BackgroundThe expression of a novel cardiac glucose transporter, SGLT1, is increased in glycogen storage cardiomyopathy secondary to mutations in PRKAG2. We sought to determine the role of SGLT1 in the pathogenesis of PRKAG2 cardiomyopathy and its role in cardiac structure and function.Methods and ResultsTransgenic mice with cardiomyocyte‐specific overexpression of human T400N mutant PRKAG2 cDNA (TGT400N) and transgenic mice with cardiomyocyte‐specific RNA interference knockdown of SGLT1 (TGSGLT1‐DOWN) were crossed to produce double‐transgenic mice (TGT400N/TGSGLT1‐DOWN). Tet‐off transgenic mice conditionally overexpressing cardiac SGLT1 in the absence of doxycycline were also constructed (TGSGLT‐ON). Relative to TGT400N mice, TGT400N/TGSGLT1‐DOWN mice exhibited decreases in cardiac SGLT1 expression (63% decrease, P<0.05), heart/body weight ratio, markers of cardiac hypertrophy, and cardiac glycogen content. TGT400N/TGSGLT1‐DOWN mice had less left ventricular dilation at age 12 weeks compared to TGT400N mice. Relative to wildtype (WT) mice, TGSGLT1‐ON mice exhibited increases in heart/body weight ratio, glycogen content, and markers of cardiac hypertrophy at ages 10 and 20 weeks. TGSGLT1‐ON mice had increased myocyte size and interstitial fibrosis, and progressive left ventricular dysfunction. When SGLT1 was suppressed after 10 weeks of overexpression (TGSGLT1‐ON/OFF), there was a reduction in cardiac hypertrophy and improvement in left ventricular failure.ConclusionsCardiac knockdown of SGLT1 in a murine model of PRKAG2 cardiomyopathy attenuates the disease phenotype, implicating SGLT1 in the pathogenesis. Overexpression of SGLT1 causes pathologic cardiac hypertrophy and left ventricular failure that is reversible. This is the first report of cardiomyocyte‐specific transgenic knockdown of a target gene.

Aims We previously reported that sodium-dependent glucose cotransporter 1 (SGLT1) is highly expressed in cardiomyocytes and is further up-regulated in ischaemia. This study aimed to determine the mechanisms by which SGLT1 contributes to ischaemia/reperfusion (I/R) injury. Methods and results Mice with cardiomyocyte-specific knockdown of SGLT1 (TGSGLT1-DOWN) and wild-type controls were studied. In vivo, the left anterior descending coronary artery was ligated for 30 min and reperfused for 48 h. Ex vivo, isolated perfused hearts were exposed to 20 min no-flow and up to 2 h reperfusion. In vitro, HL-1 cells and isolated adult murine ventricular cardiomyocytes were exposed to 1 h hypoxia and 24 h reoxygenation (H/R). We found that TGSGLT1-DOWN hearts were protected from I/R injury in vivo and ex vivo, with decreased infarct size, necrosis, dysfunction, and oxidative stress. 5’-AMP-activated protein kinase (AMPK) activation increased SGLT1 expression, which was abolished by extracellular signal-related kinase (ERK) inhibition. Co-immunoprecipitation studies showed that ERK, but not AMPK, interacts directly with SGLT1. AMPK activation increased binding of the hepatocyte nuclear factor 1 and specificity protein 1 transcription factors to the SGLT1 gene, and HuR to SGLT1 mRNA. In cells, up-regulation of SGLT1 during H/R was abrogated by AMPK inhibition. Co-immunoprecipitation studies showed that SGLT1 interacts with epidermal growth factor receptor (EGFR), and EGFR interacts with protein kinase C (PKC). SGLT1 overexpression activated PKC and NADPH oxidase 2 (Nox2), which was attenuated by PKC inhibition, EGFR inhibition, and/or disruption of the interaction between EGFR and SGLT1. Conclusion During ischaemia, AMPK up-regulates SGLT1 through ERK, and SGLT1 interacts with EGFR, which in turn increases PKC and Nox2 activity and oxidative stress. SGLT1 may represent a novel therapeutic target for mitigating I/R injury.

Objective: Examine FlowTriever thrombectomy feasibility in high-risk PE patients. Background: The FlowTriever thrombectomy system (Inari Medical, Irvine, CA) can reduce right ventricle (RV) strain in acute submassive pulmonary embolism (PE) patients. This technology has not been studied in higher risk PE patients. Methods: This multicenter retrospective analysis included patients treated with FlowTriever between 2017 and 2019 if they met at least one of the following: vasopressor dependence, PE induced respiratory failure, or decreased cardiac index (CI) measured by right heart catheterization. Results: Analysis included 34 patients: 18 massive, four intubated, 12 normotensive but with CI < 1.8. Average age was 56 and their median simplified PE severity index was 2. Patients had high bleeding risk, with 13 having recent surgery, six posttrauma, and four recent strokes. Six patients received cardiopulmonary resuscitation, and two received additional mechanical circulatory support. All patients had RV dilatation and elevated biomarkers. Clot removal was successful in 32/34 patients. CI improved from 2.0 ± 0.1 L/min/m 2 before thrombectomy to 2.4 ± 0.1 L/min/m 2 after (p = .01). The mean pulmonary artery pressure decreased from 33.2 ± 1.6 mmHg to 25.0 ± 1.5 mmHg (p = .01). The two patients-both with no or minimal thrombus removed-deteriorated during the procedure: one died and the other was successfully stabilized on ECMO. There were no other major complications. All other patients were alive at the time of data collection (mean follow-up of 205 days). Conclusion: Aspiration thrombectomy appears feasible in higher risk acute PE patients with immediate hemodynamic improvement and low in-hospital mortality.

Background: Catheter-directed thrombolysis (CDL) is increasingly being used for the treatment of submassive and massive pulmonary embolism. Although this therapy has been shown to be effective at reducing right ventricle strain, the impact on clinical outcomes remains unclear. We therefore aimed to evaluate the outcomes of CDL compared to standard anticoagulation for submassive pulmonary embolism patients in a large cohort. Methods: We conducted a retrospective observational study of consecutive patients with a primary diagnosis of submassive pulmonary embolism admitted to an intensive care unit within our health system between June 2014 and April 2016. We compared the outcome of patients treated with systemic anticoagulation (medical therapy) vs. catheter-based delivery of tissue plasminogen activator (tPA) (CDL). CDL patients were matched with medical therapy controls using a propensity-score matching algorithm based on the components of the simplified pulmonary embolism severity index (sPESI) score. Results: Unadjusted mortality rates were 3.0% for CDL vs. 10.4% for medical therapy at 30 days and 8.1% for CDL vs. 22.9% for medical therapy at 1 year. In the propensity-score matched cohort, mortality rates were 3.1% for CDL vs. 6.1% for medical therapy at 30 days and 8.2% for CDL vs. 18.2% for medical therapy at 1 year. Length of stay was significantly shorter in the CDL group. The index admission bleeding and transfusion rates were not increased in the CDL group. Conclusions: In patients presenting with acute submassive pulmonary embolism who are admitted to an intensive care unit, the group treated with CDL experienced reduced mortality at 30 days and 1 year when compared to medical therapy without increase in bleeding. Further randomized studies are required to confirm these findings.

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