suggestive of CAD were excluded if subsequent investigations confirmed the diagnosis of CAD.
Echocardiographic evaluation
Transthoracic echocardiogram studies were performed using the Philips (Andover, MA, United States) EPIQ CVx ultrasound system, equipped with the X5-1 matrix-array transducer. To ensure reproducibility imaging was performed by a European Association of Cardiovascular Imaging certified cardiologist, who applied standardized protocols. High-resolution 2D images were acquired in standard parasternal, apical, and subcostal views, according to European Association of Cardiovascular Imaging guidelines. Frame rates were optimized between 50 fps and 80 fps for dynamic imaging. Pulsed-wave, continuous-wave, tissue-doppler and colour doppler modalities were used to assess intracardiac flows, valve regurgitation, and stenosis. Doppler settings were adjusted individually for flow velocities and anatomical positioning. Image processing and measurements were conducted using QLab (Philips Healthcare, Andover, MA, United States) integrated with TomTec Arena. GLS was automatically calculated for the LV using AutoStrain (TomTec Imaging Systems). The software facilitated automated contouring of endocardial borders, which were manually refined, if required, to ensure accurate tracking. GLS values were averaged across all apical views (four-chamber, two-chamber, and three-chamber) to provide a global assessment of myocardial deformation. Tracking quality was visually verified, and any segment with poor tracking was excluded from analysis. GLS values of ≥ -18% were considered abnormal and indicative of LVSD (LVSD-GLS)[6,23]. End-diastolic diameter, end-diastolic volume, end-systolic volume, septal (interventricular septum) and posterior wall thickness, left ventricular mass (LVM) and relative wall thickness were measured alongside atrial volumes. Left ventricular hypertrophy was defined as an LV mass indexed to BSA (LV mass/BSA) > 115 g/m² in males and > 95 g/m² in females. Left ventricular EF was assessed as well as diastolic parameters, including early diastolic transmitral flow velocities, and septal and lateral mitral annulus velocity (e’) velocities. Average e’ (lateral e’ + septal e’/2) and the ratio E-wave/average e’ were calculated.
Statistical analysis
The results are presented as mean ± SD for normally distributed variables, geometric mean (25th-75th percentile) for non-normally distributed variables, and percentages for categorical variables. Group comparisons were performed using a two-tailed Student’s t-test with logarithmic transformation of non-normally distributed variables (ACR, triglycerides, N-terminal pro b-type natriuretic peptide). Categorical variables were compared using the χ2 test. A priori power analyses conducted using G*Power[24] indicated that the available sample size provided 82% power to detect a medium effect size (Cohen’s d = 0.5) using a two-tailed independent samples t-test (α = 0.05), and 99% power to detect a medium effect size (w = 0.3) using a χ2 test of independence (α = 0.05). Univariate and multiple linear regression analyses were performed to identify independent explanatory variables associated with GLS. Logistic regression analyses were used to determine whether albuminuria independently increased the odds ratio (OR) of having GLS-LVSD ≥ -18, after adjusting for potential confounders. Both backward and forward strategies, examining all potentially explanatory variables, were employed to select models. The likelihood ratio test was used to compare nested models. A P < 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS software (version 28).
RESULTS
Study population
Of the 320 patients recruited between July 2019 and October 2024 in the TESEO study, 193 were included in the study (Figure 1). Table 1 shows the demographic and clinical characteristics of the enrolled patients. The cohort had a mean age of 60.6 years, with a slight predominance of males. As expected, both obesity and hypertension were highly prevalent; however, only 65.9% of hypertensive patients were receiving anti-hypertensive therapy. Mean low-density lipoprotein cholesterol levels were elevated, and 43% of patients were on statins. The cohort had a relatively short DM2 duration and good metabolic control. The majority of patients were treated with metformin; however, more than half were on new-generation anti-hyperglycemic agents. Retinopathy, albuminuria, and CKD were present in 4.1%, 13.0% (11.9% microalbuminuria), and 7.8% of the patients, respectively. Twenty-one patients had albuminuria, 11 had CKD, and 4 had both albuminuria and CKD.
GLS-LVSD was found in 21.8% of the patients. Tables 2 and 3 show the clinical and echocardiographic characteristics of the study cohort, stratified by GLS-LVSD status. There were no significant differences in metabolic parameters between the two groups, though uric acid levels showed borderline significance. Retinopathy, CKD, and albuminuria were more prevalent in the GLS-LVSD group, but only the difference in albuminuria reached statistical significance (Table 2). Patients with and without GLS-LVSD showed comparable structural LV parameters and markers of diastolic dysfunction, but EF values were significantly lower in GLS-LVSD patients (Table 3).
Table 2 Demographic and clinical characteristics of 193 type 2 diabetes subjects stratified by global longitudinal strain-left ventricular systolic dysfunction status, mean ± SD.
Table 3 Echocardiografic parameters of 193 type 2 diabetes subjects stratified by global longitudinal strain-left ventricular systolic dysfunction status, mean ± SD.
Patients with albuminuria were similar to those with normoalbuminuria in terms of clinical characteristics, differing only in systolic BP (144.04 ± 17.39 vs 134.63 ± 15.81, P = 0.007) and uric acid levels (6.17 ± 2.45 vs 5.39 ± 1.45, P = 0.032). Notably, GLS was the only echocardiographic parameter that differed significantly between subjects with and without albuminuria (Table 4) and this difference was even greater after adjustment for age and sex (P = 0.002).
Table 4 Echocardiografic parameters of 193 type 2 diabetes subjects stratified by class of albuminuria, mean ± SD.
After adjusting for age and sex, GLS values were significantly associated with WC, systolic BP, diastolic BP, natural logarithm of albumin-creatinine ratio (lnACR), uric acid, and lateral e’ in univariate analyses (Table 5). Among these variables, only lnACR [β = 0.22 (0.12-0.60), P = 0.003] and uric acid [β = 0.15 (0.00-0.22) P = 0.049] remained statistical significant when included in a multivariate regression model explaining 15.4% of GLS variance. Similar results were observed when albuminuria replaced lnACR in the multivariate regression model [albuminuria: Β = 0.223 (0.08-0.366), P = 0.002; uric acid β = 0.151 (0.006-0.30), P = 0.041].
Table 5 Linear regression analysis of clinical factors associated with the dependent variable global longitudinal strain.
A logistic regression analysis was performed to assess whether albuminuria was independently associated with an increased OR for GLS-LVSD, accounting for potential confounders and risk factors. Albuminuria demonstrated a significant association with an increased OR for GLS-LVSD, independent of age, sex, diastolic BP, and CKD (model 1). The association strengthened further after adjusting for EF, lateral e’, and uric acid (model 2) as well as treatments (model 3). In the fully adjusted model, albuminuria was linked to a six-fold increase in the OR for GLS-LVSD and emerged as the only variable significantly associated with GLS-LVSD (Table 6).
Table 6 Odd ratios for global longitudinal strain≥ -18 in the cohort of 193 type 2 diabetes patients.
This study demonstrates that albuminuria is independently associated with subclinical LVSD, as assessed by GLS measurement in asymptomatic DM2 patients with normal EF and no heart disease.
GLS is a highly sensitive and reliable early marker of LVSD, outperforming EF in detecting subclinical systolic dysfunction[25,26]. In this study, a GLS threshold of ≥ -18% was used to define LVSD. Although there is no universal consensus on the GLS threshold, as it varies depending on the STE software and the studied population, GLS values > -16% are considered abnormal and values in the range -16% to -18% in a grey zone[6,23]. In our cohort, the 75th percentile of GLS distribution was -18.4%, supporting -18% as a suitable cut-off value. Additionally, prospective studies have established the negative prognostic significance of GLS levels above -18%, emphasizing the clinical relevance of this threshold[7].
In our cohort, 21.8% of patients exhibited GLS-LVSD. A prospective study found abnormal GLS in 45% of asymptomatic DM2 patients[13], while Ernande et al[14] reported a prevalence of 32% in DM2 patients without heart disease or hypertension. The lower prevalence in our study likely reflects the shorter DM2 duration among our patients and the exclusion of those with any heart disease. However, our finding that a fifth of the patients had GLS-LVSD despite short DM2 duration and optimal glycemic control is clinically relevant as GLS-LVSD predicts HF risk and is associated with increased risks of all-cause mortality and hospitalization[13].
Subjects with and without GLS-LVSD showed no significant differences in LV structural parameters or diastolic dysfunction indices, aligning with previous findings that GLS-LVSD can occur independently of diastolic dysfunction[14] or increased LVM[13]. However, mean EF values were significantly lower in patients with GLS-LVSD, reflecting that both EF and GLS measure systolic dysfunction, with GLS being more sensitive for detecting early abnormalities.
The prevalence of albuminuria was significantly higher in patients with GLS-LVSD. Logistic regression analysis showed that albuminuria was associated with a six-fold increase in odds for GLS-LVSD, independent of age, sex, diastolic BP, CKD, EF, e’ lateral, uric acid, and treatments. Furthermore, ACR levels were significantly higher in patients with GLS-LVSD, with multivariate analysis confirming ACR/albuminuria as an independent predictor of GLS. Previous studies on the relationship between albuminuria and GLS in DM2 have yielded mixed results. Some studies linked albuminuria to GLS in cases of macroalbuminuria[17] or microalbuminuria[18], while others found no association between GLS and microvascular complications, including albuminuria[19,20]. Our findings not only demonstrate an association between albuminuria and GLS in a well-characterized cohort of DM2 patients, but also provide the first evidence of a significant link between albuminuria and increased risk of GLS-LVSD even after adjustment for CKD. This highlights the need for echocardiographic monitoring of GLS in patients with albuminuria, even when EF and filling pressures are normal, to facilitate early detection of LVSD. Of interest, GLS was the only echocardiographic parameter that differed significantly between subjects with and without albuminuria, suggesting that alterations in subendocardial longitudinal fibers may represent the earliest cardiac abnormality in patients with incipient renal damage[27,28].
In our cohort, the majority of patients exhibited microalbuminuria, with only 2 patients presenting macroalbuminuria. Therefore, patients with either micro- or macro-albuminuria were grouped together. However, it would be of interest to assess in future analyses whether stratifying patients based on albuminuria severity could provide additional information into the relationship between kidney damage and cardiac function.
The underlying cause of the relationship between albuminuria and GLS-LVSD remains unclear. Hypertension is a significant determinant of both GLS and albuminuria, and in our study systolic BP was significantly higher in patients with albuminuria, with BP showing a univariate association with GLS. However, in both multivariate and logistic regression analyses, the relationship between albuminuria and GLS/GLS-LVSD was independent of BP and LVM index. On the other hand, studies in patients with hypertrophic cardiomyopathy suggests that GLS may serve as a surrogate marker for myocardial fibrosis[29,30]. Therefore, we can speculate that albuminuria is not only an indicator of vascular damage, but also a systemic marker of a pro-fibrotic response to diabetes-induced metabolic and inflammatory stress in both the kidney and the heart, potentially aiding in the identification of individuals at higher risk for HF[31].
Patients with and without GLS-LVSD showed no significant differences in metabolic parameters, including BMI, WC, HbA1c, and lipid profiles. Poor glycemic control is a known predictor of HF, with a 15% higher HF incidence for each 1% increase in HbA1c[32]. However, evidence of a HbA1c-GLS relationship is inconsistent. Similar to our findings, Mochizuki et al[33] found no difference in glycemic control between patients with and without GLS-LVSD. In contrast, Silverii et al[20] observed an independent association between GLS and HbA1c, likely due to higher HbA1c levels in their study cohort. Indeed, GLS abnormalities are more evident in poorly controlled DM2, but comparable to controls when HbA1c is below 7%[34,35].
Regarding adiposity, there were no significant differences in BMI and WC between subjects with and without GLS-LVSD. Previous studies on asymptomatic DM2 patients without CVD and with normal EF have reported an independent association between LVSD-GLS and fat mass[36]. However, results were not adjusted for albuminuria and in our study the significant univariate association between WC and GLS was no longer significant after inclusion of ACR and other confounders in the model. Similarly, uric acid levels were higher in GLS-LVSD patients, but the difference was not significant and uric acid did not reach statistical significance in the logistic model. A large epidemiological study in the general population reported an association between uric acid and GLS-LVSD; however, the authors did not account for albuminuria.
The independent association between albuminuria and GLS-LVSD observed in our study may have important clinical implications. The concept of pre-HF was introduced to highlight the progressive nature of HF and to encourage preventive strategies; thus, early recognition is essential. However, its subclinical presentation often leads to underdiagnosis. Furthermore, pre-HF represents a heterogeneous group of patients, and reliable biomarkers to identify those at higher risk of progression are currently lacking. Our findings suggest that incorporating albuminuria into HF risk stratification scores may aid in identifying individuals with pre-HF and/or those at increased risk of progression to overt HF. This is particularly relevant given the growing availability of therapeutic interventions - such as renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, and non-steroidal mineralocorticoid receptor antagonists - that may prevent HF progression[37,38]. Notably, renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists are effective in treating albuminuria. This supports the hypothesis of shared pathogenic mechanisms - such as endothelial dysfunction, chronic low-grade inflammation, and fibrosis - linking albuminuria and LVSD, and raises the possibility that these agents may confer dual benefits for both cardiac and renal function. This study has several strengths. First, the study was conducted on a cohort of DM2 patients with a short disease duration and good glycemic control, minimizing the confounding effects of glycemic decompensation and the multiple chronic complications often associated with long-standing diabetes. Second, individuals with confounding clinical conditions were excluded. Third, our cohort is representative of contemporary patients with recently diagnosed DM2. Finally, the STE analysis was performed in real-time during the echocardiographic examination, rather than on digitized images analyzed retrospectively and all echocardiographic analyses were conducted by the same operator, minimizing operator-dependent variability. However, this study also has limitations. Due to the cross-sectional design, causal relationships between albuminuria and GLS-LVSD cannot be established and results need to be confirmed in future longitudinal studies. In addition, future studies with larger cohorts may benefit from the application of explainable machine learning approaches to enhance predictive modeling and the interpretation of key variables.
CONCLUSION
In conclusion, this study in DM2 patients demonstrates that albuminuria is independently associated with GLS-LVSD, supporting the hypothesis that albuminuria and subclinical LVSD may share common pathogenic mechanisms. Prospective studies are needed to determine whether risk scores incorporating albuminuria can improve early detection and risk stratification of pre-HF. The development of artificial intelligence-based models for GLS-LVSD also holds great promise for advancing our understanding in this area and guiding future research. Additionally, pharmacological intervention trials targeting patients with GLS-LVSD and elevated albuminuria are warranted to evaluate the efficacy of biomarker-guided treatment in high-risk populations.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Endocrinology and metabolism
Country of origin: Italy
Peer-review report’s classification
Scientific Quality: Grade A, Grade A, Grade B, Grade B, Grade B, Grade B, Grade B
Novelty: Grade B, Grade B, Grade B, Grade C
Creativity or Innovation: Grade B, Grade B, Grade B, Grade C
Scientific Significance: Grade A, Grade A, Grade B, Grade B
P-Reviewer: Cai L, MD, PhD, Professor, United States; Dabla PK, MD, Professor, India; Hwu CM, MD, Professor, Taiwan; Huo WQ, PhD, Associate Professor, China; Wang XD, MD, PhD, China S-Editor: Bai Y L-Editor: A P-Editor: Xu ZH
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