Ischaemic events in hypertrophic cardiomyopathy patients with and without atrial fibrillation: a systematic review and meta-analysis.

Hypertrophic cardiomyopathy predisposes to acute cerebrovascular events including ischaemic stroke, transient ischaemic attack and systemic thromboembolism. Atrial fibrillation confers even higher risk. We aim to report the incidence of these complications and to investigate the impact of atrial fibrillation on the ischaemic risk in patients with hypertrophic cardiomyopathy. A literature search was performed on PubMed, Scopus, Embase/Ovid and Cochrane library from inception to 20th March 2021. We compared the incidence of ischaemic strokes, transient ischaemic attack, non-specified thromboembolism events and systemic thromboembolism in hypertrophic cardiomyopathy patients with or without atrial fibrillation. Non-specified thromboembolism events in our paper referred to thromboembolic events whereby types were not specified in the studies. Meta-analysis was performed using StataSE 16 software, and heterogeneity was assessed using I2 test. A total of 713 studies were identified. Thirty-five articles with 42,570 patients were included. The pooled incidence of stroke/ transient ischaemic attack was 7.45% (95% confidence interval [CI] 5.80-9.52, p < 0.001) across 24 studies with a total of 37,643 hypertrophic cardiomyopathy patients. Atrial fibrillation significantly increased the risk of total stroke/ transient ischaemic attack (Risk Ratio 3.26, 95% CI 1.75-6.08, p < 0.001, I2 = 76.0). The incidence of stroke/ transient ischaemic attack was 9.30% (95% CI 6.64-12.87, p = 0.316) in the apical hypertrophic cardiomyopathy subgroup. Concomitant atrial fibrillation in hypertrophic cardiomyopathy increases the risk of thromboembolic events including ischaemic stroke and transient ischaemic attack. The apical subgroup shows a similar risk of acute cerebrovascular events as the overall hypertrophic cardiomyopathy population.

Development of a CRISPRi Human Retinal Pigmented Epithelium Model for Functional Study of Age-Related Macular Degeneration Genes.

Age-related macular degeneration (AMD) is a blinding disease characterised by dysfunction of the retinal pigmented epithelium (RPE) which culminates in disruption or loss of the neurosensory retina. Genome-wide association studies have identified >60 genetic risk factors for AMD; however, the expression profile and functional role of many of these genes remain elusive in human RPE. To facilitate functional studies of AMD-associated genes, we developed a human RPE model with integrated CRISPR interference (CRISPRi) for gene repression by generating a stable ARPE19 cell line expressing dCas9-KRAB. We performed transcriptomic analysis of the human retina to prioritise AMD-associated genes and selected TMEM97 as a candidate gene for knockdown study. Using specific sgRNAs, we showed that knockdown of TMEM97 in ARPE19 reduced reactive oxygen species (ROS) levels and exerted a protective effect against oxidative stress-induced cell death. This work provides the first functional study of TMEM97 in RPE and supports a potential role of TMEM97 in AMD pathobiology. Our study highlights the potential for using CRISPRi to study AMD genetics, and the CRISPRi RPE platform generated here provided a useful in vitro tool for functional studies of AMD-associated genes.

Association Between Calcium Supplementation and the Risk of Cardiovascular Disease and Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Some observational studies and randomised controlled trials (RCTs) have reported an association between calcium supplementation and increased risk of cardiovascular disease. Previous meta-analyses on the topic, based on data from RCTs and observational studies, have contradictory findings. This meta-analysis was conducted to determine the difference in associated risks of calcium supplementation with cardiovascular disease and stroke in RCTs. METHODS: Relevant studies published from database inception to 6 August 2021 were sourced from PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials. Any RCTs focusing on the relationship between calcium supplementation and incidence of cardiovascular disease or stroke were included. Articles were screened independently by two authors, according to the PICO criteria, with disagreements resolved by a third author. RESULTS: Twelve RCTs were included in the meta-analysis. Calcium supplementation was not associated with myocardial infarction, total stroke, heart failure admission, and all-cause/cardiovascular mortality. Subgroup analysis focusing on calcium monotherapy/calcium co-therapy with vitamin D, female sex, follow-up duration, and geographical region did not affect the findings. CONCLUSION: Calcium supplementation was not associated with myocardial infarction, total stroke, heart failure admission, and cardiovascular/all-cause mortality. Further studies are required to examine and understand these associations.

A Meta-Analysis and Systematic Review on the Global Prevalence, Risk Factors, and Outcomes of Coronary Artery Disease in Liver Transplantation Recipients.

The shift in the changing etiology of cirrhosis requiring liver transplantation (LT) has resulted in an increasing prevalence of coronary artery disease (CAD) that can potentially impact post-LT outcomes. This systematic review and meta-analysis evaluates the prevalence of CAD, risk factors, and outcomes of patients diagnosed with CAD before LT. MEDLINE and EMBASE were searched for articles describing CAD in pre-LT patients. Meta-analysis of proportions using the generalized linear mix model was conducted to analyze the pooled prevalence of CAD in pre-LT patients. Associated risk factors for CAD in pre-LT patients and outcomes were evaluated in conventional pairwise meta-analysis. A total of 39 studies were included. The pooled prevalence of patients diagnosed with CAD before LT was 15.9% (95% CI, 9.8%-24.7%). Age, male sex, diabetes mellitus, hypertension, hyperlipidemia, smoking, nonalcoholic steatohepatitis, hepatitis B virus, and hepatocellular carcinoma were significantly associated with CAD. Patients from high-income countries especially North America, Europe, and South America, with the associated risk factors were at increased risk for CAD before LT. CAD before LT was associated with an increased odds of overall mortality (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.4-1.4; P = 0.01) and cardiac-related mortality (OR, 1.2; 95% CI, 1.1-1.3; P = 0.03). A total of 48.7% of included articles considered the presence of cardiovascular risk factors for CAD screening. However, 10.3% of the studies screened for CAD in pre-LT patients via invasive coronary angiography only, without stress testing or risk stratification. This study demonstrates the high prevalence of CAD in pre-LT patients, associated risk factors, and outcomes. There is heterogeneity among guidelines and practice in screening for pre-LT CAD, and more studies are needed to establish consensus.

Effects of Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA) on Cardiac Structure and Function: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials.

PURPOSE: Recent trials suggest glucagon-like peptide-1 receptor agonists (GLP-1RAs) may have a cardioprotective role by reducing major adverse cardiac events, stroke mortality and heart failure-related hospitalisations. We examined whether and how GLP-1RAs affect cardiac function in cardiovascular and metabolic diseases including type 2 diabetes, heart failure and post-myocardial infarction. METHODS: In this PRISMA-adherent systematic review and meta-analysis, three databases were searched from inception to July 2021 and registered on PROSPERO (CRD42021259661). RESULTS: 20 reports of 19 randomized placebo-controlled trials including 2062 participants were meta-analyzed. Among type 2 diabetes patients, GLP-1RA resulted in improved systolic function measured by circumferential strain (mean difference [MD]= -5.48; 95% CI: -10.47 to -0.49; P= 0.03; I2= 89%) and diastolic dysfunction measured by E / A (MD= -0.15; 95% CI: -0.25 to -0.05; P= 0.003; I2= 0%). For post-myocardial infarction patients, GLP-1RA reduced infarct size (g) (MD= -5.36; 95% CI: -10.68 to -0.04; P= 0.05; I2= 78%). Liraglutide, but not exenatide, demonstrated improved systolic function, by increasing left ventricular ejection fraction (MD= 4.89; 95% CI: 3.62 to 6.16; P< 0.00001; I2= 0%) and reducing left ventricular end-systolic volume (MD= -4.15; 95% CI: -7.49 to -0.81; P = 0.01; I2= 0%). Among heart failure patients, no significant changes were noted. CONCLUSION: GLP-1RA drugs may improve systolic and diastolic function in type 2 diabetes and reduce infarct size post-acute myocardial infarction with no demonstrable effect on cardiac function in heart failure. Tailored recommendations for the use of GLP-1RAs for cardioprotection should be considered for each patient's condition.

Effects of Sodium-Glucose Cotransporter 2 on Amputation Events: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are increasingly utilized in the treatment of diabetes mellitus as well as therapeutic extra-glycemic effects. However, there are still concerns over complications such as amputation events, given the results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial. Hence, we conducted a systematic review and meta-analysis of randomized-controlled trials to investigate the effect of SGLT2 inhibitors on amputation events. METHODS: Four electronic databases (PubMed, Embase, Cochrane, and SCOPUS) were searched on November 21, 2020, for articles published from January 1, 2000, up to November 21, 2020, for studies that examined the effect of SGLT2 inhibitors on amputation events. Random-effect pair-wise meta-analysis for hazard ratios and fixed-effect Peto odds ratio meta-analysis were utilized to summarize the studies. RESULTS: A total of 15 randomized-controlled trials were included with a combined cohort of 63,716 patients. We demonstrated that there was no significant difference in amputation events across different types of SGLT2 inhibitors, different baseline populations, and different duration of SGLT2 inhibitor use. DISCUSSION/CONCLUSIONS: In this meta-analysis, SGLT2 inhibitors were not associated with a significant difference in amputation events.

MuLV-related endogenous retroviral elements and Flt3 participate in aberrant end-joining events that promote B-cell leukemogenesis.

During V(D)J recombination of immunoglobulin genes, p53 and nonhomologous end-joining (NHEJ) suppress aberrant rejoining of DNA double-strand breaks induced by recombinase-activating genes (Rags)-1/2, thus maintaining genomic stability and limiting malignant transformation during B-cell development. However, Rag deficiency does not prevent B-cell leukemogenesis in p53/NHEJ mutant mice, revealing that p53 and NHEJ also suppress Rag-independent mechanisms of B-cell leukemogenesis. Using several cytogenomic approaches, we identified a novel class of activating mutations in Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase important for normal hematopoiesis in Rag/p53/NHEJ triple-mutant (TM) B-cell leukemias. These mutant Flt3 alleles were created by complex genomic rearrangements with Moloney leukemia virus (MuLV)-related endogenous retroviral (ERV) elements, generating ERV-Flt3 fusion genes encoding an N-terminally truncated mutant form of Flt3 (trFlt3) that was transcribed from ERV long terminal repeats. trFlt3 protein lacked most of the Flt3 extracellular domain and induced ligand-independent STAT5 phosphorylation and proliferation of hematopoietic progenitor cells. Furthermore, expression of trFlt3 in p53/NHEJ mutant hematopoietic progenitor cells promoted development of clinically aggressive B-cell leukemia. Thus, repetitive MuLV-related ERV sequences can participate in aberrant end-joining events that promote development of aggressive B-cell leukemia.

Prevalence and Risk Factors of Cardiac Amyloidosis in Heart Failure: A Systematic Review and Meta-Analysis.

AIMS: Heart failure (HF) is one of the leading causes of mortality worldwide. Heart failure is also one of the most common presentations of cardiac amyloidosis (CA). Contemporary epidemiological data of CA in HF patients is lacking. Hence, this systematic review and meta-analysis was conducted to determine the prevalence of amyloidosis in HF patients, and to clarify the risk factors of concomitant CA and HF. METHODS: A systematic review and meta-analysis was performed. Studies were retrieved from Medline, EMBASE, Scopus and Cochrane library. The search was not restricted in time, type or language of publication. The prevalence of CA in HF grouped according to diagnostic techniques and risk factors of CA with HF was analysed. RESULTS: Eleven (11) studies were included, involving 3,303 patients. The pooled prevalence of CA in HF was 13.7%. The overall prevalence of CA in HF with preserved ejection fraction was 15.1%, and that of HF with reduced ejection fraction was 11.3%. The main factors associated with the diagnosis of CA in HF included older age, males, raised NT pro-BNP, increased interventricular septal thickness in diastole, apical sparing, and reduced left ventricular systolic function. CONCLUSION: A high index of clinical suspicion is required to identify HF patients with CA. Supportive investigations may be helpful when clinically correlated. A considerable proportion of HF patients have CA and certain risk factors may be helpful in increasing suspicion of CA in HF.

Inter-Ethnic Differences in Valvular Dysfunction, Aortopathy, and Progression of Disease of an Asian Bicuspid Aortic Valve Population.

BACKGROUND: There are differences in bicuspid aortic valve (BAV) characteristics between Asian and European populations, but little is known about the inter-ethnic differences in bicuspid valve function and aortic root dimensions within the diverse Asian population. METHODS: From 1992-2017, 562 patients with index echocardiographic diagnosis of BAV in a tertiary health care institution in Singapore were analysed according to their ethnic groups: Chinese, Malay, Indian, and Eurasian. Study outcomes included BAV complications (infective endocarditis, aortic dissection) and clinical outcomes (aortic valve surgery, aortic root surgery, all-cause mortality). Total events were defined as composite outcome of all BAV complications and outcomes. Aortic dimensions and aortic dilatation rates were also studied. RESULTS: There were 379 (67.5%) Chinese, 79 (14.0%) Malay, 73 (13.0%) Indian, and 31 (5.5%) Eurasian patients. Type 1 BAV (58.5%) was the most prevalent BAV morphology, with moderate-to-severe aortic stenosis (AS) (36.8%) being the most common complication in the overall population. There was a higher prevalence of type 0 BAV in Chinese and Indian groups, and type 1 BAV with fusion of left-right coronary cusp in Eurasian and Malay groups (p=0.082). There was no difference in significant AS among groups. The highest prevalence of moderate-to-severe aortic regurgitation was observed amongst the Eurasian group, followed by Chinese, Indian, and Malay groups (p=0.033). The Chinese group had the largest mean indexed diameters of the aortic root. Multivariable linear regression demonstrated that only the Chinese had significantly larger indexed diameters in the aortic annulus, sinotubular junction (STJ), and ascending aorta (AA), relative to the Eurasian group, after adjusting for age, sex, smoking, hypertension, hyperlipidaemia, diabetes, and aortic regurgitation. On follow-up echocardiography, there was a trend towards the highest dilatation rates of sinus of Valsalva and STJ amongst Indian, and AA amongst Malay groups. Kaplan-Meier curves showed the highest incidence of total events amongst Chinese, followed by Malay, Indian and Eurasian (log-rank=9.691; p=0.021) patients. CONCLUSION: There were differences in BAV morphology, valve dysfunction, aortopathy, and prognosis within the Asian population. Chinese patients had one of the highest prevalence of significant aortic regurgitation, with the largest aortic dimensions and worst outcomes compared with other Asian ethnicities. Closer surveillance is warranted in BAV patients within the Asian population.

Evaluating the Initiation of Sodium/Glucose Cotransporter 2 Inhibitors within 2 Weeks of an Acute Hospital Admission: A Systematic Review and Meta-Analysis of Nine Clinical Trials.

OBJECTIVE: Recent studies have increasingly shown the benefits of using sodium/glucose cotransporter 2 inhibitor (SGLT2i). However, there are concerns regarding the initiation of SGLT2i during acute hospital admissions due to the potential increased risk of complications. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of SGLT2i initiation within 2 weeks of an acute hospital admission. METHODS: Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched for articles published from inception up to 27 March 2021 that evaluated the efficacy and/or safety of SGLT2i initiation within 2 weeks of an acute hospital admission. Random-effects pair-wise meta-analysis models were utilized to summarize the studies. The protocol was registered with PROSPERO (CRD42021245492). RESULTS: Nine clinical trials were included with a combined cohort of 1,758 patients. Patients receiving SGLT2i had a mean increase in 24-h urine volume of +487.55 mL (95% CI 126.86-848.25; p = 0.008) compared to those not started on SGLT2i. Patients with heart failure treated with SGLT2i had a 27% relative risk reduction in rehospitalizations for heart failure, compared to controls (risk ratio 0.73; p = 0.005). There were no differences in other efficacy and safety outcomes examined. CONCLUSION: There was no increased harm with initiation of SGLT2i within 2 weeks of an acute hospital admission, and its use reduced the relative risk of rehospitalizations for heart failure in patients with heart failure. It was also associated with increased urine output. However, current evidence pool is limited, especially in specific population subtypes.

Comparing the clinical outcomes across different sodium/glucose cotransporter 2 (SGLT2) inhibitors in heart failure patients: a systematic review and network meta-analysis of randomized controlled trials.

PURPOSE: Empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin have been shown in randomized controlled trials to improve cardiovascular, metabolic, and renal outcomes in heart failure patients. To date, there has not been any meta-analysis examining the differences in clinical outcomes across different SGLT2 inhibitors in heart failure patients. METHODS: Four electronic databases (PubMed, Embase, Cochrane, SCOPUS) were searched on 13 September 2020 for articles published from 1 January 2000 to 13 September 2020 examining the effect of SGLT2 inhibitors on cardiovascular, renal, and metabolic outcomes in heart failure patients. Frequentist network meta-analysis was performed on extracted data. RESULTS: Ten randomized controlled trials were included with a combined cohort of 15,373 patients. In heart failure patients, frequentist network meta-analysis demonstrated no demonstrable difference in treatment effect across the SGLT2 inhibitors for heart failure hospitalization, cardiovascular deaths, composite of cardiovascular deaths and heart failure hospitalizations, all-cause mortality, and a composite of cardiovascular deaths and non-fatal myocardial infarction and non-fatal stroke. There was no demonstrable difference in treatment effect for worsening renal function or the weighted mean difference for weight, hemoglobin A1c, and systolic blood pressure. CONCLUSIONS: There were no demonstrable treatment differences across SGLT2 inhibitors across cardiovascular, renal, and metabolic outcomes, although this needs to be interpreted considering the wide confidence intervals, limited number of included studies, and heterogeneity present. Future research of different SGLT2 inhibitors in head-to-head studies is warranted to determine if there is a drug class effect.

Drusen in patient-derived hiPSC-RPE models of macular dystrophies.

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, the mechanisms underlying their progression remain ill-defined. This is partly due to the lack of disease models recapitulating the human pathology. Furthermore, in vivo studies have yielded limited understanding of the role of specific cell types in the eye vs. systemic influences (e.g., serum) on the disease pathology. Here, we use human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) derived from patients with three dominant MDs, Sorsby's fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy/malattia Leventinese (DHRD), and autosomal dominant radial drusen (ADRD), and demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases. Consistent with clinical studies, sub-RPE basal deposits were present beneath both control (unaffected) and patient hiPSC-RPE cells. Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid- and protein-rich "drusen-like" composition. Furthermore, increased accumulation of COL4 was observed in ECM isolated from control vs. patient hiPSC-RPE cultures. Interestingly, RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD). Finally, although serum exposure was not necessary for drusen formation, COL4 accumulation in ECM, and complement pathway gene alteration, it impacted the composition of drusen-like deposits in patient hiPSC-RPE cultures. Together, the drusen model(s) of MDs described here provide fundamental insights into the unique biology of maculopathies affecting the RPE-ECM interface.

Screening of CRISPR/Cas base editors to target the AMD high-risk Y402H complement factor H variant.

Purpose: To evaluate the efficacy of using a CRISPR/Cas-mediated strategy to correct a common high-risk allele that is associated with age-related macular degeneration (AMD; rs1061170; NM_000186.3:c.1204T>C; NP_000177.2:p.His402Tyr) in the complement factor H (CFH) gene. Methods: A human embryonic kidney cell line (HEK293A) was engineered to contain the pathogenic risk variant for AMD (HEK293A-CFH). Several different base editor constructs (BE3, SaBE3, SaKKH-BE3, VQR-BE3, and Target-AID) and their respective single-guide RNA (sgRNA) expression cassettes targeting either the pathogenic risk variant allele in the CFH locus or the LacZ gene, as a negative control, were evaluated head-to-head for the incidence of a cytosine-to-thymine nucleotide correction. The base editor construct that showed appreciable editing activity was selected for further assessment in which the base-edited region was subjected to next-generation deep sequencing to quantify on-target and off-target editing efficacy. Results: The tandem use of the Target-AID base editor and its respective sgRNA demonstrated a base editing efficiency of facilitating a cytosine-to-thymine nucleotide correction in 21.5% of the total sequencing reads. Additionally, the incidence of insertions and deletions (indels) was detected in only 0.15% of the sequencing reads with virtually no off-target effects evident across the top 11 predicted off-target sites containing at least one cytosine in the activity window (n = 3, pooled amplicons). Conclusions: CRISPR-mediated base editing can be used to facilitate a permanent and stably inherited cytosine-to-thymine nucleotide correction of the rs1061170 SNP in the CFH gene with minimal off-target effects.

Heterogeneous silicon mesostructures for lipid-supported bioelectric interfaces.

Silicon-based materials have widespread application as biophysical tools and biomedical devices. Here we introduce a biocompatible and degradable mesostructured form of silicon with multi-scale structural and chemical heterogeneities. The material was synthesized using mesoporous silica as a template through a chemical vapour deposition process. It has an amorphous atomic structure, an ordered nanowire-based framework and random submicrometre voids, and shows an average Young's modulus that is 2-3 orders of magnitude smaller than that of single-crystalline silicon. In addition, we used the heterogeneous silicon mesostructures to design a lipid-bilayer-supported bioelectric interface that is remotely controlled and temporally transient, and that permits non-genetic and subcellular optical modulation of the electrophysiology dynamics in single dorsal root ganglia neurons. Our findings suggest that the biomimetic expansion of silicon into heterogeneous and deformable forms can open up opportunities in extracellular biomaterial or bioelectric systems.

ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy.

AIMS: We identified a novel homozygous truncating mutation in the gene encoding alpha kinase 3 (ALPK3) in a family presenting with paediatric cardiomyopathy. A recent study identified biallelic truncating mutations of ALPK3 in three unrelated families; therefore, there is strong genetic evidence that ALPK3 mutation causes cardiomyopathy. This study aimed to clarify the mutation mechanism and investigate the molecular and cellular pathogenesis underlying ALPK3-mediated cardiomyopathy. METHODS AND RESULTS: We performed detailed clinical and genetic analyses of a consanguineous family, identifying a new ALPK3 mutation (c.3792G>A, p.W1264X) which undergoes nonsense-mediated decay in ex vivo and in vivo tissues. Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs. Multi-electrode array analysis and calcium imaging demonstrated an extended field potential duration and abnormal calcium handling in mutant contractile cultures. CONCLUSIONS: This study validates the genetic evidence, suggesting that mutations in ALPK3 can cause familial cardiomyopathy and demonstrates loss of function as the underlying genetic mechanism. We show that ALPK3-deficient cardiomyocytes derived from pluripotent stem cell models recapitulate the ultrastructural and electrophysiological defects observed in vivo. Analysis of differentiated contractile cultures identified abnormal calcium handling as a potential feature of cardiomyocytes lacking ALPK3, providing functional insights into the molecular mechanisms underlying ALPK3-mediated cardiomyopathy.

NMNAT2 is a druggable target to drive neuronal NAD production.

Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.

Natural history of initially asymptomatic severe aortic stenosis: a one-stage meta-analysis.

BACKGROUND: Current guidelines on the management strategy for patients with asymptomatic severe aortic stenosis (AS) remain unclear. This uncertainty stems from the lack of data regarding the natural history of these patients. To address this gap, we performed a systematic review and meta-analysis examining the natural history of asymptomatic severe AS patients receiving conservative treatment. METHODS: The PubMed, Cochrane, and Embase databases were searched from inception to 24 January 2024 using the keywords "asymptomatic" AND "aortic" AND "stenosis". We included studies examining patients with asymptomatic severe AS. In interventional trials, only data from conservatively managed arms were collected. A one-stage meta-analysis was conducted using individual patient data reconstructed from published Kaplan-Meier curves. Sensitivity analysis was performed for major adverse cardiovascular outcomes in patients who remained asymptomatic throughout follow-up. RESULTS: A total of 46 studies were included (n = 9545). The median time to the development of symptoms was 1.11 years (95% CI 0.90-1.53). 49.36% (40.85-58.59) of patients who were asymptomatic had suffered a major adverse cardiovascular event by 5 years. The median event-free time for heart failure hospitalization (HFH) was 5.50 years (95% CI 5.14-5.91) with 36.34% (95% CI 33.34-39.41) of patients experiencing an HFH by year 5. By 5 years, 79.81% (95% CI 69.26-88.58) of patients developed symptoms (angina, dyspnoea, syncope and others) and 12.36% (95% CI 10.01-15.22) of patients died of cardiovascular causes. For all-cause mortality, the median survival time was 9.15 years (95% CI 8.50-9.96) with 39.43% (CI 33.41-36.40) of patients dying by 5 years. The median time to AVR was 4.77 years (95% CI 4.39-5.17), with 52.64% (95% CI 49.85-55.48) of patients requiring an AVR by 5 years. CONCLUSION: Our results reveal poor cardiovascular outcomes for patients with asymptomatic severe AS on conservative treatment. A significant proportion eventually requires an AVR. Further research is needed to determine if early intervention with AVR is more effective than conservative treatment.

Clinical predictors and outcomes of ST-elevation myocardial infarction related cardiogenic shock in the Asian population.

Background: Cardiogenic shock (CS) complicating myocardial infarction is associated with poor outcomes. Data among Asian populations are scarce. We aimed to investigate the long-term outcomes, prognostic factors, and predictors of CS among Asian ST elevation myocardial infarction (STEMI) patients. Methods: This was a retrospective cohort study of consecutive patients undergoing primary percutaneous coronary intervention (PPCI) for STEMI within our regional STEMI network between 2015 and 2019. The long-term outcomes of those with and without CS were compared. Clinical predictors of outcomes and development of CS were investigated. Results: A total of 1791 patients who underwent PPCI were included. Patients completed at least 2 years' follow-up with a median follow-up period of 2.6 years (IQR 1.0, 3,9). Overall, 208/1791 (11.6 %) STEMI patients developed CS. These patients were older (61.1 ± 12.5 vs 57.8 ± 12.2, P < 0.001) and mostly men (87.0 %). All-cause mortality (59.9 % vs 4.7 % P < 0.001), cardiac mortality (43.8 % vs 2.2 %, P < 0.001) and major adverse cardiovascular events (MACE) was significantly higher in the CS group (59.1 % vs 14.0 %, P < 0.001). Independent predictors of survival were higher index LVEF (adjusted hazards ratio [aHR] 0.967, 95 %CI 0.951-0.984, p < 0.001) and higher arterial pH at onset of shock (aHR 0.750, 0.626-0.897, p = 0.002). Increased serum lactate concentration independently predicts poor prognosis (aHR 1.084, 95 % CI 1.046-1.124, p < 0.001). Conclusion: In Asian STEMI patients who underwent PPCI, CS was associated with poor outcomes. Higher LVEF on index admission was associated with better outcomes; while lactic acidosis independently predicted mortality.

Snare vegetectomy for right-sided endocarditis.

INTRODUCTION: A middle-aged male developed right-sided endocarditis from an infection of an implantable cardiac defibrillator (ICD) system. Following percutaneous device and lead explantation, a very large pedunculated vegetation (19 mm × 14 mm) was found on the Eustachian valve. We decided to remove the vegetation percutaneously using a wire snare instead of open heart surgery. CASE REPORT: Real-time three-dimensional transesophageal echocardiography and fluoroscopy were used to guide the procedure. Access was from the right femoral vein. Using a triple-loop wire snare through a deflectable sheath, the vegetation was successfully removed in its entirety without complications. CONCLUSION: Percutaneous snare vegetectomy is feasible and may be a viable option in place of open heart surgery in selected patients.