RESUMO
AIMS: Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodeling and atrial fibrillation is frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial antiarrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. METHODS AND RESULTS: Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green-2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment with the CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with NHE1 inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. CONCLUSION: We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to antiarrhythmic effects in patients with HFpEF.
RESUMO
Targeted chemotherapy and immune checkpoint inhibitors (ICPi) have expanded the spectrum of therapies for patients with relapsed/refractory (r/r) Hodgkin's disease and significantly improved the proportion of patients with long-term disease control. However, there is no standardized therapeutic option in case of further progression. Recently, we demonstrated that therapy with MEPED (metronomic chemotherapy, everolimus, pioglitazone, etoricoxib, dexamethasone) is highly effective in patients with r/r Hodgkin's disease. The benefit after pre-treatment with ICPi has not been studied, yet. Here, we report a patient with progressive Hodgkin's disease on Pembrolizumab for the first time who achieved sustained complete remission (CR) after initiation of MEPED therapy. A 57-year-old patient was pre-treated with brentuximab vedotin for relapsed advanced Hodgkin's disease and had received Pembrolizumab for progression from November 2020 to July 2022. Due to further progression, MEPED therapy was started in August 2022 and continued until May 2023. It consisted of a strictly oral daily (28-day cycle) application of low-dose treosulfan 250 mg, everolimus 15 mg, pioglitazone 45 mg, etoricoxib 60 mg, and dexamethasone 0.5 mg. Treatment response was evaluated by F-18 FDG-PET/CT (PET/CT). CR was defined by a negative Deauville score (DS) of 1-3. Already 3 months after starting MEPED, a CR (DS: 3) was confirmed by PET/CT in November 2022. The next follow-up in May 2023 continued to show CR (DS: 3). The therapy was very well tolerated. No hematological or other organ toxicity was observed. However, in May 2023 the patient presented with leg edema and weight gain, most likely due to pioglitazone and the PET/CT revealed suspected everolimus-induced pneumonitis, so MEPED was discontinued and diuretic therapy and treatment with prednisolone was started with gradual dose reduction. This resulted in a rapid complete resolution of the symptoms. The next PET-CT in July 2023 continued to show CR (DS: 3) without evidence of pneumonitis. Currently, therapy with MEPED has not been resumed. In conclusion, we demonstrate for the first time that MEPED therapy is highly effective in a patient with Hodgkin's disease who has been refractory to ICPi. Sustained CR was achieved over 11 months after initiation of MEPED therapy. Further studies on a larger patient cohort should be performed.