Key result
Combined levosimendan and Sacubitril/Valsartan was superior to either monotherapy in preserving left ventricular ejection fraction and reducing inflammatory biomarkers after double IR injury (p<0.0001).
Why the study?
Cardiorenal syndrome remains a leading cause of death in hospitalized patients, and this study tested whether combining levosimendan and Sacubitril/Valsartan is superior to monotherapy against simultaneous heart and kidney ischemia-reperfusion injury.
Does combined levosimendan and Sacubitril/Valsartan improve cardiac and renal function in a rat model of cardiorenal syndrome?
Does combined levosimendan and Sacubitril/Valsartan improve cardiac and renal function in a rat model of cardiorenal syndrome?
p-value: p=<0.0001
Combined levosimendan and sacubitril/valsartan provides superior cardioprotection and renoprotection compared to either therapy alone in a rat model of cardiorenal syndrome.
Combined levosimendan-Sac/Val protected rat heart/kidney post-IR; hypothesis-generating for human CRS trials.
BACKGROUND: Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS). METHODS AND RESULTS: Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1-5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1-5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p < 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p < 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p < 0.0001). CONCLUSION: Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury.
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Sung et al. (2022) studied Cardiorenal syndrome (n=40). Combined levosimendan and Sacubitril/Valsartan vs. Sham, double IR alone, or monotherapies was evaluated on Left-ventricular-ejection fraction (LVEF) and biomarkers (p=<0.0001). Combined levosimendan and Sacubitril/Valsartan was superior to either monotherapy in preserving left ventricular ejection fraction and reducing inflammatory biomarkers after double IR injury (p<0.0001).
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