Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction. METHODS: We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function. RESULTS: Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle. CONCLUSIONS: We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.

Cyclin D1 controls development of cerebellar granule cell progenitors through phosphorylation and stabilization of ATOH1.

During development, neural progenitors are in proliferative and immature states; however, the molecular machinery that cooperatively controls both states remains elusive. Here, we report that cyclin D1 (CCND1) directly regulates both proliferative and immature states of cerebellar granule cell progenitors (GCPs). CCND1 not only accelerates cell cycle but also upregulates ATOH1 protein, an essential transcription factor that maintains GCPs in an immature state. In cooperation with CDK4, CCND1 directly phosphorylates S309 of ATOH1, which inhibits additional phosphorylation at S328 and consequently prevents S328 phosphorylation-dependent ATOH1 degradation. Additionally, PROX1 downregulates Ccnd1 expression by histone deacetylation of Ccnd1 promoter in GCPs, leading to cell cycle exit and differentiation. Moreover, WNT signaling upregulates PROX1 expression in GCPs. These findings suggest that WNT-PROX1-CCND1-ATOH1 signaling cascade cooperatively controls proliferative and immature states of GCPs. We revealed that the expression and phosphorylation levels of these molecules dynamically change during cerebellar development, which are suggested to determine appropriate differentiation rates from GCPs to GCs at distinct developmental stages. This study contributes to understanding the regulatory mechanism of GCPs as well as neural progenitors.

Transcriptional features of low-grade neuroepithelial tumors with the BRAF V600E mutation associated with epileptogenicity.

Low-grade neuroepithelial tumors are major causes of drug-resistant focal epilepsy. Clinically, these tumors are defined as low-grade epilepsy-associated neuroepithelial tumors (LEATs). The BRAF V600E mutation is frequently observed in LEAT and linked to poor seizure outcomes. However, its molecular role in epileptogenicity remains elusive. To understand the molecular mechanism underlying the epileptogenicity in LEAT with the BRAF V600E genetic mutation (BRAF V600E-LEAT), we conducted RNA sequencing (RNA-seq) analysis using surgical specimens of BRAF V600E-LEAT obtained and stored at a single institute. We obtained 21 BRAF V600E-LEAT specimens and 4 control specimens, including 24 from Japanese patients and 1 from a patient of Central Asian origin, along with comprehensive clinical data. We submitted the transcriptome dataset of 21 BRAF V600E-LEAT plus 4 controls, as well as detailed clinical information, to a public database. Preliminary bioinformatics analysis using this dataset identified 2134 differentially expressed genes between BRAF V600E-LEAT and control. Additionally, gene set enrichment analysis provided novel insights into the association between estrogen response-related pathways and the epileptogenicity of BRAF V600E-LEAT patients. Our datasets and findings will contribute toward the understanding of the pathology of epilepsy caused by LEAT and the identification of new therapeutic targets.

Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness because of the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum, but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. The administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for 7 weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.

A rare case of echo enhancing agent anaphylaxis complicated by acute coronary syndrome.

Enhancing agents in echocardiography are used frequently to improve endocardial border visualization and assessment of structural heart disease. We present a unique case of anaphylactic shock with acute coronary syndrome following administration of sulfur hexafluoride echo enhancing agent. This case emphasizes the importance of recognizing anaphylaxis to enhancing agents, as well as recognizing the potential relationship between anaphylaxis and acute coronary syndrome with in-stent thrombosis.

The role of SCFSkp2 and SCFß-TrCP1/2 in the cerebellar granule cell precursors.

A proper balance between proliferation and differentiation of cerebellar granule cell precursors (GCPs) is required for appropriate cerebellar morphogenesis. The Skp1-Cullin1-F-box (SCF) complex, an E3 ubiquitin ligase complex, is involved in polyubiquitination and subsequent degradation of various cell cycle regulators and transcription factors. However, it remains unknown how the SCF complex affects proliferation and differentiation of GCPs. In this study, we found that the scaffold protein Cullin1, and F-box proteins Skp2, ß-TrCP1 and ß-TrCP2 are expressed in the external granule layer (EGL). Knockdown of these molecules in the EGL showed that Cullin1, Skp2 and ß-TrCP2 enhanced differentiation of GCPs. We also observed accumulation of cyclin-dependent kinase inhibitor p27 in GCPs when treated with a Cullin1 inhibitor or proteasome inhibitor. Furthermore, knockdown of p27 rescued enhancement of differentiation by Cullin1 knockdown. These results suggest that the SCF complex is involved in the maintenance of the proliferative state of GCPs through p27 degradation. In addition, inhibition of Cullin1 activity also prevented cell proliferation and enhanced accumulation of p27 in Daoy cells, a cell line derived from the sonic hedgehog subtype of medulloblastoma. This suggested that excess degradation of p27 through the SCF complex causes overproliferation of medulloblastoma cells.

Temporary mechanical circulatory support devices: updates from recent studies.

PURPOSE OF REVIEW: Over the past several years, the role of short-term mechanical circulatory support (MCS) devices has become the dominant focus in efforts to improve outcomes in patients with cardiogenic shock (CS). Alongside these efforts, temporary MCS devices have been increasingly used to support patients prior to cardiac surgery, during high-risk percutaneous coronary intervention, awaiting cardiac transplantation, and in the setting of refractory cardiac arrest. The present review aims to provide an update on the recent literature evaluating the evolving role of temporary MCS devices, and to provide insights into the current challenges and future directions of MCS research. RECENT FINDINGS: Recent observational data have demonstrated potential roles for intra-aortic balloon pump preoperatively in high-risk patients awaiting coronary artery bypass grafting, and advanced heart failure patients awaiting transplantation. Impella continues to demonstrate promising results as part of an early MCS strategy in CS, as a temporary bridge to transplantation, and as a mechanism for left ventricular unloading in patients on venoarterial extracorporeal membrane oxygenation (ECMO). Finally, the first randomized trial of ECMO facilitated resuscitation in the United States demonstrated improved survival in patients with refractory out of hospital cardiac arrest. SUMMARY: Though randomized data remains limited, observational data continue to support the role of temporary MCS devices in a variety of clinical settings.

[The role of advance care planning and palliative care in new york city during COVID-19 pandemic].

New York City faced an explosive spread of Coronavirus disease 2019 (COVID-19), causing the city's death toll to spike owing to the high virulence of COVID-19. The health care system was on the verge of collapse. Advance care planning (ACP), informed assent, and palliative care played significant roles in supporting patient self-determination and dignity, facilitating decision making, and promoting better care. The importance of these strategies was revisited. Learning from the COVID-19 pandemic in New York City, it is anticipated that several approaches such as ACP and palliative intervention may attract more attention and become increasingly essential to the healthcare system in Japan.

Impaired left ventricular global longitudinal strain is associated with elevated left ventricular filling pressure after myocardial infarction.

Left ventricular (LV) global longitudinal strain (GLS) has emerged as a significant prognostic marker in patients after myocardial infarction (MI). Although elevated LV filling pressure after MI might alter GLS, direct evidence for this is lacking. This study aimed to clarify the association between GLS and LV filling pressure in a large animal MI model. A total of 104 Yorkshire pigs underwent both echocardiographic and hemodynamic assessments 1-4 wk after induction of large anterior MI. GLS was measured in the apical four-chamber view using a semiautomated speckle-tracking software. LV pressure-volume relationship was invasively measured using a high-fidelity pressure-volume catheter. GLS >-14% was considered impaired. Compared with pigs with LV ejection fraction (LVEF) >40% and preserved GLS (n = 29), those with LVEF >40% and impaired GLS (n = 37) and those with LVEF ≤40% (n = 38) had significantly higher LV end-diastolic pressure (15.5 ± 5.5 vs. 19.7 ± 5.8 and 19.6 ± 6.6 mmHg; P = 0.008 and P = 0.026, respectively) and higher LV mean diastolic pressure (7.1 ± 2.9 vs. 10.4 ± 4.5 and 11.1 ± 5.4 mmHg; P = 0.013 and P = 0.002, respectively). GLS was modestly correlated with τ (r = 0.21, P = 0.039) and slope of LV end-diastolic pressure-volume relationship (r = 0.43, P < 0.001). Impaired GLS was associated with higher LV end-diastolic and mean-diastolic pressures after adjusting for LVEF and baseline characteristics (P = 0.026 and P = 0.001, respectively). Impaired GLS assessed by speckle-tracking echocardiography was associated with elevated LV filling pressure after MI. GLS has an incremental diagnostic value for detecting elevated LV filling pressure and may be particularly useful for evaluating post-MI patients with preserved LVEF.NEW & NOTEWORTHY Strain analysis was performed in 104 pigs after MI, and its relationship to invasive hemodynamic measurements was studied. Impaired longitudinal strain was associated with high ventricular filling pressure independent of LVEF in post-MI setting. Global longitudinal strain is a potential prognostic marker after MI.

Antithrombotic strategies after transcatheter aortic valve implantation: Insights from a network meta-analysis.

OBJECTIVES: We aimed to investigate the efficacy and safety of different antithrombotic strategies in patients undergoing transcatheter aortic valve implantation (TAVI) using network meta-analyses. BACKGROUND: Meta-analyses comparing single antiplatelet therapy (SAPT) vs. dual antiplatelet therapy (DAPT), ± oral anticoagulant (OAC) was conducted to determine the appropriate post TAVI antithrombotic regimen. However, there was limited direct comparisons across the different therapeutic strategies. METHODS: MEDLINE and EMBASE were searched through December 2018 to investigate the efficacy and safety of different antithrombotic strategies (SAPT, DAPT, OAC, OAC + SAPT, and OAC + DAPT) in patients undergoing TAVI. The main outcome were all-cause mortality, major or life-threatening bleeding events, and stroke. RESULTS: Our search identified 3 randomized controlled trials and 10 nonrandomized studies, a total of 20,548 patients who underwent TAVI. All OACs were vitamin K antagonists. There was no significant difference on mortality except that OAC + DAPT had significantly higher rates of mortality compared with others (p < .05, I2 = 0%). SAPT had significantly lower rates of bleeding compared with DAPT, OAC+SAPT, and OAC+DAPT (hazard ratio [HR]: 0.59 [0.46-0.77], p < .001, HR: 0.58 [0.34-0.99], p = .045, HR: 0.41 [0.18-0.93], p = .033, respectively, I2 = 0%). There was no significant difference on stroke among all antithrombotic strategies. CONCLUSION: Patients who underwent TAVI had similar all-cause mortality rates among different antithrombotic strategies except OAC+DAPT. Patients on SAPT had significantly lower bleeding risk than those on DAPT, OAC + SAPT, and OAC + DAPT. Our results suggest SAPT is the preferred regimen when there is no indication for DAPT or OAC. When DAPT or OAC is indicated, DAPT + OAC should be avoided.

Meis1 Coordinates Cerebellar Granule Cell Development by Regulating Pax6 Transcription, BMP Signaling and Atoh1 Degradation.

Cerebellar granule cell precursors (GCPs) and granule cells (GCs) represent good models to study neuronal development. Here, we report that the transcription factor myeloid ectopic viral integration site 1 homolog (Meis1) plays pivotal roles in the regulation of mouse GC development. We found that Meis1 is expressed in GC lineage cells and astrocytes in the cerebellum during development. Targeted disruption of the Meis1 gene specifically in the GC lineage resulted in smaller cerebella with disorganized lobules. Knock-down/knock-out (KO) experiments for Meis1 and in vitro assays showed that Meis1 binds to an upstream sequence of Pax6 to enhance its transcription in GCPs/GCs and also suggested that the Meis1-Pax6 cascade regulates morphology of GCPs/GCs during development. In the conditional KO (cKO) cerebella, many Atoh1-positive GCPs were observed ectopically in the inner external granule layer (EGL) and a similar phenomenon was observed in cultured cerebellar slices treated with a bone morphogenic protein (BMP) inhibitor. Furthermore, expression of Smad proteins and Smad phosphorylation were severely reduced in the cKO cerebella and Meis1-knock-down GCPs cerebella. Reduction of phosphorylated Smad was also observed in cerebellar slices electroporated with a Pax6 knock-down vector. Because it is known that BMP signaling induces Atoh1 degradation in GCPs, these findings suggest that the Meis1-Pax6 pathway increases the expression of Smad proteins to upregulate BMP signaling, leading to degradation of Atoh1 in the inner EGL, which contributes to differentiation from GCPs to GCs. Therefore, this work reveals crucial functions of Meis1 in GC development and gives insights into the general understanding of the molecular machinery underlying neural differentiation from neural progenitors.SIGNIFICANCE STATEMENT We report that myeloid ectopic viral integration site 1 homolog (Meis1) plays pivotal roles in the regulation of mouse granule cell (GC) development. Here, we show Meis1 is expressed in GC precursors (GCPs) and GCs during development. Our knock-down and conditional knock-out (cKO) experiments and in vitro assays revealed that Meis1 is required for proper cerebellar structure formation and for Pax6 transcription in GCPs and GCs. The Meis1-Pax6 cascade regulates the morphology of GCs. In the cKO cerebella, Smad proteins and bone morphogenic protein (BMP) signaling are severely reduced and Atoh1-expressing GCPs are ectopically detected in the inner external granule layer. These findings suggest that Meis1 regulates degradation of Atoh1 via BMP signaling, contributing to GC differentiation in the inner EGL, and should provide understanding into GC development.

SNP- and haplotype-based genome-wide association studies for growth, carcass, and meat quality traits in a Duroc multigenerational population.

BACKGROUND: The aim of the present study was to compare the power of single nucleotide polymorphism (SNP)-based genome-wide association study (GWAS) and haplotype-based GWAS for quantitative trait loci (QTL) detection, and to detect novel candidate genes affecting economically important traits in a purebred Duroc population comprising seven-generation pedigree. First, we performed a simulation analysis using real genotype data of this population to compare the power (based on the null hypothesis) of the two methods. We then performed GWAS using both methods and real phenotype data comprising 52 traits, which included growth, carcass, and meat quality traits. RESULTS: In total, 836 animals were genotyped using the Illumina PorcineSNP60 BeadChip and 14 customized SNPs from regions of known candidate genes related to the traits of interest. The power of SNP-based GWAS was greater than that of haplotype-based GWAS in a simulation analysis. In real data analysis, a larger number of significant regions was obtained by SNP-based GWAS than by haplotype-based GWAS. For SNP-based GWAS, 23 genome-wide significant SNP regions were detected for 17 traits, and 120 genome-wide suggestive SNP regions were detected for 27 traits. For haplotype-based GWAS, 6 genome-wide significant SNP regions were detected for four traits, and 11 genome-wide suggestive SNP regions were detected for eight traits. All genome-wide significant SNP regions detected by haplotype-based GWAS were located in regions also detected by SNP-based GWAS. Four regions detected by SNP-based GWAS were significantly associated with multiple traits: on Sus scrofa chromosome (SSC) 1 at 304 Mb; and on SSC7 at 35-39 Mb, 41-42 Mb, and 103 Mb. The vertnin gene (VRTN) in particular, was located on SSC7 at 103 Mb and was significantly associated with vertebrae number and carcass lengths. Mapped QTL regions contain some candidate genes involved in skeletal formation (FUBP3; far upstream element binding protein 3) and fat deposition (METTL3; methyltransferase like 3). CONCLUSION: Our results show that a multigenerational pig population is useful for detecting QTL, which are typically segregated in a purebred population. In addition, a novel significant region could be detected by SNP-based GWAS as opposed to haplotype-based GWAS.

Cryopreservation method affects DNA fragmentation in trophectoderm and the speed of re-expansion in bovine blastocysts.

This study investigated re-expansion dynamics during culture of bovine blastocysts cryopreserved either by slow-freezing or vitrification. Also, the extent and localization of membrane damage and DNA fragmentation in re-expanded embryos were studied. Frozen-thawed embryos showed a significantly lower re-expansion rate during 24 h of post-thawing culture compared to vitrified embryos. Vitrified embryos reached the maximum level of re-expansion rate by 12 h of culture whereas frozen embryos showed a gradual increase in re-expansion rate by 24 h of culture. When assayed by Hoechst/propidium iodide staining there was no difference in the numbers and ratio of membrane damaged cells between re-expanded frozen and vitrified embryos; however, the extent of membrane damage in blastomeres was significantly higher in both groups compared with non-cryopreserved embryos (control). TUNEL assay combined with differential ICM and TE staining revealed a significantly higher number and ratio of TE cells showing DNA-fragmentation in frozen-thawed re-expanded blastocysts compared to vitrified ones; however, vitrification also resulted in an increased extent of DNA fragmentation in TE cells compared with control blastocysts. In frozen-thawed blastocysts increased extent of DNA fragmentation was associated with reduced numbers and proportion of TE cells compared with vitrified and control embryos. The number and ratio of ICM cells and the extent of DNA fragmentation in ICM did not differ among control, frozen and vitrified groups. In conclusion, compared with vitrified embryos, blastocysts preserved by slow-freezing showed a delayed timing of re-expansion which was associated with an increased frequency of DNA fragmentation in TE cells.

Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation.

In the central nervous system, astrocytes enable appropriate synapse function through glutamate clearance from the synaptic cleft; however, it remains unclear how astrocytic glutamate transporters function at peri-synaptic contact. Here, we report that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synapse formation and function in the developing cerebellum. Dscam-mutant mice show defects in CF synapse translocation as is observed in loss of function mutations in the astrocytic glutamate transporter GLAST expressed in Bergmann glia. These mice show impaired glutamate clearance and the delocalization of GLAST away from the cleft of parallel fibre (PF) synapse. GLAST complexes with the extracellular domain of DSCAM. Riluzole, as an activator of GLAST-mediated uptake, rescues the proximal impairment in CF synapse formation in Purkinje cell-selective Dscam-deficient mice. DSCAM is required for motor learning, but not gross motor coordination. In conclusion, the intercellular association of synaptic and astrocyte proteins is important for synapse formation and function in neural transmission.

Do Patients With Non-Viable Myocardium From Ischemic Cardiomyopathy Benefit From Revascularization? A Systematic Review And Meta-Analysis.

BACKGROUND: Myocardial viability assessment is used to select patients who will derive the greatest benefit from revascularization. It remains controversial whether revascularization only benefits patients with ischemic cardiomyopathy who have viable myocardium. The objective of this meta-analysis was to compare mortality between patients with ischemic cardiomyopathy and non-viable myocardium who underwent revascularization and those who underwent medical therapy alone. METHODS: The MEDLINE database was searched using PubMed to retrieve studies published up to December 2021. Inclusion criteria were 1. studies that evaluated the impact of revascularization (revascularization group) versus medical therapy alone (control group) following myocardial viability assessment; 2. patients who had coronary artery disease that was amenable to coronary artery bypass grafting or percutaneous coronary intervention; and 3. patients who had non-viable myocardium. The main outcome measure was all-cause mortality. RESULTS: A total of 12 studies were included, evaluating 1363 patients with non-viable myocardium, of whom 501 patients underwent revascularization and 862 patients received medical therapy alone. There was a significant reduction in all-cause mortality (RR 0.76, 95 % CI: 0.62-0.93, I2 = 0) in the revascularization group compared to the control group. There was no association between the type of viability imaging modality and the risk of all-cause mortality (P-interaction = 0.58). CONCLUSIONS: The findings of this meta-analysis suggest a benefit from revascularization compared to medical therapy in patients with ischemic cardiomyopathy despite the lack of myocardial viability.

Cerebrospinal fluid-contacting neuron tracing reveals structural and functional connectivity for locomotion in the mouse spinal cord.

Cerebrospinal fluid-contacting neurons (CSF-cNs) are enigmatic mechano- or chemosensory cells lying along the central canal of the spinal cord. Recent studies in zebrafish larvae and lampreys have shown that CSF-cNs control postures and movements via spinal connections. However, the structures, connectivity, and functions in mammals remain largely unknown. Here we developed a method to genetically target mouse CSF-cNs that highlighted structural connections and functions. We first found that intracerebroventricular injection of adeno-associated virus with a neuron-specific promoter and Pkd2l1-Cre mice specifically labeled CSF-cNs. Single-cell labeling of 71 CSF-cNs revealed rostral axon extensions of over 1800 µm in unmyelinated bundles in the ventral funiculus and terminated on CSF-cNs to form a recurrent circuitry, which was further determined by serial electron microscopy and electrophysiology. CSF-cNs were also found to connect with axial motor neurons and premotor interneurons around the central canal and within the axon bundles. Chemogenetic CSF-cNs inactivation reduced speed and step frequency during treadmill locomotion. Our data revealed the basic structures and connections of mouse CSF-cNs to control spinal motor circuits for proper locomotion. The versatile methods developed in this study will contribute to further understanding of CSF-cN functions in mammals.

Clinical impact of pulmonary artery catheter in patients with cardiogenic shock: A systematic review and meta-analysis.

BACKGROUND: The clinical utility of the pulmonary artery catheter (PAC) for the management of cardiogenic shock (CS) remains controversial. We performed a systematic review and meta-analysis exploring the association between PAC use and mortality among patients with CS. METHODS: Published studies of patients with CS treated with or without PAC hemodynamic guidance were retrieved from MEDLINE and PubMed databases from January 1, 2000, to December 31, 2021. The primary outcome was mortality, which was defined as a combination of in-hospital mortality and 30-day mortality. Secondary outcomes assessed 30-day and in-hospital mortality separately. To assess the quality of nonrandomized studies, the Newcastle-Ottawa Scale (NOS), a well-established scoring system was used. We analyzed outcomes for each study using NOS with a threshold value of >6, indicating high quality. We also performed analyses based on the countries of the studies conducted. RESULTS: Six studies with a total of 930,530 patients with CS were analyzed. Of these, 85,769 patients were in the PAC-treated group, and 844,761 patients did not receive a PAC. PAC use was associated with a significantly lower risk of mortality (PAC: 4.6 % to 41.5 % vs control: 18.8 % to 51.0 %) (OR 0.63, 95 % CI: 0.41-0.97, I2 = 0.96). Subgroup analyses demonstrated no difference in the risk of mortality between NOS ≥ 6 studies and NOS < 6 studies (p-interaction = 0.57), 30-day and in-hospital mortality (p-interaction = 0.83), or the country of origin of studies (p-interaction = 0.08). CONCLUSIONS: The use of PAC in patients with CS may be associated with decreased mortality. These data support the need for a randomized controlled trial testing the utility of PAC use in CS.