Gene Therapy for Cardiovascular Disease: Clinical Perspectives.

Cardiovascular disease (CVD) stands as one of the leading causes of death in the United States, with its prevalence steadily on the rise. Traditional therapeutic approaches, such as pharmacological treatment, cardiovascular intervention, and surgery, have inherent limitations. In response to these challenges, cardiac gene therapy has emerged as a promising alternative for treating CVD patients. However, several obstacles persist, including the low efficiency of gene transduction, immune reactions to vectors or transduced cells, and the occurrence of off-target effects. While preclinical research has demonstrated significant success in various CVD model in both small and large animals, the translation of these findings to clinical applications has, for the most part, yielded disappointing results, except for some early, albeit small, trials. This review aims to provide a comprehensive summary of recent preclinical and clinical studies on gene therapy for various CVDs. Additionally, we discuss the existing limitations and challenges that hinder the widespread clinical application of cardiac gene therapy.

Effect of statin use on head and neck cancer prognosis in a multicenter study using a Common Data Model.

Few studies have found an association between statin use and head and neck cancer (HNC) outcomes. We examined the effect of statin use on HNC recurrence using the converted Observational Medical Outcome Partnership (OMOP) Common Data Model (CDM) in seven hospitals between 1986 and 2022. Among the 9,473,551 eligible patients, we identified 4669 patients with HNC, of whom 398 were included in the target cohort, and 4271 were included in the control cohort after propensity score matching. A Cox proportional regression model was used. Of the 4669 patients included, 398 (8.52%) previously received statin prescriptions. Statin use was associated with a reduced rate of 3- and 5-year HNC recurrence compared to propensity score-matched controls (risk ratio [RR], 0.79; 95% confidence interval [CI], 0.61-1.03; and RR 0.89; 95% CI 0.70-1.12, respectively). Nevertheless, the association between statin use and HNC recurrence was not statistically significant. A meta-analysis of recurrence based on subgroups, including age subgroups, showed similar trends. The results of this propensity-matched cohort study may not provide a statistically significant association between statin use and a lower risk of HNC recurrence. Further retrospective studies using nationwide claims data and prospective studies are warranted.

Characteristic alterations of gut microbiota in uncontrolled gout.

Microbiome research has been on the rise recently for a more in-depth understanding of gout. Meanwhile, there is a need to understand the gut microbiome related to uric acid-lowering drug resistance. In this study, 16S rRNA gene-based microbiota analysis was performed for a total of 65 stool samples from 17 healthy controls and 48 febuxostat-treated gout patients (including 28 controlled subjects with decreased uric acid levels and 20 uncontrolled subjects with non-reduced uric acid levels). Alpha diversity of bacterial community decreased in the healthy control, controlled, and uncontrolled groups. In the case of beta diversity, the bacterial community was significantly different among groups (healthy control, controlled, and uncontrolled groups). Taxonomic biomarker analysis revealed the increased population of g-Bifidobacterium in healthy controls and g-Prevotella in uncontrolled patients. PCR further confirmed this result at the species level. Additionally, functional metagenomics predictions led to the exploration of various functional biomarkers, including purine metabolism. The results of this study can serve as a basis for developing potential new strategies for diagnosing and treating gout from microbiome prospects.

Association between lifestyle factors and metabolic syndrome in general populations with depressive symptoms in cross-setional based cohort study of Ansung-Ansan.

BACKGROUND: Metabolic syndrome (MetS) is caused by both genetic and environmental factors, such as daily calorie intake, smoking, and alcohol consumption. Lifestyle factors, such as alcohol consumption, are considered to be related to the prevalence of MetS and plays an essential role in the pathogenesis and prognosis of depression. METHODS: We investigated the bidirectional association between lifestyle factors and MetS among Korean adults with depressive symptoms in third wave of a community-based cohort study. A total of 1,578 individuals, aged 39-72 years, who had MetS at baseline were recruited. Participants were divided into two groups according to depressive symptoms. Logistic regression models were used to estimate the risk of MetS. RESULTS: The percentage of heavy drinkers was lower in men with depressive symptoms compared to those who did not (7.0% vs. 7.1%), while the percentage of current smokers were higher in participants who had depressive symptoms (40.2% vs. 30.0%). After adjusting for age, education, monthly income, body mass index (BMI), sleep duration, and volume of drinking and smoking status, logistic regression analysis demonstrated that male heavy drinkers with depressive symptoms were 2.75 times more likely to have MetS than those without depressive symptom. Conversely, depressive women with a high BMI were 3.70 times more likely to have MetS than in those with lower BMI. Limitations The cross-sectional nature of the study, and the study population ethnicity and ages were limitations. CONCLUSIONS: Lifestyle factors, such as alcohol consumption, may be associated with the risk of MetS in adults with depressive symptoms.

Health-related Quality of Life Outcomes of Adalimumab for Patients With Rheumatoid Arthritis in Korea.

Objective: Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disorder that impairs patients' overall health-related quality of life (HRQOL) In this study, we evaluated the effect of adalimumab in Korean patients with active RA on HRQOL. Methods: Patients included in the study had moderate to severe active RA that did not respond to conventional drugs with a Disease Activity Score of 28 joints >32 and were biologics-naïve All patients received adalimumab 40 mg subcutaneously every other week and were followed for 24 weeks The primary endpoint was the change in baseline Health Assessment Questionnaire Disability Index (HAQ-DI) score at week 24 Secondary endpoints were changes in the EuroQol 5-dimension 3-Level (EQ-5D-3L) baseline score and Short Form 36-Item Health Survey (SF-36) domain scores at weeks 12 and 24 and change in baseline HAQ-DI score at week 12. Results: In total, 91 Korean patients were included Ninety-three percent of patients were in high disease activity with a baseline mean DAS28 value of 61 within all patients The mean change from baseline in HAQ-DI scores were -046 at week 12 and∼067 at week 24 (p<00001) Additionally, EQ-5D-3L score at weeks 12 and 24 had significantly improved (p<00001) compared to baseline SF-36 at weeks 12 and 24 had significantly improved (p<00001, p=00001) compared to baseline. Conclusion: Treatment with adalimumab resulted in significant improvement in HAQ-DI, EQ-5D-3L, and SF-36 scores at 12 and 24 weeks in Korean RA patient.

Protective effects of protocatechuic acid against cognitive impairment in an amyloid beta-induced Alzheimer's disease mouse model.

In this study, we investigated the protective effects of protocatechuic acid (PA) against cognitive impairment in an amyloid-beta (Aß)-induced Alzheimer's disease (AD) mouse model. PA was administered orally for 14 days at 100 and 200 mg/kg/day. To examine effects on cognition, we conducted behavior tests including the T-maze test, novel object recognition, and the Morris water maze test. In addition, we measured lipid peroxidation, nitric oxide (NO) production, and inflammation-related protein expression in mice tissues. The PA-administered group showed more use of novel routes, better novel object recognition, and learning and memory ability compared to the Aß25-35-injected mice in the behavior tests. The results indicated that the administration of higher PA protected against cognitive impairment. In addition, the PA-administered groups showed significantly decreased lipid peroxidation and NO production in the brain, kidney, and liver tissues. Furthermore, the PA-administered groups showed attenuated Aß25-35-induced neuroinflammation by downregulating inflammatory mediators, inducible nitric oxide synthase and cyclooxygenase-2 in the brain. The results of the present study suggest that PA may be a protective agent against AD.

Development and Validation of Prediction Model for Risk Reduction of Metabolic Syndrome by Body Weight Control: A Prospective Population-based Study.

Several studies have reported that weight control is of paramount importance in reducing the risk of metabolic syndrome. Nevertheless, this well-known association does not provide any practical information on how much weight loss in a given period would reduce the risk of metabolic syndrome in individuals in a personalized setting. This study aimed to develop and validate a risk prediction model for metabolic syndrome in 2 years, based on an individual's baseline health status and body weight after 2 years. We recruited 3,447 and 3,874 participants from the Ansan and Anseong cohorts of the Korean Genome and Epidemiology Study, respectively. Among the former, 8636 longitudinal observations of 2,412 participants (70%) and 3,570 of 1,034 (30%) were used for training and internal validation, respectively. Among the latter, all 15,739 observations of 3,874 participants were used for external validation. Compared to logistic regression, Gaussian Naïve Bayes, random forest, and deep neural network, XGBoost showed the highest performance (area under curve of 0.879) and a significantly enhanced calibration of the predictive score with the prevalence rate. The model was ported onto an application to provide the 2-year probability of developing metabolic syndrome by simulating selected target body weights, based on an individual's baseline health profiles. Further prospective studies are required to determine whether weight-control programs could lead to favorable health outcomes.

Genetically, Dietary Sodium Intake Is Causally Associated with Salt-Sensitive Hypertension Risk in a Community-Based Cohort Study: a Mendelian Randomization Approach.

PURPOSE OF REVIEW: Excessive dietary salt intake is associated with an increased risk of hypertension. Salt sensitivity, i.e., an elevation in blood pressure in response to high dietary salt intake, has been associated with a high risk of cardiovascular disease and mortality. We investigated whether a causal association exists between dietary sodium intake and hypertension risk using Mendelian randomization (MR). RECENT FINDINGS: We performed an MR study using data from a large genome-wide association study comprising 15,034 Korean adults in a community-based cohort study. A total of 1282 candidate single nucleotide polymorphisms associated with dietary sodium intake, such as rs2960306, rs4343, and rs1937671, were selected as instrumental variables. The inverse variance weighted method was used to assess the evidence for causality. Higher dietary sodium intake was associated with salt-sensitive hypertension risk. The variants of SLC8E1 rs2241543 and ADD1 rs16843589 were strongly associated with increased blood pressure. In the logistic regression model, after adjusting for age, gender, smoking, drinking, exercise, and body mass index, the GRK4 rs2960306TT genotype was inversely associated with hypertension risk (OR, 0.356; 95% CI, 0.236-0.476). However, the 2350GG genotype (ACE rs4343) exhibited a 2.11-fold increased hypertension risk (OR, 2.114; 95% CI, 2.004-2.224) relative to carriers of the 2350AA genotype, after adjusting for confounders. MR analysis revealed that the odds ratio for hypertension per 1 mg/day increment of dietary sodium intake was 2.24 in participants with the PRKG1 rs12414562 AA genotype. Our findings suggest that dietary sodium intake may be causally associated with hypertension risk.

Increased risk of atherosclerosis associated with pesticide exposure in rural areas in Korea.

Atherosclerosis is a progressive inflammation in systemic vessels, and pesticide exposure has been emerging as its risk factor. This cross-sectional study investigated the association between pesticide exposure and the risk of atherosclerosis in a rural population in Korea using carotid intima-media thickness (CIMT). This study used dataset from the baseline survey of the Korea Farmers Cohort Study between November 2005 and January 2008, and the final analysis included 477 participants. Well-structured questionnaires were used to estimate pesticide exposure. CIMT ≥ 0.9 mm was established for carotid atherosclerosis. Multiple logistic regression analyses were undertaken to evaluate the association between pesticide exposure and atherosclerosis, adjusting demographic and health-related confounders. Even after adjustments, the increased risk of atherosclerosis was significantly associated with pesticide exposure, such as a lifetime history of farming (odds ratio [OR] 3.25 95% confidence interval [CI] 1.51-6.98), a history of using pesticide (OR 3.42 95% CI 1.63-7.16), using pesticide 10 times or more annually (OR 2.55 95% CI 1.21-5.39), and higher cumulative exposure index level (OR 3.63 95% CI 1.65-7.97). Further prospective studies are required to elucidate effects of pesticide exposure on the risk of atherosclerosis.

Association between serotonin 2A receptor (HTR2A) genetic variations and risk of hypertension in a community-based cohort study.

BACKGROUND: Hypertension is one of the risk factors for obesity-related cardiovascular diseases. We investigated whether genetic variations in serotonin 2A receptor (HTR2A) were associated with hypertension. METHODS: We carried out a cross-sectional study in cohorts A (Ansan-Ansung cohort, N = 6039) and B (Wonju-Pyengchang cohort, N = 7524). Several genetic variants in HTR2A including rs7330636, rs9590999, rs2183057, and rs4942595 were selected and genotyped. RESULTS: In hypertensive participants in cohort A, the baseline systolic blood pressure and body mass index were 141.80 ± 17.20 mg/dL and 24.48 ± 4.75 kg/m2, respectively, which were higher than in those without hypertension (p < 0.001). rs4942595TC genotype was associated with hypertension in cohort A (OR = 0.739), after adjusting for variables. Subjects with rs4942578AA genotype had a decreased risk of hypertension after adjusting for clinical factor (OR = 0.735) in cohort B, and an elevated risk of hypertension in cohort A (OR = 1.562). The logistic regression analysis showed that participants with rs4941573TC genotype were 1.327 times more likely to have a higher blood pressure than those with TT genotype (95% CI 1.101-1.599) in cohort B. Whereas, the OR for developing hypertension in subjects with rs17069883CC genotype compared to those with AA genotype was 1.447 (95% CI 1.018-2.056; p for trend = 0.040) in cohort A. CONCLUSIONS: HTR2A genetic variations were associated with hypertension risk in our study.

Association between Serum Urate and Risk of Hypertension in Menopausal Women with XDH Gene.

Elevated serum urate (sUA) concentrations have been associated with an increased risk of hypertension. We aimed to examine the association of sUA concentration on the risk of hypertension in pre- and post-menopausal women and investigated the association between the polymorphism of the xanthine dehydrogenase gene and the risk of hypertension. Among 7294 women, 1415 premenopausal and 5879 postmenopausal women were recruited. Anthropometric parameters as risk factors of hypertension were identify by logistic regression models. In addition, we investigated an association between xanthine dehydrogenase gene and sUA and their combined associations on the risk of hypertension. Body mass index (BMI) and waist circumference (WC) were significantly increased in accordance to the increase of sUA levels (p < 0.001). Multivariate logistic regression analysis showed postmenopausal women with a high sUA and high BMI were 3.18 times more likely to have hypertension than in those with normal and lower sUA (Odds ratio: 3.18, 95% confidence interval: 2.54-3.96). Postmenopausal women with a high WC were 1.62 times more likely to have hypertension than in those with normal and lower sUA. Subjects with the AG genotype of rs206860 was found to be at lower risk of hypertension (odd ratio: 0.287, 95% confidence interval: 0.091-0.905, p = 0.033). This cross-sectional study indicated a high sUA is associated with a higher risk of hypertension in postmenopausal women. Further well-designed prospective studies in other populations are warranted to validate our results.

Long Working Hours and Poor Self-Rated Health in the Young Working Population in Korea.

: This cross-sectional study investigated the association between long working hours and prevalence of poor self-rated health (SRH) in Korean young workers using data from the 6th Korea Youth Panel Survey 2007. A total of 3317 young wage workers were included. Weekly working hours were divided into four groups (36 to 40 hours, 41 to 52 hours, 53 to 60 hours, and more than 60 hours per week). Multiple logistic regression was performed to investigate the association between long working hours and SRH, adjusting for demographic and work-related factors. Long working hours were associated with increased risk of poor SRH, in both the men and women. Legal restriction on working hours should be suitably applied to help improve the health status of Korean young workers.

Association Between Chronic Exposure to Pesticide and Suicide.

OBJECTIVE: We investigated the association between suicide and pesticide exposure in a community-based cohort study. METHODS: We performed a longitudinal analysis of 6333 who participated in the initial survey of the Korean Genome and Epidemiology Study. Data were collected using a questionnaire to assess the prevalence of suicide. We calculated the hazard ratios (HRs) for suicide by pesticide exposure using the Cox proportional hazard model. RESULTS: After adjusting for variables, participants exposed to pesticides had a 1.88-fold increased risk of suicide (HR, 1.88; 95% confidence interval [CI], 1.11 to 3.16) than those who were not exposed. Study populations with greater pesticide use (HR, 2.42; 95% CI, 1.27 to 4.60) and pesticide addiction had the highest suicide rates (HR, 1.91; 95% CI, 1.03 to 3.56). CONCLUSIONS: Pesticide exposure for suicide should be considered during the development and implementation of suicide prevention in rural area.

Exposure to pesticides and the prevalence of diabetes in a rural population in Korea.

BACKGROUND: Among the adverse health effects of exposure to pesticides, an association with diabetes has been reported. However, there is a lack of epidemiologic studies on the health effects of exposure to pesticides, particularly investigating the association between occupational pesticide exposure and diabetes prevalence. PURPOSE: The present study examined the association between pesticide exposure and prevalence of diabetes in a rural population in Korea. METHODS: This cross-sectional study used data from the Korea Farmers Cohort study, and included 2559 participants in the baseline survey between November 2005 and January 2008. We performed a clinical examination including blood sampling and assessed data on diabetes diagnosis, demographics, and pesticide exposure. Logistic regression was performed to evaluate the association between pesticide exposure and diabetes prevalence, adjusting for age, sex, monthly income, and marital status. In addition, a stratified analysis by body mass index (BMI) was conducted, with two categories: normal weight (<25 kg/m2) and overweight or obese (≥25 kg/m2). RESULTS: At baseline, the prevalence of diabetes was 9.30%. Pesticide exposure was associated with the risk of diabetes after adjustment for covariates. In the analysis stratified by BMI, all the variables related to pesticide exposure were associated with prevalence of diabetes in the overweight or obese group, whereas no significant association was found in the normal weight group. CONCLUSION: Exposure to pesticides was associated with diabetes, and this association was stronger in overweight or obese individuals than in normal weight individuals. Further longitudinal studies that consider information on BMI are necessary.

Contribution of obesity as an effect regulator to an association between serum leptin and incident metabolic syndrome.

BACKGROUND: We investigated whether serum leptin can be a predictor for incident cases of MetS in a population-based study. METHODS: This is a prospective cohort study of 1590 adults aged between 40 and 70 years, who did not have MetS in 2005-2008 (at baseline) and 2008-2011 (follow-up). The baseline serum leptin concentrations were measured by radioimmunoassay. RESULTS: During an average of 2.8 years of follow-up, 113 men (17.1%) and 148 women (15.9%) developed MetS. In multivariable adjusted models, the odds ratio of incident MetS when comparing the lowest to the highest quartiles of leptin levels was 3.17 in men and 2.79 in women; nevertheless, the significance disappeared after adjusting for the body mass index (BMI). In subsidiary analyses by BMI, logistic regression analysis showed that subjects with the highest tertile of serum leptin level were 3.04 and 2.12 times more likely to have MetS than those with the lowest tertile in lean subjects (OR 3.04; 95% CI 1.44-6.41; p = .004 in men vs. OR 2.12; 95% CI 1.06-4.25; p = .036 in women, respectively). CONCLUSIONS: Obesity is an effect regulator, which can predict an association between increased serum leptin level and the incidence of MetS in lean subjects.

Radon Exposure-induced Genetic Variations in Lung Cancers among Never Smokers.

BACKGROUND: Lung cancer in never smokers (LCINS) differs etiologically and clinically from lung cancer attributed to smoking. After smoking, radon exposure is the second leading cause and the primary risk factor of lung cancer among never smokers. Exposure to radon can lead to genetic and epigenetic alterations in tumor genomes affecting genes and pathways involved in lung cancer development. The present study sought to explore genetic alterations associated with LCINS exposed to radon gas indoors. METHODS: Genetic associations were assessed via a case-control study of LCINS (39 cases and 30 controls) using next generation sequencing. Associations between genetic mutations and high exposure to radon were investigated by OncoPrint and heatmap graphs. Bioinformatic analysis was conducted using various tools. According radon exposure levels, we divided subjects in two groups of cases and controls. RESULTS: We found that ABL2 rs117218074, SMARCA4 rs2288845, PIK3R2 rs142933317, MAPK1 rs1803545, and androgen receptor (AR) rs66766400 were associated with LCINS exposed to high radon levels. Among these, Chromodomain helicase DNA-binding protein 4 (CHD4) rs74790047, TSC2 rs2121870, and AR rs66766408 were identified as common exonic mutations in both lung cancer patients and normal individuals exposed to high levels of radon indoor. CONCLUSION: We identified that CHD4 rs74790047, TSC2 rs2121870, and AR rs66766408 are found to be common exonic mutations in both lung cancer patients and normal individuals exposed to radon indoors. Further analysis is needed to determine whether these genes are completely responsible for LCINS exposed to residential radon.

Waist-to-height ratio index for predicting incidences of hypertension: the ARIRANG study.

BACKGROUND: Several anthropometric indices such as body mass index (BMI) and waist circumference (WC) have been examined as indicators of cardiovascular diseases, in both adults and children. However, the waist-to-height ratio (WHtR) is considered a better predictor for the detection of cardiovascular risk factors, than BMI. We investigated the association between the WHtR and incident hypertension. METHODS: A total of 1718 participants, aged 39-72 years, were recruited in this longitudinal study. Participants were divided into 2 groups according to the development of hypertension during 2005-2008 (baseline) and 2008-2011 (follow-up). Logistic regression models were used to evaluate the WHtR as a significant predictor of hypertension. RESULTS: During the 2.8 years of follow-up, 185 new cases of hypertension (10.8%) were diagnosed, with an incidence rate of approximately 4% per year. The WHtR was significantly higher in the participants who had developed hypertension than in those who had not (0.54 ± 0.05 vs. 0.51 ± 0.05, p < 0.001). After adjusting for age, sex, smoking status, alcohol intake, regular exercise status, total cholesterol, and systolic blood pressure, at the baseline, the logistic regression analysis indicated that the participants with the highest quartile of the WHtR (WHtR≥0.54) were 4.51 times more likely to have hypertension than those with the lowest quartile (odds ratio 4.51; 95% confidence interval 2.41-8.43; p < .0001). The area under the curve for the WHtR, in identifying hypertension risk, was significantly greater than that for the BMI (p = 0.0233). CONCLUSION: A positive association between WHtR and the incidence of hypertension was observed in Korean adults. The findings of the present community-based prospective study suggest that the WHtR may be a better predictor of incident hypertension.

Erratum: Novel Genetic Associations Between Lung Cancer and Indoor Radon Exposure.

[This corrects the article on p. 234 in vol. 22, PMID: 29302581.].

Serum Fibroblast Growth Factor 21 and New-Onset Metabolic Syndrome: KoGES-ARIRANG Study.

PURPOSE: Fibroblast growth factor 21 (FGF21) is a crucial metabolic regulator, with multiple favorable effects on glucose homeostasis and lipid metabolism. Since serum FGF21 level has been implicated as a potential marker for the early identification of metabolic syndrome (MetS), we investigated the association between serum FGF21 level and the development of MetS in a population-based prospective study. MATERIALS AND METHODS: We conducted a prospective study of 221 randomly sampled adults without MetS from a general population-based cohort study who were examined from 2005-2008 (baseline) and from 2008-2011 (follow-up). Baseline serum FGF21 levels were analyzed using enzyme-linked immunosorbent assay. RESULTS: During the average 2.8-year follow-up period, 82 participants (36.6%) developed new-onset MetS. Serum FGF21 levels were significantly higher in patients with new-onset MetS than in those without MetS (209.56±226.80 vs. 110.09±81.10, p<0.01). In multivariate adjusted models, the odds for MetS development were greater in patients with serum FGF21 levels in the highest quartile, compared to those in the lowest quartile (3.84, 95% confidence interval: 1.59-9.28). CONCLUSION: Serum FGF21 level was an independent predictor for new-onset MetS in a population-based prospective study.

Erratum: Novel Genetic Associations Between Lung Cancer and Indoor Radon Exposure.

[This corrects the article on p. 234 in vol. 22, PMID: 29302581.].