Low Serum Uric Acid Predicts Risk of a Composite Disease Endpoint.

Background and objectives: Mortality may increase in hypouricemia as well as inhyperuricemia. We assessed the predictive value of low serum uric acid (SUA) levels on the risk of overall mortality or a composite endpoint of death and nonfatal events. Materials and Methods: In 1013 community-based middle-aged adults, free of uncontrolled diabetes and coronary heart disease at baseline, the association of sex-specific SUA tertiles with defined outcomes was evaluated prospectively by logistic regression, stratified to gender and presence of type-2 diabetes, using recent criteria. Results: Totally, 43 deaths and additional incident nonfatal events in 157 cases were recorded at a median 3.4 years' follow-up. Multivariable linear regression disclosed SUA to be significantly associated among non-diabetic individuals positively with creatinine, triglycerides, and body mass index in women further with fasted glucose. In multivariable-adjusted logistic regression analysis, sex-specifically dichotomized baseline uric acid (<5.1 and <4.1 mg/dL vs. higher values) significantly predicted the non-fatal events in the whole sample (relative risk (RR) 1.51 [95% confidence interval (CI) 1.02; 2.26]), as well as in men, while composite endpoint in the whole sample tended to rise (RR 1.38). Compared with the intermediate one, the top and bottom SUA tertiles combined tended to confer mortality risk (RR 2.40 [95% CI 0.89; 6.51]). Adverse outcomes in diabetic women were predicted by tertiles 2 and 3. Conclusions: Inverse association of SUA with adverse outcomes, especially in men, is consistent with the involvement of uric acid mass in autoimmune activation. The positive association of uric acid with adverse outcomes in diabetic women is likely mediated by concomitant high-density lipoprotein dysfunction.

Sex-specific associations of TCF7L2 variants with fasting glucose, type 2 diabetes and coronary heart disease among Turkish adults.

OBJECTIVE: TCF7L2 is a repressor and transactivator of genes, and its variants are strongly associated with diabetes. This study aimed to evaluate the sex-specific relationship between the most common TCF7L2 gene variants (-98368G>T, rs12255372 and -47833C>T, rs7903146) with diabetes and coronary heart disease in Turkish Adult Risk Factor (TARF) Study. METHODS: Single nucleotide variants (SNVs) have been genotyped using the TaqMan allelic discrimination assays in 2,024 (51.3% in women, age: 55±11.8) Turkish adults participating in the TARF study. Statistical analyses were used to investigate the association of genotypes with clinical and biochemical measurements. RESULTS: Among the TARF study participants, 11.7%, 24.3%, 14.1%, and 38.3% had diabetes, hypertension, coronary heart disease (CHD), and obesity, respectively. The frequencies of T allele for -47833C>T and -98368G>T in Turkish adults were determined to be 0.35 and 0.33, respectively. -47833C>T was significantly associated with higher fasting glucose concentrations in all participants, especially in men. Both SNVs were significantly associated with diabetes and CHD in all participants (p<0.05). When study population was stratified according to sex, -98368G>T was associated with diabetes in women (p=0.041) and -47833C>T was associated with diabetes and CHD in men (p=0.018 and p=0.032, respectively). Also, both SNVs and the diplotypes of common haplotype (H1) remained strongly associated with type 2 diabetes after risk factors were adjusted (p<0.05). CONCLUSION: T allele homozygosity of two SNVs as well as the diplotype H1-/H1- reflects risk of diabetes primarily in men. Enhanced CHD risk is determined by the presence of diplotype H1-/H1- among nondiabetic participants.

Non-Contact Respiratory Rate Estimation in Real-Time With Modified Joint Unscented Kalman Filter.

It can be life-saving to monitor the respiratory rate (RR) even for healthy people in real-time. It is reported that the infected people with coronavirus disease 2019 (COVID-19), generally develop mild respiratory symptoms in the early stage. It will be more important to continuously monitor the RR of people in nursing homes and houses with a non-contact method. Conventional, contact-based, methods are not suitable for long-term health monitoring especially in-home care services. The potentials of wireless radio signals for health care applications, such as fall detection, etc., are examined in literature. In this paper, we focus on a device-free real-time RR monitoring system using wireless signals. In our recent study, we proposed a non-contact RR monitoring system with a batch processing (delayed) estimation method. In this paper, for real-time monitoring, we modify the standard joint unscented Kalman filter (JUKF) method for this new and time-critical problem. Due to the nonlinear structure of the RR estimation problem with respect to the measurements, a novel modification is proposed to transform measurement errors into parameter errors by using the hyperbolic tangent function. It is shown in the experiments conducted with the real measurements taken using healthy volunteers that the proposed modified joint unscented Kalman filter (ModJUKF) method achieves the highest accuracy according to the windowing-based methods in the time-varying RR scenario. It is also shown that the ModJUKF not only reduces the computational complexity approximately 8.54% but also improves the accuracy 36.7% with respect to the standard JUKF method.

Optimal anthropometric measures to predict incidence of coronary heart disease in adults in Turkey.

Background: We aimed to identify the most suited anthropometric measure for the prediction of risk for incident coronary heart disease (CHD) among the Turkish population. Methods: We collected data on body mass index, waist circumference (WC), hip circumference, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and a body shape index. We analysed these using both C-statistics and Cox regression models adjusted for age, systolic blood pressure, glucose and high-density lipoprotein (HDL)-cholesterol for assessing risk of incident CHD among 3203 Turkish Adult Risk Factor (TARF) study participants (mean [SD] age 48.5 [11] years). Results: Over a mean follow-up of 9.93 years, new CHD developed in 573 individuals. Multi-adjusted C-statistics were highest for WHtR followed by WC, in both sexes. Except WHR, all measures were significantly associated with incident CHD in combined sexes in the full model. There was a sex difference, however, in the mediation of the three risk factors for adiposity; these attenuated hazard ratios (HRs) in males, whereas in females, significant prediction of incident CHD persisted for each measure. WC (HR 1.36 [95% CI 1.13; 1.64]), followed by WHtR (HR 1.24 [95% CI 1.10; 1.40]), were in combined sex, as in females, the most informative surrogates of adiposity. Hip circumference did not protect, but rather conferred modest CHD risk, especially in females, rendering a low utility of predictive value for WHR. The CHD risk curve did not have a J shape. Conclusions: WC is the most suitable of five adiposity surrogates for CHD risk among Turkish adults, while in males, unmediated adiposity risk was similarly identified by WHtR. Retention of the large part of CHD risk in females perhaps reflects the underlying autoimmune activation.

High-normal thyroid-stimulating hormone in euthyroid subjects is associated with risk of mortality and composite disease endpoint only in women.

INTRODUCTION: The aim of the study was to evaluate whether serum thyroid-stimulating hormone (TSH) within the normal range in euthyroid subjects (having normal free triiodothyronine (fT3) and thyroxine (fT4)) is related to the risk of overall mortality or a composite endpoint of death and nonfatal events. MATERIAL AND METHODS: In 614 middle-aged adult hospital screenees, free of uncontrolled diabetes at baseline, the association of sex-specific TSH tertiles with death was prospectively assessed using Cox regression, with the composite endpoint assessed using logistic regression in adjusted analyses, stratified by gender. RESULTS: In total, 64 deaths and additional incident nonfatal events in 141 cases were recorded at a mean 7.55 years' follow-up. Multivariable linear regression revealed TSH to be significantly associated among men with age (p = 0.006), but in women inversely with fT3 and fT4 (p < 0.001, and p = 0.024 respectively). In logistic regression analysis, adjusted for age, fT3, fT4, systolic blood pressure and serum total cholesterol, sex-specific baseline TSH tertiles were associated in men neither with the risk of death nor with composite endpoint. In contrast, in women, the highest compared with the bottom TSH tertile predicted the risk of composite endpoint (relative risk: 2.02, 95% CI: 1.07-3.82) and, much more strongly, the mortality risk, independently of fT4 increments. CONCLUSIONS: The significant association of higher range of normal serum TSH in euthyroid middle-aged adults with the risk of death and nonfatal adverse outcomes in women alone cannot be accounted for by the action of thyroid hormone and is consistent with involvement of TSH in the pro-inflammatory state.

Autoimmune activation as a determinant of atrial fibrillation among Turks: A prospective evaluation.

Although low-grade inflammation has been linked to the prediction of atrial fibrillation (AF), evidence from some reports suggest that autoimmune activation might potentially be a relevant mechanism. We assessed the predictive value of inflammation and other markers for the risk of incident AF.A score of age-controlled anthropometric, lipid, and nonlipid variables was compared in participants with recorded nonvalvular persistent/permanent AF (n = 110) to those of a nested cohort sample (n = 1126) of the Turkish Adult Risk Factor study. Available values preceding by 2 (±1) years the development of AF were used regarding incident AF (n = 87) in multivariable regression.Comparing age-controlled inflammation and other markers across the 2 groups, low apolipoprotein (apo) B and total cholesterol levels differed highly significantly in each sex. Moreover, low-density lipoprotein (LDL)-cholesterol and fasting insulin concentrations were significantly lower, sex hormone binding globulin (SHBG), glucose and systolic blood pressure higher in women alone, while C-reactive protein levels were similar. A model of multivariable logistic regression analyses for overall AF and 2 models for incident AF demonstrated a consistent inverse predictive value for apoB in each gender [relative risk (RR) 0.44 (95% confidence interval (CI), 95% CI 0.30-0.66], along with age, as main determinants. SHBG in females and waist circumference in males were further significantly associated with initial AF. Never smoking (compared with ever smoking) tended to predict AF.These findings, collectively, are highly consistent with an autoimmune process in which damaged epitope of apoB due to proinflammatory state emerge as a basic mechanism in the development of AF. ApoB level is likely only apparently reduced due to partial escape from assay.

Population-based serum omentin-1 levels: paradoxical association with cardiometabolic disorders primarily in men.

AIM: The conflicting relationships of serum omentin with inflammation markers and cardiometabolic disorders were investigated. Results & methods: Unselected 864 population-based middle-aged adults were cross-sectionally studied by sex-specific omentin tertiles. Men in the lowest omentin tertile (T1) had lower systolic blood pressure, HbA1c and glucose values and tended in T3 to higher lipoprotein(a) levels. Logistic regression analysis, adjusted for four covariates, revealed significant independent associations with the presence of hypertension and diabetes only in men. Sex- and age-adjusted odds ratio in gender combined for T2 & T3 versus T1 was 1.34 (95% CI: 1.00-1.79) for metabolic syndrome. DISCUSSION & CONCLUSION: The elicited adverse relationships of omentin-1 support the notion of oxidative stress-induced proinflammatory conversion of omentin, rendering loss of anti-inflammatory properties.

Modified risk associations of lipoproteins and apolipoproteins by chronic low-grade inflammation.

INTRODUCTION: Lipoproteins and the apolipoproteins (apo) that they carry are major determinants of cardiovascular diseases (CVD) as well as metabolic, renal and inflammatory chronic disorders either directly or through mediation of risk factors. The notion that elevated low-density lipoprotein cholesterol (LDL-C) and apoB levels are related to the acquisition of CVD and, high-density lipoprotein cholesterol (HDL-C) and apoA-I indicate protection against CVD has been challenged in the past decade. Advanced age, adiposity, ethnicity or impaired glucose intolerance rendered autoimmune activation in an environment of pro-inflammatory state/oxidative stress and may disrupt the linear risk association between lipoproteins. Areas covered: This review summarizes the modified risk associations of lipoproteins and apolipoprotein by an environment of chronic systemic low-grade inflammation with special emphasis on the non-linear relationship of lipoprotein(a) [Lp(a)], a biomarker of renewed interest in cardiometabolic risk. Expert commentary: It seems that autoimmune activation in an environment of pro-inflammatory state/oxidative stress not only disrupts the linear risk association between lipoproteins, but also may cause interference in immunoassays. Hence, methodological improvement in immunoassays and much further research focusing on population segments susceptible to a pro-inflammatory state is necessary for further advances in knowledge.

Turkey's top publications in cardiovascular medicine in the past 25 years: evaluation of its impact.

OBJECTIVE: To identify "genuine" publications from Turkey's institutions since 1992 that have cumulatively contributed the most to global cardiovascular medicine. METHODS: Based on data from the Web of Science, 146 publications from Turkey were identified having received ≥50 citations as of late July, 2017. Papers with more than a minor share by international authors were excluded. RESULTS: Hundred and ten primary authors generated 147 medical papers which received ≥50 (interquartile range, 54; 86) citations. These articles corresponded in quality to the top 12% global papers. Half of the articles were published from 2002 to late 2007, with a median exposure period of 12 years. Peak performance was reached in 2004-'07, with a mean of 15-20 papers annually, which then regressed to five papers in 2008-'13, representing an estimated 50% decline. Cardiology generated 105 articles (20 in collaboration with other branches), cardiovascular surgery generated 27 articles, and pediatric cardiology generated 5 articles. Publications arose from 26 medical faculties, Gülhane Military Academy, and 9 hospitals not which were not academically affiliated. The performance of many related Turkish institutions was disappointing. CONCLUSION: Turkey's contribution to cardiovascular medicine has further declined slightly in the current assessment, particularly since 2007. To prevent a further gap in Turkey's contribution to the field, an undelayed return is needed by building an environment that allows focusing on research with a potential to contribute to medicine.

Tenth categories of total and HDL cholesterol fail to independently predict death risk in middle-aged Turkish adults.

OBJECTIVE: The aim of this study was to delineate in detail the longitudinal association of total cholesterol (TC) and highdensity lipoprotein cholesterol (HDL-C) levels with overall mortality in middle-aged participants of the biennial Turkish Adult Risk Factor study. METHODS: Baseline lipid variables were analyzed in sex-specific deciles. A baseline age of 45 to 84 years as an inclusion criterion led to the enrollment of 2121 men and women. Cox regression analyses were performed. RESULTS: Deaths were recorded in 237 and 306 women and men, respectively, during a mean 8.85±4.4 years of follow-up. After adjustment for age, smoking status, lipid-lowering and antihypertensive drug usage, prevalent diabetes, and coronary heart disease, and using the lowest decile as referent, neither TC (p trend=0.94 and 0.96, respectively), nor HDL-C categories (p trend=0.20 and 0.31, respectively) were significantly predictive of mortality in either gender. TC deciles exhibited a gender difference insofar as hazard ratios in females tended to be reciprocal to those in males in deciles 2 through 5. CONCLUSION: The findings on TC deciles may be attributed to a comparatively higher death rate in the female (compared with male) bottom decile, reflecting the autoimmune process-induced elevated risk in the lowest decile. Observations on HDLC confirmed presumed pro-inflammatory conversion in levels >50 mg/dL. These results have important clinical implications.

Determinants of obstructive sleep apnea syndrome: Pro-inflammatory state and dysfunction of high-density lipoprotein.

OBJECTIVE: The goal of this study was to determine variables preceding and predicting incident obstructive sleep apnea syndrome (OSAS) in the population at large. METHODS: Anthropometric, lipid, and non-lipid variables in participants with newly developing OSAS (n = 131) were compared with those of a cohort sample (n = 2615) of the Turkish Adult Risk Factor study. Available values preceding (by a median of 32 mo) the development of OSAS were used in multivariable Cox regression models. RESULTS: Significant determinants of OSAS assessed by group differences were waist/neck circumference and fibrinogen. Fasting triacylglycerols, systolic blood pressure, and C-reactive protein in men and low sex hormone-binding globulin and elevated homeostatic model assessment in women were further significant covariates. Cox regression analysis for the risk of incident OSAS confirmed the independent predictive value of central obesity measures, especially neck circumference (having a twofold hazard ratio) and younger age. Age-adjusted former smoking status and-compared with the lowest tertile-the upper two tertiles of fibrinogen (relative risk = 1.66, 95% confidence interval: 1.05-2.63) were significant predictors. Elevated triacylglycerols in males and high apolipoprotein B and lowest high-density lipoprotein cholesterol tertile in females also predicted subsequent OSAS. Systolic blood pressure and total cholesterol did not prove to be independent predictors in multivariable adjusted Cox models in which partial sex-dependent independence of obesity measures of the previously stated five variables was essentially retained. CONCLUSIONS: An enhanced pro-inflammatory state appeared to be the underlying pathophysiologic mechanism for OSAS, whereas in men, the added factor of high-density lipoprotein dysfunction was suggested. Because it contributes to the pro-inflammatory state, discontinuance of smoking was another further significant predictor of OSAS.

Female and urban participants demonstrate an adverse trend in overall mortality in Turkey - and a report on the TARF survey 2016.

OBJECTIVE: This study is an examination of 1) overall mortality trend in the Turkish Adult Risk Factor (TARF) study stratified by sex and place of residence, and 2) brief report on main aspects of the 2016 survey. METHODS: The period of last 18 years was divided into 2 for trend analysis of data. Required information on deaths was obtained. Baseline age ≥40 years at the beginning of each period was the inclusion criterion. Cox regression analyses were performed. RESULTS: Among over 2500 participants in each, deaths were recorded in 281 and 334 individuals in Periods 1 and 2, respectively, and baseline mean age was 54.6 years and 56.4 years, respectively, in each period. Age-adjusted hazard ratio for mortality in Period 2 remained virtually the same for rural males, rose to borderline significance for urban males and rural females (p=0.06, p=0.09), and increased 1.72-fold for urban females (p=0.006), as compared to Period 1. Whereas males gained an average of 3.8 years of survival in the later period compared with the earlier period, females gained only 1.8 years. This narrowed the difference in mean age at death in favor of women from 2.5 years to 0.5 year. Of 1144 participants to be surveyed in the TARF 2016, 48 were lost to follow-up, 695 were examined, and 39 participants were ascertained to be deceased. In 362 cases, verbal information was obtained regarding health status. CONCLUSION: Gain in survival in Turkish women has distinctly stagnated compared with men, and hazard of death has risen significantly for women and urban residents in the past decade, suggesting interaction between female sex and urban residence. Both phenomena require recognition and adoption of appropriate measures.

Lower circulating migration inhibitory factor protein is associated with metabolic syndrome and diabetes.

AIM: The controversial relationship between macrophage migration inhibitory factor (MIF) and the likelihood of cardiometabolic diseases was investigated. Results/methodology: Assayed MIF protein from 1225 adults was cross-sectionally analyzed. MIF was independently inversely associated with age, total testosterone and positively with high-density lipoprotein-cholesterol. In men MIF correlation with age, testosterone and waist circumference converted from inverse in the upper to positive in the bottom MIF third. Both metabolic syndrome and diabetes were significantly associated, in combined gender, with the intermediate (vs the highest) MIF tertile at an odds ratio 1.6. Coronary heart disease was not significantly related with MIF in either gender. DISCUSSION/CONCLUSION: Findings are consistent with oxidative damage to MIF protein and its involvement in autoimmune activation, likely more extensive in women.

Lipoprotein(a)-activated immunity, insulin resistance and new-onset diabetes.

OBJECTIVES: Some evidence suggests that serum lipoprotein[Lp](a) may be inversely linked to type-2 diabetes. We aimed to determine in nondiabetic people the relationship of serum [Lp](a) with insulin resistance and new-onset diabetes (NOD). MATERIALS AND METHODS: Population-based middle-aged adults (n = 1685) were categorized by fasting glucose and stratified to gender, having excluded prevalent diabetic subjects. NOD (n = 90) occurred over a median 5 years' follow-up. RESULTS: Subjects that subsequently developed NOD, derived both from the normoglycemia and impaired fasting glucose (IFG) groups,were distinguished, among others, primarily by significantly elevated serum gamma glutamyltransferase, reduced Lp(a) (by 31%) and, compared to IFG, by low total cholesterol levels. Partial correlation of Lp(a) with homeostatic model assessment (HOMA) was inverse in normoglycemic men; such correlation, neutral in normoglycemic women, proved inverse in IFG (r = -0.17). Circulating Lp(a) in individuals with paired measures increased significantly (1.55-fold) in the period from baseline up to NOD. Multivariable-adjusted logistic regression analysis for NOD in combined sexes indicated independent and additive prediction by serum Lp(a), albeit inverse in direction (RR 0.84, [95%CI 0.72; 0.97]). CONCLUSION: Lp(a) is significantly reduced in the period preceding NOD and is inversely associated with HOMA index, observations consistent with underlying autoimmune activation.

Use of Repeated Blood Pressure and Cholesterol Measurements to Improve Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis.

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.

Algorithm for predicting CHD death risk in Turkish adults: conventional factors contribute only moderately in women.

OBJECTIVE: To assist the management strategy of individuals, we determined an algorithm for predicting the risk of coronary heart disease (CHD) death in Turkish adults with a high prevalence of metabolic syndrome (MetS). METHODS: The risk of CHD death was estimated in 3054 middle-aged adults, followed over 9.08±4.2 years. Cox proportional hazard regression was used to predict risk. Discrimination was assessed using C-statistics. RESULTS: CHD death was identified in 233 subjects. In multivariable analysis, the serum high-density lipoprotein-cholesterol (HDL-C) level was not predictive in men and the non-HDL-C level was not predictive in women. Age, presence of diabetes, systolic blood pressure ≥160 mm Hg, smoking habit, and low physical activity were predictors in both sexes. The exclusion of coronary disease at baseline did not change the risk estimates materially. Using an algorithm of the 7 stated variables, individuals in the highest category of risk score showed a 19- to 50-fold higher spread in the absolute risk of death from CHD than those in the second lowest category. C-index of the model using age alone was as high as 0.774 in men and 0.836 in women (p<0.001 each), while the incorporation of 6 conventional risk factors contributed to a C-index of 0.058 in males and 0.042 in females. CONCLUSION: In a middle-aged population with prevalent MetS, men disclosed anticipated risk parameters (except for high HDL-C levels) as determinants of the risk of CHD death. On the other hand, serum non-HDL-C levels and moderate systolic hypertension were not relevant in women. The moderate contribution of conventional risk factors (beyond age) to the estimation of the risk of CHD death in women is consistent with the operation of autoimmune activation.