Mice lacking MBNL1 and MBNL2 exhibit sudden cardiac death and molecular signatures recapitulating myotonic dystrophy.

Myotonic dystrophy (DM) is caused by expansions of C(C)TG repeats in the non-coding regions of the DMPK and CNBP genes, and DM patients often suffer from sudden cardiac death due to lethal conduction block or arrhythmia. Specific molecular changes that underlie DM cardiac pathology have been linked to repeat-associated depletion of Muscleblind-like (MBNL) 1 and 2 proteins and upregulation of CUGBP, Elav-like family member 1 (CELF1). Hypothesis solely targeting MBNL1 or CELF1 pathways that could address all the consequences of repeat expansion in heart remained inconclusive, particularly when the direct cause of mortality and results of transcriptome analyses remained undetermined in Mbnl compound knockout (KO) mice with cardiac phenotypes. Here, we develop Myh6-Cre double KO (DKO) (Mbnl1-/-; Mbnl2cond/cond; Myh6-Cre+/-) mice to eliminate Mbnl1/2 in cardiomyocytes and observe spontaneous lethal cardiac events under no anesthesia. RNA sequencing recapitulates DM heart spliceopathy and shows gene expression changes that were previously undescribed in DM heart studies. Notably, immunoblotting reveals a nearly 6-fold increase of Calsequestrin 1 and 50% reduction of epidermal growth factor proteins. Our findings demonstrate that complete ablation of MBNL1/2 in cardiomyocytes is essential for generating sudden death due to lethal cardiac rhythms and reveal potential mechanisms for DM heart pathogenesis.

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice.

BACKGROUND: CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator's anti-aging efficacy. METHODS: We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging. RESULTS: Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice. CONCLUSIONS: Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperetin could act as a functional food or as a skincare product for fighting skin aging.

Mitral Valve Repair vs. Replacement by Different Etiologies　- A Nationwide Population-Based Cohort Study.

BACKGROUND: When mitral valve (MV) surgery is indicated, repair is preferred over replacement; however, this preference is not supported by evidence from clinical trials. Furthermore, the benefits of MV repair may not be universal for all etiologies of MV disease.Methods and Results: This study identified a total of 18,428 patients who underwent MV repair (n=4,817) or MV replacement (n=13,611) during 2001-2018 from Taiwan's National Health Insurance Research Database. These patients were classified into 4 etiologies: infective endocarditis (IE, n=2,678), rheumatic heart disease (RHD, n=4,524), ischemic mitral regurgitation (IMR, n=3,893), and degenerative mitral regurgitation (DMR, n=7,333). After propensity matching, all-cause mortality during follow-up was lower among patients receiving MV repair than among patients receiving MV replacement in the IE, IMR, and DMR groups (hazard ratio [HR]=0.72, 95% confidence interval [CI]: 0.55-0.93; HR=0.82, 95% CI: 0.73-0.92; and HR 0.73, 95% CI: 0.64-0.84, respectively). However, in the RHD group, the MV reoperation rate was higher after MV repair than after MV replacement (subdistribution HR=1.91, 95% CI: 1.02-3.55). CONCLUSIONS: In comparison with MV replacement, MV repair was associated with a lower late mortality in patients with IE, IMR, and DMR, and a higher risk of reoperation in patients with RHD.

Hypermethylation of ACADVL is involved in the high-intensity interval training-associated reduction of cardiac fibrosis in heart failure patients.

BACKGROUND: Emerging evidence suggests that DNA methylation can be affected by physical activities and is associated with cardiac fibrosis. This translational research examined the implications of DNA methylation associated with the high-intensity interval training (HIIT) effects on cardiac fibrosis in patients with heart failure (HF). METHODS: Twelve HF patients were included and received cardiovascular magnetic resonance imaging with late gadolinium enhancement for cardiac fibrosis severity and a cardiopulmonary exercise test for peak oxygen consumption ([Formula: see text]O2peak). Afterwards, they underwent 36 sessions of HIIT at alternating 80% and 40% of [Formula: see text]O2peak for 30 min per session in 3-4 months. Human serum from 11 participants, as a means to link cell biology to clinical presentations, was used to investigate the exercise effects on cardiac fibrosis. Primary human cardiac fibroblasts (HCFs) were incubated in patient serum, and analyses of cell behaviour, proteomics (n = 6) and DNA methylation profiling (n = 3) were performed. All measurements were conducted after completing HIIT. RESULTS: A significant increase (p = 0.009) in [Formula: see text]O2peak (pre- vs. post-HIIT = 19.0 ± 1.1 O2 ml/kg/min vs. 21.8 ± 1.1 O2 ml/kg/min) was observed after HIIT. The exercise strategy resulted in a significant decrease in left ventricle (LV) volume by 15% to 40% (p < 0.05) and a significant increase in LV ejection fraction by approximately 30% (p = 0.010). LV myocardial fibrosis significantly decreased from 30.9 ± 1.2% to 27.2 ± 0.8% (p = 0.013) and from 33.4 ± 1.6% to 30.1 ± 1.6% (p = 0.021) in the middle and apical LV myocardium after HIIT, respectively. The mean single-cell migration speed was significantly (p = 0.044) greater for HCFs treated with patient serum before (2.15 ± 0.17 µm/min) than after (1.11 ± 0.12 µm/min) HIIT. Forty-three of 1222 identified proteins were significantly involved in HIIT-induced altered HCF activities. There was significant (p = 0.044) hypermethylation of the acyl-CoA dehydrogenase very long chain (ACADVL) gene with a 4.474-fold increase after HIIT, which could activate downstream caspase-mediated actin disassembly and the cell death pathway. CONCLUSIONS: Human investigation has shown that HIIT is associated with reduced cardiac fibrosis in HF patients. Hypermethylation of ACADVL after HIIT may contribute to impeding HCF activities. This exercise-associated epigenetic reprogramming may contribute to reduce cardiac fibrosis and promote cardiorespiratory fitness in HF patients. TRIAL REGISTRATION: NCT04038723. Registered 31 July 2019, https://clinicaltrials.gov/ct2/show/NCT04038723 .

Using T1 mapping indices to evaluate muscle function and predict conservative treatment outcomes in diabetic patients with peripheral arterial disease.

OBJECTIVES: To investigate interstitial muscle fibrosis via T1 mapping indices and its relationships with muscle function and conservative treatment outcomes. METHODS: A total of 49 DM patients with PAD were prospectively recruited from 2016 to 2017. All PAD patients underwent pre-treatment MRI with conservative treatment via a rehabilitation program and antiplatelet therapy. The need to require percutaneous transluminal angioplasty intervention was recorded as intolerance to conservative treatment outcomes. We quantified calf interstitial muscle fibrosis using T1 mapping indices (native T1, post-contrast T1, and the extracellular volume fraction [ECV]). Muscle function was evaluated using a 6-min walking test (6MWT) and a 3-min stepping test (3MST). PAD patients were divided into two groups according to their tolerance or intolerance of the conservative treatment. Pearson's correlation, reproducibility, and multivariable Cox hazard analyses were performed with p < 0.05 indicating statistical significance. RESULTS: Among the T1 mapping indices in the posterior compartment of the calf in PAD patients, the native T1 value was significantly correlated with 6MWT (r = -0.422, p = 0.010) and 3MST (r = -0.427, p = 0.009). All T1 mapping indices showed excellent intra-observer and inter-observer correlations. ECV was an independent predictor of conservative treatment intolerance (average ECV, hazard ratio: 1.045, 95% confidence interval: 1.011-1.079, p = 0.009). CONCLUSIONS: T1 mapping measurements are reproducible with excellent intra-observer and inter-observer correlations. T1 mapping indices may be predictive of treatment and functional outcomes and carry promise in patient evaluation. TRIAL REGISTRATION: Clinical Trials Identifier: NCT02850432 . KEY POINTS: • T1 mapping measurements of the calf muscles are reproducible with excellent intra-observer and inter-observer correlations (0.98 and 0.95 for anterior and posterior compartment muscle extracellular volume matrix [ECV] measurements, respectively). • ECV is shown to independently predict conservative treatment intolerance. • T1 mapping indices may be predictive of treatment and functional outcomes and carry promise in patient evaluation.

Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice.

BACKGROUND: The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. METHODS: Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging. RESULTS: Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age. CONCLUSIONS: Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2.

Cisd2 is essential to delaying cardiac aging and to maintaining heart functions.

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart's electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction.

Rejuvenation: Turning Back Time by Enhancing CISD2.

The aging human population with age-associated diseases has become a problem worldwide. By 2050, the global population of those who are aged 65 years and older will have tripled. In this context, delaying age-associated diseases and increasing the healthy lifespan of the aged population has become an important issue for geriatric medicine. CDGSH iron-sulfur domain 2 (CISD2), the causative gene for Wolfram syndrome 2 (WFS2; MIM 604928), plays a pivotal role in mediating lifespan and healthspan by maintaining mitochondrial function, endoplasmic reticulum integrity, intracellular Ca2+ homeostasis, and redox status. Here, we summarize the most up-to-date publications on CISD2 and discuss the crucial role that this gene plays in aging and age-associated diseases. This review mainly focuses on the following topics: (1) CISD2 is one of the few pro-longevity genes identified in mammals. Genetic evidence from loss-of-function (knockout mice) and gain-of-function (transgenic mice) studies have demonstrated that CISD2 is essential to lifespan control. (2) CISD2 alleviates age-associated disorders. A higher level of CISD2 during natural aging, when achieved by transgenic overexpression, improves Alzheimer's disease, ameliorates non-alcoholic fatty liver disease and steatohepatitis, and maintains corneal epithelial homeostasis. (3) CISD2, the expression of which otherwise decreases during natural aging, can be pharmaceutically activated at a late-life stage of aged mice. As a proof-of-concept, we have provided evidence that hesperetin is a promising CISD2 activator that is able to enhance CISD2 expression, thus slowing down aging and promoting longevity. (4) The anti-aging effect of hesperetin is mainly dependent on CISD2 because transcriptomic analysis of the skeletal muscle reveals that most of the differentially expressed genes linked to hesperetin are regulated by hesperetin in a CISD2-dependent manner. Furthermore, three major metabolic pathways that are affected by hesperetin have been identified in skeletal muscle, namely lipid metabolism, protein homeostasis, and nitrogen and amino acid metabolism. This review highlights the urgent need for CISD2-based pharmaceutical development to be used as a potential therapeutic strategy for aging and age-associated diseases.

Rejuvenating the Aging Heart by Enhancing the Expression of the Cisd2 Prolongevity Gene.

Aging is the major risk factor for cardiovascular disease, which is the leading cause of mortality worldwide among aging populations. Cisd2 is a prolongevity gene that mediates lifespan in mammals. Previously, our investigations revealed that a persistently high level of Cisd2 expression in mice is able to prevent age-associated cardiac dysfunction. This study was designed to apply a genetic approach that induces cardiac-specific Cisd2 overexpression (Cisd2 icOE) at a late-life stage, namely a time point immediately preceding the onset of old age, and evaluate the translational potential of this approach. Several discoveries are pinpointed. Firstly, Cisd2 is downregulated in the aging heart. This decrease in Cisd2 leads to cardiac dysfunction and impairs electromechanical performance. Intriguingly, Cisd2 icOE prevents an exacerbation of age-associated electromechanical dysfunction. Secondly, Cisd2 icOE ameliorates cardiac fibrosis and improves the integrity of the intercalated discs, thereby reversing various structural abnormalities. Finally, Cisd2 icOE reverses the transcriptomic profile of the aging heart, changing it from an older-age pattern to a younger pattern. Intriguingly, Cisd2 icOE modulates a number of aging-related pathways, namely the sirtuin signaling, autophagy, and senescence pathways, to bring about rejuvenation of the heart as it enters old age. Our findings highlight Cisd2 as a novel molecular target for developing therapies targeting cardiac aging.

Peripheral arterial disease: the role of extracellular volume measurements in lower limb muscles with MRI.

OBJECTIVES: Peripheral arterial disease (PAD) is characterised by arterial occlusion and fibrosis in the lower extremities. Extracellular volume matrix fraction (ECV) is a biomarker of skeletal muscle fibrosis, but has not been applied to the lower extremities with PAD. This study investigated the clinical feasibility of using ECV for calf muscle fibrosis quantification by comparing normal controls (NC) and PAD patients. METHODS: From October 2016 to December 2017, we recruited patients with PAD, and patients with head and neck cancer receiving fibular flap as NC group. All participants underwent magnetic resonance imaging (MRI) to determine the ECV of the calves and the differences between the NC and PAD groups. ECV was calculated from T1 values at steady-state equilibrium, defined as the point in time after contrast agent injection when the variance of T1 relaxation time in blood and muscle becomes less than 5%. RESULTS: A total of 46 patients (18 in the NC group and 28 in the PAD group) were recruited. Steady-state equilibrium was reached at 11-12 min after contrast agent injection. The NC group had significantly lower mean ECV than the PAD group (12.71% vs. 31.92%, respectively, p < 0.001). In the PAD group, the mean ECV was slightly lower in patients with collateral vessels than in those without (26.58% vs. 34.88%, respectively, p = 0.047). CONCLUSION: Evaluation of skeletal fibrosis in PAD using ECV is feasible. ECV can help identify PAD patients with collateral vessel formation and lay the foundation for future research in PAD management. KEY POINTS: • Steady-state equilibrium for ECV measurement of the lower limbs can be reached at around 11-12 min. • Quantification of lower limb muscle fibrosis by measuring ECV is clinically feasible and can be used to differentiate between patients with PAD and histologically proven normal controls. • ECV can differentiate PAD patients with or without visible collateral vessels, further expanding its role in identifying the presence of collateral supply in clinical decision-making.

Mitochondria and Calcium Homeostasis: Cisd2 as a Big Player in Cardiac Ageing.

The ageing of human populations has become a problem throughout the world. In this context, increasing the healthy lifespan of individuals has become an important target for medical research and governments. Cardiac disease remains the leading cause of morbidity and mortality in ageing populations and results in significant increases in healthcare costs. Although clinical and basic research have revealed many novel insights into the pathways that drive heart failure, the molecular mechanisms underlying cardiac ageing and age-related cardiac dysfunction are still not fully understood. In this review we summarize the most updated publications and discuss the central components that drive cardiac ageing. The following characters of mitochondria-related dysfunction have been identified during cardiac ageing: (a) disruption of the integrity of mitochondria-associated membrane (MAM) contact sites; (b) dysregulation of energy metabolism and dynamic flexibility; (c) dyshomeostasis of Ca2+ control; (d) disturbance to mitochondria-lysosomal crosstalk. Furthermore, Cisd2, a pro-longevity gene, is known to be mainly located in the endoplasmic reticulum (ER), mitochondria, and MAM. The expression level of Cisd2 decreases during cardiac ageing. Remarkably, a high level of Cisd2 delays cardiac ageing and ameliorates age-related cardiac dysfunction; this occurs by maintaining correct regulation of energy metabolism and allowing dynamic control of metabolic flexibility. Together, our previous studies and new evidence provided here highlight Cisd2 as a novel target for developing therapies to promote healthy ageing.

The risk of diabetic renal function impairment in the first decade after diagnosed of diabetes mellitus is correlated with high variability of visit-to-visit systolic and diastolic blood pressure: a case control study.

BACKGROUND: The variability of visit-to-visit (VVV) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) is proved as a predictor of renal function deterioration in patients with non-diabetic chronic kidney disease. The purpose of this study was to investigate the relationship of the variability in SBP and the magnitude of renal function impairment for normal renal function patients in the first 10-years diagnosed with type II diabetes mellitus (DM). METHODS: We retrospectively reviewed the electronic medical records of 789 patients who were first diagnosed with diabetes mellitus during 2000-2002 and regularly followed for 10 years with a total of 53,284 clinic visits. The stages of Chronic Kidney Disease (CKD) of every patient were determined using estimated glomerular filtration rate. The occurrence of nephropathy was defined in those patients whose CKD stages elevated equal or larger than three. RESULTS: Patients were categorized according to the VVV of systolic and diastolic BP into three groups. Patients with high VVV of both SBP and DBP had a 2.44 fold (95% CI: 1.88-3.17, p < 0.001) increased risk of renal function impairment compared with patients with low VVV of both SBP and DBP. Risk of renal function impairment for patients with high VVV of either SBP or DBP had a 1.43-fold increase (95% CI: 1.08-1.89, p = 0.012) compared with patients with low VVV of both SBP and DBP. Cox regression analysis also demonstrated that every 1-year increase of DM diagnosed age significantly raised the risk of renal function impairment with a hazard ration of 1.05 (95% CI: 1.04-1.06, p < 0.001). CONCLUSIONS: Not only VVV of SBP but also VVV in DBP is correlated with diabetic nephropathy in the first decade for patients diagnosed with type 2 DM.

ExPRESS miniature glaucoma shunt for intractable secondary glaucoma in superior vena cava syndrome - a case report.

BACKGROUND: The aim of this study was to clarify the pathogenic mechanism and to evaluate an intervention for intractable secondary glaucoma in superior vena cava (SVC) syndrome. CASE PRESENTATION: A 66-year-old female with underlying hypertension, diabetes mellitus, ischaemic heart disease and end-stage renal disease complained of bilateral puffy eyelids for 3 months. Over three years, the patient experienced a progressive, marked face and neck swelling, which was accompanied by dyspnoea and nocturnal coughing. The patient has been under haemodialysis for the past 5 years; there were several occurrences of vascular access re-establishment for susceptibility to vascular thrombosis, and she was also diagnosed with SVC syndrome 2 years after haemodialysis. The patient's best-corrected visual acuity (BCVA) was 20/60 in the right eye and 20/400 in the left eye. Pneumatic tonometry revealed a gradual increase in the intraocular pressure (IOP), even with the use of three types of anti-glaucoma agents. The ratio was 0.7 and bilaterally symmetric; optical coherence tomography indicated a thinning of the superior and inferior retina nerve fibre layers, and standard automated perimetry showed partial to generalized depression in both eyes. Filtering surgery for the left eye was performed, but postoperatively, the IOP increased gradually over three months. The subsequent placement of the ExPRESS miniature glaucoma device p200 effectively lowered the IOP. Postoperatively, the IOP of the left eye remained under 20 mmHg without a further decrease in visual acuity, while the right eye, which was controlled with only medication, had an IOP of greater than 30 mmHg. Because this patient refused cardiovascular intervention, conventional trabeculectomy was used to redirect the aqueous humour to the subconjunctival space to form a bleb, but failed. Fortunately, the subsequent ExPRESS implant effectively facilitated aqueous outflow through the intrascleral space, resulting in the maintenance of a normal IOP at 6 months, postoperatively. CONCLUSION: Sustained high IOP may occur after conventional filtration surgery for secondary glaucoma in SVC syndrome. To facilitate aqueous outflow, an ExPRESS glaucoma implant can be used to effectively control the IOP.

Bronchoscopic finding determined outcome after chemoradiotherapy in esophageal cancer patients with airway invasion.

BACKGROUND: We studied whether the bronchoscopic findings could be help to predict outcome after chemoradiotherapy (CRT) in patients with airway invasion by esophageal cancer. METHOD: Between 2000 and 2010, we retrospectively investigated esophageal cancer patients with T4 disease due to airway invasion who had received CRT as first line treatment. Airway invasion is defined as infiltration of the tracheobronchial wall or protruded intraluminal growth on bronchoscopy. The total radiation dose of CRT was 60 Gy and divided into two cycles. Bronchoscopic findings were evaluated together with other clinical parameters and correlated with overall survival (OS). RESULT: There were 68 patients with a mean age of 54.5 years. After the first cycle of CRT, bronchoscopic examination showed complete regression of endobronchial lesion in 16 patients. OS was 26% at 1 year and 5% at 3 years with the median survival time (MST) of 7 months. Multivariate analysis revealed vocal cord palsy (unfavorable, OR [95% CI]:2 [1.07-3.84], P = 0.03), carina involvement (unfavorable, OR [95% CI]:2.6 [1.12-6], P = 0.025) and intraluminal tumor growth (unfavorable, OR [95% CI]:1.9 [1.1-3.3], P = 0.023) as independent factors for survival. The MST after CRT was 12.1, 6.1, 5.7 months in patients with 0, 1, 2 factors, respectively (P < 0.001). CONCLUSION: Bronchoscopic finding determined outcome after CRT in esophageal cancer patients with airway invasion.

Trainability for cardiopulmonary fitness is low in patients with peripheral artery disease.

AIMS: In patients with peripheral arterial disease (PAD), exercise therapy is recommended to relieve leg symptoms, as noted in the 2016 AHA/ACC and 2017 ESC/ESVS guidelines. We assessed the trainability for cardiopulmonary fitness (CPF) and quality of life (QOL); three distinct patient types, namely, PAD, heart failure (HF), and stroke, were compared. METHODS AND RESULTS: This is a multicentre, retrospective analysis of prospectively collected data from three clinical studies. Data collected from 123 patients who completed 36 sessions of supervised aerobic training of moderate intensity were analysed, with 28 PAD, 55 HF, and 40 stroke patients totalling 123. Before and after training, cardiopulmonary exercise testing with non-invasive cardiac output monitoring and QOL evaluation using a 36-Item Short Form Survey (SF-36) were performed. Non-response was defined as a negative change in the post-training value compared with that in the pre-training value. The result showed an improvement in CPF in all three groups. However, cardiorespiratory fitness (CRF) increased by a lesser extent in the PAD group than in the HF and stroke groups; the physical and mental component scores (MCS) of SF-36 exhibited a similar pattern. Non-response rates of peak V˙O2, oxygen uptake efficiency slope, and MCS were higher in the PAD group. In the PAD group, non-responders regarding peak V˙O2 had a higher pulse wave velocity than responders. CONCLUSION: In patients with PAD following exercise therapy, CRF and QOL improved to a lesser extent on average; their non-response rate was also higher compared with that of HF or stroke patients. Therefore, a higher dose of exercise might be needed to elicit adaptation in PAD patients, especially those with high pulse wave velocity.

Effects of mitral valve disease etiology on the outcomes of mechanical and biological valve replacement: retrospective cohort study.

INTRODUCTION: The choice of an artificial mitral valve (MV) is a crucial clinical decision that affects the long-term survival and quality of life of patients. However, current guidelines recommend selecting MV based on patient age and life expectancy at the time of mitral valve replacement (MVR), without considering the etiology of MV disease. This study aimed to investigate whether MV disease etiology should be considered when choosing a valve for MVR and to evaluate the impact of MV disease etiology on long-term patient survival. METHODS: Using data (2002-2018) from Taiwan's National Health Insurance Research Database, the authors conducted a nationwide retrospective cohort study to compare the biological and mechanical valves in terms of all-cause mortality as the primary outcome. The inverse probability of the treatment weighting method was used to reduce the effects of the confounding factors. The following etiologies were assessed: infective endocarditis, rheumatic heart disease, ischemic mitral regurgitation, and degenerative mitral regurgitation. RESULTS: In patients aged below 70 years, it was observed that mechanical valves demonstrated an association with benefits compared to biological valves in the context of survival. In patients with infective endocarditis aged below 72 years, mechanical valves were associated with survival benefits, but not in those with stroke during hospitalization. These valves were also found to be linked with survival advantages for patients with rheumatic heart disease aged below 60 years and for those with degenerative mitral regurgitation aged below 72 years. However, no age-dependent effects of valve type on all-cause mortality were observed in patients with ischemic mitral regurgitation. CONCLUSION: The etiology of MV disease appears to be important in the selection of a suitable MV and determination of a cutoff age for mechanical and biological MVR.

Lymph node dissection after chemoradiation in esophageal cancer: a subgroup analysis of patients with and without pathological response.

BACKGROUND: Extensive lymph node dissection (LND) is beneficial in primarily resected esophageal cancer patients. Such benefit was believed to be seen in neoadjuvant chemoradiotherapy (CRT)-treated patients, but evidence was inconsistent. We hypothesized that CRT might offset the benefit of LND in certain subgroup of patients, especially in major responders. METHODS: The clinical pathological data and survival of esophageal squamous cell carcinoma patients who received curative resection after CRT between 1996 and 2007 were analyzed. On the basis of the mean LND number of the cohort, patients were divided into two groups: group 1, lower LND, and group 2, higher LND. RESULTS: The cohort comprised 303 patients (295 men and 8 women) with a mean age of 55.4 years. There were 179 patients in group 1 and 124 patients in group 2. One hundred one patients had pathological complete response (pCR). There were more pCR in group 1 (38 vs. 26.6%, P = 0.039) and more lymph node positive cases in group 2 (16 vs. 27.4%, P = 0.018). Extent of LND had no survival difference in the entire cohort (overall survival 32 vs. 38%, P = 0.31). With the stratification analysis according to tumor response, inadequate LND exhibited negative impact in patients who did not experience pCR (P = 0.027). Without adequate LND, the survival of ypTxN0 was equally poor as ypN-positive cases (overall survival 15 vs. 16%, P = 0.791). In the pCR group, the extent of LND had an impact on survival. CONCLUSIONS: The effect of LND was influenced by tumor response after CRT. There is a strong survival benefit for extensive LND after CRT in esophageal squamous cell carcinoma, especially in non-pCR patients.

Impact of the number of lymph nodes sampled on outcome in ypT0N0 esophageal squamous cell carcinoma patients.

BACKGROUND: Higher extent of lymph node dissection (LND) is beneficial in primarily resected esophageal cancer patients by providing accurate staging and better tumor control. Achieving pathological complete response (pCR) after chemoradiotherapy (CRT) also represents better outcome. We studied the controversial question whether higher LND could further improve survival after pCR. METHOD: Between 1996 and 2007, Esophageal squamous cell carcinoma (ESCC) patients with pCR after CRT were included. Based on the median number of dissected lymph node, patients were divided into two groups (Group 1: Lower LND; Group 2: Higher LND). We compared the demographic features, perioperative outcomes, recurrence, and survival between groups. RESULTS: The cohort comprised 101 patients (100 males and one female) with a mean age of 58 years. There were 56 and 45 patients in Group 1 and 2, respectively. Clinical features and perioperative outcome were similar between groups. During a mean follow-up of 78.8 months, 32 (33.7%) patients died of the disease and 35.8% of patients developed recurrence. There was no difference in locoregional (11.3% vs. 9.5%, P=0.78) or distant recurrence (22.6% vs. 33.3%, P=0.18) between the two groups. Patients with lowest LND also had similar outcomes as those with the highest LND. The 5-year disease specific survival rate was 65 and 64% in Group 1 and 2, respectively. CONCLUSION: In ESCC patients, the number of negative lymph nodes had no prognostic impact after pCR.

Mono or Dual Antiplatelet Therapy for Treating Patients with Peripheral Artery Disease after Lower Extremity Revascularization: A Systematic Review and Meta-Analysis.

The efficacy of dual antiplatelet therapy (DAPT) for patients with peripheral artery disease (PAD) after lower-limb intervention remains controversial. Currently, the prescription of DAPT after an intervention is not fully recommended in guidelines due to limited evidence. This study compares and analyzes the prognosis for symptomatic PAD patients receiving DAPT versus monotherapy after lower-limb revascularization. Up to November 2021, PubMed/MEDLINE, Embase, and Cochrane databases were searched to identify studies reporting the efficacy, duration, and bleeding complications when either DAPT or monotherapy were used to treat PAD patients after revascularization. Three randomized controlled trials and seven nonrandomized controlled trials were included in our study. In total, 74,651 patients made up these ten studies. DAPT in PAD patients after intervention was associated with lower rates of all-cause mortality (HR = 0.86; 95% CI, 0.79−0.94; p < 0.01), major adverse limb events (HR = 0.60; 95% CI, 0.47−0.78; p < 0.01), and major amputation (HR = 0.78; 95% CI, 0.64−0.96) when follow-up was for more than 1-year. DAPT was not associated with major bleeding events when compared with monotherapy (OR = 1.22; 95% CI, 0.69−2.18; p = 0.50) but was associated with a higher rate of minor bleeding as a complication (OR = 2.54; 95% CI, 1.59−4.08; p < 0.01). More prospective randomized studies are needed to provide further solid evidence regarding the important issue of prescribing DAPT.

Artificial-Intelligence-Assisted Discovery of Genetic Factors for Precision Medicine of Antiplatelet Therapy in Diabetic Peripheral Artery Disease.

An increased risk of cardiovascular events was identified in patients with peripheral artery disease (PAD). Clopidogrel is one of the most widely used antiplatelet medications. However, there are heterogeneous outcomes when clopidogrel is used to prevent cardiovascular events in PAD patients. Here, we use an artificial intelligence (AI)-assisted methodology to identify genetic factors potentially involved in the clopidogrel-resistant mechanism, which is currently unclear. Several discoveries can be pinpointed. Firstly, a high proportion (>50%) of clopidogrel resistance was found among diabetic PAD patients in Taiwan. Interestingly, our result suggests that platelet function test-guided antiplatelet therapy appears to reduce the post-interventional occurrence of major adverse cerebrovascular and cardiac events in diabetic PAD patients. Secondly, AI-assisted genome-wide association study of a single-nucleotide polymorphism (SNP) database identified a SNP signature composed of 20 SNPs, which are mapped into 9 protein-coding genes (SLC37A2, IQSEC1, WASHC3, PSD3, BTBD7, GLIS3, PRDM11, LRBA1, and CNR1). Finally, analysis of the protein connectivity map revealed that LRBA, GLIS3, BTBD7, IQSEC1, and PSD3 appear to form a protein interaction network. Intriguingly, the genetic factors seem to pinpoint a pathway related to endocytosis and recycling of P2Y12 receptor, which is the drug target of clopidogrel. Our findings reveal that a combination of AI-assisted discovery of SNP signatures and clinical parameters has the potential to develop an ethnic-specific precision medicine for antiplatelet therapy in diabetic PAD patients.