Derivation of sex and age-specific reference intervals for clinical chemistry analytes in healthy Ghanaian adults.

OBJECTVIES: This study is aimed at establishing reference intervals (RIs) of 40 chemistry and immunochemistry analytes for Ghanaian adults based on internationally harmonized protocol by IFCC Committee on Reference Intervals and Decision Limits (C-RIDL). METHODS: A total of 501 healthy volunteers aged ≥18 years were recruited from the northern and southern regions of Ghana. Blood samples were analyzed with Beckman-Coulter AU480 and Centaur-XP/Siemen auto-analyzers. Sources of variations of reference values (RVs) were evaluated by multiple regression analysis (MRA). The need for partitioning RVs by sex and age was guided by the SD ratio (SDR). The RI for each analyte was derived using parametric method with application of the latent abnormal values exclusion (LAVE) method. RESULTS: Using SDR≥0.4 as threshold, RVs were partitioned by sex for most enzymes, creatinine, uric acid (UA), bilirubin, immunoglobulin-M. MRA revealed age and body mass index (BMI) as major source of variations of many analytes. LAVE lowered the upper limits of RIs for alanine/aspartate aminotransferase, γ-glutamyl transaminase and lipids. Exclusion of individuals with BMI≥30 further lowered the RIs for lipids and CRP. After standardization based on value-assigned serum panel provided by C-RIDL, Ghanaian RIs were found higher for creatine kinase, amylase, and lower for albumin and urea compared to other collaborating countries. CONCLUSIONS: The LAVE effect on many clinical chemistry RIs supports the need for the secondary exclusion for reliable derivation of RIs. The differences in Ghanaian RIs compared to other countries underscore the importance of country specific-RIs for improved clinical decision making.

The potential role of sesquiterpene lactones isolated from medicinal plants in the treatment of the metabolic syndrome - A review.

Metabolic syndrome comprises a cluster of metabolic disorders related to the development of cardiovascular disease and type 2 diabetes mellitus. In latter years, plant secondary metabolites have become of special interest because of their potential role in preventing and managing metabolic syndrome. Sesquiterpene lactones constitute a large and diverse group of biologically active compounds widely distributed in several medicinal plants used for the treatment of metabolic disorders. The structural diversity and the broad spectrum of biological activities of these compounds drew significant interests in the pharmacological applications. This review describes selected sesquiterpene lactones that have been experimentally validated for their biological activities related to risk factors of metabolic syndrome, together with their mechanisms of action. The potential beneficial effects of sesquiterpene lactones discussed in this review demonstrate that these substances represent remarkable compounds with a diversity of molecular structure and high biological activity, providing new insights into the possible role in metabolic syndrome management.

Camel milk ameliorates hyperglycaemia and oxidative damage in type-1 diabetic experimental rats.

This study was designed to assess anti-diabetic potential of goat, camel, cow and buffalo milk in streptozotocin (STZ) induced type 1 diabetic albino wistar rats. A total of 48 rats were taken for the study where one group was kept as non-diabetic control group (8 rats) while others (40 rats) were made diabetic by STZ (50 mg/kg of body weight) injection. Among diabetic rats, a control group (8 rats) was kept and referred as diabetic control whereas other four groups (8 rats each) of diabetic rats were fed on 50 ml of goat or camel or cow or buffalo milk for 4 weeks. All the rats (non-diabetic and diabetic) were maintained on standard diet for four weeks. STZ administration resulted in enhancement of glucose, total cholesterol, triglyceride, low density lipoprotein, HbA1c and reduction in high density lipoprotein in plasma and lowering of antioxidative enzymes (catalase, glutathione peroxidase and superoxide dismutase) activities in pancreas, kidney, liver and RBCs, coupled with enhanced levels of TBARS and protein carbonyls in pancreas, kidney, liver and plasma. OGTT carried out at the end of 4 week milk feeding indicated that all milks helped in early maintenance of glucose level. All milks reduced atherogenic index. In camel milk fed diabetic group, insulin concentration enhanced to level noted for non-diabetic control while goat, cow and buffalo milk failed to restore insulin level. HbA1c level was also restored only in camel milk fed diabetic group. The level of antioxidative enzymes (catalase, GPx and SOD) in pancreas enhanced in all milk fed groups. Camel milk and to a reasonable extent goat milk reduced formation of TBARS and PCs in tissues and blood. It can be concluded that camel milk ameliorates hyperglycaemia and oxidative damage in type-1 diabetic experimental rats. Further, only camel milk completely ameliorated oxidative damage in pancreas and normalised insulin level.

Meta-analysis of the effects of smoking and smoking cessation on triglyceride levels.

Smoking increases lipid levels, including triglycerides, leading to increased cardiovascular disease risk. We performed a meta-analysis to quantify the effects of smoking and smoking cessation on triglyceride levels. The PubMed and Scopus databases were searched to identify studies reporting either triglyceride levels in smokers and non-smokers or the effects of smoking cessation on triglyceride levels. Fixed- and random-effects models were used to perform the analyses when three or more studies/comparisons were available. We identified 169 and 21 studies evaluating the effects of smoking and smoking cessation, respectively, on triglyceride levels. Triglyceride levels were 0.50 mmol/L (95% confidence interval: 0.49-0.50 mmol/L) higher in smokers than non-smokers, but the effect differed widely across studies. No statistically significant effect was observed on triglyceride levels between baseline and 6 weeks (mean difference [MD] = 0.02 [-0.09, 0.12] mmol/L), 2 months (MD = 0.03 [-0.21, 0.27] mmol/L), 3 months (MD = 0.08 [-0.03, 0.21] mmol/L), or 1 year (MD = 0.04 [-0.06, 0.14] mmol/L) after quitting. However, a slightly significant decrease in triglyceride levels was observed at 1 month after cessation (MD = -0.15 [-0.15, -0.01] mmol/L). The results of this meta-analysis provide a basis for understanding the effects of smoking and smoking cessation on triglyceride levels, which could have important implications for public health.

Autoimmune Reaction Associated With Long COVID Syndrome and Cardiovascular Disease: A Genetic Case Report.

A 35-year-old woman with history of cardiovascular disease presented with shortness of breath, lightheadedness, fatigue, chest pain, and premature ventricular contractions 3 weeks after her second COVID-19 vaccine. Symptoms subsided following catheter ablation and ibuprofen except for chest pain and fatigue, which persisted following ablation and subsequent SARS-CoV-2 infection. The case suggests causal associations between COVID-19 vaccine/infection and recurrence of cardiovascular disease, including long-COVID-like symptoms. (Level of Difficulty: Advanced.).

Assessing the effectiveness of a DASH diet in hypertensive patients attending the Ngaoundere Regional Hospital - Cameroon: a case-control study.

Hypertension remains a public health issue in Cameroon, though lifestyle and dietetic measures are the main approaches for the prevention and management of hypertension. The present study aimed at evaluating the impact of a Dietary Approaches to Stop Hypertension (DASH) diet using local foodstuffs on the status of hypertensive patients at the Ngaoundere Regional Hospital. A case-control study was carried out with 160 hypertensive patients divided into two groups, a test and a control group. A food questionnaire was used to evaluate the food habits of patients and design the sheet of the DASH diet to provide a maximum of 2000 kcal/d. The DASH diet was administered to the test group (eighty-eight patients), while the control group (seventy-two patients) consumed their normal diet. Both groups were followed up for 8 weeks. The systolic and diastolic blood pressures (SBP, DBP), body mass index (BMI), triglycerides, HDL-c, LDL-c and total-cholesterol levels of patients of the two groups were measured before and after the intervention. The results indicate that the DASH diet improves all the markers of hypertension in the test group with significant decreases in BMI, SBP, DBP, LDL-c and total-cholesterol. Patients of the control group had fourteen and seven times more risk of having increased systolic and diastolic pressures, respectively, and are thus exposed to hypertension complications. The DASH diet established in this study is therefore effective for the management of hypertension.

The effect of evolocumab alone and in combination with atorvastatin on atherosclerosis progression and TLRs expression.

Evolocumab, a PCSK-9 inhibitor, is known for its ability to reduce low-density lipoprotein cholesterol (LDL-C). This study aimed to investigate the effects of evolocumab, alone or in combination with atorvastatin, on the progression of atherosclerosis. Fifty male domestic rabbits were randomly assigned to five groups: control, high cholesterol diet, evolocumab vehicle (dimethyl sulfoxide, DMSO), evolocumab alone, and evolocumab plus atorvastatin. Serum levels of interleukin 10 (IL-10), IL-17, IL-1ß, intracellular adhesion molecule (ICAM), and vascular adhesion molecule (VCAM) were measured. Toll-like receptor (TLR) expression on monocytes was evaluated using flow cytometry. Histopathological examination and measurement of intimal thickness (IT) were also conducted. The results revealed that the evolocumab produced a statistically significant (p<0.05) reduction in lipid profile at 5 weeks, with the peak effect occurring at 10 weeks. Furthermore, the inhibitor reduced TLRs at 10 weeks to 10.83±1.8 and intimal thickness to 160.66±9.45. IL-17, IL-1ß, ICAM, and VCAM were significantly reduced by evolocumab treatment, with the improvement of the histopathological changes in the aortic wall. The combination of evolocumab and atorvastatin caused a more statistically significant reduction in TLRs at 10 weeks to 5.08±1.2 and intimal thickness to 121.79±5.3. IL-17, IL-1ß, ICAM, and VCAM were significantly (p<0.05) reduced by the combination, and the histopathological changes in the aortic wall were significantly improved. In conclusion, evolocumab delays the progression of atherosclerosis by modulating inflammatory pathways.

Hepatitis B virus infection combined with nonalcoholic fatty liver disease: Interaction and prognosis.

Hepatitis B virus (HBV) infection is still one kind of the infectious diseases that seriously threaten human health. Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. HBV infection complicated with NAFLD is increasingly common. This review mainly describes the interaction between HBV infection and NAFLD, the interaction between steatosis and antiviral drugs, and the prognosis of HBV infection complicated with NAFLD. Most studies suggest that HBV infection may reduce the incidence of NAFLD. NAFLD can promote the spontaneous clearance of hepatitis B surface antigen (HBsAg), but whether it affects antiviral efficacy has been reported inconsistently. HBV infection combined with NAFLD can promote the progression of liver fibrosis, especially in patients with severe steatosis. The outcome of HBV infection combined with NAFLD predisposing to the progression of HCC remains controversial.

Liraglutide Lowers Endothelial Vascular Cell Adhesion Molecule-1 in Murine Atherosclerosis Independent of Glucose Levels.

The authors determined the effect of the GLP-1 receptor agonist liraglutide on endothelial surface expression of vascular cell adhesion molecule (VCAM)-1 in murine apolipoprotein E knockout atherosclerosis. Contrast-enhanced ultrasound molecular imaging using microbubbles targeted to VCAM-1 and control microbubbles showed a 3-fold increase in endothelial surface VCAM-1 signal in vehicle-treated animals, whereas in the liraglutide-treated animals the signal ratio remained around 1 throughout the study. Liraglutide had no influence on low-density lipoprotein cholesterol or glycated hemoglobin, but reduced TNF-α, IL-1ß, MCP-1, and OPN. Aortic plaque lesion area and luminal VCAM-1 expression on immunohistology were reduced under liraglutide treatment.

Patient experiences align with the familial hypercholesterolemia global call to action.

Objective: To explore alignment of perspectives from individuals and families with familial hypercholesterolemia (FH) to the FH Global Call to Action recommendations. Methods: Interviews and focus groups were conducted with individuals and families with FH from multiple U.S. health systems and the Family Heart Foundation community to capture lived experiences and to identify barriers to diagnosis, cascade testing, and treatment. Participant perspectives were examined and classified, according to their alignment to recommendations of the FH Global Call to Action. Results: A total of 75 lived experiences were analyzed. Participants were majority female, mostly white, older, and well-educated. Participants most frequently mentioned recommendations were family-based care (84%) and screening, testing, & diagnosis (84%), followed by treatment (69%), advocacy (60%), cost & value (59%), awareness (56%), research & registries (43%), and severe & homozygous FH (11%). An average of 4.65 (SD 1.76) recommendations were mentioned. Conclusions: The FH Global Call to Action was driven by the persistent unmet needs of those living with FH in receiving a timely diagnosis, appropriate care, and support to prevent early morbidity and mortality. Patient- and family-centric perspectives suggest the FH Global Call to Action captures these concerns. Acting on recommendations, particularly improvements in screening and family-based care, will address patient, and public health, concerns.

Homozygous Familial Hypercholesterolemia: Luck Meets Opportunity Meets Knowledge.

This case report describes a 67-year-old African-American woman with homozygous familial hypercholesterolemia caused by 2 pathogenic variants in the LDLR gene. Initial surgical, pharmacological, and low-density lipoprotein apheresis interventions were insufficient; the addition of proprotein convertase subtilisin-kexin type 9 and angiopoietin-like 3 inhibitors lowered her low-density lipoprotein cholesterol to <70 mg/dL. (Level of Difficulty: Advanced.).

Cardiometabolic Comorbidities in Cancer Survivors: JACC: CardioOncology State-of-the-Art Review.

There are nearly 17 million cancer survivors in the United States, including those who are currently receiving cancer therapy with curative intent and expected to be long-term survivors, as well as those with chronic cancers such as metastatic disease or chronic lymphocytic leukemia, who will receive cancer therapy for many years. Current clinical practice guidelines focus on lifestyle interventions, such as exercise and healthy eating habits, but generally do not address management strategies for clinicians or strategies to increase adherence to medications. We discuss 3 cardiometabolic comorbidities among cancer survivors and present the prevalence of comorbidities prior to a cancer diagnosis, treatment of comorbidities during cancer therapy, and management considerations of comorbidities in long-term cancer survivors or those on chronic cancer therapy. Approaches to support medication adherence and potential methods to enhance a team approach to optimize care of the individual with cancer across the continuum of disease are discussed.

The burden of severe hypercholesterolemia and familial hypercholesterolemia in a population-based setting in the US.

Background: Contemporary prevalence, awareness, and control of severe hypercholesterolemia (SH) and familial hypercholesterolemia (FH) and the associated atherosclerotic cardiovascular disease risk in the US are unknown. Method: Using electronic health records, we assessed the burden of SH and FH in Olmsted County, Minnesota, US, between 2004 and 2015. We defined SH as low-density lipoprotein cholesterol (LDL-C) level ≥190 mg/dl without secondary causes of hypercholesterolemia and FH as a Dutch Lipid Clinic Network score ≥6. Controls were age- and sex-matched individuals with LDL-C level <190 mg/dl. Results: The age- and sex-adjusted point and period prevalence (age-recursive method) of SH was 4.44% and 8.95%, respectively; 1 in 21 had FH (∼1:233 adults), and 46.2% had a recorded diagnosis. Guideline recommended targets (LDL-C <100 mg/dl and <70 mg/dl in the primary and secondary prevention settings, respectively) were achieved in 33.1% and 21.2% of SH cases, with less women overall achieving the target than men (18.6% vs. 23.7%, p=0.022). After adjustment for conventional risk factors, the hazard ratio for incident coronary heart disease (CHD) in those with SH was 1.21 (1.05-1.39; p=0.010), in those with SH and a family history of CHD was 2.16 (1.57-2.96; p<0.001) and in those with FH was 4.61 (2.66-7.97; p<0.001). The association of SH with CHD was modified by age (p-interaction = 0.015), such that the risk was greater at younger ages. Conclusions: SH was prevalent and an independent risk factor for incident CHD. Awareness and control were low, highlighting a treatment gap (more prominent in women) that needs to be addressed.

When LDL Cholesterol Is Not LDL Cholesterol: LpX, A Clinical Lesson.

LpX is a lipoprotein formed in cholestatic conditions and often erroneously reported as LDL-C. A low ApoB level can support the diagnosis of LpX. Treatment should not automatically focus on lowering serum lipid levels, but primarily on resolving the cause of cholestasis. (Level of Difficulty: Advanced.).

Implementation of Novel Lipid Therapies in a Refractory Heterozygous Familial Hypercholesterolemia Patient With Atherosclerotic Disease.

Compound heterozygous familial hypercholesterolemia patients are phenotypically similar to homozygous familial hypercholesterolemia patients, present with significant elevations of low-density lipoprotein cholesterol, and are at risk of cardiovascular disease. Although new treatment options are emerging, the stepwise approach to the use of different therapies has not been well described. (Level of Difficulty: Intermediate.).

Influence of cholesterol level on long-term survival and cardiac events after surgical coronary revascularization.

Objective: Statins have been shown to delay the inevitable progression of atherosclerosis in native coronaries and saphenous vein grafts, thereby reducing ischemic events after surgical coronary revascularization. However, there is significant controversy as to whether titrating statin therapy to concrete cholesterol targets is appropriate. Methods: A single-center retrospective analysis of 309 consecutive patients who underwent isolated coronary artery bypass graft in 2007 and 2008 was performed. Measurements of lipid profile subcomponents, namely total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, in mmol/L, were obtained by retrospective review of electronic health records. The primary end point was cardiac death. The secondary end point was the composite of cardiac events, including cardiac death, nonfatal myocardial infarction, hospitalization for unstable angina, and target lesion revascularization. Database lock date was August 15, 2020. Results: The median follow-up duration was 12.5 years. Cardiac death occurred in 6.8% of the cohort. Cardiac events occurred in 21.7% of the cohort. New-onset myocardial infarction occurred in 8.7% (n = 27), of which 48.1% (n = 13) underwent repeat revascularization. A 2-level nested Cox proportional hazards regression model was constructed to determine whether cholesterol target attainment was independently associated with cardiac events. After risk adjustment, LDL-C, non-HDL-C, total cholesterol (TC), and TC/HDL-C ratio were independently associated with cardiac death. In receiver operating characteristics analyses, the optimal cut-off values for non-HDL-C, LDL-C, and TC/HDL-C ratio were 3.2 mmol/L, 2.3 mmol/L, and 3.5, respectively. Conclusions: Exposure to elevated LDL-C and non-HDL-C cholesterol levels independently predicted long-term cardiac death after coronary artery bypass graft.

Residual Inflammatory Risk and its Association With Events in East Asian Patients After Coronary Intervention.

Background: East Asian population has a low level of inflammation compared with Western population. The prognostic implication of residual inflammatory risk (RIR) remains uncertain in East Asians. Objectives: This study sought to provide an analysis to estimate early-determined RIR and its association with clinical outcomes in East Asian patients with coronary artery disease (CAD). Methods: In an East Asian registry including patients with CAD undergoing percutaneous coronary intervention (PCI) (n = 4,562), RIR status was determined by measuring high-sensitivity C-reactive protein (hsCRP) serially at admission and at 1-month follow-up. Patients were stratified into 4 groups according to hsCRP criteria (≥2 mg/L): 1) persistent low RIR (lowon admission-low1 month: 51.0%); 2) fortified RIR (lowon admission-high 1 month: 10.3%); 3) attenuated RIR (highon admission-low1 month: 20.5%); and 4) persistent high RIR (highon admission-high1 month: 18.3%). The risks of all-cause death, ischemic events, and major bleeding were evaluated. Results: In our cohort, median levels of hsCRP were significantly decreased over time (1.3 to 0.9 mg/L; P < 0.001). Compared with hsCRP on admission, hsCRP at 1 month showed the greater associations with all-cause death and ischemic event. During clinical follow-up, risks of clinical events were significantly different across the groups (log-rank test, P < 0.001). Compared with other RIR groups, persistent high RIR showed the higher risk for all-cause death (HRadjusted, 1.92; 95% CI: 1.44 to 2.55; P < 0.001), ischemic events (HRadjusted, 1.26; 95% CI: 1.02 to 1.56; P = 0.032), and major bleeding (HRadjusted, 1.98; 95% CI: 1.30 to 2.99; P < 0.001), respectively. Conclusions: Approximately one-fifth of East Asian patients with CAD have persistent high RIR, which shows the close association with occurrence of ischemic and bleeding events. (Gyeongsang National University Hospital Registry [GNUH]; NCT04650529).

Lipoprotein(a) and Cardiovascular Disease in Chinese Population: A Beijing Heart Society Expert Scientific Statement.

Elevated concentration of lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease, including coronary artery disease, stroke, peripheral artery disease, and so on. Emerging data suggest that Lp(a) contributes to the increased risk for cardiovascular events even in the setting of effective reduction of plasma low-density lipoprotein cholesterol. Nevertheless, puzzling issues exist covering potential genetic factors, Lp(a) assay, possible individuals for analysis, a cutoff point of increased risk, and clinical interventions. In the Chinese population, Lp(a) exhibited a distinctive prevalence and regulated various cardiovascular diseases in specific ways. Hence, it is valuable to clarify the role of Lp(a) in cardiovascular diseases and explore prevention and control measures for the increase in Lp(a) prevalence in the Chinese population. This Beijing Heart Society experts' scientific statement will present the detailed knowledge concerning Lp(a)-related studies combined with Chinese population observations to provide the key points of reference.

Effect of Atorvastatin on Serial Changes in Coronary Physiology and Plaque Parameters.

Background: The effects of statin on coronary physiology have not been well evaluated. Objectives: The authors performed this prospective study to investigate changes in coronary flow indexes and plaque parameters, and their associations with atorvastatin therapy in patients with coronary artery disease (CAD). Methods: Ninety-five patients with intermediate CAD who received atorvastatin therapy underwent comprehensive physiological assessments with fractional flow reserve (FFR), coronary flow reserve, index of microcirculatory resistance, and intravascular ultrasound at the index procedure, and underwent the same evaluations at 12-month follow-up. Optimal low-density lipoprotein cholesterol (LDL-C) was defined as LDL-C <70 mg/dL or ≥50% reduction from the baseline. The primary endpoint was a change in the FFR. Results: Baseline FFR, minimal lumen area, and percent atheroma volume (PAV) were 0.88 ± 0.05, 3.87 ± 1.28, 55.92 ± 7.30, respectively. During 12 months, the percent change in LDL-C was -33.2%, whereas FFR was unchanged (0.87 ± 0.06 at 12 months; P = 0.694). Vessel area, lumen area, and PAV were significantly decreased (all P values <0.05). The achieved LDL-C level and the change of PAV showed significant inverse correlations with the change in FFR. In patients with optimally modified LDL-C, the FFR had increased (0.87 ± 0.06 vs 0.89 ± 0.07; P = 0.014) and the PAV decreased (56.81 ± 6.44% vs 55.18 ± 8.19%; P = 0.031), whereas in all other patients, the FFR had decreased (0.88 ± 0.05 vs 0.86 ± 0.06; P = 0.025) and the PAV remained unchanged. Conclusions: In patients with CAD, atorvastatin did not change FFR despite a decrease in the PAV. However, in patients who achieved the optimal LDL-C target level with atorvastatin, the FFR had significantly increased with decrease of the PAV. (Effect of Atorvastatin on Fractional Flow Reserve in Coronary Artery Disease [FORTE]; NCT01946815).

Lifestyle habits to prevent the development of benign prostatic hyperplasia: Analysis of Japanese nationwide datasets.

Objectives: Benign prostatic hyperplasia (BPH) refers to nonmalignant hyperplasia of prostate tissue, which causes lower urinary tract symptoms and has become a global public health concern in the aging population. The purpose of this study is to identify modifiable factors, which would prevent or delay BPH development. Methods: The association between BPH marker drugs and climate-, socioeconomic-, health condition-, and lifestyle habits-related variables was investigated by analyzing nationwide datasets which were collected in 2018, aggregated by prefecture (administrative unit), and published by Japanese ministries. Uroselective α1 receptor blockers and dutasteride were used as marker drugs referring to BPH prevalence. Correlation analysis, multiple linear regression analysis, and binomial logistic regression analysis were conducted with 47 Japanese prefectures as the unit. Results: The variables which showed |r| > 0.5 by correlation analysis were exercise habits (r = -0.5696), smoking habits (r = 0.6116), and daily drinking (r = 0.6001) for uroselective α1 receptor blockers, and antihypertensive medication (r = 0.5971), smoking habits (r = 0.6598), a small amount of drinking (r = -0.5292), and serum alanine aminotransferase (r = 0.6814) for dutasteride. Multiple linear regression equations were constructed by including these variables (R 2  = 0.5453 for uroselective α1 receptor blockers and R 2  = 0.5673 for dutasteride). Binomial logistic regression analysis found a significant association between climate in the resident area and BPH development. Conclusion: This ecological study, analyzing Japanese nationwide datasets, demonstrates that healthy lifestyle habits, especially avoidance of smoking, implementation of exercise in daily life, and a small amount of alcohol consumption, are important to prevent or delay BPH development. High blood pressure and high serum alanine aminotransferase are suggested as risk factors of BPH development.