Type and Severity of Migraine Determines Risk of Atrial Fibrillation in Women

OBJECTIVE: To evaluate sex differences in the risk of atrial fibrillation (AF) according to the type and severity of migraine. METHODS: We analyzed the nationwide health screening recipients in 2009 without previous AF diagnosis from the Korean National Health Insurance Service data. The diagnosis, type, and severity of migraine were determined using claims data. Newly developed AF was identified during a 10-year follow-up. Sex-difference in the effect of migraine on AF was evaluated. RESULTS: A total of 4,020,488 subjects were enrolled from January 1, to December 31, 2009 and followed-up through December 31, 2018; 4,986 subjects had migraine with aura (age 50.6 ± 14.0 years, men 29.3%); and 105,029 had migraine without aura (age 51.6 ± 14.3 years, men 30.9%). Risk of AF in a mild degree of migraine was similar to that in the control group, regardless of sex or the presence of aura. Severe migraine without aura modestly but significantly increased the risk of AF in both men and women compared to controls, with increase in AF risk being most prominent in women who had severe migraine with aura [incidence rate (IR) = 3.39, hazard ratio (HR)(adjust) = 1.48, 95% confidence intervals (CI) = 1.18–1.85]. No significant association according to aura was observed in men with severe migraines (p for interaction 0.011). CONCLUSION: Severe migraine with aura significantly increased the risk of incident AF in women, but not in men. Surveillance for incident AF and prompt lifestyle modification may be beneficial, particularly for young women suffering from severe migraine with aura

Cumulative burden of metabolic syndrome and its components on the risk of atrial fibrillation:a nationwide population-based study

BackgroundThe metabolic syndrome (MetS) and its components are associated with the development of atrial fibrillation (AF). However, the impact of time-burden of MetS on the risk of AF is unknown. We investigated the effect of the cumulative longitudinal burden of MetS on the development of AF.MethodsWe included 2 885 189 individuals without AF who underwent four annual health examinations during 2009-2013 from the database of the Korean national health insurance service. Metabolic burdens were evaluated in the following three ways: (1) cumulative number of MetS diagnosed at each health examination (0-4 times); (2) cumulative number of each MetS component diagnosed at each health examination (0-4 times per MetS component); and (3) cumulative number of total MetS components diagnosed at each health examination (0 to a maximum of 20). The risk of AF according to the metabolic burden was estimated using Cox proportional-hazards models.ResultsOf all individuals, 62.4%, 14.8%, 8.7%, 6.5%, and 7.6% met the MetS diagnostic criteria 0, 1, 2, 3, and 4 times, respectively. During a mean follow-up of 5.3 years, the risk of AF showed a positive association with the cumulative number of MetS diagnosed over four health examinations: adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of 1, 2, 3, and 4 times compared to 0 times were 1.18 (1.13-1.24), 1.31 (1.25-1.39), 1.46 (1.38-1.55), and 1.72 (1.63-1.82), respectively; P for trend ConclusionsGiven the positive correlations between the cumulative metabolic burdens and the risk of incident AF, maximal effort to detect and correct metabolic derangements even before MetS development might be important to prevent AF and related cardiovascular diseases

Associations between obesity parameters and the risk of incident atrial fibrillation and ischaemic stroke in the different age groups

OBJECTIVE: Obesity and aging are important predisposing factors to atrial fibrillation (AF) and ischaemic stroke (IS). However, limited data comprehensively evaluated the relationships between obesity measurements and AF and IS in different ages. METHODS: A total of 9,432,332 adults from the Korean National Health Insurance Service Database were included. The study population was categorized into the six age subgroups by an increase every decade from the twenties. We evaluated AF and IS risk according to body mass index (BMI) and waist circumference (WC) in the different age groups. RESULTS: During a mean follow-up of 8.2 ± 1.0 years, BMI-AF presented a J-shaped association across ages. The highest hazard ratio (HR) of the BMI ≥ 30 kg/m(2) group was observed in subjects aged 30–39 years [HR 1.80, 95% CI 1.63–1.98, p 60 years. Among the BMI ≥ 30 kg/m(2) groups, subjects aged 20–29 years presented the highest risk of IS [HR 3.00, 95% CI (2.34–3.84), p < 0.001]. Overall, WC-AF and WC-IS showed positive linear correlations, but the WC-IS association was weak in subjects aged ≥ 40 years. CONCLUSION: The higher risks of AF and IS according to an increment of BMI and WC were most apparent among the young ages. The association between obesity measurements and IS was not significantly above the midlife. Weight management in the young and integrated risk factor management in the elderly are warranted

Impact of components of metabolic syndrome on the risk of adverse renal outcomes in patients with atrial fibrillation: a nationwide cohort study

Background: The renal effect of metabolic syndrome components is unclear in patients with atrial fibrillation. This study aimed to investigate the association between metabolic syndrome components and incident end-stage renal disease among patients with atrial fibrillation. Methods: A total of 202,434 atrial fibrillation patients without prevalent end-stage renal disease were identified from the National Health Insurance Service database between 2009 and 2016. We defined the metabolic score range from 0 to 5 points such that a patient received every 1 point if the patient met each component listed in the diagnostic criteria of metabolic syndrome. The population was divided into 6 groups: MS 0–MS 5 for a metabolic score of 0–5, respectively. Multivariate Cox regression analysis was used to estimate the risks of end-stage renal disease. Results: There were 12,747, 31,059, 40,361, 48,068, 46,630, and 23,569 patients for MS 0–MS 5, respectively. Compared with MS 0, MS 5 had a higher CHA 2DS 2-VASc score (3.8 vs. 1.0) (P &lt;.001). During a median follow-up of 3.5 years, compared with MS 0, MS 1–MS 5 were associated with a gradually increasing incidence of end-stage renal disease, in relation to an increase in the metabolic score, (log-rank P &lt;.001). After multivariate adjustment, a higher metabolic score was associated with a greater risk of incident end-stage renal disease: adjusted hazard ratio [95% confidence interval] = 1.60 [0.78–3.48], 2.08 [1.01–4.31], 2.94 [1.43–6.06], 3.71 [1.80–7.66], and 4.82 [2.29–10.15], for MS 1–MS 5, respectively. Conclusions: Metabolic syndrome components additively impacts the risk of incident end-stage renal disease among patients with atrial fibrillation.</p

Impact of mental disorders on the risk of atrial fibrillation in patients with diabetes mellitus:a nationwide population-based study

BACKGROUND: It is unclear whether mental disorders are an independent risk factor for atrial fibrillation (AF) in patients with diabetes. We aimed to investigate whether patients with diabetes who have mental disorders have an increased risk for AF. METHODS: Using the Korea National Health Insurance Service database, we enrolled 2,512,690 patients diagnosed with diabetes without AF between 2009 and 2012. We assessed five mental disorders: depression, insomnia, anxiety, bipolar disorder, and schizophrenia. Newly diagnosed AF was identified during the follow-up period, and multivariate Cox regression analysis was performed. RESULTS: Among the 2,512,690 patients (mean age 57.2 ± 12.3 years; 60.1% men), 828,929 (33.0%) had mental disorders. Among the five mental disorders, anxiety (68.1%) was the most common, followed by insomnia (40.0%). During a median follow-up duration of 7.1 years, new-onset AF was diagnosed in 79,525 patients (4.66 per 1,000 person-years). Patients with diabetes who had mental disorders showed a higher risk for AF (adjusted hazard ratio [HR] 1.19; 95% confidence interval [CI] 1.17–1.21; p-value < 0.001). Depression, insomnia, and anxiety were significantly associated with higher risk for AF (adjusted HR [95% CI]: 1.15 [1.12–1.17], 1.15 [1.13–1.18], and 1.19 [1.67–1.21], respectively; all p-values < 0.001), whereas bipolar disorder and schizophrenia were not. CONCLUSIONS: Mental disorders, especially depression, insomnia, and anxiety, were associated with an increased risk for AF in patients with diabetes. Greater awareness with a prompt diagnosis of AF should be considered for patients with both DM and mental disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-022-01682-7

CHO/hPEPT1 cells overexpressing the human peptide transporter (hPEPT1) as an alternative in vitro model for peptidomimetic drugs

The present study characterized Chinese hamster ovary cells overexpressing a human intestinal peptide transporter, CHO/hPEPT1 cells, as an in vitro model for peptidomimetic drugs. The kinetic parameters of Gly-Sar uptake were determined in three different cell culture systems such as untransfected CHO cells (CHO–K1), transfected CHO cells (CHO/hPEPT1) and Caco-2 cells. V max in CHO/hPEPT1 cells was approximately 3-fold higher than those in Caco-2 cells and CHO–K1 cells, while K m values were similar in all cases. The uptake of β -lactam antibiotics in CHO/hPEPT1 cells was three to twelve fold higher than that in CHO–K1 cells, indicating that CHO/hPEPT1 cells significantly enhanced the peptide transport activity. However, amino acid drugs also exhibited high cellular uptake in both CHO–K1 and CHO/hPEPT1 cells due to the high background level of amino acid transporters. Thus, cellular uptake study in CHO/hPEPT1 cells is not sensitive enough to distinguish the peptidyl drugs from amino acid drugs. The potential of CHO/hPEPT1 cells as an in vitro model for peptidomimetic drugs was also examined through the inhibition study on Gly-Sar uptake. Peptidomimetic drugs such as β -lactam antibiotics and enalapril significantly inhibited Gly-Sar uptake whereas the nonpeptidyl compounds, l -dopa and α -methyldopa, did not compete with Gly-Sar for cellular uptake within the therapeutic concentrations. In conclusion, the present study demonstrates the further characterization of CHO/hPEPT1 cells as an uptake model as well as inhibition study and suggests their utility as an alternative in vitro model for drug candidates targeting the hPEPT1 transporter.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34496/1/11_ftp.pd

Non-alcoholic Fatty Liver Disease and the Risk of Incident Atrial Fibrillation in Young Adults:A Nationwide Population-Based Cohort Study

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a multisystem disease including cardiovascular. However, the association between NAFLD and the risk of incident atrial fibrillation (AF), especially in young adults, remains unclear. We aimed to evaluate the association between NAFLD as assessed by the fatty liver index (FLI) and the risk of AF in young adults. METHODS: We identified individuals aged 20–39 years who underwent health examinations conducted by the Korean National Health Insurance Corporation between January 2009 and December 2012. Individuals with significant liver disease, heavy alcohol consumption, or prevalent AF were excluded. We categorized based on FLI: <30, 30 to <60, and ≥60. Incident AF was evaluated as the primary outcome. RESULTS: We included 5,333,907 subjects (mean age, 31 ± 5 years; men, 57%). During a mean follow-up of 7.4 ± 1.1 years, 12,096 patients had newly diagnosed AF (incidence rate 0.31 per 1,000 person-years). After adjustment, subjects with FLI 30 to <60 and FLI ≥60 showed a higher risk of AF compared to those with FLI <30 (hazard ratio [HR] 1.21, 95% confidence interval [CI, 1.15–1.27] and HR 1.47, 95% CI [1.39–1.55], p < 0.001, respectively). In women, the increased AF risk was accentuated in the higher FLI group than in the individuals with FLI <30, compared with men (p-for-interaction = 0.023). A higher incident AF risk in the higher FLI groups was consistently observed in various subgroups. CONCLUSION: Among young adults, NAFLD assessed using FLI was positively correlated with the AF risk. These findings support the evidence of AF screening in young adults with high FLI scores

Habitual Alcohol Intake and Risk of Atrial Fibrillation in Young Adults in Korea

IMPORTANCE: Guidelines recommend that all risk factors for early-onset atrial fibrillation, including lifestyle factors, be proactively managed, considering the poor prognosis of the disease. Not much is known about the association of cumulative alcohol intake with the risk of atrial fibrillation in young adults aged 20 to 39 years, especially among heavy drinkers. OBJECTIVE: To explore the association of alcohol consumption with the risk of incident atrial fibrillation in young adults. DESIGN, SETTING, AND PARTICIPANTS: Using the National Health Insurance Service database, a nationwide population-based cohort study of adults aged 20 to 39 years without prior atrial fibrillation who underwent 4 serial annual health examinations between 2009 and 2012 was conducted. The cumulative alcohol consumption burden over 4 years was calculated by assigning 1 point to more than moderate drinking (≥105 g of alcohol per week) each year. Additionally, a semiquantitative cumulative burden was calculated by assigning 0, 1, 2, and 3 points to non, mild (<105 g per week), moderate (105-210 g per week), and heavy (≥210 g per week) drinking, respectively. Data were analyzed from May to June 2021. EXPOSURE: Amount of alcohol intake in 4 years. MAIN OUTCOMES AND MEASURES: The primary outcome was incident atrial fibrillation during the follow-up period. RESULTS: A total of 1 537 836 participants (mean [SD] age 29.5 [4.1] years, 1 100 099 [71.5%] male) were included in the final analysis. According to the 4-year cumulative burden of alcohol consumption stratified by moderate to heavy drinking, 889 382 participants (57.8%) were in the burden 0 group, 203 374 participants (13.2%) in the burden 1 group, 148 087 participants (9.6%) in the burden 2 group, 144 023 participants (9.4%) in the burden 3 group, and 152 970 participants (9.9%) in the burden 4 group. During a median (IQR) follow-up of 6.13 (4.59-6.48) years, atrial fibrillation was newly diagnosed in 3066 participants (0.36 per 1000 person-years). Participants with a cumulative burden of 4 points who continued more than moderate drinking for 4 years showed a 25% higher risk of atrial fibrillation compared with 0-point participants who kept non-to-mild drinking over 4 years (adjusted HR, 1.25; 95% CI, 1.12-1.40). In a semiquantitative analysis, participants who sustained heavy drinking for 4 consecutive years were associated with a 47% higher atrial fibrillation risk than those who remained nondrinkers over 4 years (aHR, 1.47, CI 1.18-1.83). CONCLUSIONS AND RELEVANCE: Persistent moderate to heavy drinking and higher cumulative alcohol consumption burden might increase the risk of atrial fibrillation even in young adults aged 20 to 39 years

Carbonic anhydrase 9 is a predictive marker of survival benefit from lower dose of bevacizumab in patients with previously treated metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Carbonic anhydrase 9 (CA9) is a marker for hypoxia and acidosis, which is linked to a poor prognosis in human tumors. The purpose of this comparative analysis was to evaluate whether CA9 and VEGF expression are associated with survival outcomes in patients with metastatic colorectal cancer (mCRC) after treatment with bevacizumab as second or later line treatment.</p> <p>Methods</p> <p>Thirty-one mCRC patients who were treated with bevacizumab-containing chemotherapy as second or later line treatment and who had analyzable tumor paraffin blocks were selected for this study. The planned dose of bevacizumab was 5 mg/kg/2-week. Immunohistochemical (IHC) staining of CA9 and VEGF was performed and their expression was scored by the intensity multiplied by percentage of stained area.</p> <p>Results</p> <p>The overall response rate was 19.4% and the disease control rate (DCR) was 61.3% with 6 partial responses and 13 cases of stable disease. The DCR was significantly higher in patients with a lower CA9 expression score compared to those with a higher score (80.0% vs. 27.3%, respectively, P = 0.004). The patients with a low CA9 expression score also showed better outcomes with regard to the median progression-free survival (P = 0.028) and overall survival (P = 0.026). However, VEGF expression was not associated with the DCR and survival.</p> <p>Conclusion</p> <p>Lower degree of CA9 expression was associated with better clinical outcomes in patients with mCRC treated with lower dose bevacizumab-based chemotherapy. Prospective studies are now needed to determine the correlation between CA9 expression and clinical outcomes after bevacizumab treatment, at different doses and in varied settings.</p

Carriage of the V279F Null Allele within the Gene Encoding Lp-PLA2 Is Protective from Coronary Artery Disease in South Korean Males

The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA₂) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA₂ in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted.PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66-0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69-0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA₂ activity and CAD risk.Natural deficiency in Lp-PLA₂ activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA₂ and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD