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Cardiac Energy Metabolism and the Role of SGLT2 Inhibitors in Heart Failure
- Author / Creator
- Byrne, Nikole
Heart failure (HF) is a condition where the cardiac muscle exhibits contractile dysfunction, limiting its ability to deliver adequate amounts of oxygen to organs throughout the body. Despite improved survival seen with pharmacological and mechanical treatment strategies, HF patients continue to experience high hospitalization and mortality rates, resulting in poor quality of life and a significant burden on healthcare. As such, the need for better therapies for HF has helped expand our understanding of the development and progression of the disease, including the role that metabolic perturbances may play. Particularly, it is becoming more evident that cardiac substrate metabolism is impaired at the transcriptional level of metabolic enzymes, playing an important role in HF pathogenesis. Researchers, therefore, believe that therapeutic approaches designed to optimize cardiac energy production may be beneficial in the treatment and management of clinical HF. However, whether or not this loss of metabolic flexibility in the failing heart is permanent and thus cannot be corrected by interventions remains unclear.
In addition, the sodium/glucose cotransporter (SGLT) 2 inhibitor, empagliflozin, has been shown to profoundly reduce cardiovascular mortality and HF hospitalization in diabetic patients with high-risk of cardiovascular disease. Of importance, empagliflozin is thought to exert cardiovascular benefit upon improving substrate availability and myocardial energetics, and therefore may be of benefit in established HF even in the absence of diabetes. Furthermore, empagliflozin has also been shown to induce hemodynamic, diuretic and anti-inflammatory effects in the setting of diabetes, highlighting additional mechanisms that may be involved in facilitating these profound cardiovascular improvements.
In order to better understand the role of cardiac substrate metabolism and/or the effects of empagliflozin in the regression of HF, we used an experimental model of pressure overload, where the transverse aorta is constricted to induce HF. In the first set of experiments, debanding (DB) surgery was performed to remove the aortic constriction once systolic cardiac function had severely declined (ejection fraction < 30%) and both fatty acid and glucose oxidation were significantly impaired. At 1- and 3- weeks following DB, cardiac remodeling, systolic and diastolic function, myocardial substrate metabolism and expression of markers of hypertrophy/HF and metabolic genes were assessed. In another set of experiments, mice with moderate HF (ejection fraction < 45%) were treated with 10 mg/kg/day empagliflozin via oral gavage for two weeks to determine whether empagliflozin improves cardiac remodeling, systolic and diastolic function in the absence of diabetes. We also explored whether empagliflozin induces changes in circulating ketone bodies, cardiac substrate oxidation or increased cardiac ATP production in nondiabetic HF. Lastly, we further investigated whether empagliflozin induced beneficial outcomes associated with improved hemodynamics, diuretic effects and anti-inflammation responses in the heart.
We observed that following reversal of the elevated aortic afterload in HF, there is near complete recovery of systolic and diastolic function by 3-weeks following DB and transcriptional levels of several markers for hypertrophy/HF were restored to that observed in control hearts. Of note, myocardial oxidation of both glucose and fatty acids was restored at 1-week post-DB, leading us to believe that normalization of cardiac substrate utilization precedes full recovery of contractile function in the regression of HF. In addition, treatment with empagliflozin was found to blunt the decline in systolic dysfunction in mice with HF in the absence of diabetes. Surprisingly, these beneficial effects of empagliflozin in HF were not associated with any improvements in myocardial glucose, fatty acid or ketone metabolism. Furthermore, since the cardiac benefit of empagliflozin in HF in the absence of diabetes occurred without elevating circulating ketone bodies, weight loss, hemodynamic improvements or altering electrolyte concentrations, it is apparent that these prevailing theories may not be essential to the cardiovascular benefits of empagliflozin. Nonetheless, we show for the first time that empagliflozin reduces cardiac inflammation in a nondiabetic setting via reduced activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome, and this occurs in a Ca2+-dependent manner, independent of renal SGTL2 inhibition. Altogether, these data suggest that although improvements in myocardial energetics may be beneficial to the failing heart, increasing cardiac energy production is not a pre-requisite to improving cardiac contractile function. Furthermore, these findings provide important translational clues for the ongoing studies of SGLT2 inhibitors in diabetic and nondiabetic patients with HF.
- Graduation date
- Fall 2019
- Type of Item
- Doctor of Philosophy
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