Myocardial Strain and Diastolic Functions are Impaired in Treatment-Naive Papillary Thyroid Carcinoma Patients

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To evaluate subclinical myocardial dysfunction in treatment-naive, euthyroid PTC patients and investigate associations with integrin αvβ3 levels and central thyroid hormone resistance. Methods This case-control study included 36 untreated PTC patients and 20 benign nodular goiter controls. Comprehensive cardiac assessment utilized transthoracic echocardiography, tissue Doppler imaging, and two-dimensional speckle-tracking echocardiography. Serum integrin αvβ3 and tumor necrosis factor-alpha (TNF-α) levels were quantified via enzyme-linked immunosorbent assay. Central thyroid hormone sensitivity was assessed using the Thyroid Feedback Quantile-based Index (TFQI). Results PTC patients demonstrated significant subclinical cardiac dysfunction, including impaired left ventricular diastolic function and reduced myocardial contractility, as evidenced by compromised global longitudinal strain (GLS). Serum integrin αvβ3 and TNF-α levels were significantly elevated in PTC patients. Importantly, multivariable regression analysis revealed that elevated integrin αvβ3 was independently associated with impaired GLS (β = 0.412, P = 0.004) and diastolic dysfunction (RR = 1.101, 95% CI: 1.012–1.199, P = 0.026). TFQI FT4 levels were increased in PTC patients and notably showed a positive correlation with circulating integrin αvβ3 concentrations as well as an independent association with impaired GLS. Conclusions This study provides first evidence of subclinical CV dysfunction in treatment-naive PTC patients. Elevated integrin αvβ3 levels and central thyroid hormone resistance may synergistically contribute to early myocardial injury, highlighting the systemic cardiometabolic impact of PTC. Integrin αvβ3 emerges as a promising biomarker for CV risk stratification in PTC patients. Health sciences/Biomarkers Health sciences/Cardiology Health sciences/Diseases Health sciences/Medical research Papillary thyroid carcinoma left ventricular diastolic dysfunction global longitudinal strain integrin αvβ3 and thyroid feedback quantile-based Index Figures Figure 1 Figure 2 Introduction Well-differentiated thyroid carcinoma (DTC), comprising papillary and follicular thyroid cancer, demonstrates an excellent prognosis with appropriate treatment and a 5-year mortality rate of less than 1% [ 1 ]. However, emerging evidence suggests an increased risk of cardiovascular (CV) complications in DTC patients, including higher incidence of atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD) [ 2 – 4 ]. Notably, DTC patients exhibit a 3.3-fold higher risk of CV mortality and a 4.4-fold higher risk of all-cause mortality compared to controls, independent of traditional CV risk factors [ 5 ]. A meta-analysis of 193 320 DTC patients confirmed significantly increased risks of AF, CAD, and overall mortality [ 6 ], though some studies report conflicting results [ 7 ]. These discrepancies highlight the complex relationship between DTC and CV risk, influenced by confounding factors including thyroid function status, medication effects, and prior treatments. The contribution of malignant processes to cardiovascular disease (CVD) development in DTC patients remains poorly understood. With excellent survival rates, understanding CV morbidity has become essential for optimizing long-term management strategies. Despite advances in cardiac imaging technologies and the growing recognition of diastolic dysfunction as an early predictor of adverse CV outcomes [ 8 ], a comprehensive cardiac assessment has not yet been conducted in newly diagnosed patients with papillary thyroid carcinoma (PTC). This study focuses on treatment-naive, euthyroid PTC patients without known CVD to investigate whether the malignancy itself contributes to early cardiac alterations. To elucidate these potential cardiac effects, we employed two-dimensional speckle-tracking echocardiography (2D-STE), a sensitive modality capable of detecting early subclinical myocardial dysfunctions. Specifically, global longitudinal strain (GLS) was used to assess subtle impairments in left ventricular systolic function that may precede conventional echocardiographic abnormalities [ 9 , 10 ]. Importantly, diastolic dysfunction often precedes systolic impairment and serves as a reliable early marker of myocardial involvement across various clinical settings. Tissue Doppler imaging complements this evaluation by providing detailed insights into left ventricular relaxation and filling pressures [ 11 ]. Thus, the integration of advanced echocardiographic techniques is essential for uncovering the early effects of PTC on CV function, offering valuable implications for both pathophysiological understanding and clinical risk stratification. Various molecular markers have been investigated in thyroid cancer [ 12 , 13 ], among which integrin αvβ3, a plasma membrane receptor expressed on proliferating endothelial, cancer, and cardiac fibroblast cells, has gained attention as a potential molecular link between thyroid cancer and CVD [ 14 – 18 ]. This receptor functions as a non-genomic thyroid hormone receptor, mediating pro-angiogenic signaling and promoting tumor-associated angiogenesis. In vitro studies demonstrate that papillary and follicular thyroid cancer cell proliferation depends on integrin αvβ3-mediated pathways [ 19 ]. In parallel with these molecular insights, recent advances in thyroid homeostasis assessment have introduced thyroid hormone sensitivity indices, which provide more accurate thyroid function evaluation than traditional TSH and free thyroxine (FT4) measurements [ 20 ]. Among these, the Thyroid Feedback Quantile-based Index (TFQI) has been linked to both thyroid cancer [ 21 ] and CVD [ 22 ]. However, the interplay between altered thyroid hormone sensitivity and integrin αvβ3—and their combined role in CV vulnerability—remains unexplored in thyroid cancer. Therefore, this study aimed to investigate early myocardial abnormalities in newly diagnosed, euthyroid PTC patients using advanced cardiac imaging techniques, and to assess their relationship with integrin αvβ3 and central thyroid hormone sensitivity. Specifically, we aimed to: (1) identify baseline cardiac dysfunction; (2) determine associated clinical and molecular factors; and (3) evaluate the roles of integrin αvβ3 and TFQI in subclinical myocardial involvement. Findings from this study may help refine CV risk stratification and follow-up strategies in thyroid cancer patients. Methods Participants This cross-sectional case-control study was conducted at the Department of Endocrinology and Metabolism, Gülhane Faculty of Medicine, between July 31, 2021, and July 31, 2022. From a total of 225 patients assessed during this period, 56 participants were selected based on predefined inclusion and exclusion criteria. Inclusion criteria were age ≥ 18 years and normal thyroid function tests, while exclusion criteria included history of thyroid dysfunction (hypo- or hyperthyroidism), previous thyroid surgery, established CVDs, diabetes mellitus, severe hepatic or renal failure, connective tissue disorders, previous malignancy, pregnancy or lactation, or use of medications affecting thyroid or cardiac function (including corticosteroids, levothyroxine, or anti-thyroid drugs). The study comprised 36 patients with newly diagnosed PTC without distant metastasis and 20 patients with benign nodular goiter (BNG). All participants were consecutively recruited from the outpatient clinic. PTC diagnosis was confirmed by final histopathological examination, while the BNG group was matched to the PTC group for age, gender, and body mass index (BMI). Comprehensive medical histories were obtained from all participants, followed by thorough physical examinations to identify atypical symptoms and exclude structural heart disease. All participants were evaluated in accordance with the American Thyroid Association (ATA) guidelines [ 23 ]. Data collection Demographic, clinical, and laboratory data were collected. Body weight, height, waist circumstance, and blood pressure were measured according to standard protocols. Body mass index was calculated as body weight (kg) divided by the square of the body height (m 2 ). Body composition parameters of the participants were evaluated after the first voiding in the morning and with light clothes using a segmental body composition analyzer (BC-418, Tanita Corp., Tokyo, Japan). Serum levels of TSH, FT4, and FT3 were measured with the automated immunochemiluminescent assay (ICMA) kits (Roche GmbH, Mannheim, Germany). The Coefficients of variation for these thyroid profile assays were all below 10%. Euthyroid was defined as TSH (0.38–5.33 mIU/L), FT4 (0.58–1.38 ng/dL), and FT3 (2.0-4.4 pg/mL) within the reference ranges. Carotid artery intima-media thickness Carotid artery intima-media thickness (CIMT) was assessed using B-mode ultrasound (MyLabSeven: Esaote) with a linear-array transducer operating at a frequency of at least 7 MHz by an observer blinded to the participant’s clinical data. Participants were examined in the supine position with the head slightly extended and rotated away from the observer. Right and left carotid artery segments were scanned longitudinally (common, proximal internal carotid arteries and the carotid bulb) through B-mode grayscale imaging. CIMT was measured from images of the distal 1 cm of the far wall of common carotid artery, between the intimal luminal and the medial-adventitial interfaces of the carotid artery wall. Three measurements at three sites of the common carotid artery were averaged to assess mean CIMT. The mean value of the right and left mean CIMT measurements was used in the analysis. Echocardiographic examination Transthoracic 2D-ECHO recordings of all participants in our study were obtained using a Philips Epiq 7 (Philips Medical Systems, Bothell, WA) system equipped with a 3.5 MHz transducer. Images were acquired after expiration, ensuring that each recording included at least three consecutive cardiac cycles in the left lateral decubitus position, to minimize artifacts caused by respiratory or cycle-to-cycle variability and to ensure reliable data acquisition. Two experienced operators blinded to the participants’ clinical details conducted the 2D-ECHO evaluations to ensure unbiased data interpretation. Echocardiographic examinations were performed according to the criteria of the American Society of Echocardiography (ASE) guidelines [ 24 ]. The following parameters were assessed on the M-mode recordings: left ventricular end-diastolic diameters (LVEDd), left ventricular posterior wall thickness end diastole (LVPWd), interventricular septum thickness end diastole (IVSd), and left atrial diameter (LAD). Left ventricular (LV) systolic function was evaluated using the ejection fraction (EF) calculated according to the Teichholz formula [ 24 ]. LV mass (LVM) was calculated by Devereux's formula [ 25 ] and indexed to the body surface area (BSA). LV hypertrophy was defined as LVM index (LVMI) > 120 g/m 2 for men and > 116 g/m 2 for women [ 26 ]. Doppler studies provided indexes of ventricular filling derived from the mitral inflow velocity curves at both the early diastolic phase (E wave) and the peak late diastolic flow (A wave), as well as the E/A ratio. In addition, the isovolumic relaxation time (IVRT) and deceleration time (DT) were measured. LV diastolic function was evaluated by E wave, A wave, E/A ratio and also DT and IVRT. Tissue Doppler imaging Tissue Doppler imaging was performed using transducer frequencies of 3.5-4.0 MHz. The spectral pulsed Doppler signal filters were adjusted until a Nyquist limit of 15–20 cm/sec was achieved and the minimal optimal gain was used. Myocardial velocities named as peak systolic (S m ), early diastolic (E m ), and late diastolic (A m ) were obtained at the lateral mitral and lateral tricuspid annulus. 2D speckle tracking echocardiography analysis Left ventricular GLS was measured using 2D-STE to detect early myocardial deformation even when traditional echocardiographic parameters, such as left ventricular ejection fraction, remain normal. For this purpose, apical 2-, 3-, and 4-chamber views were obtained and analyzed offline with a commercial software (QLAB 13, TOMTEC/Philips, Andover, MA, USA), following established professional guidelines. The mean GLS was measured by averaging the peak GLS values of apical four-, three-, and two- chamber images. A 17-segment polar plot (Bulls’ eye), which uses a color-coded display of peak systolic strain values, was employed to provide a detailed evaluation of segmental myocardial function. This comprehensive approach provided both global and regional insights into cardiac performance, facilitating a thorough understanding of myocardial mechanics and structural adaptations. Integrin αvβ3 and TNF-α analysis Fasting blood samples were collected from each participant between 8:00 and 10:00 a.m., then immediately centrifuged at 3000 RPM for 10 minutes and stored at -80°C until analysis. Serum levels of integrin αvβ3 and TNF-α were measured using commercial enzymatic immunoassay kits, following the manufacturer’s instructions (BT Lab, Korain Biotech). Serum integrin αvβ3 levels were reported in ng/mL, with a sensitivity of 0.094 ng/mL and serum TNF-α levels were reported in ng/L, with a sensitivity of 1.52 ng/L. The inter- and intra-assay coefficients of variation for all three kits were below 10%. Index of central thyroid hormone sensitivity The index of central thyroid hormone sensitivity included the Thyroid Feedback Quantile-based Index (TFQI). TFQI FT4 was calculated using the algorithm TFQI = cdfFT4- (1-cdfTSH) developed by Laclaustra et al [ 20 ]. The index range is ± 1. Negative values indicate that the hypothalamus-pituitary-thyroid (HPT) axis is more sensitive to changes in THs, whereas positive values indicated lower sensitivity to thyroid hormones. Statistical analysis Statistical analysis was performed using SPSS for Windows version 26.0. The Kolmogorov-Smirnov and Shapiro-Wilk tests were used to evaluate the distribution pattern of numerical data. Continuous variables with normal distributions were expressed as mean \(\:\pm\:\) standard deviation (SD) while categorical variables were presented as frequencies (%). Student’s t-test was used for the mean comparison of parametric variables and Mann Whitney test was used if the distribution was nonparametric. Chi-square tests were used to compare categorical variables. Pearson’s or Spearman test was used for parametric and non-parametric correlations, respectively. To determine the independent variables likely to affect the GLS, a multivariate linear regression analysis was performed. Moreover, logistic regression analysis model was used and confounders were adjusted to explore the correlation between integrin \(\:{\alpha\:}\) v \(\:{\beta\:}\) 3 levels and the indecence of LV diastolic dysfunction. A significance level of P ≤ 0.05 was considered to indicate a statistically significant difference. The sample size of the study was determined using the G ∗ Power 3.1.9.4 program. A priori minimum required sample size was calculated based on an alpha of 0.05, a power of 80%, and 20 individuals for each group. Ethical considerations The study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Gülhane Training and Research Hospital (Date 24.03.2021/No 2021/6). Written informed consent was obtained from all participants before enrollment. Results Patient characteristics The clinical and laboratory characteristics of all study participants are summarized in Table 1 . By design, euthyroid BNG patients and those with PTC were well matched with respect to age, gender, BMI, body surface area, and waist-to-hip ratio. There were no statistically significant differences in systolic and diastolic blood pressure, heart rate, and CIMT between both groups (Table 1 ). In addition, biochemical characteristics did not differ between the two groups (Table 1 ). Cardiovascular assessment The echocardiographic results are reported in Table 2 . The mean EF was similar in both groups. No differences were observed in the two-dimensional measurements in the PTC group compared with BNG group. Regarding LV diastolic function, patients with PTC showed impaired diastolic function as demonstrated by decreased E/A ratio and the prolonged DT. With reference to the study by Nagueh et al. [ 27 ], stage 1 diastolic dysfunction was present in 20 (55.6%) in the PTC group and 5 (25%) in the BNG group (P = 0.028) (Table 2 ). In tissue Doppler measurements, the left ventricular early myocardial diastolic velocity (E m ) and lateral systolic myocardial velocity (S m ) in patients with PTC were significantly lower than the BNG group (11.22 ± 3.09 cm/sec, 13.68 ± 2.84 cm/sec, P = 0.005; 8.38 ± 1.89 cm/sec, 9.60 ± 1.84 cm/sec, P = 0.024, respectively). Other tissue Doppler variables were similar between the groups (Table 2 ). The evaluation of the myocardial tissue properties with 2D-STE imaging demonstrated that the group of the PTC had significantly impaired GLS as compared with the group of the BNG (-17.33 ± 3.25, -20.35 ± 2.61, P = 0.001, respectively) (Table 2 ). Integrin αvβ3 and TNF-α The integrin \(\:{\alpha\:}\) v \(\:{\beta\:}\) 3 and TNF- \(\:{\alpha\:}\) concentrations were significantly higher in the PTC group than in BNG subjects (24.27 ± 8.01 ng/mL, 15.47 ± 7.18 ng/mL; 271.68 ng/L (29.5-752.5), 194.5 ng/L (6.11-704.07); respectively, P < 0.001) (Fig. 1 ). In addition, the integrin \(\:{\alpha\:}\) v \(\:{\beta\:}\) 3 and TNF- \(\:{\alpha\:}\) concentrations in the PTC patients with lymph node metastasis (n = 14) were also statistically significantly higher than those in the PTC patients without lymph node metastasis (29.52 ± 7.85 ng/mL, 23.16 ± 6.08 ng/mL, P = 0.017; 313.84 ng/L (29.52-752.03), 228.95 ng/L (65.43-596.11), P = 0.019, respectively). Index of central thyroid hormone sensitivity The PTC patients had significantly higher levels of TFQI FT4 compared to the BNG subjects (Fig. 1 ). Correlations There was a positive correlation between integrin \(\:{\alpha\:}\) v \(\:{\beta\:}\) 3 concentration and TNF- \(\:{\alpha\:}\) (r = 0.652, P < 0.001), TFQI FT4 (r = 0.271, P = 0.043), and GLS (r = 0.306, P = 0.022), whereas age was negatively correlated with integrin \(\:{\alpha\:}\) v \(\:{\beta\:}\) 3 concentration (r = -0.0396, P = 0.002) in the whole group. In addition, there was a positive correlation between GLS and TFQI FT4 (r = 0.275, P = 0.040). Regression analyses Serum integrin αvβ3 levels were identified as an independent predictor of GLS values across various models in the multivariable linear regression analysis conducted on the entire study population (Table 3 ). Similarly, TFQI FT4 emerged as an independent predictor of GLS (Table 4 ). A scatter plot illustrating the relationship between integrin αvβ3 levels and TFQI FT4 with average GLS values is presented in Fig. 2 . Moreover, as shown in Table 5 , integrin αvβ3 levels demonstrated a significant association with the presence of LV diastolic dysfunction in logistic regression analysis [P = 0.026, RR (95% CI) = 1.101 (1.012–1.194)]. Discussion The present study demonstrates, for the first time, that treatment-naive euthyroid PTC patients exhibit subclinical cardiac dysfunction characterized by left ventricular diastolic dysfunction and reduced myocardial contractility. Using advanced cardiac imaging modalities including transthoracic 2D-ECHO, tissue Doppler imaging, and 2D-STE, we identified significant changes in cardiac parameters including decreased E/A ratio, prolonged DT, and impaired GLS compared to patients with benign thyroid disease. In addition, integrin αvβ3 and TFQI FT4 levels were elevated in PTC patients. Multivariate analysis revealed that increased integrin αvβ3 levels were independently associated with impaired GLS and diastolic dysfunction, similarly elevated TFQI FT4 levels also demonstrated an independent association with impaired GLS. While DTC typically carries a favorable prognosis, with increasing incidence and long-term survival expected, studies suggest that mortality in these patients is also attributed to causes other than thyroid cancer itself [ 5 ]. Previous studies have demonstrated that deaths from non-thyroid malignancies represent 30.1–31.1% of mortality, thyroid cancer-specific deaths account for 22.8–46.4%, and CV-related deaths constitute 9.8–21.3% of cases [ 28 – 30 ]. These findings highlight the importance of developing a more comprehensive understanding of the factors contributing to CVDs in patients with thyroid cancer. Most prior studies assessing CV risks in DTC patients have focused on those undergoing TSH suppression therapy, employing observational designs that often exclude treatment-naive patients [ 5 , 31 , 6 , 32 ]. However, despite these methodological limitations, the existing literature consistently supports the presence of both systolic and diastolic dysfunction in DTC patients. Taillard et al. [ 33 ] reported that moderate TSH suppression therapy is associated with diastolic dysfunction, while Abdulrahman et al. [ 34 ] documented both systolic and diastolic impairments in patients receiving long-term therapy. However, our study identified early cardiac dysfunctions that develop independently of therapeutic interventions such as TSH suppression therapy. These findings are particularly significant, as they suggest that myocardial impairment may be present at baseline, highlighting the potential direct impact of the malignant process on cardiac structure and function. Our study demonstrated that circulating integrin αvβ3 levels were significantly higher in patients with PTC compared to those with benign thyroid disease. Importantly, regression analyses in our cohort revealed that elevated integrin αvβ3 levels were independently associated with both impaired GLS and diastolic dysfunction. Integrin αvβ3, a plasma membrane receptor abundantly expressed on malignant thyroid cells and proliferating vascular endothelium, has previously been implicated in tumor progression and CV remodeling [ 14 , 15 , 19 ]. This integrin mediates non-genomic thyroid hormone signaling pathways and facilitates angiogenesis and tissue fibrosis through enhanced endothelial activation, fibroblast migration, and extracellular matrix deposition [ 15 , 35 ]. Taken together, our findings highlight integrin αvβ3 as a potential biomarker for early cardiovascular risk stratification in PTC patients, given its elevated levels and independent association with subclinical cardiac dysfunction. Our study additionally showed that TNF-α levels were significantly elevated in patients with PTC, with particularly pronounced increases in both TNF-α and integrin αvβ3 levels observed in cases presenting with lymph node metastasis. These findings suggest that an inflammatory tumor microenvironment may play a pivotal role in more aggressive PTC phenotypes. Although no statistically significant correlation was established between TNF-α levels and cardiac function parameters, the elevation of integrin αvβ3 levels and their robust association with cardiac parameters emerge as an important biomarker reflecting the potential interplay between tumor biology, systemic inflammatory responses, and early cardiac remodeling processes. In this context, integrin αvβ3 may be considered not merely as a marker indicating thyroid cancer progression, but also as a potential mediator of subclinical CV injury. Our findings emphasize the necessity of comprehensive CV screening in PTC patients even during the pre-treatment period and suggest that integrin αvβ3 could be integrated into clinical practice as both a novel therapeutic target and a prognostic risk stratification tool. To evaluate central thyroid hormone sensitivity, the TFQI was first described by Laclaustra and colleagues [ 20 ] who demonstrated that impaired TFQI was significantly associated with type 2 diabetes and diabetes-related mortality. Subsequent studies have reported that impaired sensitivity of the HPT axis to THs may be linked to various adverse clinical conditions, including type 2 diabetes [ 20 ], gestational diabetes [ 36 ], non-alcoholic fatty liver disease (NAFLD) [ 37 ], and CVDs [ 38 ]. In accordance with previous literature [ 21 , 39 ], our study demonstrated significantly elevated TFQI FT4 levels in PTC patients compared to individuals with BNG. This finding suggests that central thyroid hormone sensitivity is compromised in PTC patients. Moreover, we identified significant associations between central thyroid hormone resistance and both impaired GLS and elevated integrin αvβ3 levels. These findings indicate that diminished central thyroid hormone sensitivity and enhanced integrin αvβ3 activity may exert synergistic detrimental effects on CV function, potentially mediated through mechanisms involving vascular remodeling and myocardial deformation processes. Collectively, our findings indicate that PTC may represent not merely a localized endocrine malignancy, but rather a more comprehensive disease entity with potential implications for CV and metabolic systems. This underscores the necessity for multidisciplinary monitoring strategies and comprehensive baseline risk assessments in PTC patients. This study has several limitations, yet these do not undermine its significance as a novel contribution to the literature. First, the relatively small sample size may limit the generalizability of our findings. However, despite the limited cohort, the study provides pioneering insights into the relationship between elevated integrin αvβ3 levels, impaired central thyroid hormone sensitivity, and subclinical cardiac dysfunction in treatment-naive PTC patients, which has not been reported previously. Second, the cross-sectional design prevents us from establishing causal relationships between these parameters and CV outcomes. Longitudinal studies are needed to elucidate the long-term impact of these findings on CV morbidity and mortality. Third, the lack of tissue-level analysis of integrin αvβ3 expression is a notable limitation. Assessing its expression in thyroid tumor, myocardial, and vascular tissues could yield more comprehensive mechanistic insights into its site-specific roles, particularly regarding local tumor aggressiveness and CV remodeling processes. Despite these limitations, our study offers novel mechanistic insights into CV risk stratification in PTC patients and identifies integrin αvβ3 as a promising biomarker for CV surveillance in this population. These findings carry immediate clinical implications for the identification of high-risk individuals who may benefit from intensified CV monitoring and early preventive strategies. Furthermore, they provide a strong rationale for future multi-center prospective studies aimed at validating the prognostic utility of integrin αvβ3 in thyroid cancer–associated CV risk. In conclusion, this study provides the first evidence that treatment-naive euthyroid PTC patients exhibit subclinical cardiac dysfunction independent of therapeutic interventions, with elevated integrin αvβ3 levels serving as an independent predictor of both impaired GLS and diastolic dysfunction. The concomitant impairment of central thyroid hormone sensitivity further compounds CV risk through synergistic mechanisms involving vascular remodeling and myocardial deformation processes, positioning PTC as a systemic disease with significant CV implications that manifest even before treatment initiation. Identifying integrin αvβ3 as a mediator of subclinical CV injury opens new avenues for personalized risk stratification and targeted interventions, necessitating comprehensive CV screening in routine PTC management, and provides a foundation for future studies aimed at validating its prognostic value in predicting CV events. Declarations Disclosures: No competing financial interests to declare. Conflict of interest: The authors declare that they have no conflict of interest. Author Contribution Author Contributions: S.A. and N.E.G. performed the conceptualization; S.A., G.G.A., M.A.G., M.C., U.C.Y., and C.E. conducted the data acquisition; S.A. and N.E.G. conducted data analysis; S.A. and N.E.G. drafted the manuscript; S.A. and N.E.G. revised the manuscript and served as scientific advisors. The final manuscript was read and approved by all authors. Data Availability Some or all datasets generated during or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request. References Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics, 2022. 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Clin Cardiol 47:e24271. https://doi.org/10.1002/clc.24271 Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L (2016) 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:1-133. https://doi.org/10.1089/thy.2015.0020 Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 16:233-270. https://doi.org/10.1093/ehjci/jev014 Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N (1986) Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 57:450-458. https://doi.org/10.1016/0002-9149(86)90771-x Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322:1561-1566. https://doi.org/10.1056/NEJM199005313222203 Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Alexandru Popescu B, Waggoner AD, Houston T, Oslo N, Phoenix A, Nashville T, Hamilton OC, Uppsala S, Ghent, Liege B, Cleveland O, Novara I, Rochester M, Bucharest R, St. Louis M (2016) Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 17:1321-1360. https://doi.org/10.1093/ehjci/jew082 Lee YK, Hong N, Park SH, Shin DY, Lee CR, Kang SW, Lee J, Jeong JJ, Nam KH, Chung WY, Lee EJ (2019) The relationship of comorbidities to mortality and cause of death in patients with differentiated thyroid carcinoma. Sci Rep 9:11435. https://doi.org/10.1038/s41598-019-47898-8 Kim KJ, Jang S, Kim KJ, An JH, Kim NH, Shin DY, Yoo HJ, Kim HY, Seo JA, Kim NH, Lee J, Choi KM, Baik SH, Kim SG (2020) Actual causes of death in thyroid cancer patients in Korea: A Nationwide Case Control Cohort Study. Eur J Endocrinol 182:103-110. https://doi.org/10.1530/EJE-19-0548 Ahn HY, Lee J, Kang J, Lee EK (2024) Increased risk of diabetes mellitus and hyperlipidemia in patients with differentiated thyroid cancer. Eur J Endocrinol 190:248-255. https://doi.org/10.1093/ejendo/lvae026 Toulis KA, Viola D, Gkoutos G, Keerthy D, Boelaert K, Nirantharakumar K (2019) Risk of incident circulatory disease in patients treated for differentiated thyroid carcinoma with no history of cardiovascular disease. Clin Endocrinol (Oxf) 91:323-330. https://doi.org/10.1111/cen.13990 Klein Hesselink EN, Lefrandt JD, Schuurmans EP, Burgerhof JG, Groen B, Gansevoort RT, van der Horst-Schrivers AN, Dullaart RP, Van Gelder IC, Brouwers AH, Rienstra M, Links TP (2015) Increased Risk of Atrial Fibrillation After Treatment for Differentiated Thyroid Carcinoma. J Clin Endocrinol Metab 100:4563-4569. https://doi.org/10.1210/jc.2015-2782 Taillard V, Sardinoux M, Oudot C, Fesler P, Rugale C, Raingeard I, Renard E, Ribstein J, du Cailar G (2011) Early detection of isolated left ventricular diastolic dysfunction in high-risk differentiated thyroid carcinoma patients on TSH-suppressive therapy. Clin Endocrinol (Oxf) 75:709-714. https://doi.org/10.1111/j.1365-2265.2011.04138.x Abdulrahman RM, Delgado V, Hoftijzer HC, Ng AC, Ewe SH, Marsan NA, Holman ER, Hovens GC, Corssmit EP, Romijn JA, Bax JJ, Smit JW (2011) Both exogenous subclinical hyperthyroidism and short-term overt hypothyroidism affect myocardial strain in patients with differentiated thyroid carcinoma. Thyroid 21:471-476. https://doi.org/10.1089/thy.2010.0319 Lin HY, Tang HY, Keating T, Wu YH, Shih A, Hammond D, Sun M, Hercbergs A, Davis FB, Davis PJ (2008) Resveratrol is pro-apoptotic and thyroid hormone is anti-apoptotic in glioma cells: both actions are integrin and ERK mediated. Carcinogenesis 29:62-69. https://doi.org/10.1093/carcin/bgm239 Safak Akin PU, Busra Sen Yildirim, Eda Karaismailoglu, Ozhan Ozdemir, Nese Ersoz Gulcelik. (2024) Impaired central sensitivity to triiodothyronine is associated with gestational diabetes mellitus. International Journal of Diabetes in Developing Countries. https://doi.org/10.1007/s13410-024-01347-z Lai S, Li J, Wang Z, Wang W, Guan H (2021) Sensitivity to Thyroid Hormone Indices Are Closely Associated With NAFLD. Front Endocrinol (Lausanne) 12:766419. https://doi.org/10.3389/fendo.2021.766419 Qin Z, Muhanhali D, Ling Y (2024) Impaired Thyroid Hormone Sensitivity Increases Risk of Cardiovascular Events in Patients Undergoing Coronary Angiography. J Clin Endocrinol Metab 109:1550-1564. https://doi.org/10.1210/clinem/dgad735 Sun J, Liu J, Wu TT, Gu ZY, Zhang XW (2023) Sensitivity to thyroid hormone indices are associated with papillary thyroid carcinoma in Chinese patients with thyroid nodules. BMC Endocr Disord 23:126. https://doi.org/10.1186/s12902-023-01381-8 Tables Tables 1 to 5 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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16:38:14","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":151535,"visible":true,"origin":"","legend":"","description":"","filename":"dd6afac85fd0440bb74055be7ddcc1de1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7437247/v1/e26b896a505e84c85bd9d209.xml"},{"id":93062709,"identity":"b422ebc7-5159-4ec0-a642-4fcde279957a","added_by":"auto","created_at":"2025-10-08 16:38:02","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":167705,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7437247/v1/7c1efb7e7b05781977745392.html"},{"id":93063057,"identity":"93aa74e6-811d-4659-86ec-527a6864ed9c","added_by":"auto","created_at":"2025-10-08 16:38:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":120492,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of integrin αvβ3, TNF-α, and TFQI\u003csub\u003eFT4\u003c/sub\u003e between PTC patients and patients with BNG. Scatter diagrams A-C show the comparisons of integrin αvβ3, TNF-α, and TFQI\u003csub\u003eFT4\u003c/sub\u003e between PTC patients and patients with BNG respectively. Thick black lines represent the mean value and thinner black lines represent the standard deviation for all parameters.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7437247/v1/f4c96627c026e87f37ab7ee7.png"},{"id":93063022,"identity":"8fceee5b-834b-4e0c-938c-9b59e729f856","added_by":"auto","created_at":"2025-10-08 16:38:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":129318,"visible":true,"origin":"","legend":"\u003cp\u003eIntegrin αvβ3 and TFQI\u003csub\u003eFT4\u003c/sub\u003e are associated with impaired GLS. Integrin αvβ3 is plotted on the x-axis, with GLS on the y-axis (A) and TFQI\u003csub\u003eFT4\u003c/sub\u003e is plotted on the the x-axis, with GLS on the y-axis (B).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7437247/v1/f687b001ccc82deb150025ae.png"},{"id":104250800,"identity":"c993d20d-9a96-477e-b555-155f12b5a615","added_by":"auto","created_at":"2026-03-09 16:08:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":827521,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7437247/v1/a3d31bbb-5834-467e-bccf-f029987fe35f.pdf"},{"id":93063025,"identity":"58ad9fee-df7a-433f-8652-f883dadb79e5","added_by":"auto","created_at":"2025-10-08 16:38:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":42595,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7437247/v1/d2140da55ca3287866a44083.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Myocardial Strain and Diastolic Functions are Impaired in Treatment-Naive Papillary Thyroid Carcinoma Patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWell-differentiated thyroid carcinoma (DTC), comprising papillary and follicular thyroid cancer, demonstrates an excellent prognosis with appropriate treatment and a 5-year mortality rate of less than 1% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, emerging evidence suggests an increased risk of cardiovascular (CV) complications in DTC patients, including higher incidence of atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD) [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Notably, DTC patients exhibit a 3.3-fold higher risk of CV mortality and a 4.4-fold higher risk of all-cause mortality compared to controls, independent of traditional CV risk factors [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. A meta-analysis of 193 320 DTC patients confirmed significantly increased risks of AF, CAD, and overall mortality [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], though some studies report conflicting results [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These discrepancies highlight the complex relationship between DTC and CV risk, influenced by confounding factors including thyroid function status, medication effects, and prior treatments.\u003c/p\u003e\u003cp\u003eThe contribution of malignant processes to cardiovascular disease (CVD) development in DTC patients remains poorly understood. With excellent survival rates, understanding CV morbidity has become essential for optimizing long-term management strategies. Despite advances in cardiac imaging technologies and the growing recognition of diastolic dysfunction as an early predictor of adverse CV outcomes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], a comprehensive cardiac assessment has not yet been conducted in newly diagnosed patients with papillary thyroid carcinoma (PTC). This study focuses on treatment-naive, euthyroid PTC patients without known CVD to investigate whether the malignancy itself contributes to early cardiac alterations. To elucidate these potential cardiac effects, we employed two-dimensional speckle-tracking echocardiography (2D-STE), a sensitive modality capable of detecting early subclinical myocardial dysfunctions. Specifically, global longitudinal strain (GLS) was used to assess subtle impairments in left ventricular systolic function that may precede conventional echocardiographic abnormalities [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Importantly, diastolic dysfunction often precedes systolic impairment and serves as a reliable early marker of myocardial involvement across various clinical settings. Tissue Doppler imaging complements this evaluation by providing detailed insights into left ventricular relaxation and filling pressures [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Thus, the integration of advanced echocardiographic techniques is essential for uncovering the early effects of PTC on CV function, offering valuable implications for both pathophysiological understanding and clinical risk stratification.\u003c/p\u003e\u003cp\u003eVarious molecular markers have been investigated in thyroid cancer [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], among which integrin αvβ3, a plasma membrane receptor expressed on proliferating endothelial, cancer, and cardiac fibroblast cells, has gained attention as a potential molecular link between thyroid cancer and CVD [\u003cspan additionalcitationids=\"CR15 CR16 CR17\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This receptor functions as a non-genomic thyroid hormone receptor, mediating pro-angiogenic signaling and promoting tumor-associated angiogenesis. In vitro studies demonstrate that papillary and follicular thyroid cancer cell proliferation depends on integrin αvβ3-mediated pathways [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In parallel with these molecular insights, recent advances in thyroid homeostasis assessment have introduced thyroid hormone sensitivity indices, which provide more accurate thyroid function evaluation than traditional TSH and free thyroxine (FT4) measurements [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Among these, the Thyroid Feedback Quantile-based Index (TFQI) has been linked to both thyroid cancer [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and CVD [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, the interplay between altered thyroid hormone sensitivity and integrin αvβ3\u0026mdash;and their combined role in CV vulnerability\u0026mdash;remains unexplored in thyroid cancer.\u003c/p\u003e\u003cp\u003eTherefore, this study aimed to investigate early myocardial abnormalities in newly diagnosed, euthyroid PTC patients using advanced cardiac imaging techniques, and to assess their relationship with integrin αvβ3 and central thyroid hormone sensitivity. Specifically, we aimed to: (1) identify baseline cardiac dysfunction; (2) determine associated clinical and molecular factors; and (3) evaluate the roles of integrin αvβ3 and TFQI in subclinical myocardial involvement. Findings from this study may help refine CV risk stratification and follow-up strategies in thyroid cancer patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eParticipants\u003c/h2\u003e\u003cp\u003eThis cross-sectional case-control study was conducted at the Department of Endocrinology and Metabolism, G\u0026uuml;lhane Faculty of Medicine, between July 31, 2021, and July 31, 2022. From a total of 225 patients assessed during this period, 56 participants were selected based on predefined inclusion and exclusion criteria. Inclusion criteria were age\u0026thinsp;\u0026ge;\u0026thinsp;18 years and normal thyroid function tests, while exclusion criteria included history of thyroid dysfunction (hypo- or hyperthyroidism), previous thyroid surgery, established CVDs, diabetes mellitus, severe hepatic or renal failure, connective tissue disorders, previous malignancy, pregnancy or lactation, or use of medications affecting thyroid or cardiac function (including corticosteroids, levothyroxine, or anti-thyroid drugs). The study comprised 36 patients with newly diagnosed PTC without distant metastasis and 20 patients with benign nodular goiter (BNG). All participants were consecutively recruited from the outpatient clinic. PTC diagnosis was confirmed by final histopathological examination, while the BNG group was matched to the PTC group for age, gender, and body mass index (BMI). Comprehensive medical histories were obtained from all participants, followed by thorough physical examinations to identify atypical symptoms and exclude structural heart disease. All participants were evaluated in accordance with the American Thyroid Association (ATA) guidelines [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eDemographic, clinical, and laboratory data were collected. Body weight, height, waist circumstance, and blood pressure were measured according to standard protocols. Body mass index was calculated as body weight (kg) divided by the square of the body height (m\u003csup\u003e2\u003c/sup\u003e). Body composition parameters of the participants were evaluated after the first voiding in the morning and with light clothes using a segmental body composition analyzer (BC-418, Tanita Corp., Tokyo, Japan). Serum levels of TSH, FT4, and FT3 were measured with the automated immunochemiluminescent assay (ICMA) kits (Roche GmbH, Mannheim, Germany). The Coefficients of variation for these thyroid profile assays were all below 10%. Euthyroid was defined as TSH (0.38\u0026ndash;5.33 mIU/L), FT4 (0.58\u0026ndash;1.38 ng/dL), and FT3 (2.0-4.4 pg/mL) within the reference ranges.\u003c/p\u003e\n\u003ch3\u003eCarotid artery intima-media thickness\u003c/h3\u003e\n\u003cp\u003eCarotid artery intima-media thickness (CIMT) was assessed using B-mode ultrasound (MyLabSeven: Esaote) with a linear-array transducer operating at a frequency of at least 7 MHz by an observer blinded to the participant\u0026rsquo;s clinical data. Participants were examined in the supine position with the head slightly extended and rotated away from the observer. Right and left carotid artery segments were scanned longitudinally (common, proximal internal carotid arteries and the carotid bulb) through B-mode grayscale imaging. CIMT was measured from images of the distal 1 cm of the far wall of common carotid artery, between the intimal luminal and the medial-adventitial interfaces of the carotid artery wall. Three measurements at three sites of the common carotid artery were averaged to assess mean CIMT. The mean value of the right and left mean CIMT measurements was used in the analysis.\u003c/p\u003e\n\u003ch3\u003eEchocardiographic examination\u003c/h3\u003e\n\u003cp\u003eTransthoracic 2D-ECHO recordings of all participants in our study were obtained using a Philips Epiq 7 (Philips Medical Systems, Bothell, WA) system equipped with a 3.5 MHz transducer. Images were acquired after expiration, ensuring that each recording included at least three consecutive cardiac cycles in the left lateral decubitus position, to minimize artifacts caused by respiratory or cycle-to-cycle variability and to ensure reliable data acquisition. Two experienced operators blinded to the participants\u0026rsquo; clinical details conducted the 2D-ECHO evaluations to ensure unbiased data interpretation. Echocardiographic examinations were performed according to the criteria of the American Society of Echocardiography (ASE) guidelines [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The following parameters were assessed on the M-mode recordings: left ventricular end-diastolic diameters (LVEDd), left ventricular posterior wall thickness end diastole (LVPWd), interventricular septum thickness end diastole (IVSd), and left atrial diameter (LAD). Left ventricular (LV) systolic function was evaluated using the ejection fraction (EF) calculated according to the Teichholz formula [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. LV mass (LVM) was calculated by Devereux's formula [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and indexed to the body surface area (BSA). LV hypertrophy was defined as LVM index (LVMI)\u0026thinsp;\u0026gt;\u0026thinsp;120 g/m\u003csup\u003e2\u003c/sup\u003e for men and \u0026gt;\u0026thinsp;116 g/m\u003csup\u003e2\u003c/sup\u003e for women [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Doppler studies provided indexes of ventricular filling derived from the mitral inflow velocity curves at both the early diastolic phase (E wave) and the peak late diastolic flow (A wave), as well as the E/A ratio. In addition, the isovolumic relaxation time (IVRT) and deceleration time (DT) were measured. LV diastolic function was evaluated by E wave, A wave, E/A ratio and also DT and IVRT.\u003c/p\u003e\n\u003ch3\u003eTissue Doppler imaging\u003c/h3\u003e\n\u003cp\u003eTissue Doppler imaging was performed using transducer frequencies of 3.5-4.0 MHz. The spectral pulsed Doppler signal filters were adjusted until a Nyquist limit of 15\u0026ndash;20 cm/sec was achieved and the minimal optimal gain was used. Myocardial velocities named as peak systolic (S\u003csub\u003em\u003c/sub\u003e), early diastolic (E\u003csub\u003em\u003c/sub\u003e), and late diastolic (A\u003csub\u003em\u003c/sub\u003e) were obtained at the lateral mitral and lateral tricuspid annulus.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2D speckle tracking echocardiography analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eLeft ventricular GLS was measured using 2D-STE to detect early myocardial deformation even when traditional echocardiographic parameters, such as left ventricular ejection fraction, remain normal. For this purpose, apical 2-, 3-, and 4-chamber views were obtained and analyzed offline with a commercial software (QLAB 13, TOMTEC/Philips, Andover, MA, USA), following established professional guidelines. The mean GLS was measured by averaging the peak GLS values of apical four-, three-, and two- chamber images. A 17-segment polar plot (Bulls\u0026rsquo; eye), which uses a color-coded display of peak systolic strain values, was employed to provide a detailed evaluation of segmental myocardial function. This comprehensive approach provided both global and regional insights into cardiac performance, facilitating a thorough understanding of myocardial mechanics and structural adaptations.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eIntegrin αvβ3 and TNF-α analysis\u003c/h2\u003e\u003cp\u003eFasting blood samples were collected from each participant between 8:00 and 10:00 a.m., then immediately centrifuged at 3000 RPM for 10 minutes and stored at -80\u0026deg;C until analysis. Serum levels of integrin αvβ3 and TNF-α were measured using commercial enzymatic immunoassay kits, following the manufacturer\u0026rsquo;s instructions (BT Lab, Korain Biotech). Serum integrin αvβ3 levels were reported in ng/mL, with a sensitivity of 0.094 ng/mL and serum TNF-α levels were reported in ng/L, with a sensitivity of 1.52 ng/L. The inter- and intra-assay coefficients of variation for all three kits were below 10%.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eIndex of central thyroid hormone sensitivity\u003c/h3\u003e\n\u003cp\u003eThe index of central thyroid hormone sensitivity included the Thyroid Feedback Quantile-based Index (TFQI). TFQI\u003csub\u003eFT4\u003c/sub\u003e was calculated using the algorithm TFQI\u0026thinsp;=\u0026thinsp;cdfFT4- (1-cdfTSH) developed by Laclaustra et al [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The index range is \u0026plusmn; 1. Negative values indicate that the hypothalamus-pituitary-thyroid (HPT) axis is more sensitive to changes in THs, whereas positive values indicated lower sensitivity to thyroid hormones.\u003c/p\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analysis was performed using SPSS for Windows version 26.0. The Kolmogorov-Smirnov and Shapiro-Wilk tests were used to evaluate the distribution pattern of numerical data. Continuous variables with normal distributions were expressed as mean\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\pm\\:\\)\u003c/span\u003e\u003c/span\u003estandard deviation (SD) while categorical variables were presented as frequencies (%). Student\u0026rsquo;s t-test was used for the mean comparison of parametric variables and Mann Whitney test was used if the distribution was nonparametric. Chi-square tests were used to compare categorical variables. Pearson\u0026rsquo;s or Spearman test was used for parametric and non-parametric correlations, respectively. To determine the independent variables likely to affect the GLS, a multivariate linear regression analysis was performed. Moreover, logistic regression analysis model was used and confounders were adjusted to explore the correlation between integrin \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}\\)\u003c/span\u003e\u003c/span\u003ev\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\beta\\:}\\)\u003c/span\u003e\u003c/span\u003e3 levels and the indecence of LV diastolic dysfunction. A significance level of P\u0026thinsp;\u0026le;\u0026thinsp;0.05 was considered to indicate a statistically significant difference. The sample size of the study was determined using the G\u003csup\u003e\u0026lowast;\u003c/sup\u003ePower 3.1.9.4 program. A priori minimum required sample size was calculated based on an alpha of 0.05, a power of 80%, and 20 individuals for each group.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eEthical considerations\u003c/h2\u003e\u003cp\u003e The study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of G\u0026uuml;lhane Training and Research Hospital (Date 24.03.2021/No 2021/6). Written informed consent was obtained from all participants before enrollment.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003eThe clinical and laboratory characteristics of all study participants are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. By design, euthyroid BNG patients and those with PTC were well matched with respect to age, gender, BMI, body surface area, and waist-to-hip ratio. There were no statistically significant differences in systolic and diastolic blood pressure, heart rate, and CIMT between both groups (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). In addition, biochemical characteristics did not differ between the two groups (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eCardiovascular assessment\u003c/h2\u003e\n \u003cp\u003eThe echocardiographic results are reported in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The mean EF was similar in both groups. No differences were observed in the two-dimensional measurements in the PTC group compared with BNG group. Regarding LV diastolic function, patients with PTC showed impaired diastolic function as demonstrated by decreased E/A ratio and the prolonged DT. With reference to the study by Nagueh et al. [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], stage 1 diastolic dysfunction was present in 20 (55.6%) in the PTC group and 5 (25%) in the BNG group (P\u0026thinsp;=\u0026thinsp;0.028) (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eIn tissue Doppler measurements, the left ventricular early myocardial diastolic velocity (E\u003csub\u003em\u003c/sub\u003e) and lateral systolic myocardial velocity (S\u003csub\u003em\u003c/sub\u003e) in patients with PTC were significantly lower than the BNG group (11.22\u0026thinsp;\u0026plusmn;\u0026thinsp;3.09 cm/sec, 13.68\u0026thinsp;\u0026plusmn;\u0026thinsp;2.84 cm/sec, P\u0026thinsp;=\u0026thinsp;0.005; 8.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.89 cm/sec, 9.60\u0026thinsp;\u0026plusmn;\u0026thinsp;1.84 cm/sec, P\u0026thinsp;=\u0026thinsp;0.024, respectively). Other tissue Doppler variables were similar between the groups (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eThe evaluation of the myocardial tissue properties with 2D-STE imaging demonstrated that the group of the PTC had significantly impaired GLS as compared with the group of the BNG (-17.33 \u0026plusmn; 3.25, -20.35 \u0026plusmn; 2.61, P\u0026thinsp;=\u0026thinsp;0.001, respectively) (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eIntegrin \u0026alpha;v\u0026beta;3 and TNF-\u0026alpha;\u003c/h2\u003e\n \u003cp\u003eThe integrin \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}\\)\u003c/span\u003e\u003c/span\u003ev\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\beta\\:}\\)\u003c/span\u003e\u003c/span\u003e3 and TNF- \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}\\)\u003c/span\u003e\u003c/span\u003e concentrations were significantly higher in the PTC group than in BNG subjects (24.27 \u0026plusmn; 8.01 ng/mL, 15.47 \u0026plusmn; 7.18 ng/mL; 271.68 ng/L (29.5-752.5), 194.5 ng/L (6.11-704.07); respectively, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). In addition, the integrin \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}\\)\u003c/span\u003e\u003c/span\u003ev\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\beta\\:}\\)\u003c/span\u003e\u003c/span\u003e3 and TNF- \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}\\)\u003c/span\u003e\u003c/span\u003e concentrations in the PTC patients with lymph node metastasis (n\u0026thinsp;=\u0026thinsp;14) were also statistically significantly higher than those in the PTC patients without lymph node metastasis (29.52 \u0026plusmn; 7.85 ng/mL, 23.16 \u0026plusmn; 6.08 ng/mL, P\u0026thinsp;=\u0026thinsp;0.017; 313.84 ng/L (29.52-752.03), 228.95 ng/L (65.43-596.11), P\u0026thinsp;=\u0026thinsp;0.019, respectively).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eIndex of central thyroid hormone sensitivity\u003c/h2\u003e\n \u003cp\u003eThe PTC patients had significantly higher levels of TFQI\u003csub\u003eFT4\u003c/sub\u003e compared to the BNG subjects (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eCorrelations\u003c/h2\u003e\n \u003cp\u003eThere was a positive correlation between integrin \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}\\)\u003c/span\u003e\u003c/span\u003ev\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\beta\\:}\\)\u003c/span\u003e\u003c/span\u003e3 concentration and TNF- \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}\\)\u003c/span\u003e\u003c/span\u003e (r\u0026thinsp;=\u0026thinsp;0.652, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), TFQI\u003csub\u003eFT4\u003c/sub\u003e (r\u0026thinsp;=\u0026thinsp;0.271, P\u0026thinsp;=\u0026thinsp;0.043), and GLS (r\u0026thinsp;=\u0026thinsp;0.306, P\u0026thinsp;=\u0026thinsp;0.022), whereas age was negatively correlated with integrin \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}\\)\u003c/span\u003e\u003c/span\u003ev\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\beta\\:}\\)\u003c/span\u003e\u003c/span\u003e3 concentration (r = -0.0396, P\u0026thinsp;=\u0026thinsp;0.002) in the whole group. In addition, there was a positive correlation between GLS and TFQI\u003csub\u003eFT4\u003c/sub\u003e (r\u0026thinsp;=\u0026thinsp;0.275, P\u0026thinsp;=\u0026thinsp;0.040).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eRegression analyses\u003c/h2\u003e\n \u003cp\u003eSerum integrin \u0026alpha;v\u0026beta;3 levels were identified as an independent predictor of GLS values across various models in the multivariable linear regression analysis conducted on the entire study population (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Similarly, TFQI\u003csub\u003eFT4\u003c/sub\u003e emerged as an independent predictor of GLS (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). A scatter plot illustrating the relationship between integrin \u0026alpha;v\u0026beta;3 levels and TFQI\u003csub\u003eFT4\u003c/sub\u003e with average GLS values is presented in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Moreover, as shown in Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e, integrin \u0026alpha;v\u0026beta;3 levels demonstrated a significant association with the presence of LV diastolic dysfunction in logistic regression analysis [P\u0026thinsp;=\u0026thinsp;0.026, RR (95% CI)\u0026thinsp;=\u0026thinsp;1.101 (1.012\u0026ndash;1.194)].\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study demonstrates, for the first time, that treatment-naive euthyroid PTC patients exhibit subclinical cardiac dysfunction characterized by left ventricular diastolic dysfunction and reduced myocardial contractility. Using advanced cardiac imaging modalities including transthoracic 2D-ECHO, tissue Doppler imaging, and 2D-STE, we identified significant changes in cardiac parameters including decreased E/A ratio, prolonged DT, and impaired GLS compared to patients with benign thyroid disease. In addition, integrin αvβ3 and TFQI\u003csub\u003eFT4\u003c/sub\u003e levels were elevated in PTC patients. Multivariate analysis revealed that increased integrin αvβ3 levels were independently associated with impaired GLS and diastolic dysfunction, similarly elevated TFQI\u003csub\u003eFT4\u003c/sub\u003e levels also demonstrated an independent association with impaired GLS.\u003c/p\u003e\u003cp\u003eWhile DTC typically carries a favorable prognosis, with increasing incidence and long-term survival expected, studies suggest that mortality in these patients is also attributed to causes other than thyroid cancer itself [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Previous studies have demonstrated that deaths from non-thyroid malignancies represent 30.1\u0026ndash;31.1% of mortality, thyroid cancer-specific deaths account for 22.8\u0026ndash;46.4%, and CV-related deaths constitute 9.8\u0026ndash;21.3% of cases [\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. These findings highlight the importance of developing a more comprehensive understanding of the factors contributing to CVDs in patients with thyroid cancer. Most prior studies assessing CV risks in DTC patients have focused on those undergoing TSH suppression therapy, employing observational designs that often exclude treatment-naive patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, despite these methodological limitations, the existing literature consistently supports the presence of both systolic and diastolic dysfunction in DTC patients. Taillard et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] reported that moderate TSH suppression therapy is associated with diastolic dysfunction, while Abdulrahman et al. [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] documented both systolic and diastolic impairments in patients receiving long-term therapy. However, our study identified early cardiac dysfunctions that develop independently of therapeutic interventions such as TSH suppression therapy. These findings are particularly significant, as they suggest that myocardial impairment may be present at baseline, highlighting the potential direct impact of the malignant process on cardiac structure and function.\u003c/p\u003e\u003cp\u003eOur study demonstrated that circulating integrin αvβ3 levels were significantly higher in patients with PTC compared to those with benign thyroid disease. Importantly, regression analyses in our cohort revealed that elevated integrin αvβ3 levels were independently associated with both impaired GLS and diastolic dysfunction. Integrin αvβ3, a plasma membrane receptor abundantly expressed on malignant thyroid cells and proliferating vascular endothelium, has previously been implicated in tumor progression and CV remodeling [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This integrin mediates non-genomic thyroid hormone signaling pathways and facilitates angiogenesis and tissue fibrosis through enhanced endothelial activation, fibroblast migration, and extracellular matrix deposition [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Taken together, our findings highlight integrin αvβ3 as a potential biomarker for early cardiovascular risk stratification in PTC patients, given its elevated levels and independent association with subclinical cardiac dysfunction. Our study additionally showed that TNF-α levels were significantly elevated in patients with PTC, with particularly pronounced increases in both TNF-α and integrin αvβ3 levels observed in cases presenting with lymph node metastasis. These findings suggest that an inflammatory tumor microenvironment may play a pivotal role in more aggressive PTC phenotypes. Although no statistically significant correlation was established between TNF-α levels and cardiac function parameters, the elevation of integrin αvβ3 levels and their robust association with cardiac parameters emerge as an important biomarker reflecting the potential interplay between tumor biology, systemic inflammatory responses, and early cardiac remodeling processes. In this context, integrin αvβ3 may be considered not merely as a marker indicating thyroid cancer progression, but also as a potential mediator of subclinical CV injury. Our findings emphasize the necessity of comprehensive CV screening in PTC patients even during the pre-treatment period and suggest that integrin αvβ3 could be integrated into clinical practice as both a novel therapeutic target and a prognostic risk stratification tool.\u003c/p\u003e\u003cp\u003eTo evaluate central thyroid hormone sensitivity, the TFQI was first described by Laclaustra and colleagues [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] who demonstrated that impaired TFQI was significantly associated with type 2 diabetes and diabetes-related mortality. Subsequent studies have reported that impaired sensitivity of the HPT axis to THs may be linked to various adverse clinical conditions, including type 2 diabetes [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], gestational diabetes [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], non-alcoholic fatty liver disease (NAFLD) [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], and CVDs [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In accordance with previous literature [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], our study demonstrated significantly elevated TFQI\u003csub\u003eFT4\u003c/sub\u003e levels in PTC patients compared to individuals with BNG. This finding suggests that central thyroid hormone sensitivity is compromised in PTC patients. Moreover, we identified significant associations between central thyroid hormone resistance and both impaired GLS and elevated integrin αvβ3 levels. These findings indicate that diminished central thyroid hormone sensitivity and enhanced integrin αvβ3 activity may exert synergistic detrimental effects on CV function, potentially mediated through mechanisms involving vascular remodeling and myocardial deformation processes. Collectively, our findings indicate that PTC may represent not merely a localized endocrine malignancy, but rather a more comprehensive disease entity with potential implications for CV and metabolic systems. This underscores the necessity for multidisciplinary monitoring strategies and comprehensive baseline risk assessments in PTC patients.\u003c/p\u003e\u003cp\u003eThis study has several limitations, yet these do not undermine its significance as a novel contribution to the literature. First, the relatively small sample size may limit the generalizability of our findings. However, despite the limited cohort, the study provides pioneering insights into the relationship between elevated integrin αvβ3 levels, impaired central thyroid hormone sensitivity, and subclinical cardiac dysfunction in treatment-naive PTC patients, which has not been reported previously. Second, the cross-sectional design prevents us from establishing causal relationships between these parameters and CV outcomes. Longitudinal studies are needed to elucidate the long-term impact of these findings on CV morbidity and mortality. Third, the lack of tissue-level analysis of integrin αvβ3 expression is a notable limitation. Assessing its expression in thyroid tumor, myocardial, and vascular tissues could yield more comprehensive mechanistic insights into its site-specific roles, particularly regarding local tumor aggressiveness and CV remodeling processes. Despite these limitations, our study offers novel mechanistic insights into CV risk stratification in PTC patients and identifies integrin αvβ3 as a promising biomarker for CV surveillance in this population. These findings carry immediate clinical implications for the identification of high-risk individuals who may benefit from intensified CV monitoring and early preventive strategies. Furthermore, they provide a strong rationale for future multi-center prospective studies aimed at validating the prognostic utility of integrin αvβ3 in thyroid cancer\u0026ndash;associated CV risk.\u003c/p\u003e\u003cp\u003eIn conclusion, this study provides the first evidence that treatment-naive euthyroid PTC patients exhibit subclinical cardiac dysfunction independent of therapeutic interventions, with elevated integrin αvβ3 levels serving as an independent predictor of both impaired GLS and diastolic dysfunction. The concomitant impairment of central thyroid hormone sensitivity further compounds CV risk through synergistic mechanisms involving vascular remodeling and myocardial deformation processes, positioning PTC as a systemic disease with significant CV implications that manifest even before treatment initiation. Identifying integrin αvβ3 as a mediator of subclinical CV injury opens new avenues for personalized risk stratification and targeted interventions, necessitating comprehensive CV screening in routine PTC management, and provides a foundation for future studies aimed at validating its prognostic value in predicting CV events.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eDisclosures:\u003c/h2\u003e\n\u003cp\u003eNo competing financial interests to declare.\u003c/p\u003e\n\u003ch2\u003eConflict of interest:\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eAuthor Contributions: S.A. and N.E.G. performed the conceptualization; S.A., G.G.A., M.A.G., M.C., U.C.Y., and C.E. conducted the data acquisition; S.A. and N.E.G. conducted data analysis; S.A. and N.E.G. drafted the manuscript; S.A. and N.E.G. revised the manuscript and served as scientific advisors. The final manuscript was read and approved by all authors.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eSome or all datasets generated during or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics, 2022. CA Cancer J Clin 72:7-33. https://doi.org/10.3322/caac.21708\u003c/li\u003e\n\u003cli\u003eLi Q, Liu F, Tang Y, Lee S, Lang C, Bai L, Xia Y (2021) The Distribution of Cardiovascular-Related Comorbidities in Different Adult-Onset Cancers and Related Risk Factors: Analysis of 10 Year Retrospective Data. 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Clin Cardiol 47:e24271. https://doi.org/10.1002/clc.24271\u003c/li\u003e\n\u003cli\u003eHaugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L (2016) 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:1-133. https://doi.org/10.1089/thy.2015.0020\u003c/li\u003e\n\u003cli\u003eLang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 16:233-270. https://doi.org/10.1093/ehjci/jev014\u003c/li\u003e\n\u003cli\u003eDevereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N (1986) Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. 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J Clin Endocrinol Metab 100:4563-4569. https://doi.org/10.1210/jc.2015-2782\u003c/li\u003e\n\u003cli\u003eTaillard V, Sardinoux M, Oudot C, Fesler P, Rugale C, Raingeard I, Renard E, Ribstein J, du Cailar G (2011) Early detection of isolated left ventricular diastolic dysfunction in high-risk differentiated thyroid carcinoma patients on TSH-suppressive therapy. Clin Endocrinol (Oxf) 75:709-714. https://doi.org/10.1111/j.1365-2265.2011.04138.x\u003c/li\u003e\n\u003cli\u003eAbdulrahman RM, Delgado V, Hoftijzer HC, Ng AC, Ewe SH, Marsan NA, Holman ER, Hovens GC, Corssmit EP, Romijn JA, Bax JJ, Smit JW (2011) Both exogenous subclinical hyperthyroidism and short-term overt hypothyroidism affect myocardial strain in patients with differentiated thyroid carcinoma. Thyroid 21:471-476. https://doi.org/10.1089/thy.2010.0319\u003c/li\u003e\n\u003cli\u003eLin HY, Tang HY, Keating T, Wu YH, Shih A, Hammond D, Sun M, Hercbergs A, Davis FB, Davis PJ (2008) Resveratrol is pro-apoptotic and thyroid hormone is anti-apoptotic in glioma cells: both actions are integrin and ERK mediated. Carcinogenesis 29:62-69. https://doi.org/10.1093/carcin/bgm239\u003c/li\u003e\n\u003cli\u003eSafak Akin PU, Busra Sen Yildirim, Eda Karaismailoglu, Ozhan Ozdemir, Nese Ersoz Gulcelik. (2024) Impaired central sensitivity to triiodothyronine is associated with gestational diabetes mellitus. International Journal of Diabetes in Developing Countries. https://doi.org/10.1007/s13410-024-01347-z\u003c/li\u003e\n\u003cli\u003eLai S, Li J, Wang Z, Wang W, Guan H (2021) Sensitivity to Thyroid Hormone Indices Are Closely Associated With NAFLD. Front Endocrinol (Lausanne) 12:766419. https://doi.org/10.3389/fendo.2021.766419\u003c/li\u003e\n\u003cli\u003eQin Z, Muhanhali D, Ling Y (2024) Impaired Thyroid Hormone Sensitivity Increases Risk of Cardiovascular Events in Patients Undergoing Coronary Angiography. J Clin Endocrinol Metab 109:1550-1564. https://doi.org/10.1210/clinem/dgad735\u003c/li\u003e\n\u003cli\u003eSun J, Liu J, Wu TT, Gu ZY, Zhang XW (2023) Sensitivity to thyroid hormone indices are associated with papillary thyroid carcinoma in Chinese patients with thyroid nodules. BMC Endocr Disord 23:126. https://doi.org/10.1186/s12902-023-01381-8\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Papillary thyroid carcinoma, left ventricular diastolic dysfunction, global longitudinal strain, integrin αvβ3, and thyroid feedback quantile-based Index","lastPublishedDoi":"10.21203/rs.3.rs-7437247/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7437247/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003ePapillary thyroid carcinoma (PTC) may contribute to cardiovascular (CV) morbidity through pro-inflammatory signaling, endothelial dysfunction, and altered thyroid hormone pathways, yet subclinical myocardial effects remain poorly characterized. To evaluate subclinical myocardial dysfunction in treatment-naive, euthyroid PTC patients and investigate associations with integrin αvβ3 levels and central thyroid hormone resistance.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis case-control study included 36 untreated PTC patients and 20 benign nodular goiter controls. Comprehensive cardiac assessment utilized transthoracic echocardiography, tissue Doppler imaging, and two-dimensional speckle-tracking echocardiography. Serum integrin αvβ3 and tumor necrosis factor-alpha (TNF-α) levels were quantified via enzyme-linked immunosorbent assay. Central thyroid hormone sensitivity was assessed using the Thyroid Feedback Quantile-based Index (TFQI).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003ePTC patients demonstrated significant subclinical cardiac dysfunction, including impaired left ventricular diastolic function and reduced myocardial contractility, as evidenced by compromised global longitudinal strain (GLS). Serum integrin αvβ3 and TNF-α levels were significantly elevated in PTC patients. Importantly, multivariable regression analysis revealed that elevated integrin αvβ3 was independently associated with impaired GLS (β\u0026thinsp;=\u0026thinsp;0.412, P\u0026thinsp;=\u0026thinsp;0.004) and diastolic dysfunction (RR\u0026thinsp;=\u0026thinsp;1.101, 95% CI: 1.012\u0026ndash;1.199, P\u0026thinsp;=\u0026thinsp;0.026). TFQI\u003csub\u003eFT4\u003c/sub\u003e levels were increased in PTC patients and notably showed a positive correlation with circulating integrin αvβ3 concentrations as well as an independent association with impaired GLS.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis study provides first evidence of subclinical CV dysfunction in treatment-naive PTC patients. Elevated integrin αvβ3 levels and central thyroid hormone resistance may synergistically contribute to early myocardial injury, highlighting the systemic cardiometabolic impact of PTC. Integrin αvβ3 emerges as a promising biomarker for CV risk stratification in PTC patients.\u003c/p\u003e","manuscriptTitle":"Myocardial Strain and Diastolic Functions are Impaired in Treatment-Naive Papillary Thyroid Carcinoma Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-08 15:59:20","doi":"10.21203/rs.3.rs-7437247/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-26T11:52:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-26T05:04:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246299925545814569681620392325623878509","date":"2025-12-24T04:59:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5782967159871708189494776622078281014","date":"2025-12-23T20:43:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-19T02:22:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"86720244005082497291835017441784829413","date":"2025-10-13T20:40:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321515791395848790140958775866311708926","date":"2025-10-09T22:47:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-25T13:05:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-25T13:00:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-04T16:29:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-01T19:25:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-09-01T19:22:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"709fa15e-2f7e-4b5e-830e-064c031af496","owner":[],"postedDate":"October 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":55787653,"name":"Health sciences/Biomarkers"},{"id":55787654,"name":"Health sciences/Cardiology"},{"id":55787655,"name":"Health sciences/Diseases"},{"id":55787656,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-03-09T16:05:16+00:00","versionOfRecord":{"articleIdentity":"rs-7437247","link":"https://doi.org/10.1038/s41598-026-41816-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-03-06 15:59:36","publishedOnDateReadable":"March 6th, 2026"},"versionCreatedAt":"2025-10-08 15:59:20","video":"","vorDoi":"10.1038/s41598-026-41816-5","vorDoiUrl":"https://doi.org/10.1038/s41598-026-41816-5","workflowStages":[]},"version":"v1","identity":"rs-7437247","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7437247","identity":"rs-7437247","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}