Background: MicroRNAs (miRs) regulate nearly all biological pathways. Because the dysregulation of miRs can lead to disease progression, they are being explored as novel therapeutic targets. However, the cell type-specific effects of miRs in the heart are poorly understood. Thus, we assessed miR target regulation using miR-92a-3p as an example. Inhibition of miR-92a is known to improve endothelial cell function and recovery after acute myocardial infarction. Methods: miR-92a-3p was inhibited by locked nucleic acid (LNA)-based antimiR (LNA-92a) in mice after myocardial infarction. Expression of regulated genes was evaluated 3 days after myocardial infarction by RNA sequencing of isolated endothelial cells, cardiomyocytes, fibroblasts, and CD45(+) hematopoietic cells. Results: LNA-92a depleted miR-92a-3p expression in all cell types and derepressed predicted miR-92a-3p targets in a cell type-specific manner. RNAseq showed endothelial cell-specific regulation of autophagy-related genes. Imaging confirmed increased endothelial cell autophagy in LNA-92a treated relative to control animals. In vitro inhibition of miR-92a-3p augmented EC autophagy, derepressed autophagy-related gene 4a, and increased luciferase activity in autophagy-related gene 4a 3'UTR containing reporters, whereas miR-92a-3p overexpression had the opposite effect. In cardiomyocytes, LNA-92a derepressed metabolism-related genes, notably, the high-density lipoprotein transporter Abca8b. LNA-92a further increased fatty acid uptake and mitochondrial function in cardiomyocytes in vitro. Conclusions: Our data show that miRs have cell type-specific effects in vivo. Analysis of miR targets in cell subsets disclosed a novel function of miR-92a-3p in endothelial cell autophagy and cardiomyocyte metabolism. Because autophagy is upregulated during ischemia to supply nutrients and cardiomyocyte metabolic-switching improves available substrate utilization, these prosurvival mechanisms may diminish tissue damage.

BACKGROUND: The adult mammalian heart displays a cardiomyocyte turnover rate of approximate to 1%/y throughout postnatal life and after injuries such as myocardial infarction (MI), but the question of which cell types drive this low level of new cardiomyocyte formation remains contentious. Cardiac resident stem cells marked by stem cell antigen -1 (Sca-1, gene name Ly6a) have been proposed as an important source of cardiomyocyte renewal. However, the in vivo contribution of endogenous Sca-1(+) cells to the heart at baseline or after MI has not been investigated. METHODS: Here we generated Ly6a gene targeted mice containing either a constitutive or an inducible Cre recombinase to perform genetic lineage tracing of Sca-1(+) cells in vivo. RESULTS: We observed that the contribution of endogenous Sca-1(+) cells to the cardiomyocyte population in the heart was <0.005% throughout all of cardiac development, with aging, or after MI. In contrast, Sca-1(+) cells abundantly contributed to the cardiac vasculature in mice during physiological growth and in the post -MI heart during cardiac remodeling. Specifically, Sca-1 lineage -traced endothelial cells expanded postnatally in the mouse heart after birth and into adulthood. Moreover, pulse labeling of Sca-1(+) cells with an inducible Ly6a-MerCreMer allele also revealed a preferential expansion of Sca-1 lineage -traced endothelial cells after MI injury in the mouse. CONCLUSIONS: Cardiac -resident Sca-1 cells are not significant contributors to cardiomyocyte renewal in vivo. However, cardiac Sca1(+) cells represent a subset of vascular endothelial cells that expand postnatally with enhanced responsiveness to pathological stress in vivo.

This focused update to the American Heart Association guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care follows the Pediatric Task Force of the International Liaison Committee on Resuscitation evidence review. It aligns with the International Liaison Committee on Resuscitation's continuous evidence review process, and updates are published when the International Liaison Committee on Resuscitation completes a literature review based on new science. This update provides the evidence review and treatment recommendation for chest compression-only CPR versus CPR using chest compressions with rescue breaths for children < 18 years of age. Four large database studies were available for review, including 2 published after the 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Two demonstrated worse 30-day outcomes with chest compressiononly CPR for children 1 through 18 years of age, whereas 2 studies documented no difference between chest compression-only CPR and CPR using chest compressions with rescue breaths. When the results were analyzed for infants < 1 year of age, CPR using chest compressions with rescue breaths was better than no CPR but was no different from chest compression-only CPR in 1 study, whereas another study observed no differences among chest compression-only CPR, CPR using chest compressions with rescue breaths, and no CPR. CPR using chest compressions with rescue breaths should be provided for infants and children in cardiac arrest. If bystanders are unwilling or unable to deliver rescue breaths, we recommend that rescuers provide chest compressions for infants and children.

BACKGROUND: Acute myocardial infarction (AMI) is a major cardiovascular complication of noncardiac surgery. We aimed to evaluate the frequency, causes, and outcomes of 30-day hospital readmission after perioperative AMI. METHODS: Patients who were diagnosed with AMI during hospitalization for major noncardiac surgery were identified using the 2014 US Nationwide Readmission Database. Rates, causes, and costs of 30-day readmissions after noncardiac surgery with and without perioperative AMI were identified. RESULTS: Among 3807 357 hospitalizations for major noncardiac surgery, 8085 patients with perioperative AMI were identified. A total of 1135 patients (14.0%) with perioperative AMI died in-hospital during the index admission. Survivors of perioperative AMI were more likely to be readmitted within 30 days than surgical patients without perioperative AMI (19.1% versus 6.5%, P<0.001). The most common indications for 30-day rehospitalization were management of infectious complications (30.0%), cardiovascular complications (25.3%), and bleeding (10.4%). In-hospital mortality during hospital readmission in the first 30 days after perioperative AMI was 11.3%. At 6 months, the risk of death was 17.6% and >= 1 hospital readmission was 36.2%. CONCLUSIONS: Among patients undergoing noncardiac surgery who develop a perioperative MI, approximate to 1 in 3 suffer from in-hospital death or hospital readmission in the first 30 days after discharge. Strategies to improve outcomes of surgical patients early after perioperative AMI are warranted.

Background: Combining 2 signals of cardiomyocyte injury, cardiac troponin I (cTnI) and T (cTnT), might overcome some individual pathophysiological and analytical limitations and thereby increase diagnostic accuracy for acute myocardial infarction with a single blood draw. We aimed to evaluate the diagnostic performance of combinations of high-sensitivity (hs) cTnI and hs-cTnT for the early diagnosis of acute myocardial infarction. Methods: The diagnostic performance of combining hs-cTnI (Architect, Abbott) and hs-cTnT (Elecsys, Roche) concentrations (sum, product, ratio, and a combination algorithm) obtained at the time of presentation was evaluated in a large multicenter diagnostic study of patients with suspected acute myocardial infarction. The optimal rule-out and rule-in thresholds were externally validated in a second large multicenter diagnostic study. The proportion of patients eligible for early rule-out was compared with the European Society of Cardiology 0/1 and 0/3 hour algorithms. Results: Combining hs-cTnI and hs-cTnT concentrations did not consistently increase overall diagnostic accuracy as compared with the individual isoforms. However, the combination improved the proportion of patients meeting criteria for very early rule-out. With the European Society of Cardiology 2015 guideline recommended algorithms and cut-offs, the proportion meeting rule-out criteria after the baseline blood sampling was limited (6% to 24%) and assay dependent. Application of optimized cut-off values using the sum (9 ng/L) and product (18 ng(2)/L-2) of hs-cTnI and hs-cTnT concentrations led to an increase in the proportion ruled-out after a single blood draw to 34% to 41% in the original (sum: negative predictive value [NPV] 100% [95% confidence interval (CI), 99.5% to 100%]; product: NPV 100% [95% CI, 99.5% to 100%]) and in the validation cohort (sum: NPV 99.6% [95% CI, 99.0-99.9%]; product: NPV 99.4% [95% CI, 98.8-99.8%]). The use of a combination algorithm (hs-cTnI <4 ng/L and hs-cTnT <9 ng/L) showed comparable results for rule-out (40% to 43% ruled out; NPV original cohort 99.9% [95% CI, 99.2-100%]; NPV validation cohort 99.5% [95% CI, 98.9-99.8%]) and rule-in (positive predictive value [PPV] original cohort 74.4% [95% Cl, 69.6-78.8%]; PPV validation cohort 84.0% [95% Cl, 79.7-87.6%]). Conclusions: New strategies combining hs-cTnI and hs-cTnT concentrations may significantly increase the number of patients eligible for very early and safe rule-out, but do not seem helpful for the rule-in of acute myocardial infarction. Clinical Trial Registration: URL (APACE): https://www.clinicaltrial.gov. Unique identifier: NCT00470587. URL (ADAPT): www.anzctr.org.au. Unique identifier: ACTRN12611001069943.

Background: In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF 40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF 40%. Methods: REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF 40%, exercise PCWP 25 mmHg, and PCWP-right atrial pressure gradient 5 mmHg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise. Results: A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 709 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.56.4 mmHg in the treatment group versus 0.5 +/- 5.0 mmHg in the control group (P=0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group (P=1.0). Conclusions: In patients with HF and EF 40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02600234.