Search

Low blood pressure (BP) is associated with poor outcomes in patients with heart failure (HF). We investigated the influence of initial BP on the prognosis of HF patients at admission, and prescribing patterns of HF medications, such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and beta-blockers (BB). Data were sourced from a multicentre cohort of patients admitted for acute HF. Patients were grouped into heart failure reduced ejection fraction (HFrEF) and HF mildly reduced/preserved ejection fraction (HFmrEF/HFpEF) groups. Initial systolic and diastolic BPs were categorized into specific ranges. Among 2778 patients, those with HFrEF were prescribed ACEi, ARB, or BB at discharge, regardless of their initial BP. However, medication use in HFmrEF/HFpEF patients tended to decrease as BP decreased. Lower initial BP in HFrEF patients correlated with an increased incidence of all-cause death and composite clinical events, including HF readmission or all-cause death. However, no significant differences in clinical outcomes were observed in HFmrEF/HFpEF patients according to BP. Initial systolic (< 120 mmHg) and diastolic (< 80 mmHg) BPs were independently associated with a 1.81-fold (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.349-2.417, p < 0.001) and 2.24-fold (OR 2.24, 95% CI 1.645-3.053, p < 0.001) increased risk of long-term mortality in HFrEF patients, respectively. In conclusion, low initial BP in HFrEF patients correlated with adverse clinical outcomes, and BP < 120/80 mmHg independently increased mortality. However, this relationship was not observed in HFmrEF/HFpEF patients., (© 2024. The Author(s).)

Hypokalemia is a common electrolyte disturbance and is related to poor prognosis in patients with cardiovascular disease. However, the role of hypokalemia in patients with vasospastic angina (VSA) has not yet been studied. The present study enrolled 1454 patients diagnosed with VSA according to ergonovine provocation test results and available admission serum potassium data. The primary outcome was a composite of cardiac death, acute coronary syndrome, and new-onset life-threatening arrhythmia. Based on a hypokalemia definition as serum potassium concentration ≤ 3.5 mEq/L, the hypokalaemia group included 70 patients (4.8%). The median potassium levels were 3.4 mEq/L [interquartile range (IQR) 3.3-3.5] in the hypokalemia group and 4.1 mEq/L (IQR 3.9-4.3) in the no-hypokalemia group. The median follow-up duration was 764 days. Primary outcomes occurred in seven patients (10.0%) in the hypokalemia group and 51 patients (3.7%) in the no-hypokalemia group. The Kaplan-Meier analysis showed a higher cumulative incidence of primary outcomes in the hypokalemia group compared to that in the no-hypokalemia group (log-rank P = 0.014). Multivariate Cox regression analysis also showed that hypokalemia was an independent predictor of primary outcomes. In conclusion, hypokalemia at admission was associated with adverse clinical outcomes in VSA.

Although both angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs) are all suitable for the initiation of antihypertensive treatment, studies investigating efficacy and safety between ARBs and CCBs are limited, and there is no previous study comparing their clinical outcomes during long-term follow-up periods in real world setting. We compared cardiovascular (CV) events between ARBs and CCBs in 464,948 hypertensive adults using the Korean National Health Insurance Service database during a 3-year follow-up. The patients with hypertension without heart failure, ischemic heart disease, cerebrovascular disease, or peripheral artery disease were enrolled. The CV events between only single prescription of CCBs and ARBs were finally compared. The primary endpoint for this study was the first occurrence of a major adverse CV events, defined as the composite of all-cause death, cardiac death, nonfatal myocardial infarction, or nonfatal stroke. ARB was significantly more administered in male and patients with higher income, diabetes mellitus, chronic kidney diseases, and higher Charlson comorbidity index. The primary endpoints occurred in 10,526 patients (5.2%) in the ARB group and in 19,363 patients (7.3%) in the CCB group (p < 0.001) during a 3-year follow-up (HR 0.96, 95% CI 0.93-0.98). All the components of CV events including all-cause death, cardiac death, nonfatal myocardial infarction, and nonfatal stroke occurred more frequently in the CCB group. With multivariable models adjusting age, sex, income, diabetes, chronic kidney disease, and Charlson comorbidity index, the primary endpoints less frequently developed in the ARB group than in the CCB group (HR 0.957, 95% CI 0.933-0.983, p < 0.001). After the propensity-score matching, baseline characteristics were similar and still showed significantly better primary endpoints in ARB group than CCB group (5.3% vs. 5.8%, p < 0.001). In this nationwide population-based simple hypertension study, administration of ARBs showed superior protection against CV events than CCBs during a 3-year follow-up. Our results suggest that ARBs could be preferred over CCBs as the initial choice of antihypertensive treatment regardless of age in real-world practice.

To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell-cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Direct co-culture showed most distinct phenotype changes in MCF10A cells followed by conditioned media treatment and indirect co-culture. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell-cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells.

Coronary plaque distribution, frequency and cut-off value of percent stenosis for developing vasospasm are uncertain in patients with vasospastic angina (VA). We enrolled 2960 patients who received coronary angiography (CAG) and ergonovine provocation test prospectively in 11 university hospitals in Korea. A total of 1836 patients with VA and 867 without VA were included. Plaque and % stenosis were defined as ≥1% luminal narrowing and mean of each segmental stenosis. Overall frequency of plaque and % diameter stenosis was compared among VA-patients with index coronary spasm positive, those with index arterial spasm negative/other arterial spasm positive (INOP) and non-VA patients. Diameter stenosis associated with the spasm positivity was investigated. Overall plaque frequency and % stenosis were higher in VA patients than non-VA patients. Plaque frequency was 27.6% (243/881) in spasm positive at LAD, 16.4% (157/955) in LAD INOP and 12.6% (109/867) in non-VA with statistic difference (P < 0.001). Same trend for higher rate was observed in LCx and RCA. For % stenosis, 36.6 vs 32.4% (p = 0.010) in LAD, 36.1 vs. 28% (p < 0.001) in LCx and 35.3 vs.30.0% (p = 0.047) in RCA, respectively. Diameter stenosis of LAD with spasm positive vs. LAD INOP vs. non-VA were 38.3%, 34.0%, 32% (P = 0.002) with similar pattern in LCx and RCA. By multivariate logistic regression analysis, coronary stenosis of LAD ≥ 35% or LCx ≥35% or RCA ≥ 40% were independent predictor of developing spasm (OR 2.019, 95% CI 1.315-3.100, P = 0.001). In conclusions, spastic coronary artery had more plaque frequency, higher % stenosis than in non-spastic coronary in VA patients. The spasm related and unrelated coronary in VA patients had more plaque than in matched and unmatched coronary arteries in non-VA patients. Coronary stenosis ≥35% in LAD and LCx was an independent predictor of developing spasm.

Obesity is associated with a high risk of morbidity and mortality in the general population and is a major independent risk factor for cardiovascular disease. We sought to evaluate the effect of overweight/obesity on clinical outcomes of patients with vasospastic angina (VA) at 1-year follow-up. The VA-KOREA (Vasospastic Angina in Korea) registry was a cohort of 11 centers from 2010 to 2015. The primary endpoint was a composite of cardiac death (CD), new-onset arrhythmia, and acute coronary syndrome (ACS). Using the body mass index (BMI) cut-off for Asians, 517 patients with definite VA were divided into either an overweight/obese (BMI ≥ 23 kg/m 2 ) group (n = 378) or a normal weight (BMI 18.5-22.9 kg/m 2 ) group (n = 139). The overweight/obese group showed a significantly lower rate of the primary endpoint composite (2.4% vs 7.9%, p = 0.004) and ACS (0.8% vs 4.3%, p = 0.007) than the normal weight group in the crude population. Similarly, in propensity-score matched analysis, the overweight/obese group showed a significantly lower rate of the primary endpoint composite (2.3% vs 8.4%, p = 0.006) and ACS (1.1% vs 4.6%, p = 0.035) than the normal weight group. However, there were no significant differences in CD and new-onset arrhythmia between the two groups in both the crude and propensity-score matched population. Independent predictors of the primary endpoint were overweight/obesity and dyslipidemia. In patients with VA, the overweight/obese group was associated with a favorable 1-year primary endpoint and the difference was mainly driven by the lower rate of ACS compared with the normal weight group.

Proteolysis targeting chimeras (PROTACs) are an emerging strategy for promoting targeted protein degradation by inducing the proximity between targeted proteins and E3 ubiquitin ligases. Although successful degradation of numerous proteins by PROTACs has been demonstrated, the elements that determine the degradability of PROTAC-targeted proteins have not yet been explored. In this study, we developed von Hippel-Lindau-Cereblon (VHL-CRBN) heterodimerizing PROTACs that induce the degradation of CRBN, but not VHL. A quantitative proteomic analysis further revealed that VHL-CRBN heterodimerizing PROTACs induced the degradation of CRBN, but not the well-known immunomodulatory drug (IMiD) neo-substrates, IKAROS family zinc finger 1 (IKZF1) and -3 (IZKF3). Moreover, truncation of disordered regions of CRBN and the androgen receptor (AR) attenuated their PROTAC-induced degradation, and attachment of the disordered region to stable CRBN or AR facilitated PROTAC-induced degradation. Thus, these results suggest that the intrinsically disordered region of targeted proteins is essential for efficient proteolysis, providing a novel criterion for choosing degradable protein targets.

Anti-platelet agents are commonly used in vasospastic angina (VA) patients with comorbidity like coronary artery disease. However, long-term clinical outcomes in the use of aspirin, clopidogrel or the two agents together have rarely been investigated in VA patients. In a prospective study, we enrolled 2960 patients who received coronary angiography and ergonovine provocation test at 11 university hospitals in Korea. Among them, 1838 patients were diagnosed either with definite (n = 680) or intermediate (n = 1212) VA, using the criteria of chest pain, ECG changes and ergonovine provocation test results. They were analyzed according to their use of aspirin, clopidogrel or both, or no anti-platelet agent at all. The primary outcome was time to composite events of death from any cause, acute coronary syndrome (ACS) and symptomatic arrhythmia during a 3-year follow-up. A primary composite outcome was significantly more common in the aspirin plus clopidogrel group, at 10.8% (14/130), as compared with the non-antiplatelet group, at 4.4% (44/1011), (hazard ratio [HR] 2.41, 95% confidence interval [CI], 1.32-4.40, p = 0.004). With regard to the person-time event rate, similar results were shown, with the highest rate in the aspirin plus clopidogrel user at 4.72/1000 person months (95% CI, 2.79-7.96, log-rank test for primary outcome p = 0.016). The person-time event of the ACS rate was also highest in that group, at 2.81 (95% CI, 1.46-5.40, log-rank test for ACS p = 0.116). Kaplan-Meier survival analysis demonstrated poor prognosis in primary outcomes and ACS in aspirin plus clopidogrel users (log-rank test, p = 0.005 and p = 0.0392, respectively). Cox-proportional hazard regression analysis, adjusting for age, sex, history of coronary heart disease, hypertension, diabetes, presence or not of definite spasm, use of calcium channel blocker, demonstrated that the use of aspirin plus clopidogrel is an independent risk for the primary outcome (HR 2.01, CI: 1.07-3.81, p = 0.031). The aspirin-alone group had a similar primary and individual event rate compared to the no-antiplatelet agent group (HR 0.96, CI, 0.59-1.55, p = 0.872). Smokers using aspirin plus clopidogrel had poorer outcomes than non-smokers, with HR 6.36 (CI 2.31-17.54, p = 0.045 for interaction). In conclusion, among VA patients, aspirin plus clopidogrel use is associated with a poor clinical outcome at 3 years, especially in ACS. Aspirin alone appears to be safe for use in those patients.

The adsorption properties of various sorbent materials were investigated to assess the factors affecting biases in the sorbent tube (ST) sampling of airborne phthalates. The recovery of phthalates was assessed critically in relation to four key sampling parameters: (1) three types of sorbent materials (quartz wool (QW), glass wool (GW), and quartz wool plus Tenax TA (QWTN)), (2) the concentration level of phthalate standards, (3) purge flow rate, and (4) purge volume for analysis based on a 'sorbent tube-thermal desorption-gas chromatography-mass spectrometry (ST-TD-GC-MS)' system. Among these parameters, the type of ST was the most influential in determining the recovery of phthalates. For a given ST type, the recovery of phthalates tends to improve with increases in the concentration level of standards. In case of QW and QWTN tubes, the breakthrough of phthalates was not observed up to the maximum purge volume (100 L) tested in this work; however, in case of GW, the recovery decreased drastically to 60% even at a purge volume of 1 L for low molecular weight phthalates. The results of our study demonstrate that accurate analysis of airborne phthalates can be achieved through proper control of key sampling parameters, particularly the choice of sorbent material.

Alteration of macrophage function has an important regulatory impact on the survival of intracellular mycobacteria. We found that macrophages infected with attenuated Mycobacterium tuberculosis (Mtb) strain H37Ra had elevated expression of M1-related molecules, whereas the M2 phenotype was dominant in macrophages infected with virulent Mtb H37Rv. Further, the TLR signalling pathway played an important role in modulating macrophage polarization against Mtb infection. Interestingly, endoplasmic reticulum (ER) stress was significantly increased in M1 polarized macrophages and these macrophages effectively removed intracellular Mtb, indicating that ER stress may be an important component of the host immune response to Mtb in M1 macrophages. This improved understanding of the mechanisms that regulate macrophage polarization could provide new therapeutic strategies for tuberculosis.

Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that forms a complex with glucose-regulated protein 78 (GRP78) to induce apoptosis. Previously, we reported that ER stress-induced apoptosis is a critical host defense mechanism against Mycobacterium tuberculosis (Mtb). We sought to understand the role of Par-4 during ER stress-induced apoptosis in response to mycobacterial infection. Par-4 and GRP78 protein levels increased in response Mtb (strain: H37Ra) infection. Furthermore, Par-4 and GRP78 translocate to the surface of Mtb H37Ra-infected macrophages and induce apoptosis via caspase activation. NF-κB activation, Mtb-mediated ER stress, and Par-4 production were significantly diminished in macrophages with inhibited ROS production. To test Par-4 function during mycobacterial infection, we analyzed intracellular survival of Mtb H37Ra in macrophages with Par-4 overexpression or knockdown. Mtb H37Ra growth was significantly reduced in Par-4 overexpressing macrophages and increased in knockdown macrophages. We also observed increased Par-4, GRP78, and caspases activation in Bacillus Calmette-Guérin (BCG)-infected prostate cancer cells. Our data demonstrate that Par-4 is associated with ER stress-induced apoptosis resulting in reduced intracellular survival of mycobacteria. BCG treatment increases Par-4-dependent caspase activation in prostate cancer cells. These results suggest ER stress-induced Par-4 acts as an important defense mechanism against mycobacterial infection and regulates cancer.

Glucokinase (GK), mainly expressed in the liver and pancreatic β-cells, is critical for maintaining glucose homeostasis. GK expression and kinase activity, respectively, are both modulated at the transcriptional and post-translational levels. Post-translationally, GK is regulated by binding the glucokinase regulatory protein (GKRP), resulting in GK retention in the nucleus and its inability to participate in cytosolic glycolysis. Although hepatic GKRP is known to be regulated by allosteric mechanisms, the precise details of modulation of GKRP activity, by post-translational modification, are not well known. Here, we demonstrate that GKRP is acetylated at Lys5 by the acetyltransferase p300. Acetylated GKRP is resistant to degradation by the ubiquitin-dependent proteasome pathway, suggesting that acetylation increases GKRP stability and binding to GK, further inhibiting GK nuclear export. Deacetylation of GKRP is effected by the NAD(+)-dependent, class III histone deacetylase SIRT2, which is inhibited by nicotinamide. Moreover, the livers of db/db obese, diabetic mice also show elevated GKRP acetylation, suggesting a broader, critical role in regulating blood glucose. Given that acetylated GKRP may affiliate with type-2 diabetes mellitus (T2DM), understanding the mechanism of GKRP acetylation in the liver could reveal novel targets within the GK-GKRP pathway, for treating T2DM and other metabolic pathologies.