Impaired sensitivity to thyroid hormones is associated with different grades of hypertension: A multicenter cross-sectional study.

BACKGROUND AND AIM: Accumulating evidence suggests a potential link between thyroid function with hypertension. However, the research results are limited, and there is no research to explore the relationship between central and peripheral thyroid hormones (THs) sensitivity and different grades of hypertension in patients with coronary heart disease (CHD). This study aims to prove the complex interaction between thyroid system and blood pressure, and provides new ideas for the assessment of hypertension in patients with CHD. METHODS AND RESULTS: Calculate parameters representing central and peripheral sensitivity to THs. Logistic regression analysis was used to analyze the relationship between central and peripheral THs sensitivity of CHD patients and different grades of hypertension, especially in different ages, sexes, blood glucose levels, smoking, and drinking statuses. Among the 34,310 participants, 19,610 (57.16 %) were diagnosed with hypertension. The risk of hypertension and TSHI (OR: 0.88; 95 % CI: 0.87-0.90; P < 0.001), TT4RI (OR: 0.998; 95 % CI: 0.998-0.999; P < 0.001), TFQI (OR: 0.63; 95 % CI: 0.60-0.67; P < 0.001), PTFQI (OR: 0.63; 95 % CI: 0.59-0.67; P < 0.001) was negatively associated. The risk of hypertension was positively associated with FT3/FT4 (OR: 1.20; 95 % CI: 1.17-1.22; P < 0.001). After stratified analysis, these associations remained significant at different ages, sexes, blood glucose levels, grades of hypertension, smoking, and drinking statuses (P < 0.001). CONCLUSIONS: This study shows that the decrease in central THs sensitivity index and the increase in peripheral THs sensitivity index are associated with a higher risk of hypertension in CHD patients.

Association of thyroid hormone sensitivity index with stroke in patients with coronary artery disease.

BACKGROUND AND AIMS: Thyroid hormones (THs) will affect the occurrence and prognosis of stroke, and the research on THs sensitivity index and stroke in patients with coronary heart disease (CHD) is scarce. The goal of this study is to look into the relationship between central and peripheral THs sensitivity index and stroke in patients with CHD. METHODS: Between January 1, 2014, and September 30, 2020, 30,160 patients with CHD were enrolled in this study. By computing the thyroid feedback quantile index (TFQI), thyroid stimulating hormone index (TSHI), and thyrotropin thyroxine resistance index (TT4RI), the central sensitivity indexes to THs was assessed, and the ratio of serum free triiodothyronine (FT3) to serum free thyroxine (FT4) was used to assess peripheral THs sensitivity. The relationship between central and peripheral THs sensitivity index and stroke was investigated using logistic regression, especially in different types of stroke, ages, sexes, and blood glucose levels. RESULTS: Stroke risk is positive associated with TSHI, TFQI, and PTFQI. In subgroup analysis, the OR values of these relationships are higher in people younger than 65 years old, male, and diagnosed with diabetes. In addition, stroke risk was negatively associated with FT3/FT4, and the OR values of these relationships were lower in people older than 65 years, female, and diagnosed with prediabetes. CONCLUSIONS: This study demonstrates that the increase in the central THs sensitivity index and the decrease in the peripheral THs sensitivity index are associated with a higher risk of stroke in CHD patients, and provides new ideas for the assessment of stroke in patients with CHD.

Relationship between the circulating N-terminal pro B-type natriuretic peptide and the risk of carotid artery plaque in different glucose metabolic states in patients with coronary heart disease: a CSCD-TCM plus study in China.

OBJECTIVE: Circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) is a marker for heart failure in patients with coronary heart disease (CHD) and associated with glycemic abnormalities. Studies on the association and diagnostic value of NT-proBNP in carotid plaques (CAP) in patients with CHD are limited. METHODS: The relationships between NT-proBNP and the risk of CAP in different glucose metabolic states, sexes, and age categories were also examined using 5,093 patients diagnosed with CHD. The NT-proBNP tertiles were used to divide patients into three groups in which the NT-proBNP levels, blood glucose levels, the occurrence of CAP, and the number and nature of CAP were measured using normoglycemic (NG), prediabetes (Pre-DM), and diabetes mellitus (DM) glucose metabolic statuses. Logistic regression analyses were used to compare the relationship between NT-proBNP and the risk of CAP occurrence and the number and nature of CAP. The diagnostic value of NT-proBNP for CAP risk was measured using receiver operating characteristic (ROC) curves. RESULTS: We found a 37% relative increase in the correlation between changes in NT-proBNP per standard deviation (SD) and the incidence of CAP. After adjusting for potential confounders, NT-proBNP at the T3 level was found to be associated with an increased CAP odds ratio (OR) when T1 was used as the reference. This relationship was also present in males, patients aged > 60 years, or both pre-DM and DM states. NT-proBNP was more likely to present as hypoechoic plaques at T1 and as mixed plaques at T3. We also measured the diagnostic accuracy of CAP for NT-proBNP in patients with CHD, with an AUC value of 0.627(95% CI 0.592-0.631), sensitivity of 50.7%, and specificity of 68.0%. CONCLUSION: An increase in NT-proBNP was significantly associated with the risk of CAP in patients with CHD, especially in males and patients aged > 60 years, and exhibited specific characteristics under different glucose metabolism states. Trial registration The study was approved by the Ethics Committee of Tianjin University of Traditional Chinese Medicine (Approval number TJUTCM-EC20210007) and certified by the Chinese Clinical Trials Registry on April 4, 2022 (Registration number ChiCTR2200058296) and March 25, 2022 by ClinicalTrials.gov (registration number NCT05309343).

Associations Between Atherosclerosis and Elevated Serum Alkaline Phosphatase in Patients With Coronary Artery Disease in an Inflammatory State.

BACKGROUND AND AIM: Serum alkaline phosphatase (ALP) has been shown to be associated with cardiovascular disease (CVD) risk. Inflammation is the initiator of atherosclerosis, throughout the life of atherosclerosis. This study investigated the relationship between serum ALP and atherosclerosis in patients with coronary artery disease (CAD) in an inflammatory state. METHODS: This was a multicentre retrospective study including 22,989 patients with CAD. Serum alkaline phosphatase was converted into the quartiles. C-reactive protein (CRP) was assayed as a marker of systemic inflammation. The atherosclerosis index (AI) was used to assess the degree of atherosclerosis. Binary logistic regression was used to analyse the relationship between ALP and AI. Stratified analysis was performed according to sex and age. RESULTS: Elevated serum ALP was associated with the risk of atherosclerosis in patients with CAD, and after quartiling ALP, the OR for Q4 was 1.17 (95% CI 1.08-1.26; p<0.001) when using Q1 as reference. The odds ratio (OR) for ALP and risk of atherosclerosis was higher in patients aged ≤60 years (OR 1.33, 95% CI 1.15-1.53; p<0.001) than in patients aged >60 years (OR 1.11, 95% CI 1.01-1.23; p<0.05), and higher in males (OR 1.21, 95% CI 1.09-1.35; p<0.001) than in females (OR 1.16, 95% CI 1.03-1.31; p<0.05). Q4 (ALP >83.00 U/L) was significantly associated with increased risk of atherosclerosis in the inflammatory state (OR 1.48, 95% CI 1.18-1.86; p<0.001), and it remained after stratified analysis according to sex and age. CONCLUSIONS: The risk of atherosclerosis tended to increase with increasing ALP levels and the correlation between ALP and the degree of atherosclerosis was significantly stronger when ALP was >83.00 U/L. This relationship was more pronounced in inflammatory states, and there were sex and age differences. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04026724.

Triglyceride glucose index for the detection of the severity of coronary artery disease in different glucose metabolic states in patients with coronary heart disease: a RCSCD-TCM study in China.

BACKGROUND: Triglyceride glucose (TyG) index is a new marker associated with atherosclerosis. This study aimed to assess the association between TyG index and the severity of coronary artery disease (CAD) in patients with coronary heart disease (CHD) and further explore the association between TyG index and CAD severity in different glucose metabolic states. METHODS: This multi-centre retrospective study included 731 patients with CHD between January 1, 2014 and September 30, 2020 in China. All patients were stratified into groups based on the tertiles of TyG index (T1: 5.48 ≤ TyG index ≤ 7.17; T2: 7.18 ≤ TyG index ≤ 7.76; T3: 7.77 ≤ TyG index ≤ 10.82). The number of diseased vessels [single-vessel and multi-vessel CAD (≥ 50% stenosis in ≥ 2 large vessels)] represented the severity of CAD, which was measured using coronary angiography (CAG). Glucose metabolic states were defined by the American Diabetes Association as normal glucose regulation (NGR), prediabetes mellitus (Pre-DM), and diabetes mellitus (DM). RESULTS: The baseline analysis results showed significant differences in the clinical and biological characteristics of CHD patients according to TyG index tertiles (P < 0.05 to < 0.001). Logistic regression analysis showed that the TyG index was significantly related to the risk of multi-vessel CAD (odds ratio [OR]: 1.715; 95% confidence interval [CI] 1.339-2.197; P < 0.001). The OR for multi-vessel CAD in TyG index T3 compared to that of T1 was 2.280 (95% CI 1.530-3.398; P < 0.001). Receiver operating characteristic (ROC) curve was generated to evaluate the accuracy of the TyG index in detecting the CAD severity, and the area under the curve (AUC) of the ROC plots was 0.601 (95% CI 0.559-0.643). The association between TyG index and multi-vessel CAD was significant in patients with DM, achieving the highest OR among the different glucose metabolic states (OR: 1.717; 95% CI 1.161-2.539; P < 0.05). CONCLUSION: TyG index was associated with CAD severity in patients with CHD, and an increased TyG index could identify patients with a high risk of multi-vessel CAD. There was an association between TyG index and CAD severity for the condition of DM.

Relationship Between Serum Uric Acid and Carotid Plaque in Patients With Coronary Artery Disease by Sex and Blood Pressure Status.

The purpose of this study was to explore the sex difference and effects of blood pressure (BP) on the relationship between serum uric acid (SUA) and carotid plaque in patients with coronary heart disease (CHD). This large multicenter retrospective study included 12099 patients with CHD (aged 35-75 years) between January 1, 2014 and September 30, 2020. Patients were divided into three groups according to systolic BP (SBP) and diastolic BP (DBP), and the SUA levels in males and females were converted into three groups. Logistic regression was used to analyze the influence of sex and BP on the relationship between SUA levels and carotid plaque in patients with CHD. In the model of male BP subgroups, using the BP of group A (normal with SBP <120 mmHg and DBP <80 mmHg) as a reference, SUA levels were significantly correlated with the occurrence of carotid plaque under different BP states (P < .001). In contrast, in the model of female BP subgroups, most of these correlations were not statistically significant. Our study showed that SUA levels were significantly associated with carotid plaque occurrence in males with CHD, which remained significant across different BP states.

Remnant cholesterol for the detection of glucose metabolic states in patients with coronary heart disease angina pectoris.

BACKGROUND: This study aimed to evaluate the relationship between remnant cholesterol (RC) and glucose metabolic states in coronary heart disease (CHD) patients with angina pectoris. METHODS: This study collected data from 11,557 CHD patients with angina pectoris aged 35-75 years in Tianjin, China. Participants were divided into normal glucose regulation (NGR), prediabetes (Pre-DM) and diabetes mellitus (DM) groups according to glucose metabolic states. Linear regression analysis was used to explore the relationship between glucose metabolism [fasting blood glucose (FBG) and glycated hemoglobin (HbA1c)] and RC levels. Logistic regression was performed to analyze the relationship between RC levels and glucose metabolic states. RESULTS: Among all participants, 5883 (50.9%) had a DM state and 4034 (34.9%) had a Pre-DM state. FBG levels and HbA1c levels were positively related with RC in all patients (P < 0.001). NGR was used as a reference, multi-adjusted model showing that RC level was significantly associated with Pre-DM [Odds ratio (OR): 1.37; 95% confidence interval (CI) 1.19-1.56; P < 0.001] and DM state (OR:1.47; 95% CI 1.29-1.67; P < 0.001). When considering RC as categorical variables (tertiles), using T1 as a reference, T3 had the strongest relationship between RC levels and Pre-DM and DM state in univariate model and multivariate model. In the stratified analyses, the association between RC levels and pre-DM and DM in women was higher than that in men, and the elderly patients was higher than in the middle-aged patients. CONCLUSION: The study demonstrated a significant association between RC levels and pre-DM and DM state among CHD patients with angina pectoris, and the relationship was stronger in women and elderly patients.

Impaired Sensitivity to Thyroid Hormones Is Associated With Elevated Blood Glucose in Coronary Heart Disease.

Context: Thyroid hormones influence glucose homeostasis through central and peripheral regulation. To date, the association between thyroid hormone sensitivity and elevated blood glucose (EBG) in patients with coronary heart disease (CHD) remains unknown. The purpose of this study was to investigate the association between thyroid hormone sensitivity and risk of EBG in patients with CHD, and to further explore their association in different sexes and ages. Methods: This large multicenter retrospective study included 30,244 patients with CHD (aged 30-80 years) between 1 January 2014 and 30 September 2020. Parameters representing central and peripheral sensitivity to thyroid hormones were calculated. Central sensitivity to thyroid hormones was assessed by calculating the Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), and Thyrotropin Thyroxine Resistance Index (TT4RI), and Parametric Thyroid Feedback Quantile-based Index (PTFQI); peripheral sensitivity to thyroid hormones was evaluated using the ratio of free triiodothyronine (FT3) /free thyroxine (FT4). Taking normal glucose tolerance (NGT) as a reference, logistic regression was used to analyse the relationship between central and peripheral thyroid hormone sensitivity and EBG in patients with CHD. Results: Among the 30,244 participants, 15,493 (51.23%) had EBG. The risk of EBG was negatively correlated with TSHI (OR: 0.91; 95%CI: 0.91 to 0.92; P < 0.001), TT4RI (OR: 0.99; 95% CI: 0.99 to 0.99; P<0.001), TFQI (OR: 0.82; 95%CI: 0.80 to 0.84; P <0.001) and PTFQI (OR: 0.76; 95%CI: 0.74 to 0.78; P<0.001). Compared to males and patients aged 60 and below, the OR value for EBG was lower in females and in patients aged over 60 years old. Conversely, EBG risk was positively associated with FT3/FT4 (OR: 1.08; 95% CI: 1.07 to 1.09; P <0.001) and in the sex-categorized subgroups, males had higher OR values than females. Conclusions: This study showed that thyroid hormone sensitivity is significantly associated with EBG in patients with CHD. This association is higher in females than in males, and the association in those aged over 60 years old is higher than that in patients aged 60 years and below.

Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and Rupture.

Background: Numerous pieces of evidence have indicated that thoracic aortic dissection (TAD) is an inflammatory disease. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling is a driver in multiple inflammatory diseases. Here, we examined the S1PR2 expression in TAD lesions and explored the effect of interfering with S1PR2 on TAD formation and progression. Methods: Aorta specimens and blood samples were collected from patients with TAD and matched controls. The expression of S1PR1, S1PR2, and S1PR3 was examined. The effect of inhibiting S1PR2 on TAD was evaluated in a TAD mouse model induced by ß-aminopropionitrile fumarate (BAPN) and AngII. The presence of sphingosine kinase 1 (SPHK1), S1P, and neutrophil extracellular traps (NETs) was investigated. Further, the possible association between S1PR2 signaling and NETs in TAD was analyzed. Results: In the aortic tissues of patients with TAD and a mouse model, the S1PR2 expression was significantly up-regulated. In the TAD mouse model, JTE013, a specific S1PR2 antagonist, not only blunted the TAD formation and aortic rupture, but also preserved the elastic fiber architecture, reduced the smooth muscle cells apoptosis level, and mitigated the aortic wall inflammation. Augmented tissue protein expression of SPHK1, citrullinated histone H3 (CitH3, a specific marker of NETs), and serum S1P, CitH3 were detected in TAD patients. Surgical repair normalized the serum S1P and CitH3 levels. Immunofluorescence staining revealed that S1PR2 colocalized with NETs. The protein expression levels of SPHK1 and serum S1P levels positively correlated with the protein expression and serum levels of CitH3, separately. Furthermore, JTE013 treatment reduced NETs accumulation. Conclusion: Inhibiting S1PR2 attenuates TAD formation and prevents aortic rupture. Targeting S1PR2 may provide a promising treatment strategy against TAD.

Long-Term Effect of a Vaccine Targeting Endothelin-1 Receptor Type A in Pulmonary Arterial Hypertension.

Background: Previously, we invented a therapeutic vaccine targeting the endothelin-A receptor (termed ETRQß-002). ETRQß-002 successfully prevented the remodeling of pulmonary arterioles (PAs) and right ventricle (RV) without significant immune-mediated damage in experimental pulmonary arterial hypertension (PAH) mice models. Objective: Here, we aim to further evaluate the long-term effects of ETRQß-002. Methods: PAH mice model was induced by a combination of subcutaneous injection with Sugen5416 and chronic hypoxic conditions (10% O2). PAH mice were immunized with ETRQß-002 at different time points, and the experiment lasted for 21 weeks. Hemodynamic, histological, and biochemical analyses were conducted to evaluate the long-term effects of ETRQß-002. Results: We demonstrated that the titer of the specific antibody against ETR-002 could be maintained chronically after periodic booster immunization in PAH mice. Long-term reduction of right ventricular systolic pressure and amelioration of PA remodeling by ETRQß-002 were confirmed. Moreover, we found that ETRQß-002 also exerted antiproliferation, anti-inflammation, and antifibrosis effects in PA remodeling. Besides, ETRQß-002 durably limited pathological RV hypertrophy and fibrosis. Finally, no immune-mediated damage was observed in hepatic or renal function or by pathology in liver and kidney during the long-term administration of ETRQß-002. Conclusion: Our findings indicate that ETRQß-002 provides long-term therapeutic effects in Sugen/hypoxia-induced PAH animals and offers a promising clinical prospect for PAH treatment.

Effect of periodic pacemaker optimization on left atrial reverse remodeling in long-term cardiac resynchronization therapy.

PURPOSE: Few data exist about the effect of cardiac resynchronization therapy (CRT) on left atrial (LA) reverse remodeling and function, and whether echocardiographic (echo)-guide pacemaker optimization of atrioventricular and interventricular delays could beneficially affect LA reverse remodeling in long-term CRT therapy. METHODS: Effect of periodic pacemaker optimization on LA reverse remodeling induced by CRT was analyzed in 113 consecutive patients (mean age, 60 ± 11 years) and stratified according to periodic pacemaker optimization (group 1) and nonperiodic pacemaker optimization (group 2). Left atrial volumes index percent changes were assessed at every continuing 6-month follow-up visit. The primary endpoint was LA reverse remodeling. The secondary endpoint included left ventricular reverse remodeling and left ventricular ejection fraction. RESULTS: There is no significant difference of follow-up duration in subgroups (42.43 ± 18.94 months in group 1 vs 37.76 ± 20.24 months in group 2, p = 0.228). The responder's rate of subgroups showed similar after follow-up of 12 months (60.0 vs 53.2%, p = 0.483). After 24-month follow-up, the mean reduction of LAV index was similar in two groups (10.34 vs 7.53%, p = 0.257). The improvement effect of LA reverse remodeling induced by CRT was sustained during 24-month follow-up to the end of current study in periodic pacemaker optimization group. The degree of LAV index percent reduction was directly correlated to periodic pacemaker optimization at end of current analysis (17.13 vs 10.35%, p = 0.047). CONCLUSIONS: Periodic echo-guide pacemaker optimization of atrioventricular and interventricular delays plays a positive role on LA reverse remodeling in long-term CRT therapy.