Impact of type 2 diabetes mellitus on heart failure with preserved ejection fraction depending on the presence of atrial fibrillation

. Background. Cardiovascular diseases, including heart failure (HF) and heart failure with preserved ejection fraction (HFpEF), pose a global health challenge. HFpEF is on the rise, especially among the elderly and those with conditions like diabetes, obesity, and hypertension. Type 2 diabetes mellitus (T2DM) often coexists with HFpEF


Introduction
Cardiovascular diseases continue to be a primary cause of morbidity and mortality worldwide, presenting a multifaceted challenge to public health systems.Heart failure (HF) is a significant clinical syndrome, contributing to the global burden of cardiovascular morbidity and mortality.Among the diverse range of HF, heart failure with preserved ejection fraction (HFpEF) has emerged as a distinct and particularly challenging clinical entity [1].
HFpEF, characterized by signs and symptoms of HF in a preserved left ventricular ejection fraction (LVEF), presents a diagnostic and therapeutic challenge.It carries a significant disease burden, accounting for almost half of all HF cases.Its prevalence continues to increase alongside population ageing and the rising occurrence of comorbidities like hypertension, obesity, and diabetes melli tus [2].
Type 2 diabetes mellitus (T2DM) is a prevalent and meta bolically complex chronic disease that frequently in-Vol.19 Оригінальні дослідження / Original Researches teracts with HFpEF in a perplexing manner.The coexistence of T2DM and HFpEF has raised questions regarding their pathophysiological mechanisms, the prognosis of affected individuals, and the management strategies needed to mitigate the impact of this challenging comorbidity [3].
The presence or absence of atrial fibrillation (AF) adds complexity to this intricate relationship.AF is the most common sustained arrhythmia encountered in clinical practice.Not only does AF share risk factors with T2DM and HFpEF, but it also exerts a profound influence on the cardiovascular system, causing hemodynamic disturbances, thromboembolic complications, and exacerbating HF symptoms.The convergence of T2DM, HFpEF, and AF further complicates the clinical picture and presents a challenging scenario for both clinicians and researchers [4].
Diastolic dysfunction is a hallmark feature of HFpEF, characterized by impaired relaxation and compliance of the left ventricle during diastole, resulting in impaired filling and elevated left ventricular filling pressures.This dysfunction plays a crucial role in the pathophysiology of HFpEF and significantly contributes to its clinical manifestations [5].Recent epidemiological studies have revealed the occurrence of diastolic dysfunction amongst patients suffering from T2DM, HFpEF, and AF [6].Notably, individuals with T2DM are at an increased risk of developing diastolic dysfunction even in the absence of overt HF [7].The hyperglycemic state in T2DM may result in structural and functional alterations in the myocardium, including myocardial fibrosis and altered calcium handling, leading to diastolic dysfunction in affected patients.The presence of T2DM in conjunction with HFpEF substantially raises the incidence of diastolic dysfunction as compared to either condition alone [8].The findings imply a synergistic impact, as T2DM worsens the diastolic irregularities observed in HFpEF.Additionally, AF, a prevalent arrhythmia in both T2DM and HFpEF, can exacerbate diastolic function by creating irregular atrial contractions, decreasing the effectiveness of atrial kick, and encouraging atrial remodeling [9].
Emerging research has underscored the significance of innovative biomarkers in clarifying the pathophysiological mechanisms and predicting outcomes in individuals with HFpEF, specifically with coexisting conditions like T2DM and AF [10].Two biomarkers, soluble suppression of tumorigenicity 2 (sST2) and galectin-3, have been identified as potentially contributing to risk stratification and our understanding of the underlying molecular pathways.SST2 belongs to the interleukin-1 receptor family and is recognized as a marker for myocardial stress and fibrosis.Elevated sST2 levels have been linked to negative outcomes in patients with HFpEF, and could offer insights into the level of myocardial fibrosis, a significant factor in diastolic dysfunction [11].Furthermore, sST2 levels have been found to correlate with the presence of T2DM and AF, suggesting its potential utility in risk assessment in the complex interplay of these conditions [12].Galectin-3, a beta-galactoside-binding lectin, is involved in various inflammatory and fibrotic pathways within the myocardium [13].Elevated galectin-3 levels have been linked to myocardial fibrosis and adverse outcomes in HFpEF [14].Its association with T2DM and AF has also been explored, hinting at its role as a marker of not only HFpEF but also the comorbidities that often accompany it [15].
The purpose of this study is to thoroughly examine the impact of type 2 diabetes mellitus on both cardiac function and biomarker profiles in patients diagnosed with heart failure with preserved ejection fraction, regardless of whether they have atrial fibrillation or not.

Materials and methods
The study involved outpatients who were aged 45 years and older, had compensated T2DM, and HF II-III functional class (based on the New York Heart Association classification).Additionally, their left ventricular ejection fraction was preserved at a level greater than 50 %, and N-terminal fragment of brain natriuretic peptide precursor (NT-proBNP) levels were elevated, surpassing 125 pg/mL.All patients enrolled in the study provided informed consent, and the research adhered to the basic principles outlined in the Declaration of Helsinki.It was a single-center, cohort study comprising 448 patients diagnosed with HFpEF between December 2018 and March 2023.The participants were classified into four groups as follows: group 1 (n = 189) included patients with HFpEF alone, group 2 (n = 39) comprised patients with HFpEF and T2DM, group 3 (n = 176) consisted of patients with HFpEF and atrial fibrillation, while group 4 (n = 44) included patients with HFpEF, atrial fibrillation, and T2DM.
The diagnosis of HFpEF was based on the criteria of 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [16], atrial fibrillation -on 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation [17], diabetes mellitus -on 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD [18].All patients underwent a comprehensive clinical and instrumental examination.These studies included determination of the functional class of HF, resting echocardiography, and blood tests to evaluate the level of NT-proBNP, sST2, and galectin-3.Echocardiography was performed using a Toshiba Aplio 400 ultrasound machine.To ensure the accuracy of measurements, the average values from three or more consecutive cardiac cycles were obtained.During the study, the structural and functional parameters of the heart, Doppler parameters of left ventricular diastolic function were assessed.
In each patient, the maximum LV diameter, myocardial mass, and LVEF were determined in accordance with established guidelines [19].The values of maximum LV volume and LV myocardial mass were indexed to body surface area.LV hypertrophy was diagnosed when the myocardial mass index (LVMMi) exceeded 115 g/m 2 in men and 95 g/m 2 in women.LV diastolic function was assessed by pulsed Doppler analysis of transmitral blood flow and tissue Doppler analysis of LV baseline diastolic rise.The maximum velocities of early diastolic filling (E), filling during atrial systole (A) and their ratio (E/A), as well as the maximum velocity of diastolic rise of the LV baseline in early diastole (e') and the E/e' ratio were measured.To minimize the influence of adjacent segments, we obtained the averaged e' velocities from the interventricular septum and lateral wall.The severity of LV diastolic dysfunction was determined on the basis of the 2016 American Society of Echocardiography criteria [20].One of the reliable ultrasound indicators of increased LV diastolic dysfunction is LV dilatation.Normally, the maximum LV volume index does not exceed 34 ml/m 2 .
Laboratory studies were performed in the interdepartmental scientific laboratory of the Ivano-Frankivsk National Medical University.ELISA tests were performed on an ER500 analyzer (Healicom, Jiangsu, China).
We conducted the statistical analysis utilizing IBM SPSS Statistics version 26.0.The software was licensed with the following code: QA2WSWS3QTR5TG6Y7TG6RF59JUY7H, and a product key of AQ2WS89K09IK98J7H4S3WSF5G6.Categorical variables were presented in terms of frequencies and percentages and were compared using the χ 2 test.Fi sher's exact test was employed where appropriate.Continuous variables were reported either as mean ± standard deviation.To assess the normal distribution of continuous variables, we utilized the Kolmogorov-Smirnov and Shapiro-Wilk tests.For normally distributed continuous variables, we used independent t-tests to make comparisons between groups.Logistic analysis was performed between groups 1 vs 2, and 3 vs 4. P < 0.05 was considered statistically significant.

Results
The small difference in mean age between patients who have HFpEF without T2DM or AF and those who have T2DM but no AF indicates that T2DM may slightly influence an older patient population in the HFpEF group (Table 1).Nevertheless, the lack of a statistically significant difference stresses that age alone may not be the primary distinguishing factor between these two groups.The absence of a substantial age contrast between HFpEF patients with and without AF and T2DM implies that AF effects on age may be uniform, regardless of T2DM status.The identical gender distributions across all HFpEF groups, with or without T2DM or AF, indicate that gender may not be a primary factor in the coexistence of these comorbidities.The comparable mean body mass index (BMI) among the different groups implies that BMI alone may not distinguish the presence or absence of T2DM or AF in HFpEF patients.
Table 2 displays several echocardiographic parameters of the analyzed patients.When comparing the left ventricular mass index among the groups, there is no notable difference between the HFpEF patients who have T2DM but not AF (group 2) and those without T2DM or AF (group 1).These findings indicate that T2DM alone may not significantly affect the left ventricular mass index in HFpEF.A statistically significant difference in left ventricular mass index exists in HFpEF patients with both AF and T2DM (group 4) compared to those with only AF (group 3).This suggests that AF and T2DM together may lead to an increase in left ventricular mass index in HFpEF patients.
Additionally, left atrial volume index (LAVI) shows a significant difference between HFpEF patients with T2DM alone (group 2) and those without any comorbidities (group 1).This indicates that T2DM may be linked to a higher left atrial volume index, potentially signifying a level of left atrial enlargement in these patients.Likewise, LAVI significantly varies between HFpEF patients with AF and T2DM (group 4) and those with AF but without T2DM (group 3).This suggests that the coexistence of both AF and T2DM can worsen left atrial enlargement in HFpEF patients.The deceleration time indicates a marked difference between HFpEF patients with T2DM but no AF (group 2) and those without T2DM or AF (group 1).
This implies that T2DM could implicate the deceleration time, which could indicate an altered diastolic function in these patients.Moreover, there is a significant disparity in the deceleration time between HFpEF patients with AF and T2DM (group 4) and those with AF but not T2DM (group 3).This suggests that the combination of AF and T2DM could impact diastolic function in HFpEF patients.
The E/e' ratio, which indicates left ventricular filling pressure, significantly differed between HFpEF patients with T2DM but without AF (group 2) and those without T2DM or AF (group 1).Therefore, T2DM may be linked to increased left ventricular filling pressure in HFpEF.A notable discrepancy in the E/e' ratio is present between HFpEF patients with AF and T2DM (group 4) and those with AF Оригінальні дослідження / Original Researches alone (group 3).This suggests that the concomitant presence of both AF and T2DM may lead to elevated left ventricular filling pressures in HFpEF patients.The ejection fraction displays significant differences between HFpEF patients with T2DM alone (group 2) and those without any comorbidities (group 1).This indicates that T2DM could affect the systolic function of the left ventricle, leading to a probable decline in fractional shortening in patients with heart failure with preserved ejection fraction.We also note a substantial difference in fractional shortening between HFpEF patients with AF and T2DM (group 4) and those with AF but without T2DM (group 3).This implies that the presence of both AF and T2DM may further compromise left ventricular systolic function in HFpEF patients.
Table 3 displays the levels of three studied biomarkers.HFpEF patients with T2DM but without AF (group 2) had significantly higher galectin-3 levels than their counterparts without T2DM or AF (group 1).This implies a possible association between T2DM and increased galectin-3 levels in HFpEF patients.Elevated galectin-3 is typically indicative of inflammation and fibrosis and can suggest adverse cardiac remodeling.There is a noteworthy variation in galectin-3 levels between HFpEF patients having AF and T2DM (group 4) and those with AF unrelated to T2DM (group 3).This indicates that AF combined with T2DM could furthermore boost galectin-3 levels, signifying a higher degree of cardiac inflammation and fibrosis in such individuals.
NT-proBNP levels differ significantly between HFpEF patients with T2DM but without AF (group 2) and those without T2DM or AF (group 1).This suggests that T2DM may impact NT-proBNP levels in HFpEF patients.Elevated NT-proBNP is linked with increased cardiac stress and is a recognized marker of HF severity.Similarly, a significant difference in NT-proBNP levels is observed between HFpEF patients with AF and T2DM (group 4) and those with AF but without T2DM (group 3).The coexistence of AF and T2DM can heighten cardiac stress, as evidenced by increased NT-proBNP levels.
Notably, sST2 levels significantly vary between HFpEF patients belonging to group 1 (without T2DM or AF) and group 2 (with T2DM but without AF).These findings imply that T2DM might be linked to elevated sST2 levels in HFpEF patients.Elevated sST2 is recognized as a marker of myocardial fibrosis and adverse cardiac remodeling.There is a notable disparity in sST2 levels among HFpEF patients with AF and T2DM (group 4) versus those with AF but without T2DM (group 3), indicating that the coexistence of AF and T2DM might exacerbate elevated sST2 levels.These findings suggest that such patients may be at an elevated risk of unfavorable cardiac remodeling and myocardial fibrosis.
Logistic regression analysis was conducted to determine the factors distinguishing group 1 from group 2. Table 4 displays the specific associations within this context.Age indicates a marginally significant trend with a p-value of 0.06, implying a potential, albeit modest, correlation with the presence of T2DM in HFpEF patients without AF.Gender does not exert a significant influence on the presence of T2DM within this subgroup.BMI is not a significant predictor for T2DM presence in HFpEF patients without AF.However, several cardiac parameters, including LVMMi, LAVI, deceleration time, E/e' ratio, LVEF, galectin-3, NT-proBNP, and sST2, demonstrate substantial associations with the presence of T2DM in HFpEF patients without AF.
Table 5 differentiates group 3 (HFpEF patients with AF but without T2DM) from group 4 (HFpEF patients with both AF and T2DM).Age is not a significant determinant Оригінальні дослідження / Original Researches in distinguishing the concurrent presence of both AF and T2DM among HFpEF patients in this context.Similarly, gender does not significantly shape the concurrent presence of AF and T2DM among HFpEF patients.The analysis did not find BMI to be a reliable indicator of the co-occurrence of AF and T2DM in HFpEF patients.Rather, cardiac parameters underscore the significant impact of AF and T2DM on cardiac structural, functional, and biomarker profiles in HFpEF.
In both analyses, the convergence of comorbidities, specifically T2DM and AF, is accompanied by substantial changes in various cardiac parameters and biomarker profiles.These findings underscore the intricate clinical landscape of managing HFpEF patients grappling with these multifaceted conditions, necessitating individualized treatment strategies and vigilant monitoring of cardiac function and biomarkers to optimize patient care in this complex clinical milieu.

Discussion
Patients with both T2DM and AF often exhibit more pronounced cardiac remodeling, including increased LVMMi [21].AF, characterized by irregular and rapid atrial contractions, leads to atrial enlargement and promote left ventricular hypertrophy, exacerbating cardiac structural changes.The combination of T2DM and AF synergistically contribute to adverse cardiac remodeling in HFpEF [22].
The marked increase of LAVI in patients with HFpEF, T2DM, and AF highlights the negative impact of these conditions on atrial function.AF results in erratic atrial contractions and diminished atrial transport function, leading to atrial dilation [23].T2DM worsens these effects, causing a rise in left atrial volume and contributing to suboptimal left ventricular filling [24,25].
AF disrupts normal atrial-ventricular coordination causing irregular ventricular filling patterns.When AF is combined with T2DM, which can independently impair diastolic function, parameters of the latter experience a further decline.This is characterized by a shorter deceleration time, indicating more severe diastolic dysfunction [26].The higher E/e' ratio observed in patients with HFpEF, T2DM, and AF signifies increased left ventricular filling pressure.Atrial fibrillation can lead to swift ventricular rates that decrease diastolic filling time and intensify the elevation in filling pressure.Meanwhile, metabolic disruptions associated with T2DM can further aggravate impaired diastolic function [27][28][29].
Elevated levels of cardiac biomarkers such as galectin-3, NT-proBNP, and sST2 in HFpEF patients with T2DM and AF indicate a higher degree of cardiac stress, inflammation, and fibrosis [30,31].AF-induced atrial dysfunction and metabolic derangements related to T2DM may contribute synergistically to these adverse cardiac processes.
To summarize, the presence of T2DM and AF in HFpEF patients results in worse cardiac parameters due to the combined impact of both disorders on cardiac remodeling, atrial function, diastolic function, and biomarker profiles.The interplay among metabolic abnormalities related to T2DM, atrial dysfunction induced by atrial fibrillation, and cardiac changes related to heart failure with preserved ejection fraction emphasizes the necessity for individualized and comprehensive management of these intricate patients.

Conclusions
The interaction of type 2 diabetes mellitus and atrial fibrillation in heart failure with preserved ejection fraction results in significant changes in cardiac structure and function, exacerbating systolic and diastolic left ventricular dysfunction.This emphasizes the complex interplay of comorbidities in defining the HFpEF phenotype.HFpEF patients with concurrent T2DM and AF have heightened levels of lowgrade systemic inflammation.Novel biomarkers, including galectin-3 and sST2, have emerged as useful diagnostic tools to reflect the complicated pathophysiological mechanisms in HFpEF.Their increase in individuals with T2DM and AF highlights their potential in risk stratification and treatment monitoring.