Temporal Changes in Resting Heart Rate and Risk of Diabetes Mellitus.

Background: To investigate the association between the time-varying resting heart rate (RHR) and change in RHR (∆RHR) over time and the risk of diabetes mellitus (DM) by sex. Methods: We assessed 8,392 participants without DM or atrial fibrillation/flutter from the Korean Genome and Epidemiology Study, a community-based prospective cohort study that was initiated in 2001 to 2002. The participants were followed up until December 31, 2018. Updating RHR with biennial in-study re-examinations, the time-varying ∆RHR was calculated by assessing the ∆RHR at the next follow-up visit. Results: Over a median follow-up of 12.3 years, 1,345 participants (16.2%) had DM. As compared with RHR of 60 to 69 bpm, for RHR of ≥80 bpm, the incidence of DM was significantly increased for both male and female. A drop of ≥5 bpm in ∆RHR when compared with the stable ∆RHR group (-5< ∆RHR <5 bpm) was associated significantly with lower risk of DM in both male and female. However, an increase of ≥5 bpm in ∆RHR was significantly associated with higher risk of DM only in female, not in male (hazard ratio for male, 1.057 [95% confidence interval, 0.869 to 1.285]; and for female, 1.218 [95% confidence interval, 1.008 to 1.471]). Conclusion: In this community-based longitudinal cohort study, a reduction in ∆RHR was associated with a decreased risk of DM, while an increase in ∆RHR was associated with an increased risk of DM only in female.

Substantial Lipid Increases During Menopausal Transition in Korean Middle-Aged Women.

BACKGROUND: Adverse lipid profiles are observed in postmenopausal women. However, there is insufficient evidence of the association between lipids and reproductive aging in Korean women. We aimed to characterize lipid changes with respect to timing relative to menopause in Korean middle-aged women. METHODS: This study included 1,436 premenopausal women who had a natural menopause during the follow-up period (median = 15.76 years) from the Korean Genome and Epidemiology Study (KoGES) Ansan and Anseong cohort. Lipid levels were measured every 2 years, and the magnitudes of annual lipid changes and differences in the changes by premenopausal body mass index were estimated using piecewise linear mixed-effects models. RESULTS: All lipid levels increased greatly from 3 or 5 years before menopause to 1 year after menopause in all women, regardless of their premenopausal body mass index. During the period, high-density lipoprotein cholesterol (HDL-C) levels increased at 0.42 mg/dL per year (95% confidence interval [CI], 0.29 to 0.55 mg/dL). Nevertheless, non-HDL-C levels simultaneously increased at 3.42 mg/dL per year (95% CI, 3.11 to 3.72 mg/dL), and an annual change in the non-HDL-C to HDL-C ratio was 0.05 (95% CI, 0.04 to 0.06). One year after menopause, changes in all lipid parameters significantly slowed down, except for the non-HDL-C to HDL-C ratio (P < 0.001 for all). The ratio continued to increase until 3 years after menopause, but thereafter, the change leveled off. CONCLUSION: Women experienced remarkable increases in lipid levels during menopausal transition, highlighting the need for early intervention strategies for cardiovascular disease prevention in women.

Associations between local acidosis induced by renal LDHA and renal fibrosis and mitochondrial abnormalities in patients with diabetic kidney disease.

During the progression of diabetic kidney disease (DKD), renal lactate metabolism is rewired. The relationship between alterations in renal lactate metabolism and renal fibrosis in patients with diabetes has only been partially established due to a lack of biopsy tissues from patients with DKD and the intricate mechanism of lactate homeostasis. The role of lactate dehydrogenase A (LDHA)-mediated lactate generation in renal fibrosis and dysfunction in human and animal models of DKD was explored in this study. Measures of lactate metabolism (urinary lactate levels and LDHA expression) and measures of DKD progression (estimated glomerular filtration rate and Wilms' tumor-1 expression) were strongly negatively correlated in patients with DKD. Experiments with streptozotocin-induced DKD rat models and the rat renal mesangial cell model confirmed our findings. We found that the pathogenesis of DKD is linked to hypoxia-mediated lactic acidosis, which leads to fibrosis and mitochondrial abnormalities. The pathogenic characteristics of DKD were significantly reduced when aerobic glycolysis or LDHA expression was inhibited. Further studies will aim to investigate whether local acidosis caused by renal LDHA might be exploited as a therapeutic target in patients with DKD.

Lower number of modifiable risk factors was associated with reduced atrial fibrillation incidence in an 18-year prospective cohort study.

Prevention strategies for atrial fibrillation (AF) are lacking. This study aimed to identify modifiable risk factors (MRFs) and estimate their impact on AF in the midlife general population. We assessed 9049 participants who were free of prevalent AF at baseline from the Korean Genome and Epidemiology Study. Cox models with time-varying assessment of risk factors were used to identify significant MRFs for incident AF. The MRF burden was defined as the proportion of visits with MRFs during follow-up. Over a median follow-up of 13.1 years, 182 (2.01%) participants developed AF. Three MRFs, including systolic blood pressure (SBP) ≥ 140 mmHg, obesity with central obesity, and an inactive lifestyle were significantly associated with incident AF. Among participants with 3, 2, 1, and 0 MRFs at baseline, 16 (3.9%), 51 (2.5%), 90 (1.8%) and 25 (1.5%) had incident AF, respectively. Compared to participants with three MRFs, those with one or no MRFs had a decreased risk of AF (hazard ratio [95% CI] for one MRF, 0.483 [0.256-0.914]; and for no MRF, 0.291 [0.145-0.583]). A decreasing MRF burden was associated with reduced AF risk (hazard ratio [95% CI] per 10% decrease in burden for SBP ≥ 140 mmHg, 0.937 [0.880-0.997]; for obesity with central obesity, 0.942 [0.907-0.978]; for inactivity, 0.926 [0.882-0.973]). Maintaining or achieving MRF ≤ 1 was associated with decreased AF risk, suggesting that minimizing the burden of MRF might help prevent AF.

Impact of atrial fibrillation in patients with heart failure and reduced, mid-range or preserved ejection fraction.

OBJECTIVE: To determine the prognostic value of atrial fibrillation (AF) in patients with heart failure (HF) and preserved, mid-range or reduced ejection fraction (EF). METHODS: Patients hospitalised for acute HF were enrolled in the Korean Acute Heart Failure registry, a prospective, observational, multicentre cohort study, between March 2011 and February 2014. HF types were defined as reduced EF (HFrEF, LVEF <40%), mid-range EF (HFmrEF, LVEF 40%-49%) or preserved EF (HFpEF, LVEF ≥50%). RESULTS: Of 5414 patients enrolled, HFrEF, HFmrEF and HFpEF were seen in 3182 (58.8%), 875 (16.2%) and 1357 (25.1%) patients, respectively. The prevalence of AF significantly increased with increasing EF (HFrEF 28.9%, HFmrEF 39.8%, HFpEF 45.2%; p for trend <0.001). During follow-up (median, 4.03 years; IQR, 1.39-5.58 years), 2806 (51.8%) patients died. The adjusted HR of AF for all-cause death was 1.06 (0.93-1.21) in the HFrEF, 1.10 (0.87-1.39) in the HFmrEF and 1.22 (1.02-1.46) in the HFpEF groups. The HR for the composite of all-cause death or readmission was 0.97 (0.87-1.07), 1.14 (0.93-1.38) and 1.03 (0.88-1.19) in the HFrEF, HFmrEF and HFpEF groups, respectively, and the HR for stroke was 1.53 (1.03-2.29), 1.04 (0.57-1.91) and 1.90 (1.13-3.20), respectively. Similar results were observed after propensity score matching analysis. CONCLUSIONS: AF was more common with increasing EF. AF was seen to be associated with increased mortality only in patients with HFpEF and was associated with an increased risk of stroke in patients with HFrEF or HFpEF. TRIAL REGISTRATION NUMBER: NCT01389843.

Predicting stroke and death in patients with heart failure using CHA2DS2-VASc score in Asia.

BACKGROUND: The CHA2DS2-VASc score is used to assess risk of mortality as well as to stratify risk of stroke in patients with atrial fibrillation (AF). This study evaluated whether CHA2DS2-VASc score was predictive of 1 and 2 year risks of stroke and death in Asian patients with heart failure (HF). METHODS: Patients hospitalized for HF were enrolled in the Korean Acute Heart Failure (KorAHF) registry, a prospective observational multicenter cohort study, between March 2011 and February 2014. Patients with a history of cancer before hospitalization for HF were excluded. The discriminatory properties of the CHA2DS2-VASc score were quantified using C-statistics. RESULTS: The study included 5158 patients with HF, 2091 with and 3067 without AF. Rates of stroke in these two groups were 4.5 and 2.8%, respectively, after 1 year, and 5.5 and 3.4%, respectively, after 2 years. Each 1-point increase in CHA2DS2-VASc score was associated with significantly increased risks of stroke and all-cause death in HF patients with and without AF (p-value < 0.05). The C-statistics of the CHA2DS2-VASc score for all-cause death in patients with and without AF were 0.600 and 0.630, respectively, at 1 year and 0.626 and 0.635, respectively, at 2 years. The C-statistics for stroke ranged from 0.593 to 0.639. CONCLUSIONS: Among patients with incident HF with and without AF, CHA2DS2-VASc score was significantly associated with the risks of stroke and death. However, CHA2DS2-VASc score was only a modest predictor of stroke and death, indicating the need for studies evaluating modified CHA2DS2-VASc scores. The majority of strokes occurred relatively shortly after hospitalization for HF and that mortality rates in patients with HF remain high. Thus, early treatment after HF to prevent stroke is essential.

Trend of Prevalence of Atrial Fibrillation and use of Oral Anticoagulation Therapy in Patients With Atrial Fibrillation in South Korea (2002-2013).

BACKGROUND: This study examined the annual prevalence of atrial fibrillation (AF) and its associated comorbidities, as well as the prevalence of warfarin therapy in South Korean patients with AF. METHODS: The National Health Insurance Service-National Sample Cohort database was searched for subjects aged ≥30 years diagnosed with AF from 2002-2013. The prevalence of AF was analyzed by sex and age, as was the current status of warfarin therapy in AF patients according to CHA2DS2-VASc score and comorbidities. RESULTS: The age-standardized prevalence of AF in men and women was 0.15% and 0.14%, respectively, in 2002, increasing to 0.54% and 0.39%, respectively, in 2013. In 2013, the prevalence of AF in men and women aged 30-39 years was 0.08% and 0.03%, respectively, increasing to 2.35% and 1.71%, respectively, in those in aged ≥60 years. During 2002-2013, the prevalence of AF in men significantly increased among subjects aged ≥30 years and increased in women aged ≥60 years. The age-standardized prevalence of hypertension and diabetes mellitus among AF patients were markedly increased during 2002-2013. Of these AF patients, 86.1% had a CHA2DS2-VASc score of ≥2; however, only 39.1% of these were receiving warfarin. CONCLUSIONS: The age-standardized prevalence of AF increased 2.89-fold over the 12-year study period. The total number of patients with AF in South Korea has been drastically increasing, due to not only aging society but also increasing age-specific prevalence of AF, especially in middle-aged and elderly individuals. The rate of warfarin therapy increased slightly over the study period but remains low.

Risk of ischemic stroke after atrial fibrillation diagnosis: A national sample cohort.

Atrial fibrillation (AF) is a major risk factor for ischemic stroke and associated with a 5-fold higher risk of stroke. In this retrospective cohort study, the incidence of and risk factors for ischemic stroke in patients with AF were identified. All patients (≥30 years old) without previous stroke who were diagnosed with AF in 2007-2013 were selected from the National Health Insurance Service-National Sample Cohort. To identify factors that influenced ischemic stroke risk, Cox proportional hazard regression analysis was conducted. During a mean follow-up duration of 3.2 years, 1022 (9.6%) patients were diagnosed with ischemic stroke. The overall incidence rate of ischemic stroke was 30.8/1000 person-years. Of all the ischemic stroke that occurred during the follow-up period, 61.0% occurred within 1-year after AF diagnosis. Of the patients with CHA2DS2-VASc score of ≥2, only 13.6% were receiving warfarin therapy within 30 days after AF diagnosis. Relative to no antithrombotic therapy, warfarin treatment for >90 days before the index event (ischemic stroke in stroke patients and death/study end in non-stroke patients) associated with decreased ischemic stroke risk (Hazard Ratio = 0.41, 95%confidence intervals = 0.32-0.53). Heart failure, hypertension, and diabetes mellitus associated with greater ischemic stroke risk. AF patients in Korea had a higher ischemic stroke incidence rate than patients in other countries and ischemic stroke commonly occurred at early phase after AF diagnosis. Long-term (>90 days) continuous warfarin treatment may be beneficial for AF patients. However, warfarin treatment rates were very low. To prevent stroke, programs that actively detect AF and provide anticoagulation therapy are needed.

Incidence and Risk Factors for Atrial Fibrillation in Korea: the National Health Insurance Service Database (2002-2010).

BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) is a common arrhythmia that is known as an important independent risk factor for stroke. However, limited information is available on AF in Korea. This study evaluated the incidence of AF, its associated co-morbidities and risk factors for AF in Korea. SUBJECTS AND METHODS: The National Health Insurance Service database between 2002 and 2010 was used in the study. Individuals<30 years old and those diagnosed with AF between 2002 and 2004 were excluded. Hazard ratios (HRs) according to co-morbidities and risk factors for AF were determined using a Cox proportional hazard model. Population attributable fractions (PAFs) of AF risk factors were determined. RESULTS: During a 6-year follow-up period, 3517 (1.7%) developed AF. The incidence rates in men and women aged 30-39 years were 0.82 and 0.55 per 1000 person-years, respectively; the incidence rates further increased with age to 13.09 and 11.54 per 1000 person-years in men and women aged≥80 years, respectively. The risk factors for incident AF were age, sex, body mass index (BMI), hypertension, ischemic heart disease (IHD) and heart failure. After adjusting for variables related to AF, the risk of AF was significantly associated with hypertension (HR 1.667), IHD (HR 1.639), heart failure (HR 1.521), and the PAFs for age, sex, BMI, hypertension, IHD, heart failure and diabetes mellitus were 30.6%, 10.1%, 3.4%, 16.6%, 8.2%, 5.3% and 0.8%, respectively. CONCLUSION: Incidence of AF increased with age and was higher in men than in women. A larger proportion of AF events was attributable to hypertension than to other co-morbidities.

Difference in blood pressure between early and late menopausal transition was significant in healthy Korean women.

BACKGROUND: Although the prevalence of hypertension is higher in postmenopausal women than in premenopausal women, little is known about changes in blood pressure (BP) during the menopausal transition. We evaluated BP according to the menopausal transition and associated factors in healthy Korean women. METHODS: This cross-sectional study involved 2037 women aged 44 to 56 years who presented at a health-screening center in Seoul, Korea, from November 2012 to March 2013. The association between BP and menopausal transition and the risk factors related to elevated BP were determined using multiple linear regression analyses. Menopausal status was divided by four groups as premenopause, early menopausal transition, late menopausal transition and postmenopause. RESULTS: Both systolic and diastolic blood pressure (SBP and DBP) differed significantly according to the menopausal status. BP showed the greatest difference between early and late menopausal transition. After adjusting for variables related to hypertension, SBP (ß = 2.753, p < 0.01) and DBP (ß = 1.746, p = 0.02) were significantly higher in late than early menopausal transition. The prevalence of hypertension was significantly different between early and late menopausal transition (1.4 vs. 6.1 %). Waist circumference, glucose, and triglycerides were positively and significantly associated with SBP and DBP during menopause. CONCLUSIONS: BP and the prevalence of hypertension were significantly associated with period between early and late menopausal transition, suggesting that changes in BP during the menopausal transition are significant. Therefore, frequent monitoring will be needed for early detection of hypertension during the menopausal transition.

Structural identification and biological activity of positional isomers of long-acting and mono-PEGylated recombinant human granulocyte colony-stimulating factor with trimeric-structured methoxy polyethylene glycol N-hydroxysuccinimidyl functional group.

The individual positional isomers from the mono-PEGylated recombinant human granulocyte colony-stimulating factor (rhG-CSF) were successfully isolated with additional strong cation exchange chromatography using Source 15S. The three isolated individual positional isomers were found to be homogeneous by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), analytical size exclusion high-performance liquid chromatography (SE-HPLC), and analytical cation exchange HPLC (CIE-HPLC) and were also characterized with respect to site of PEGylation by enzymatic digestion with endoproteinase Lys-C and N-terminal sequencing. In addition, in vitro biological activity was determined by cell proliferation assay. It was determined that the three isolated individual positional isomers were PEGylated at Lys35, Met(N-terminal), and Lys17 of the rhG-CSF molecule with a 23-kDa trimer-structured methoxy polyethylene glycol N-hydroxysuccinimidyl functional group (mPEG-NHS). All individual positional isomers (Lys35-PEGylated rhG-CSF, Met(N-terminal)-PEGylated rhG-CSF, and Lys17-PEGylated rhG-CSF) retained in vitro biological activity and were found to be 18.5%, 37.6%, and 7.1%, respectively, compared with the rhG-CSF molecule. The significantly different in vitro biological activities observed in the individual positional isomers could be presumably due to interference of receptor binding or active sites on the rhG-CSF molecule. In conclusion, the individual positional isomers isolated from the mono-PEGylated rhG-CSF were well characterized with respect to the site of PEGylation involving Lys35, Met(N-terminal), and Lys17. This characterization of the individual positional isomers would be critical to provide a basis for establishing consistency in the manufacturing process.

The effects of midazolam and remifentanil on induction of anesthesia and hemodynamics during tracheal intubation under target-controlled infusion of propofol.

BACKGROUND: The combined induction using two or more agents has a potential benefit that anesthesia could be induced with smaller anesthetic agents with fewer side effects. We studied the effects of co-administration with midazolam and remifentanil on the dose of propofol, the time to loss of consciousness (LOC) and hemodynamics during tracheal intubation. METHODS: Sixty patients were randomly assigned to three groups. Group 1 was induced with target-controlled propofol alone. Group 2 received midazolam (0.05 mg/kg) and target-controlled propofol. Group 3 received midazolam (0.025 mg/kg), remifentanil (2 ng/ml) and target-controlled propofol. The time to LOC, the infused propofol dose and the effect site concentration at LOC were recorded. After LOC, rocuronium (0.6 mg/kg) was given and tracheal intubation was performed. The noninvasive blood pressure, heart rate (HR) and bispectral index were recorded. RESULTS: The time and the dose of propofol to LOC were significantly reduced in group 2, 3 than in group 1 (P < 0.05). Compared with pre-induction values, mean blood pressure at immediately after intubation was increased in group 1, 2 with no change in group 3. The HR immediately after intubation was significantly increased in all groups compared to the pre-induction values, but the rate of increase of HR in group 3 were significantly lower than those group 1, 2 (P < 0.05). CONCLUSIONS: The co-administration with midazolam and remifentanil reduces the time to LOC and the dose of propofol. That also attenuates hemodynamics during tracheal intubation under target-controlled infusion of propofol.

The effects of local anesthetic distribution on symptoms using ultrasound image after stellate ganglion block.

BACKGROUND: The aim of this study is to evaluate the effects of local anesthetic distribution on symptoms using ultrasound image after C6 stellate ganglion block (SGB). METHODS: Twenty-six patients underwent SGB via an anterior paratracheal approach at the sixth cervical level using 6 ml of 1% mepivacaine. We divided the patients into two groups by local anesthetic distribution using ultrasound image after SGB. In the group 'sub', injected local anesthetic was beneath the prevertebral fascia. In the group 'supra', some of injected local anesthetic was above the prevertebral fascia. The occurrence of Horner's syndrome, warm sensation on the face and hand, brachial plexus block, hoarseness, and foreign body sensation in the throat were evaluated. The skin temperature of the bilateral thumbs was measured pre and post SGB. RESULTS: The occurrence of hoarseness and the foreign body sensation in the throat was significantly reduced in the group 'sub' than the group 'supra' (P<0.05). The skin temperature of the ipsilateral thumb significantly increased in both groups compared to the pre SGB values, and the change of the skin temperature significantly increased in the group 'sub' than the group 'supra' (P<0.05). CONCLUSIONS: Subfascial distribution of local anesthetic under ultrasound image after SGB reduces the typical complications. It is more effective in the sympathetic block than suprafascial distribution.