Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality. Methods: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score–matched cohort. Results: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63–0.98]; P =0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site–related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%). Conclusions: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood. METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia. RESULTS: Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell–derived engineered heart tissue. CONCLUSIONS: SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection.

Background: The Society of Cardiovascular Angiography and Interventions (SCAI) have recently proposed a new classification of cardiogenic shock (CS) dividing patients into five subgroups.Objective: Aim of this study was to apply the SCAI classification to a cohort of patients presenting with CS and to evaluate its ability to predict 30‐day survival.Methods: SCAI CS subgroups were interpreted based on the recent consensus statement and then applied to N = 1,007 consecutive patients presenting with CS or large myocardial infarction (MI) between October 2009 and October 2017. The association between SCAI classification and 30‐day all‐cause mortality was assessed by logistic regression analysis.Results: Mean age in the study cohort was 67 (±15) years, 72% were male. Mean lactate at baseline was 6.05 (±5.13) mmol/l and 51% of the patients had prior cardiac arrest. Overall survival probability was 50.6% (95% confidence interval [CI] 47.5–54.0%). In view of the SCAI classification, the survival probability was 96.4% (95% CI 93.7–99.0%) in class A, 66.1% (95% CI 50.2–87.1%) in class B, 46.1% (95% CI 40.6–52.4%) in class C, 33.1% (95% CI 26.6–41.1%) in class D, and 22.6% (95% CI 17.1–30.0%) in class E. Higher SCAI classification was significantly associated with lower 30‐day survival (p < .01).Conclusion: In this large clinical cohort, the SCAI classification was significantly associated with 30‐day survival. This finding supports the rationale of the SCAI CS classification and calls for a validation in a prospective trial.

The Impella device (Impella, Abiomed, Danvers, MA) is a percutaneous transvalvular microaxial flow pump that is currently used for (1) cardiogenic shock, (2) left ventricular unloading (combination of venoarterial extracorporeal membrane oxygenation and Impella concept), (3) high-risk percutaneous coronary interventions, (4) ablation of ventricular tachycardia, and (5) treatment of right ventricular failure. Impella-assisted forward blood flow increased mean arterial pressure and cardiac output, peripheral tissue perfusion, and coronary blood flow in observational studies and some randomized trials. However, because of the need for large-bore femoral access (14 F for the commonly used Impella CP device) and anticoagulation, the incidences of bleeding and ischemic complications are as much as 44% and 18%, respectively. Hemolysis is reported in as many as 32% of patients and stroke in as many as 13%. Despite the rapidly growing use of the Impella device, there are still insufficient data on its effect on outcome and complications on the basis of large, adequately powered randomized controlled trials. The only 2 small and also underpowered randomized controlled trials in cardiogenic shock comparing Impella versus intra-aortic balloon pump did not show improved mortality. Several larger randomized controlled trials are currently recruiting patients or are in preparation in cardiogenic shock (DanGer Shock [Danish-German Cardiogenic Shock Trial; NCT01633502]), left ventricular unloading (DTU-STEMI [Door-To-Unload in ST-Segment–Elevation Myocardial Infarction; NCT03947619], UNLOAD ECMO [Left Ventricular Unloading to Improve Outcome in Cardiogenic Shock Patients on VA-ECMO], and REVERSE [A Prospective Randomised Trial of Early LV Venting Using Impella CP for Recovery in Patients With Cardiogenic Shock Managed With VA ECMO; NCT03431467]) and high-risk percutaneous coronary intervention (PROTECT IV [Impella-Supported PCI in High-Risk Patients With Complex Coronary Artery Disease and Reduced Left Ventricular Function; NCT04763200]).

Background: Lactic acidosis is associated with mortality in patients with cardiogenic shock (CS). Elevated lactate levels and systemic acidemia (low blood pH) have both been proposed as drivers of death. We, therefore, analyzed the association of both high lactate concentrations and low blood pH with 30‐day mortality in patients with CS. Methods and Results: This was a 2‐center historical cohort study of unselected patients with CS with available data for admission lactate level or blood pH. CS severity was graded using the Society for Cardiovascular Angiography and Intervention (SCAI) shock classification. All‐cause survival at 30 days was analyzed using Kaplan‐Meier curves and Cox proportional‐hazards analysis. There were 1814 patients with CS (mean age, 67.3 years; 68.5% men); 51.8% had myocardial infarction and 53.0% had cardiac arrest. The distribution of SCAI shock stages was B, 10.8%; C, 30.7%; D, 38.1%; and E, 18.7%. In both cohorts, higher lactate or lower pH predicted a higher risk of adjusted 30‐day mortality. Patients with a lactate ≥5 mmol/L or pH <7.2 were at increased risk of adjusted 30‐day mortality; patients with both lactate ≥5 mmol/L and pH <7.2 had the highest risk of adjusted 30‐day mortality. Patients in SCAI shock stages C, D, and E had higher 30‐day mortality in each SCAI shock stage if they had lactate ≥5 mmol/L or pH <7.2, particularly if they met both criteria. Conclusions: Higher lactate and lower pH predict mortality in patients with cardiogenic shock beyond standard measures of shock severity. Severe lactic acidosis may serve as a risk modifier for the SCAI shock classification. Definitions of refractory or hemometabolic shock should include high lactate levels and low blood pH.