A novel mutation in hERG gene associated with azithromycin-induced acquired long QT syndrome.

BACKGROUND: Mutations in human ether-à-go-go-related gene (hERG) potassium channels are closely associated with long QT syndrome (LQTS). Previous studies have demonstrated that macrolide antibiotics increase the risk of cardiovascular diseases. To date, the mechanisms underlying acquired LQTS remain elusive. METHODS: A novel hERG mutation I1025N was identified in an azithromycin-treated patient with acquired long QT syndrome via Sanger sequencing. The mutant I1025N plasmid was transfected into HEK-293 cells, which were subsequently incubated with azithromycin. The effect of azithromycin and mutant I1025N on the hERG channel was evaluated via western blot, immunofluorescence, and electrophysiology techniques. RESULTS: The protein expression of the mature hERG protein was down-regulated, whereas that of the immature hERG protein was up-regulated in mutant I1025N HEK-293 cells. Azithromycin administration resulted in a negative effect on the maturation of the hERG protein. Additionally, the I1025N mutation exerted an inhibitory effect on hERG channel current. Moreover, azithromycin inhibited hERG channel current in a concentration-dependent manner. The I1025N mutation and azithromycin synergistically decreased hERG channel expression and hERG current. However, the I1025N mutation and azithromycin did not alter channel gating dynamics. CONCLUSIONS: These findings suggest that hERG gene mutations might be involved in the genetic susceptibility mechanism underlying acquired LQTS induced by azithromycin.

[Synthesis of porous organic framework materials based on deep eutectic solvents and their application in solid-phase extraction].

This paper reviews the application of deep eutectic solvents (DESs) in the synthesis of metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) as well as their prospects in the field of solid-phase extraction (SPE). Porous organic frameworks (POFs) have unique properties such as a large specific surface area, high porosity, and easy modification. Thus, these materials are widely applied in the fields of catalysis, adsorption, drug delivery, gas storage, and separation. POFs include MOFs, COFs, conjugated microporous polymers (CMPs), porous aromatic frameworks (PAFs), and covalent triazine frameworks (CTFs). MOFs are constructed from metal ions/clusters and organic ligands through coordination bonds and can be extended in two or three dimensions by repeated coordination with potential voids. COFs are formed from two monomers containing light elements (such as carbon, hydrogen, oxygen, nitrogen, boron, and other elements) via coordination bonds and have large two- or three-dimensional structures. However, conventional POF synthesis methods generally suffer from disadvantages such as long synthesis times, high temperature and pressure requirements, and the use of toxic and hazardous reaction solvents. DES consists of a hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD) bound by hydrogen-bonding interactions. It is a promising green solvent for material synthesis owing to its low vapor pressure, high stability, and ease of preparation. DES can be used to prepare MOFs and COFs and, in specific cases, acts as a structure-directing agent, which has an important impact on the structure and properties of the resulting frameworks. Using appropriate DES formulations, researchers can modulate the crystal structures, pore sizes, and surface properties of MOFs and COFs, resulting in materials with excellent characteristics. SPE is an analytical technique in which a sample solution is added to an SPE column; the sample solution is forced through the stationary phase, and the target compounds are collected for analysis by elution with an organic solvent. Therefore, suitable stationary-phase materials are critical for SPE. Owing to their large specific surface areas and abundant active sites, MOFs and COFs exhibit outstanding adsorption capacity and selectivity in SPE and can effectively enrich target analytes from complex samples. DES-based MOFs and COFs have shown potential use in a wide range of applications, such as in environmental analysis, food testing, and biological sample analysis. Although DES-based MOFs and COFs for SPE are still in the early stages of development, their properties such as efficient enrichment and high selectivity offer good prospects for practical applications. Future research should continue to explore DES-based synthesis methods in depth to prepare other MOFs and COFs with the desired properties and investigate their potential applications in various fields. These efforts are expected to apply these novel materials in commercialized solid-phase extraction methods, bringing new development opportunities in the field of analytical chemistry.

Systolic Blood Pressure and Cardiovascular Risk in Normotensive Adults.

OBJECTIVE: To examine the association of systolic blood pressure (SBP) and cardiovascular risk in normotensive adults. PATIENTS AND METHODS: This study analyzed data from 7 prospective cohorts between September 29, 1948, and December 31, 2018. Complete information on history of hypertension and baseline blood pressure measurements were required for inclusion. We excluded individuals younger than 18 years old, those with a history of hypertension, and patients with baseline SBP measurements of less than 90 mm Hg or 140 mm Hg or higher. Cox proportional hazards regression and restricted cubic spline models were used to evaluate the hazards of cardiovascular outcomes. RESULTS: A total of 31,033 participants were included. The mean ± SD age was 45.3±14.8 years, 16,693 of the participants (53.8%) were female, and the mean ± SD SBP was 115.8±11.7. Over a median follow-up of 23.5 years, 7005 cardiovascular events occurred. Compared with those who had SBP levels of 90 to 99 mm Hg, participants with SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg experienced 23% (hazard ratio [HR], 1.23; 95% CI, 1.07 to 1.42), 53% (HR, 1.53; 95% CI, 1.33 to 1.76), 87% (HR, 1.87; 95% CI, 1.62 to 2.16), and 117% (HR, 2.17; 95% CI, 1.87 to 2.52) increased risks of cardiovascular events, respectively. Compared with follow-up SBP of 90 to 99 mm Hg, the HRs for cardiovascular events were 1.25 (95% CI, 1.02 to 1.54), 1.93 (95% CI, 1.58 to 2.34), 2.55 (95% CI, 2.09 to 3.10), and 3.39 (95% CI, 2.78 to 4.14), respectively, for follow-up SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg. CONCLUSION: In adults without hypertension, there is a stepwise increase in risk of cardiovascular events, with increasing SBP starting at levels as low as 90 mm Hg.

Administration of macrolide antibiotics increases cardiovascular risk.

Background: The increased risk of cardiovascular events in patients prescribed macrolides has been subject to debate for decades. Methods: Medline, EMBASE databases and ClinicalTrials.gov were searched from inception until August 31, 2022 for studies investigating the link between macrolides and cardiovascular risk. A meta-analysis was performed using a random-effects model. Results: A total of 80 studies involving 39,374,874 patients were included. No association was found between macrolides and all-cause death. However, compared with the non-macrolide group, macrolides were associated with a significantly increased risk of ventricular arrhythmia or sudden cardiac death (VA or SCD) (azithromycin, relative ratio [RR]: 1.53; 95% confidence interval [CI]: 1.19 to 1.97; clarithromycin, RR: 1.52; 95% CI: 1.07 to 2.16). Besides, administration of macrolides was associated with a higher risk of cardiovascular disease (CVD) death (azithromycin, RR: 1.63; 95% CI: 1.17 to 2.27) and a slightly increased risk of myocardial infarction (MI) (azithromycin, RR: 1.08; 95% CI: 1.02 to 1.15). Interestingly, no association was observed between roxithromycin and adverse cardiac outcomes. Increased risk of VA or SCD was observed for recent or current use of macrolides, MI for former use, and CVD death for current use. Conclusion: Administration of macrolide antibiotics and timing of macrolide use are associated with increased risk for SCD or VTA and cardiovascular death, but not all-cause death.

Dynamic Change of Cardiovascular Health Metrics and Long-Term Risk of Sudden Cardiac Death: The ARIC Study.

Background The change of cardiovascular health (CVH) status has been associated with risk of cardiovascular disease. However, no studies have explored the change patterns of CVH in relation to risk of sudden cardiac death (SCD). We aim to examine the link between baseline CVH and change of CVH over time with the risk of SCD. Methods and Results Analyses were conducted in the prospective cohort ARIC (Atherosclerosis Risk in Communities) study, started in 1987 to 1989. ARIC enrolled 15 792 individuals 45 to 64 years of age from 4 US communities (Forsyth County, North Carolina; Jackson, Mississippi; suburbs of Minneapolis, Minnesota; and Washington County, Maryland). Subjects with 0 to 2, 3 to 4, and 5 to 7 ideal metrics of CVH were categorized as having poor, intermediate, or ideal CVH, respectively. Change in CVH over 6 years between 1987 to 1989 and 1993 to 1995 was considered. The primary study outcome was physician adjudicated SCD. The study population consisted of 15 026 subjects, of whom 12 207 had data about CVH change. Over a median follow-up of 23.0 years, 583 cases of SCD were recorded. There was a strong inverse association between baseline CVH metrics and time varying CVH metrics with risk of SCD. Compared with subjects with consistently poor CVH, risk of SCD was lower in those changed from poor to intermediate/ideal (hazard ratio [HR], 0.67 [95% CI, 0.48-0.94]), intermediate to poor (HR, 0.73 [95% CI, 0.54-0.99]), intermediate to ideal (HR, 0.49 [95% CI, 0.24-0.99]), ideal to poor/intermediate CVH (HR, 0.23 [95% CI, 0.10-0.52]), or those with consistently intermediate (HR, 0.49 [95% CI, 0.36-0.66]) or consistently ideal CVH (HR, 0.31 [95% CI, 0.13-0.76]). Similar results were also observed for non-SCD. Conclusions Compared with consistently poor CVH, other patterns of change in CVH were associated with lower risk of SCD. These findings highlight the importance of promotion of ideal CVH in the primordial prevention of SCD.

Association Between Temporal Changes in Early Repolarization Pattern With Long-Term Cardiovascular Outcome: A Population-Based Cohort Study.

Background The prognostic value of early repolarization pattern (ERP) remains controversial. We aim to test the hypothesis that temporal changes in ERP are associated with increased risks for sudden cardiac death (SCD) and cardiovascular death. Methods and Results A total of 14 679 middle-aged participants from the prospective, population-based cohort were included in this analysis, with ERP status recorded at baseline and during 3 follow-up visits in the ARIC (Atherosclerosis Risk in Communities) study. We related baseline ERP, time-varying ERP, and temporal changes in ERP to cardiovascular outcomes. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. With a median follow-up of 22.5 years, there were 5033 deaths, 1239 cardiovascular deaths, and 571 SCDs. Time-varying ERP was associated with increased risks of SCD (HR, 1.59 [95% CI, 1.25-2.02]), cardiovascular death (HR, 1.70 [95% CI, 1.44-2.00]), and death from any cause (HR, 1.16 [95% CI, 1.05-1.27]). Baseline ERP was also associated with 3 outcomes. Compared with those with consistently normal ECG findings, subjects with new-onset ERP or consistent ERP experienced increased risks of developing SCD and cardiovascular death. The time-varying ERP in women, White subjects, and anterior leads and J-wave amplitudes ≥0.2 mV appeared to indicate poorer cardiovascular outcomes. Conclusions Our findings suggest that baseline ERP, time-varying ERP, new-onset ERP, and consistent ERP were independent predictors of SCD and cardiovascular death in the middle-aged biracial population. Repeated measurements of the ERP might improve its use as a risk indicator for SCD.

Longitudinal change in lung function and subsequent risks of cardiovascular events: evidence from four prospective cohort studies.

BACKGROUND: Lung function is constantly changing over the life course. Although the relation of cross-sectional lung function measure and adverse outcomes has been reported, data on longitudinal change and subsequent cardiovascular (CV) events risks are scarce. Therefore, this study is to determine the association of longitudinal change in lung function and subsequent cardiovascular risks. METHODS: This study analyzed the data from four prospective cohorts. Subjects with at least two lung function tests were included. We calculated the rate of forced respiratory volume in 1 s (FEV1) and forced vital capacity (FVC) decline for each subject and categorized them into quartiles. The primary outcome was CV events, defined as a composite of coronary heart disease (CHD), chronic heart failure (CHF), stroke, and any CV death. Cox proportional hazards regression and restricted cubic spline models were applied. RESULTS: The final sample comprised 12,899 participants (mean age 48.58 years; 43.61% male). Following an average of 14.79 (10.69) years, 3950 CV events occurred. Compared with the highest FEV1 quartile (Q4), the multivariable HRs for the lowest (Q1), 2nd (Q2), and 3rd quartiles (Q3) were 1.33 (95%CI 1.19, 1.49), 1.30 (1.16, 1.46), and 1.07 (0.95, 1.21), respectively. Likewise, compared with the reference quartile (Q4), the group that experienced a faster decline in FVC had higher HRs for CV events (1.06 [95%CI 0.94-1.20] for Q3, 1.15 [1.02-1.30] for Q2, and 1.28 [1.14-1.44] for Q1). The association remained robust across a series of sensitivity analyses and nearly all subgroups but was more evident in subjects < 60 years. CONCLUSIONS: We observed a monotonic increase in risks of CV events with a faster decline in FEV1 and FVC. These findings emphasize the value of periodic evaluation of lung function and open new opportunities for disease prevention.

[Oxalylbis(aza-nedi-yl)]bis-{[amino-(2-pyrid-yl)methyl-ene]ammonium}.

The title compound, C(14)H(16)N(8)O(2) (2+)·2ClO(4) (-), was prepared by reaction of bis-[amino-(2-pyrid-yl)methyl-ene]oxalohydrazide with perchloric acid. The mol-ecular symmetry is C(i) and thus the asymmetric unit comprises one half-mol-ecule. The dihedral angle between the aromatic ring and the plane of the oxamide group is 70.8 (3)°. The perchlorate anions and the cations are connected by inter-molecular N-H⋯O hydrogen bonds.