Effect of Digitalis on ICD or CRT-D Recipients: A Systematic Review and Meta-Analysis.

BACKGROUND: Digitalis has been widely utilized for heart failure therapy and several studies have demonstrated an association of digitalis and adverse outcome events in patients receiving implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds). Hence, we conducted this meta-analysis to assess the effect of digitalis on ICD or CRT-D recipients. METHODS: We systematically retrieved relevant studies using the Cochrane Library, PubMed, and Embase database. A random effect model was used to pool the effect estimates (hazard ratios (HRs) and 95% confidence intervals (CIs)) when the studies were of high heterogeneity, otherwise a fixed effect model was used. RESULTS: Twenty-one articles containing 44,761 ICD or CRT-D recipients were included. Digitalis was associated with an increased rate of appropriate shocks (HR = 1.65, 95% CI: 1.46-1.86, p < 0.001) and a shortened time to first appropriate shock (HR = 1.76, 95% CI: 1.17-2.65, p = 0.007) in ICD or CRT-D recipients. Furthermore, the all-cause mortality increased in ICD recipients with digitalis therapy (HR = 1.70, 95% CI: 1.34-2.16, p < 0.01), but the all-cause mortality was unchanged in CRT-D recipients (HR = 1.55, 95% CI: 0.92-2.60, p = 0.10) or patients who received ICD or CRT-D therapy (HR = 1.09, 95% CI: 0.80-1.48, p = 0.20). The sensitivity analyses confirmed the robustness of the results. CONCLUSION: ICD recipients with digitalis therapy may tend to have higher mortality rates, but digitalis may not be associated with the mortality rate of CRT-D recipients. Further studies are required to confirm the effects of digitalis on ICD or CRT-D recipients.

Comparative Cardiovascular Outcomes of SGLT2 Inhibitors in Type 2 Diabetes Mellitus: A Network Meta-Analysis of Randomized Controlled Trials.

Background: A network meta-analysis of randomized controlled trials (RCTs) was conducted to explore the cardiovascular outcomes of all the kind and dosages of sodium-glucose cotransport-2 (SGLT2) inhibitors in type 2 diabetes mellitus (T2DM) patients. Method and Result: The Cochrane Library, PubMed, and Embase databases were systematically searched for studies to compare the therapeutic effects of different SGLT2 inhibitors in T2DM patients. The effect measurements estimate chosen were odds ratios (ORs) and their corresponding 95% confidence interval (CI). Forty-seven RCTs involving a total of 70574 participants were eligible for direct and indirect comparisons. In direct comparison, treatment with dapagliflozin 5mg showed significantly lower risk of all-cause mortality compared with treatment with dapagliflozin 2.5mg (OR 0.09, 95% CI 0.01-0.70). According to NMA, interestingly, empagliflozin 10mg/25mg, and canagliflozin 100mg was associated with significantly lower risks of all-cause mortality compared with placebo (OR of 0.70, 95% CI 0.58-0.85; 0.69, 95% CI 0.57-0.84; and 0.83, 95% CI 0.73-0.95, respectively). Compared with placebo, dapagliflozin 10mg, empagliflozin 10mg and 25mg displayed the lower risks for cardiovascular events (OR 0.78, 95% CI 0.44-1.00; OR 0.47, 95% CI 0.22-0.93; and 0.43, 95% CI 0.24-0.74, respectively) by direct comparison. Moreover, canagliflozin 100/300mg showed significantly higher risks of cardiovascular events compared with empagliflozin 10mg (OR of 4.83, 95% CI 1.14-20.46 and 5.31, 95% CI 1.26-22.34, respectively) and empagliflozin 25mg (4.23, 95% CI 1.13-15.83 and 4.65, 95% CI 1.25-17.27, respectively) according to NMA. There were non-significant differences among all interventions in volume depletion in traditional pairwise meta-analysis. While in NMA, canagliflozin 100/300mg were associated with significantly increased risks of volume depletion compared with placebo (OR of 1.47, 95% CI 1.08-1.99 and 2.19, 95% CI 1.66-2.90, respectively). Conclusion: In the limitations of the NMA, this study showed that empagliflozin might be better than other SGLT2 inhibitors with low risks of all-cause mortality and cardiovascular events in patients with T2DM suggesting the need for ad hoc RCTs.

Dexmedetomidine post-conditioning alleviates myocardial ischemia-reperfusion injury in rats by ferroptosis inhibition via SLC7A11/GPX4 axis activation.

The SLC7A11/GPX4 axis plays an important role in ferroptosis during cardiac ischemia/reperfusion injury (IRI). The present study was designed to evaluate the impact of dexmedetomidine (DEX) post-conditioning on cardiac IRI and to explore whether the effect was achieved by SLC7A11/GPX4 signaling pathway regulation. Rat myocardial IRI was established by occluding the left anterior descending artery for 30 min followed by 2-h reperfusion. The infarct area was detected by diphenyltetrazolium chloride (TTC) staining; the cardiac function was evaluated by echocardiography. The levels of lipid peroxide biomarkers were measured to estimate the injury caused by lipid peroxide. HE staining and Sirius staining were utilized to assess myocardial damage and fibrosis. The mitochondrial morphology was observed by electron micrography. Western blot and quantitative real-time polymerase chain reaction were employed to measure the relative molecular characteristics. Our results showed that DEX administration at the beginning of reperfusion attenuated IRI-induced myocardial injury, alleviated mitochondrial dysfunction, decreased the level of reactive oxygen species (ROS), alleviated mitochondrial dysfunction, inhibited the activation of SLC7A11/GPX4, and modulated the expression of ferroptosis-related proteins, including SLC7A11, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH), and cyclooxygenase-2 (COX-2). Conversely, the ferroptosis activator erastin partly suppressed the DEX-mediated cardio protection. Altogether, these results reveal that DEX inhibits ferroptosis by enhancing the expression of SLC7A11 and GPX4, thereby preventing cardiac I/R injury.

Comparative Transcriptional Analysis of Pulmonary Arterial Hypertension Associated With Three Different Diseases.

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disorder with high mortality. Multiple clinical diseases can induce PAH, but the underlying molecular mechanisms shared in PAHs associated with different diseases remain unclear. The aim of this study is to explore the key candidate genes and pathways in PAH associated with congenital heart disease (CHD-PAH), PAH associated with connective tissue disease (CTD-PAH), and idiopathic PAH (IPAH). We performed differential expression analysis based on a public microarray dataset GSE113439 and identified 1,442 differentially expressed genes, of which 80.3% were upregulated. Subsequently, both pathway enrichment analysis and protein-protein interaction network analysis revealed that the "Cell cycle" and "DNA damage" processes were significantly enriched in PAH. The expression of seven upregulated candidate genes (EIF2AK2, TOPBP1, CDC5L, DHX15, and CUL1-3) and three downregulated candidate genes (DLL4, EGFL7, and ACE) were validated by qRT-PCR. Furthermore, cell cycle-related genes Cul1 and Cul2 were identified in pulmonary arterial endothelial cells (PAECs) in vitro. The result revealed an increased expression of Cul2 in PAECs after hypoxic treatment. Silencing Cul2 could inhibit overproliferation and migration of PAECs in hypoxia. Taken together, according to bioinformatic analyses, our work revealed that "Cell cycle" and "DNA damage" process-related genes and pathways were significantly dysregulated expressed in PAHs associated with three different diseases. This commonality in molecular discovery might broaden the genetic perspective and understanding of PAH. Besides, silencing Cul2 showed a protective effect in PAECs in hypoxia. The results may provide new treatment targets in multiple diseases induced by PAH.

Prevalence and impact of cardiac injury on COVID-19: A systematic review and meta-analysis.

BACKGROUND: The exact prevalence and impact of cardiac injury in hospitalized patients with coronavirus disease 2019 (COVID-19) is still controversial. Hence, we aim to investigate prevalence of cardiac injury and its impact on the outcomes in patients with COVID-19. HYPOTHESIS: Cardiac injury is common and associated with higher risk of death. METHODS: We searched the Cochrane Library, PubMed, MedRxiv, and EMBASE databases from December 2019 to July 15, 2020 for studies that evaluated the prevalence and impact of cardiac injury on COVID-19. This study has been registered with PROSPERO (International prospective register of systematic reviews)-registration number-CRD-42020186120. RESULTS: Twenty-one studies including 6297 participants were identified. The proportions of cardiac injury were 22%, 28% among hospitalized patients with COVID-19 or severe COVID-19 patients, respectively. The incidences of cardiac injury in advance age (>60 years) (30%) was about two-fold than young patients (<60 years) (15%) with COVID-19. Severe cases (42%) have seven-fold prevalence cardiac injury than in their non- severe counterparts (6%). Furthermore, cardiac injury is associated with an increased risk of all-cause mortality in patients with COVID-19 (OR 10.11, 95% CI 4.49-22.77). In patients with severe COVID-19, cardiac injury is associated with an increased risk of all-cause mortality (OR: 16.79, 95% CI: 5.52-51.02). CONCLUSIONS: This was the first meta-analysis exploring the prevalence and impact of cardiac injury on COVID-19. Cardiac injury is common in hospitalized patients and advanced age and severe COVID-19 patients prone to experience more risk of cardiac injury. Furthermore, cardiac injury is associated with increased risk of all-cause mortality.

Is Atrial Fibrillation Noninducibility by Burst Pacing After Catheter Ablation Associated With Reduced Clinical Recurrence?: A Systematic Review and Meta-Analysis.

Background To date, there is no cumulative evidence supporting the association of atrial fibrillation (AF) noninducibility after ablation and freedom from AF. We performed a systematic review and meta-analysis to determine whether AF noninducibility by burst pacing after catheter ablation is associated with reduced AF recurrence. Methods and Results We searched PubMed, Embase, Web of Science, and Cochrane Library databases through July 2019 to identify studies that evaluated AF noninducibility versus inducibility by burst pacing after catheter ablation for freedom from AF. A fixed effects model was used to estimate relative risk (RR) with 95% CIs. Twelve prospective cohort studies with AF noninducibility (n=1612) and inducibility (n=1160) were included. Compared with AF inducibility, AF noninducibility by burst pacing after ablation was associated with a reduced risk of AF recurrence (RR, 0.68; 95% CI, 0.60-0.77). Subgroup analysis showed that different AF types (paroxysmal AF and nonparoxysmal AF), different follow-up times (≤6, 6-12, and >12 months), and different degrees of burst pacing (mild, moderate, severe) had no significant impact on the RRs. However, different cut-off times for AF inducibility had a significant impact on the RR (Pinteraction=0.009), and only the cut-off time of 1 minute showed a significant correlation (RR, 0.54; 95% CI, 0.45-0.66). Conclusions AF noninducibility by burst pacing after catheter ablation is associated with reduced clinical recurrence of AF. Induction protocols with a different cut-off time for AF inducibility have a significant impact on the correlation, and the AF ≥1 minute for AF inducibility is recommended.

Factors Associated with a Large Decline in Renal Function or Progression to Renal Insufficiency in Hospitalized Atrial Fibrillation Patients with Early-Stage CKD.

Clinicians must consider renal function when administering anticoagulants for atrial fibrillation (AF). Determination of risk factors for renal function decline may enable identification of patients who require closer monitoring. We investigated the characteristics associated with renal function decline in patients with AF. The study cohort consisted of 631 AF patients who had at least one readmission during the follow-up period and stages 1-3 chronic kidney disease (CKD). The primary outcome measure was large renal function decline (≥30% decrease from baseline estimated glomerular filtration rate [eGFR]). The secondary outcome measure was a final eGFR < 60 mL/minute/1.73 m2 for those with a baseline eGFR above this level. The mean eGFR was 74.4 ± 18.5 mL/minute/1.73 m2, and the mean follow-up time was 30.2 ± 13.2 months. The primary outcome occurred in 155 patients (24.6%) and was associated with congestive heart failure (CHF), proteinuria, type of AF, and left atrial diameter (LAD) ≥ 45 mm. Among 478 patients with a baseline eGFR ≥ 60 mL/minute/1.73 m2, 137 (28.7%) progressed to renal failure (eGFR < 60 mL/minute/1.73 m2). A decreasing eGFR was associated with age ≥ 75 years, CHF, lower baseline eGFR, and LAD ≥ 45 mm. CHF, proteinuria, type of AF, and LAD ≥ 45 mm were associated with eGFR decline ≥ 30% in AF patients with CKD stages 1-3. Advanced age, CHF, lower baseline eGFR, and LAD ≥ 45 mm were associated with progression to renal insufficiency. These results should be considered when identifying patients who require more frequent monitoring of eGFR.

Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta-analysis.

Whether the presence of SCN5A mutation is a predictor of BrS risk remains controversial, and patient selection bias may have weakened previous findings. Therefore, we performed this study to clarify the clinical characteristics and outcomes of BrS probands with SCN5A mutations. We systematically retrieved eligible studies published through October 2018. A total of 17 studies enrolling 1780 BrS patients were included. Overall, our results found that compared with BrS patients without SCN5A mutations, patients with SCN5A mutations exhibited a younger age at the onset of symptoms and higher rate of the spontaneous type-1 electrocardiogram pattern, more pronounced conduction or repolarization abnormalities, and increased atrial vulnerability. In addition, the presence of SCN5A mutations was associated with an elevated risk of major arrhythmic events in both Asian (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.07-3.11; P = .03) and Caucasian (OR = 2.24, 95% CI 1.02-4.90; P = .04) populations. In conclusions, patients with SCN5A mutations exhibit more pronounced electrophysiological defects and more severe prognosis. Clinicians should be cautious when utilizing genetic testing for risk stratification or treatment guidance before determining whether the causal relationship regarding SCN5A mutation status is an independent predictor of risk.

Efficacy and Safety of the Use of Non-vitamin K Antagonist Oral Anticoagulants in Patients with Ischemic Heart Disease: A Meta-Analysis of Phase III Randomized Trials.

BACKGROUND: There are conflicting published data on non-vitamin K antagonist oral anticoagulants (NOACs), with varying evidence of benefit or harm in acute coronary syndrome (ACS) and non-ACS cohorts. To explore the efficacy and safety of NOAC use in patients with ischemic heart disease (IHD), we conducted a meta-analysis of phase III randomized controlled trials (RCTs). METHODS: We systematically searched the Cochrane Library, PubMed, and Embase databases. A random-effect model was selected to pool the effect measurement estimates (hazard ratios [HRs] and 95% confidence intervals [CIs]). RESULTS: Three RCTs with 39,492 enrolled IHD patients were included. Compared with placebo, NOACs were associated with reduced risks of major adverse cardiac events (MACE) (HR 0.83, 95% CI 0.76-0.90), cardiovascular death (HR 0.82, 95% CI 0.72-0.93), and myocardial infarction (HR 0.87, 95% CI 0.78-0.97) accompanied by increased risks of major bleeding (HR 2.46, 95% CI 1.42-4.26), but not fatal bleeding (HR 1.35, 95% CI 0.76-2.39) or intracranial hemorrhage (HR 2.19, 95% CI 0.91-5.27). Subgroup analysis revealed that NOACs were associated with an increased risk of major bleeding in patients who received dual antiplatelet therapy compared with patients who received single antiplatelet therapy (3.01, 1.82-4.98 vs. 1.66, 1.37-2.03; P for interaction 0.03) and patients with ACS compared with patients with non-ACS (3.27, 2.16-4.95 vs. 1.66, 1.36-2.02; P for interaction 0.004). CONCLUSIONS: In patients with IHD, NOACs confer protection against thrombosis-related complications, but at the cost of an increased hazard of major bleeding. NOACs plus a single antiplatelet drug seem to be a good choice for patients with IHD.

O-GlcNAcylation of cardiac Nav1.5 contributes to the development of arrhythmias in diabetic hearts.

BACKGROUND: Cardiovascular complications are major causes of mortality and morbidity in diabetic patients. The mechanisms underlying the progression of diabetic heart (DH) to ventricular arrhythmias are unclear. O-linked GlcNAcylation (O-GlcNAc) is a reversible post-translational modification for the regulation of diverse cellular processes. The purpose of this study was to assess whether the cardiac voltage-gated sodium channel (Nav1.5) is subjected to O-linked GlcNAcylation (O-GlcNAc), which plays an essential role in DH-induced arrhythmias. METHODS AND RESULTS: In this study, Sprague-Dawley rats (male, 200-230 g) were treated with a single high-dose of streptozotocin (STZ, 80 mg/kg) to generate a rat model of diabetes. STZ-induced 3-month diabetic rats displayed increased susceptibility to ventricular arrhythmias. The elevated O-GlcNAc modification was correlated with decreases in both total and cytoplasmic Nav1.5 expression in vivo and in vitro. In addition, both co-immunoprecipitation and immunostaining assays demonstrated that hyperglycemia could increase the O-GlcNAc-modified Nav1.5 levels and decrease the interaction between Nav1.5 and Nav1.5-binding proteins Nedd4-2/SAP-97. Furthermore, patch-clamp measurements in HEK-293 T cells showed that Nav1.5 current densities decreased by 30% after high-glucose treatment, and the sodium currents increased via O-GlcNAc inhibition. CONCLUSION: Our data suggested that hyperglycemia increased the O-GlcNAc modification of Nav1.5 expression and decreased the interaction between Nav1.5 and Nedd4-2/SAP-97, which led to the abnormal expression and distribution of Nav1.5, loss of function of the sodium channel, and prolongation of the PR/QT interval. Excessive O-GlcNAc modification of Nav1.5 is a novel signaling event, which may be an underlying contributing factor for the development of the arrhythmogenesis in DH.

Errata: Do Implantable Cardioverter Defibrillators Reduce Mortality in Patients With Chronic Kidney Disease at All Stages? An Updated Meta-Analysis.

The errors in the following list appeared in the article titled "Do Implantable Cardioverter Defibrillators Reduce Mortality in Patients With Chronic Kidney Disease at All Stages?: An Updated Meta-Analysis" by Linghua Fu, Qiongqiong Zhou, Wengen Zhu, Lin Huang, Ying Ding, Yang Shen, Jinzhu Hu, and Kui Hong (Vol. 58, No. 3, 371-7, 2017).

Do Implantable Cardioverter Defibrillators Reduce Mortality in Patients With Chronic Kidney Disease at All Stages?

The benefits of implantable cardioverter defibrillator (ICD) implantation in chronic kidney disease (CKD) patients with high sudden cardiac death (SCD) risk are uncertain. To clarify the effects of receiving an ICD in CKD patients, we conducted this meta-analysis to identify the effects of ICDs on patients with CKD, including those on dialysis. We searched the Cochrane library, EMBASE, PubMed, and clinical trials for studies published before July 2016. Eleven studies including 20,196 CKD patients were considered for inclusion. The pooled analysis suggested that patients with an estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73 m2 would benefit from receiving treatments with ICDs compared with patients without an ICD device (aHR = 0.74; 95% confidence interval [CI], 0.63 to 0.86). [corrected]. This is the first report of a subgroup analysis on the survival rate of ICD implantation in CKD patients according to an eGFR group. The subgroup analysis indicated a similar protective association of ICDs in stage 3 (aHR = 0.71; 95% CI, 0.61 to 0.82) and 5 (aHR = 0.71; 95% CI, 0.54 to 0.92) CKD patients [corrected] compared with the control group. However, there was no significant improvement in all-cause mortality in stage 4 CKD patients (aHR = 1.02; 95%CI, 0.75 to 1.37) [corrected]. This is the first meta-analysis reporting that ICD implantation reduces all-cause mortality in stage 3 and 5 [corrected] CKD patients. However, the data do not indicate there is any benefit to ICD implantation in stage 4 [corrected] CKD patients.

Meta-analysis of ATRIA versus CHA2DS2-VASc for predicting stroke and thromboembolism in patients with atrial fibrillation.

BACKGROUND: Several studies have compared the discriminative performances of CHA2DS2-VASc and ATRIA scores, but the results are still disputed. Therefore, we aimed to explore their predictive abilities regarding stroke and thromboembolism (TE) risk in AF patients. METHODS: We systematically searched the Cochrane Library, PubMed and ScienceDirect databases up to May 2016 for studies regarding CHA2DS2-VASc and ATRIA scores. The data were extracted and then pooled using Review Manager software version 5.30. RESULTS: Six cohort studies with 363,432 participants were included. Using the published cut-off points, the pooled C-statistics were 0.66 for ATRIA and 0.63 for CHA2DS2-VASc (Pdiff>0.05). Using the optimized cut-off points, the C-statistics were 0.66 for ATRIA and 0.65 for CHA2DS2-VASc (Pdiff>0.05). However, the ATRIA score presented a positive net reclassification improvement (NRI) value compared with the CHA2DS2-VASc score. In contrast, the CHA2DS2-VASc score classified fewer patients as low and moderate risk than the ATRIA score. The CHA2DS2-VASc score had lower event rates (either events per person or events per 100 person-years) in both the low and moderate risk categories compared with the ATRIA score. CONCLUSIONS: In combination with C-statistics and NRI values, the ATRIA score performed better than the CHA2DS2-VASc score for stroke risk prediction. In contrast, the CHA2DS2-VASc score was superior to the ATRIA score for identifying truly "low risk" AF patients.