Inherited cardiomyopathies are among the major causes of heart failure and associated with significant mortality and morbidity. Currently, over 70 genes have been linked to the etiology of various ...forms of cardiomyopathy, some of which are X-linked. Due to the lack of appropriate cell and animal models, it has been difficult to model these X-linked cardiomyopathies. With the advancement of induced pluripotent stem cell (iPSC) technology, the ability to generate iPSC lines from patients with X-linked cardiomyopathy has facilitated in vitro modelling and drug testing for the condition. Nonetheless, due to the mosaicism of the X-chromosome inactivation, disease phenotypes of X-linked cardiomyopathy in heterozygous females are also usually more heterogeneous, with a broad spectrum of presentation. Recent advancements in iPSC procedures have enabled the isolation of cells with different lyonisation to generate isogenic disease and control cell lines. In this review, we will summarise the current strategies and examples of using an iPSC-based model to study different types of X-linked cardiomyopathy. The potential application of isogenic iPSC lines derived from a female patient with heterozygous Danon disease and drug screening will be demonstrated by our preliminary data. The limitations of an iPSC-derived cardiomyocyte-based platform will also be addressed.
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by
. Nonetheless, the pathophysiological roles of
in the etiology of intrinsic cardiac abnormality and sudden death remain unclear. ...In this study, we performed a detailed functional studies (calcium and electrophysiological analysis) and RNA-sequencing-based transcriptome analysis of a pair of isogenic RTT female patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) that expressed either
or
allele and iPSC-CMs from a non-affected female control. The observations were further confirmed by additional experiments, including Wnt signaling inhibitor treatment, siRNA-based gene silencing, and ion channel blockade. Compared with
and control iPSC-CMs,
iPSC-CMs exhibited prolonged action potential and increased frequency of spontaneous early after polarization. RNA sequencing analysis revealed up-regulation of various Wnt family genes in
iPSC-CMs. Treatment of
iPSC-CMs with a Wnt inhibitor XAV939 significantly decreased the β-catenin protein level and
expression and ameliorated their abnormal electrophysiological properties. In summary, our data provide novel insight into the contribution of activation of the Wnt/β-catenin signaling cascade to the cardiac abnormalities associated with
mutations in RTT.
Abstract
Objectives
The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) vs dipeptidyl peptidase-4 inhibitors (DPP4I) on the risk of new-onset gout remains unknown. This study aims to ...compare the effects of SGLT2I against DPP4I on gout risks.
Methods
This was a retrospective population-based cohort study of patients with type-2 diabetes mellitus treated with SGLT2I or DPP4I between 1 January 2015 and 31 December 2020 in Hong Kong. The study outcomes are new-onset gout and all-cause mortality. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I was performed. Univariable and multivariable Cox regression models were conducted. Competing risks models and multiple approaches based on the propensity score were applied.
Results
This study included 43 201 patients median age: 63.23 years old (Interquartile range, IQR): 55.21–71.95, 53.74% males; SGLT2I group: n = 16 144; DPP4I group: n = 27 057 with a median follow-up of 5.59 years (IQR: 5.27–5.81 years) since initial drug exposure. The incidence rate of developing gout Incidence rate (IR): 2.5; 95% CI: 2.2, 2.9 among SGLT2I users was significantly lower than DPP4I users (IR: 5.2; 95% CI: 4.8, 5.8). SGLT2I was associated with 51% lower risks of gout (HR: 0.49; 95% CI: 0.42, 0.58; P-value < 0.0001) and 51% lower risks of all-cause mortality (HR: 0.49; 95% CI: 0.42, 0.58; P-value < 0.0001) after adjusting for significant demographics, past comorbidities, medications and laboratory results. The results remained consistent on competing risk and other propensity score approaches.
Conclusions
SGLT2I use was associated with lower risks of new gout diagnosis compared with DPP4I use.
Hypertension and arthritis are two common diseases in the general population, with multiple common risk factors. This study aimed to assess the association between hypertension (HTN) and arthritis.
...This cohort study included 48,372 eligible non-pregnant participants aged ≥ 20 years who had valid data on hypertension and arthritis from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. The association between hypertension and arthritis was studied by logistic regression, adjusting for demographics, socioeconomic factors, excess sodium intake, physical activity, ever smoking, diabetes status and body mass index (BMI).
Among the participants, 48.0% (95% CI: 47.2-48.9) had hypertension and 24.5% (95% CI: 23.8-25.3) had self-reported arthritis. Hypertension was associated with arthritis OR = 2.90, (95% CI: 2.74-3.07), p < 0.01, which remained significant OR = 1.27, (95% CI:1.18-1.37), p < 0.01 after adjustments. Stratified by the types of arthritis, the association remained significant in rheumatoid arthritis (RA) OR = 1.25, (95% CI: 1.11-1.41), p < 0.01 and osteoarthritis (OA) OR = 1.32, (95% CI: 1.16-1.50); p < 0.01. There was no clear association between hypertension and OA in participants aged 60 years old and above OR = 1.08, (95% CI: 0.92-1.26); p = 0.37.
In this large nationally representative survey over 20 years, arthritis, including both RA and OA, was strongly associated with hypertension. Our study demonstrates a need for hypertension screening and blood control among patients with arthritis.
Key Messages
Arthritis was associated with hypertension.
Both rheumatoid arthritis and osteoarthritis are strongly associated with hypertension.
There is an urgency for hypertension screening and blood control among patients with arthritis.
Data regarding diabetic complications with chronic statin use among Asian population is very limited. Hence, we investigated diabetic progression in diabetic patients receiving statin therapy by ...evaluating the association with acute and chronic diabetic complications.
This retrospective population-based cohort study included patients aged 40 years or older who were diagnosed with type-2 diabetes mellitus (T2DM) in Hong Kong between January 1st, 2009 and December 31st, 2009 and followed up till December 31st, 2019. Patients were divided into statin users and non-users, and propensity score matching (PSM) was performed based on demographics, prior comorbidities, and medications. The study outcomes were new-onset Diabetic Ketoacidosis/ Hyperosmolar Hyperglycaemic State (DKA/HHS), new diabetic ophthalmological, neurological, and renal complications.
After 1:1 PSM, the study cohort consisted of 3,247 statin users (48.6% male, age 65.03±11.99 years, mean follow-up 5.68±2.39 years) and 3,247 (50.5% male, age 63.20±12.15 years, mean follow-up 5.78±2.34 years) matched statin non-users. Cox proportional hazards model analyses showed that statin therapy was associated with a higher risk of new diabetic renal complications (HR: 1.44, 1.21-1.71, p<0.001), new diabetic ophthalmological complications (HR: 1.44, 1.19-1.73, p<0.001), and new diabetic neurological complications (HR: 1.47, 1.09-1.96, p<0.01), although it was not associated with a higher risk of DKA/HHS (HR: 1.31, 95% CI, 0.89-1.94, p=0.167). The statistical significance of the associations was not maintained under sensitivity analysis which involved excluding patients with previous coronary heart disease.
Amongst T2DM patients, statin use was associated with higher risk of developing chronic diabetic complications after PSM with multiple adjustments.
X-linked dystonia parkinsonism (XDP) is a rare X-linked recessive degenerative movement disorder that only affects Filipino descent, predominantly males. Its underlying cause is associated with the ...genetic alterations in the TAF1/DYT3 multiple transcription system. SINE-VNTR-Alu (SVA) retrotransposon insertion was suggested to be the responsible genetic mutation. Clinically, it initially presents as focal dystonia and generalizes within years. Parkinsonism arises years later and coexists with dystonia. Nonmotor symptoms like cognitive impairment and mood disorders are also common among XDP patients. XDP diagnosis relies on clinical history and physical examination. On imaging, abnormalities of the striatum, such as atrophy, are widely seen and can explain the clinical presentations with a three-model pathway of the striatum. Treatments aim for symptomatic relief of dystonia and parkinsonism and to prevent complications. Oral medications, chemo-denervation, and surgery are used in XDP patients. This review summarizes the currently important information regarding XDP, providing a synoptic overview and understanding of XDP for future studies.
•Edoxaban use is associated with lower risks of new onset hip fractures, medically attended falls and mortality risks compared to warfarin.•This relationship was observed after propensity score ...matching adjusting for significant confounders.
The three direct oral anticoagulants (DOAC), rivaroxaban, apixaban and dabigatran have been associated with lower risks of fractures compared to warfarin. However, no large scale studies have explored the associations with the newest DOAC, edoxaban, with fracture risk. The present study aims to elucidate the effects of edoxaban on the risk of hip fracture amongst elderly patients by comparing the incidence of new onset hip fracture between edoxaban and warfarin users in a Chinese population.
This was a retrospective population-based cohort study of patients with edoxaban or warfarin use between January 1st, 2016 and December 31st, 2019 in Hong Kong, China. Patients with less than one-month exposure, medication switching between warfarin and edoxaban, those who died within 30 days after drug exposure, prior human immunodeficiency virus infection, age <50 years old, and those with prior hip fractures were excluded. Propensity score matching (1:2) between edoxaban and warfarin users using the nearest neighbour method was performed based on demographics, prior comorbidities, and use of different medications. The study outcomes were new onset hip fractures, medically attended falls and all-cause mortality.
A total of 5014 patients including 579 edoxaban users and 4435 warfarin users (median age: 70 years old interquartile range (IQR): 62–79, 56.66% males) with a median follow-up of 637.5 (IQR: 320–1073) days were included. In the matched cohort, edoxaban users had significantly lower rates of new onset hip fractures, medically attended falls and all-cause mortality. The protective value of edoxaban use against new onset hip fracture (hazard ratio HR: 0.13, 95% confidence interval CI: 0.03–0.54, p = 0.0051), medically attended falls (HR: 0.47, 0.29–0.75, p = 0.0018) and all-cause mortality (HR: 0.61, 0.42–0.87, p = 0.0059) in comparison to warfarin use persisted after matching. The significant relationship between edoxaban use and lower fracture risk was preserved in all sensitivity analyses using different approaches using the propensity score.
Edoxaban use is associated with lower risks of new onset hip fractures, medically attended falls and mortality risks compared to warfarin after propensity score matching.
Aims
To gain insights on the cardiovascular effects of metformin and sulphonylurea, the present study compares the rates of incident atrial fibrillation, stroke, cardiovascular mortality and ...all-cause mortality between metformin and sulphonylurea users in type 2 diabetes mellitus.
Methods
This was a retrospective population-based cohort study of type 2 diabetes mellitus patients receiving either sulphonylurea or metformin monotherapy between January 1, 2000, and December 31, 2019. The primary outcome was new-onset AF or stroke. Secondary outcomes were cardiovascular, non-cardiovascular and all-cause mortality. Propensity score matching (1:2 ratio) between sulphonylurea and metformin users was performed, based on demographics, CHA-DS-VASc score, past comorbidities and medication use. Cox regression was used to identify significant risk factors. Competing risk analysis was conducted using cause-specific and subdistribution hazard models. Sensitivity analyses using propensity score stratification, high-dimensional propensity score and inverse probability of treatment weighting were conducted. Subgroup analyses were conducted for age and gender in the matched cohort.
Results
A total of 36,228 sulphonylurea users and 72,456 metformin users were included in the propensity score-matched cohort. Multivariable Cox regression showed that sulphonylurea users had higher risks of incident AF (hazard ratio HR: 2.89, 95% confidence interval CI: 2.75–3.77
;
P <
0.0001
)
, stroke (HR: 3.23, 95% CI: 3.01–3.45;
P <
0.0001), cardiovascular mortality (HR: 3.60, 95% CI: 2.62–4.81;
P <
0.0001) and all-cause mortality (HR: 4.35, 95% CI: 3.16–4.75;
P <
0.0001) compared to metformin users. Similarly, significant results were observed using cause-specific and subdistribution hazard models. Sensitivity analysis using techniques based on the propensity score also yielded similar results.
Conclusions
Sulphonylurea use was associated with higher risks of incident AF, stroke, cardiovascular mortality and all-cause mortality compared to metformin. Males and patients older than 65 years with sulphonylurea use were exposed to the highest risks.
Introduction
The risk of new onset depression associated with sodium-glucose co-transporter 2 inhibitor (SGLT2I) use in patients with type 2 diabetes mellitus (T2DM) remains unclear. This study ...investigated the risk of new onset depression between SGLT2I and dipeptidyl peptidase 4 inhibitor (DPP4I) users.
Methods
This was a population-based cohort study of T2DM patients in Hong Kong between January 1st, 2015, and December 31st, 2019. T2DM patients over 18 with either SGLT2I or DPP4I use were included. 1:1 propensity-score matching using the nearest-neighbour method was conducted based on demographics, past comorbidities and non-DPP4I/SGLT2I medication use. Cox regression analysis models were used to identify significant predictors for new onset depression.
Results
The study cohort included a total of 18,309 SGLT2I users and 37,269 DPP4I users (55.57% male, mean age: 63.5 ± 12.9 years) with a median follow-up duration of 5.56 (IQR: 5.23–5.8) years. After propensity score matching, SGLT2I use was associated with a lower risk of new onset depression compared to DPP4I use (HR: 0.52, 95% CI: 0.35, 0.77,
P
= 0.0011). These findings were confirmed by Cox multivariable analysis and sensitive analyses.
Conclusion
SGLT2I use is associated with significantly lower risk of depression compared to DPP4 use in T2DM patients using propensity score matching and Cox regression analyses.
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