Yusuf Karadeniz

Advances in understanding gender difference in cardiometabolic disease risk

ABSTRACT Gender differences exist in cardiovascular or metabolic disease risk, beyond the protective effect of estrogens, mostly burdening the postmenopausal female. We aimed to review herein sex differences in pro-inflammatory states, the independence of inflammation from insulin resistance, differences in high-density lipoprotein dysfunction, in gene-environment interactions, and in the influence of current and former smoking on cardiometabolic risk. Sex differences in absorption of long-chain fatty acids are highlighted. Differences exist in the first manifestation of cardiovascular disease, men being more likely to develop coronary heart disease as a first event, compared to women who have cerebrovascular disease or heart failure as a first event. Autoimmune activation resulting from pro-inflammatory states, a fundamental mechanism for numerous chronic diseases in people prone to metabolic syndrome, is much more common in women, and these constitute major determinants. Therapeutic approaches to aspects related to sex difference are briefly reviewed.

Type-2 diabetes and coronary heart disease: common physiopathology, viewed from autoimmunity

Two highly prevalent diseases, Type-2 diabetes mellitus and coronary heart disease (CHD), share risk factors. Excess levels of LDL-cholesterol have been overemphasized to uniformly encompass the development of CHD, and the origin of insulin resistance underlying Type-2 diabetes has not been fully elucidated. Autoimmune response has been recognized to be responsible only of a small minority of diabetes. The increasing trend in the worldwide prevalence of diabetes and the risk factors for both diseases are reviewed, the independent mediation for CHD of (central) adiposity in both diseases and the ‘hypertriglyceridemic waist’ phenotype are outlined. Evidence is described that serum lipoprotein (Lp)(a) concentrations, not only in excess, but also in apparently ‘reduced’ levels, as a result of autoimmune response, underlie both disorders and are closely related to insulin resistance.

Prediction by Low Plasma HbA1c of Mortality, Cardiac and Noncardiac Disease Risk: Modulation by Diabetic Status and Sex

Aim The aim of the study was to evaluate the predictive value of HbA1c for risk of overall mortality or a composite endpoint of death and nonfatal events. Methods Logistic regression retrospectively assessed the longitudinal association of measured HbA1c with outcome in 746 middle-aged adults, recruited from a tertiary health center and stratified to absence or presence of type 2 diabetes, using the recent American Diabetes Association criteria. Results A total of 70 deaths and additional incident nonfatal events in 82 cases were recorded at a median of 3.1-year follow-up. Multivariable linear regression revealed among nondiabetic individuals HbA1c to be significantly associated—independent of fasted glucose—inversely with triglycerides and high-density lipoprotein cholesterol, distinct from the diabetic sample. Sex and diabetes status differed in baseline HbA1c values with respect to the development of outcome. Nondiabetic men who subsequently died exhibited significantly lower HbA1c, as did men and women with incident coronary heart disease. Similar difference was observed for incident hypothyroidism and nondiabetic subjects developing malignancy. In logistic regression analysis, adjusted for sex, age, and fasting glucose, each 0.7% (SD, 1) decrement of baseline HbA1c predicted the composite endpoint in the nondiabetic sample (risk estimates, 1.49%; 95% confidence interval, 1.07–2.04), but not in the diabetic sample, whereas overall mortality in the whole sample was increased (risk estimates, 1.51%; 95% confidence interval, 1.05–2.17). Conclusions Inverse association of HbA1c with adverse outcomes in men and nondiabetic people indicates the involvement of HbA1c levels in autoimmune activation. The weaker inverse association with prevalent diabetes and in women is consistent with the operation of more pronounced confounding autoimmune processes.

Sex-Specific Predictors of Metabolic Syndrome Independent of Its Components.

To what extent is the metabolic syndrome (MetS) determined beyond its recognized components? In 1702, middle-aged men and women without MetS at baseline, MetS development was identified in 546 participants at a mean of 10.1-year follow-up. Participants subsequently developing MetS had, beyond higher values of MetS traits, significantly higher total and low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein (CRP), γ-glutamyl transferase (GGT), and lower high-density lipoprotein cholesterol. Females were significantly more frequent never smokers and males had lower values of total testosterone. In logistic regression analyses, adjusted for sex, age, and smoking status, MetS was predicted disparately in the sexes, whereas males exhibited, beyond abdominal obesity, CRP, GGT, and sex hormone-binding globulin (SHBG) as independent predictors, abdominal obesity was not an independent predictor in females in whom other than age, CRP conferred MetS risk, whereas SHBG was and current smoking tended to be protective. A surrogate of hepatic steatosis proved a major mediator of abdominal obesity in determining incident MetS (relative risk, 5.6 [95% confidence interval, 3.4-9.3]) in each sex. We confirm that GGT and SHBG are novel independent MetS determinants. Hepatic steatosis is the major predictor of MetS mediating adiposity in each sex. Abdominal obesity is not an independent determinant in Turkish women in whom autoimmune activation seems to prevail before MetS development.

Twenty-five years of the TARF study: The 2015 survey, and temporal trends in mortality and loss to follow-up

OBJECTIVE The aims of the present study were to examine, first, overall mortality in the Turkish Adult Risk Factor (TARF) 2015 survey, and second, distribution of cumulative mortality and temporal losses to follow-up in the 7 geographic regions of Turkey over 25 years. METHODS Information on mode of death was obtained from first-degree relatives and/or primary health center personnel. Information regarding survivors was based on history, examination of the cardiovascular system, and Minnesota coding of electrocardiograms. RESULTS Of the 1304 participants to be screened, 58 were lost to follow-up, 787 were examined, and 39 participants had died. In 420 subjects, verbal reporting alone was used to determine health status. Deaths were attributed to coronary heart disease in 16 subjects, and cerebrovascular event and cancer in 8 cases each. However, evidence suggested underlying autoimmune activation in 85% of cases. Cumulative 25-year assessment of the entire cohort, comprising 863 deaths over a mean follow-up of 20.5 years, corresponded to a rate of 11.4 per 1000 person-years. A significantly lower mortality rate was found in the Southeast. The 1992 participants lost to follow-up represented a rate of 22.5 per 1000 person-years. CONCLUSION The generally high overall mortality in Turkey is similar among geographic regions, with the exception of a lower rate in Southeastern Anatolia. One of every 45 surviving participants is lost to follow-up each year.

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.

Proinflammatory State, Diverse Protective Plasma Proteins Including High-Density Lipoprotein Particles, and Outcome

The population-based CANHEART (Cardiovascular Health in Ambulatory Care Research Team) “big data” cohort examining the relationship between high-density lipoprotein cholesterol (HDL-C) and cause-specific mortality rates was of interest in several aspects [(1)][1]. These investigators found that

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.

[Turkish Adult Risk Factor survey 2014: Overall mortality and coronary disease incidence in Turkey's geographic regions].

OBJECTIVE This study aimed to examine the overall and coronary mortality in the 2014 Turkish Adult Risk Factor Study survey, and the distribution of cumulative mortality and incident coronary heart disease (CHD) across 7 geographic regions. METHODS Information on mode of death was appropriately obtained. Information collected from survivors was based on history, examination of the cardiovascular system and the Minnesota coding of electrocardiograms. Cox regression analyses were performed. RESULTS Of the 1.323 participants to be surveyed, 87 were lost to follow-up, 753 examined, and 35 ascertained as deceased. In 448 subjects, verbal information alone was obtained regarding health status. Nineteen deaths were of coronary and cerebrovascular origin. Cumulative 24-year assessment of the entire cohort in the age bracket 45-74 years disclosed high coronary mortality, at 7.3 per 1000 person-years in men and 3.8 in women, and recorded a limited decline of 18% since the year 2000. Age-adjusted Cox regression analysis, comprising 614 deaths and 482 incident CHD over a follow-up of 9.6 years, revealed higher mortality rates in the Mediterranean region and in men in the Black Sea and Marmara regions. The age-adjusted CHD incidence was significantly higher in males of the Mediterranean and females of the Southeast regions. An estimated 400-420.000 incident CHD cases develop currently each year in Turkey. CONCLUSION The generally high age-adjusted overall mortality in Turkey displays significant differences across geographic regions. Age-adjusted CHD incidence is not regressing sufficiently, and is especially high among men of the Mediterranean and women of the Southeast regions.

Low acylation stimulating protein levels are associated with cardiometabolic disorders–secondary to autoimmune activation?

Objective: We investigated the possible association of serum acylation stimulating protein (ASP) with cardiometabolic disorders and the evidence of autoimmune activation. Methods: Population-based randomly selected 1024 participants were cross-sectionally and prospectively analyzed. ASP concentrations were measured with a validated ELISA kit. Correlations were sought separately in subjects with no cardiometabolic disorders (n=427) designated as “healthy.” Results: ASP was positively correlated with total testosterone and inversely correlated with platelet activating factor (PAF), PAF-acetylhydrolase (AH), in each gender, and positively correlated in “healthy” men with lipoprotein [Lp](a) and apolipoprotein B. Correlations of ASP with PAF values ≥22 nmol/L were abolished, contrasted to a strongly inverse one in subjects with PAF <22 nmol/L. In linear regression analyses in the whole sample, ASP was inversely associated independently with PAF and PAF-AH and, in men, positively with Lp(a) and sex hormone-binding globulin. Prevalent and (at 2.0 years’ follow-up) incident metabolic syndrome (MetS, n=393), diabetes (n=154), and coronary heart disease (CHD, n=171) were analyzed by sex-, age-, and Lp(a)-adjusted logistic regression, using tertiles of ASP and PAF. The lower two (<42 nmol/L) ASP tertiles were a risk factor in combined sexes for MetS and diabetes. In women, incident CHD was predicted by either reduced or elevated ASP tertiles. Conclusion: Findings can be explained by the notion of operation of immune responses against both ASP and oxidized PAF-like lipids of Lp(a) to yield for “reduced” values and increased likelihood of cardiometabolic disorders.