Comparison of First-Line Dual Combination Treatments in Hypertension: Real-World Evidence from Multinational Heterogeneous Cohorts

BACKGROUND AND OBJECTIVES: 2018 ESC/ESH Hypertension guideline recommends 2-drug combination as initial anti-hypertensive therapy. However, real-world evidence for effectiveness of recommended regimens remains limited. We aimed to compare the effectiveness of first-line anti-hypertensive treatment combining 2 out of the following classes: angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blocker (A), calcium channel blocker (C), and thiazide-type diuretics (D). METHODS: Treatment-naïve hypertensive adults without cardiovascular disease (CVD) who initiated dual anti-hypertensive medications were identified in 5 databases from US and Korea. The patients were matched for each comparison set by large-scale propensity score matching. Primary endpoint was all-cause mortality. Myocardial infarction, heart failure, stroke, and major adverse cardiac and cerebrovascular events as a composite outcome comprised the secondary measure. RESULTS: A total of 987,983 patients met the eligibility criteria. After matching, 222,686, 32,344, and 38,513 patients were allocated to A+C vs. A+D, C+D vs. A+C, and C+D vs. A+D comparison, respectively. There was no significant difference in the mortality during total of 1,806,077 person-years: A+C vs. A+D (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.97-1.20; p=0.127), C+D vs. A+C (HR, 0.93; 95% CI, 0.87-1.01; p=0.067), and C+D vs. A+D (HR, 1.18; 95% CI, 0.95-1.47; p=0.104). A+C was associated with a slightly higher risk of heart failure (HR, 1.09; 95% CI, 1.01-1.18; p=0.040) and stroke (HR, 1.08; 95% CI, 1.01-1.17; p=0.040) than A+D. CONCLUSIONS: There was no significant difference in mortality among A+C, A+D, and C+D combination treatment in patients without previous CVD. This finding was consistent across multi-national heterogeneous cohorts in real-world practice.ope

프랙탈 영역 위에서의 비선형 작용소 및 비선형 포물형 편미분 방정식의 균질화

학위논문(박사) -- 서울대학교대학원 : 자연과학대학 수리과학부, 2021.8. 이기암.프랙탈 영역 위에서의 해석학은 해석적 접근과 확률론적 접근을 통해 다양하게 연구되고 있다. 본 학위논문에서는 프랙탈 영역에서 2차항을 포함하는 비선형 타원 방정식를 구성하고, 해석적 논증을 이용하여 해의 정칙성을 구하고자 한다. 프랙탈 영역에서는 기존의 편미분 이론을 사용할 수 없기 때문에, 우리의 접근 방식은 그래프 근사 논증을 이용하여 디리클레 형식을 구성하는 것에 기반을 두고 있다. 가장 중점적인 개념은 프랙탈 영역의 특수한 기하학적 특성을 사용하여 적절한 차단 함수와 가중치 부등식을 찾는 것이다. 본 학위논문의 또 다른 주제는 완전 비선형 포물형 방정식에 대한 균질화 이론이다. 특히, 우리는 진동 변수들의 척도가 기존과 다른 경우에 대해서 다룬다. 흥미로운 점은 시공간 빠른 변수의 척도가 일치하지 않기 때문에 균질화가 시간과 공간에 대해 개별적으로 발생한다는 점이다. 또한 이 현상은 기존과 다른 수렴속도를 야기한다.The analysis of fractals has been studied extensively in both analysis and probability approaches. In this thesis, we construct the non-linear elliptic equation involving second order terms on fractal spaces, and our main object is to exhibit the regularity of their solutions by using an analytic argument. Since a calculus on fractals is not available, our approach is based on the graph approximation argument to construct Dirichlet forms. The central concept is in finding suitable cut-off functions and weighted inequalities, which can be obtained by using the special geometric properties of the fractal domain. Another topic in this thesis is the homogenization theory for fully non-linear parabolic equations. In particular, we treat the case with different scales of the oscillating variables. The interesting point is that the homogenization occurs separately for time and space due to a mismatch in the scale of time and space fast variables. In addition, this phenomenon causes different order of convergence rates.1 Introduction 1 1.1 Part I : Non-linear operators on the fractal domains 1 1.2 Part II : Homogenization for fully non-linear parabolic equations 3 2 Preliminaries 7 2.1 Part I : Non-linear operators on the fractal domains 7 2.1.1 Sierpinski gasket 7 2.1.2 Dirichlet forms and harmonic functions 9 2.2 Part II : Homogenization for fully non-linear parabolic equations 15 2.2.1 Cell problem 15 2.2.2 Effective operators and e effective limits 20 3 Non-linear operators of divergence form on the Sierpinski gasket 26 3.1 Introduction 26 3.1.1 Main results 27 3.1.2 Main strategies 28 3.1.3 Outline 30 3.2 L-harmonic functions 30 3.3 Weighted inequalities 37 3.3.1 Barriers 38 3.3.2 Weighted inequalities 40 3.4 Harnack inequality 55 3.4.1 Caccioppoli type inequality and local boundedness 56 3.4.2 Harnack inequality 64 4 Homogenization of fully non-linear parabolic equations with different oscillations in space and time 73 4.1 Introduction 73 4.1.1 Main results 75 4.1.2 Heuristics discussion and main strategies 78 4.1.3 Outline 84 4.2 basic homogenization process 84 4.3 Homogenization when k \in (0,2) 86 4.3.1 The effective operator and the effective limit 86 4.3.2 Rate of convergence for the homogenization 90 4.4 Homogenization when k \in (2,\infty) 104 4.4.1 The effective operator and the effective limit 104 4.4.2 Rate of convergence for the homogenization 108 5 Higher order convergence rate for the homogenization of soft inclusions with non-divergence structure 121 5.1 Introduction 121 5.1.1 Main results 124 5.1.2 Heuristics discussion and main strategies 127 5.1.3 Outline 128 5.2 Homogenization and correctors 128 5.2.1 Basic homogenization process and regularity of solutions 128 5.2.2 Asymptotic expansions and correctors 139 5.2.3 Higher order interior correctors 145 5.3 Higher order convergence rate 153 Bibliography 159 Abstract (in Korean) 166 Acknowledgement (in Korean) 167박

Phenotypic and Functional Analysis of Human NK Cell Subpopulations According to the Expression of FcεRIγ and NKG2C

Human memory-like NK cells are commonly defined by either a lack of FcεRIγ or gain of NKG2C expression. Here, we investigated the heterogeneity of human CD56dim NK cell subpopulations according to the expression of FcεRIγ and NKG2C in a large cohort (n = 127). Although the frequency of FcεRIγ- and NKG2C+ NK cells positively correlated, the FcεRIγ- and NKG2C+ NK cell populations did not exactly overlap. The FcεRIγ+NKG2C+, FcεRIγ-NKG2C+, and FcεRIγ-NKG2C- NK cell populations were only evident after HCMV infection, but each had distinct characteristics. Among the subpopulations, FcεRIγ-NKG2C+ NK cells exhibited the most restricted killer immunoglobulin-like receptor repertoire, suggesting clonal expansion. Moreover, FcεRIγ-NKG2C+ NK cells exhibited the lowest Ki-67 and highest Bcl-2 expression, indicating the long-lived quiescent memory-like property. Functionally, FcεRIγ-NKG2C+ NK cells had weak natural effector function against K562 but strong effector functions by CD16 engagement, whereas FcεRIγ+NKG2C+ NK cells had strong effector functions in both settings. Anatomically, the FcεRIγ+NKG2C+, FcεRIγ-NKG2C+, and FcεRIγ-NKG2C- NK cell populations were present in multiple human peripheral organs. In conclusion, we demonstrate the heterogeneity of memory-like NK cells stratified by FcεRIγ and NKG2C and suggest both markers be utilized to better define these cells.ope

Nelumbo nucifera Receptaculum Extract Suppresses Angiotensin II-Induced Cardiomyocyte Hypertrophy

Nelumbo nucifera Gaertn. (lotus) is an important medicinal plant, and many parts of the plant have been investigated for their therapeutic effects. However, the therapeutic effect of receptacles of lotuses on pathological cardiomyocyte hypertrophy has not been investigated yet. Therefore, the current study aimed to determine the protective effect of lotus against angiotensin II (Ang II)-induced cardiomyocyte hypertrophy in vitro. Ang II was used to induce hypertrophy of H9c2 cells. The lotus receptacle powder (MeOH extract of receptaculum Nelumbinis; MRN) used in the experiments was prepared by MeOH extraction and subsequent evaporation. To evaluate the effect of MRN on cardiomyocyte hypertrophy, cell size, protein synthesis, and hypertrophic marker expressions were examined. The antioxidant ability of MRN was determined by using CM-H2DCFDA, a general oxidative stress indicator. Ang II-induced cardiomyocyte hypertrophy was significantly attenuated by 5 µg/mL of MRN, as confirmed by the reductions in cell size, protein synthesis, and hypertrophic marker expression. MRN also attenuated Ang II-induced excessive intracellular reactive oxygen species (ROS) production through the suppression of protein kinase C (PKC), extracellular-signal-regulated kinase (ERK), and NF-κB activation and subsequent type I angiotensin receptor (AT1R), receptor for advanced glycation end products (RAGE), and NADPH oxidase (NOX) expression. MRN exerted a significant protective effect against Ang II-induced cardiomyocyte hypertrophy through suppression of PKC-ERK signaling, and this subsequently led to attenuation of intracellular ROS production.ope

2018 Korean society of hypertension guidelines for the management of hypertension: part III-hypertension in special situations

Treatment of hypertension improves cardiovascular, renal, and cerebrovascular outcomes. However, the benefit of treatment may be different according to the patients' characteristics. Additionally, the target blood pressure or initial drug choice should be customized according to the special conditions of the hypertensive patients. In this part III, we reviewed previous data and presented recommendations for some special populations such as diabetes mellitus, chronic kidney disease, elderly people, and cardio-cerebrovascular disease.ope

The Association of Smoothness Index of Central Blood Pressure With Ambulatory Carotid Femoral Pulse Wave Velocity After 20-week Treatment With Losartan in Combination With Amlodipine Versus Hydrochlorothiazide

Objectives: The aim of this study was to identify associations between the smoothness index of central SBP (CSBP) and changes of ambulatory carotid femoral pulse wave velocity in response to 20-week treatments with losartan and amlodipine vs. losartan and hydrochlorthiazide combinations. Methods: For 142 (losartan and hydrochlorthiazide: 72, losartan and hydrochlorthiazide: 70) patients examined with ambulatory central blood pressure (BP) monitoring device, we calculated smoothness indices and trough-to-peak ratios of brachial SBP, CSBP, ambulatory pulse pressure amplification (APPA), ambulatory augmentation index at heart rate 75 beats per minute (AAIx75) and ambulatory carotid femoral pulse wave velocity (AcfPWV). Results: Mean age was 58.9 ± 12.3 years, and women accounted for 25.9%. Changes in office SBP/DBP were not different between groups (losartan and hydrochlorthiazide: -15.2 ± 15.0/-7.8 ± 8.0 vs. losartan and amlodipine: -14.9 ± 13.7/-9.2 ± 7.5 mmHg). Reduction of 24-h CSBP was not significantly different (losartan and hydrochlorthiazide: 6.4 ± 1.1 vs. losartan and amlodipine: 9.2 ± 1.1 mmHg, P = 0.074). Reduction in nocturnal AcfPWV was greater in the losartan and amlodipine group (losartan and hydrochlorthiazide: 0.09 ± 0.05 vs. losartan and amlodipine: 0.26 ± 0.05 m/s, P = 0.0216). Intraindividual SIs for CSBP were higher in the losartan and amlodipine group (0.40 ± 0.57 vs. 0.65 ± 0.74, P = 0.022). In multivariable regression analysis, smoothness index of CSBP was independently associated with the losartan and amlodipine group. In model additionally considering the changes in arterial stiffness, decrease in AcfPWV instead of the treatment group was independently associated with smoothness indices. In mediation analysis, smoothness index was fully mediated by reduction in night-time AcfPWV. Conclusion: Losartan and amlodipine combination was superior to the losartan and hydrochlorthiazide combination in terms of achieving higher smoothness index for CSBP after 20-week treatments. The effect of losartan and amlodipine on smoothness index was fully mediated by reduction of night-time AcfPWV.ope

Metabolic syndrome, not menopause, is a risk factor for hypertension in peri-menopausal women

Background: It has been long debated whether menopause itself is a risk factor for hypertension in peri-menopausal women. We aimed to assess the association between menopause and hypertension, and whether metabolic syndrome (MetS) has an influence on its effect. Methods: Data for 1502 women aged 42 to 53 from the Korean Genome and Epidemiology Study (KoGES) database were retrospectively analyzed. The KoGES database consists of 10,038 participants, of which 52.6% (5275) were female. Subjects were followed up for 4 years, and compared according to menopausal status. Additionally, 1216 non-hypertensive subjects were separately analyzed to assess whether a change in menopausal status was associated with development of hypertension. Results: The prevalence of hypertension, diabetes, and MetS for menopausal and non-menopausal subjects at baseline was 24.4% vs. 16.7%, 5.8% vs. 2.9%, and 25.4% vs. 16.6%, respectively (p < 0.01 for all comparisons). Among non-hypertensive subjects at baseline, prevalence of hypertension at 4-year follow-up was 9.4%, 19.7%, and 13.1% for non-menopausal, those who became menopause during follow-up, and those who were menopause at baseline, respectively. Development of hypertension was positively correlated with MetS (HR 3.90, 95% CI 2.51-6.07) and increased BMI (HR 1.09, 95% CI 1.03-1.16), while association with menopause was not significant. Conclusions: Menopause is closely associated with increased incidence of hypertension, but the increase may not be attributable to menopause itself but to increased prevalence of MetS.ope

Association between localised retinal nerve fibre layer defects and cardiovascular risk factors

Localised retinal nerve fibre layer defects (RNFLDs) are reported to indicate the degree of glaucomatous damage but can also be sequelae of retinal vascular insufficiency as a result of systemic vascular factors. We investigated the association between RNFLDs and cardiovascular risk factors. RNFLDs were detected in 440 (29.2%) of 1508 subjects. The presence of RNFLDs was associated with higher HbA1c (odds ratio [OR] 1.289, p < 0.001), higher 24-h mean systolic blood pressure (SBP; OR 1.013, p < 0.005), and lower estimated glomerular filtration rate (eGFR; OR 0.995, p < 0.005). An increasing number of RNFLDs was correlated with higher SBP (r = 0.186, p < 0.001), higher HbA1c (r = 0.128, p < 0.010), lower eGFR (r = -0.112, p < 0.020), and younger age (r = -0.303, p < 0.001). Subjects with RNFLDs had a higher predicted 10-year risk of atherosclerotic cardiovascular disease than did those without RNFLDs (9.7% vs 7.9%, p = 0.008 in middle-aged subjects, 25.6% vs 23.2%, p = 0.040 in older subjects). In conclusion, RNFLDs are associated with SBP, eGFR, and HbA1c. Concomitant cardiovascular risk factors should be considered when evaluating patients with localised RNFLDs.ope

Home blood pressure monitoring: a position statement from the Korean Society of Hypertension Home Blood Pressure Forum

Home blood pressure measurement (HBPM) has the advantage of measuring blood pressure (BP) multiple times over a long period. HBPM effectively diagnoses stress-induced transient BP elevations (i.e., white coat hypertension), insufficient BP control throughout the day (i.e., masked hypertension), and even BP variability. In most cases, HBPM may increase self-awareness of BP, increasing the compliance of treatment. Cumulative evidence has reported better improved predictive values of HBPM in cardiovascular morbidity and mortality than office BP monitoring. In this position paper, the Korean Society of Hypertension Home Blood Pressure Forum provides comprehensive information and clinical importance on HBPM.ope

What is new in the 2018 Chinese hypertension guideline and the implication for the management of hypertension in Asia?

The new Chinese hypertension guideline comprehensively covers almost all major aspects in the management of hypertension. In this new guideline, hypertension remains defined as a systolic/diastolic blood pressure of at least 140/90 mm Hg. For risk assessment, a qualitative approach is used similarly as in previous Chinese guidelines according to the blood pressure level and the presence or absence of other risk factors, target organ damage, cardiovascular complications, and comorbid diseases. The therapeutic target is 140/90 mm Hg in general, and if tolerated, especially in high-risk patients, can be more stringent, that is, 130/80 mm Hg. However, a less stringent target, that is, 150/90 mm Hg, is used in the younger (65-79 years, if tolerated, 140/90 mm Hg) and older elderly (>= 80 years). Five classes of antihypertensive drugs, including beta-blockers, can be used either in initial monotherapy or combination. The guideline also provided information on the management of hypertension in several special groups of patients and in the presence of secondary causes of hypertension. To implement the guideline recommendations, several nationwide hypertension control initiatives are being undertaken with new technology. The new technological platforms hopefully will help improve the management of hypertension and generate scientific evidence for future hypertension guidelines, including a possible Asian hypertension guideline in the near future.ope