The SGLT2i Dapagliflozin Reduces RV Mass Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding.

BACKGROUND: Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored. HYPOTHESIS: We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle. METHODS: Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5 mg/kg/day) or vehicle by oral gavage. After 6 weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. RESULTS: PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05). SIGNIFICANCE: Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

Impact of sodium glucose linked cotransporter-2 inhibition on renal microvascular oxygen tension in a rodent model of diabetes mellitus.

BACKGROUND: The mechanisms whereby inhibitors of sodium-glucose linked cotransporter-2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2-rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors. METHODS: We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (Pk O2 ), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on Pk O2 in a region-specific manner, in vivo, in diabetic and non-diabetic rats. Superficial renal cortical or deeper cortical and outer medullary Pk O2 were measured utilizing excitations with blue and red light wavelengths, respectively. RESULTS: In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in Pk O2 . By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in Pk O2 in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia-responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all). CONCLUSIONS: These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT-2 inhibition on tissue metabolism. This reduction in deeper Pk O2 had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count.

Renal microvascular oxygen tension during hyperoxia and acute hemodilution assessed by phosphorescence quenching and excitation with blue and red light.

PURPOSE: The kidney plays a central physiologic role as an oxygen sensor. Nevertheless, the direct mechanism by which this occurs is incompletely understood. We measured renal microvascular partial pressure of oxygen (PkO2) to determine the impact of clinically relevant conditions that acutely change PkO2 including hyperoxia and hemodilution. METHODS: We utilized two-wavelength excitation (red and blue spectrum) of the intravascular phosphorescent oxygen sensitive probe Oxyphor PdG4 to measure renal tissue PO2 in anesthetized rats (2% isoflurane, n = 6) under two conditions of altered arterial blood oxygen content (CaO2): 1) hyperoxia (fractional inspired oxygen 21%, 30%, and 50%) and 2) acute hemodilutional anemia (baseline, 25% and 50% acute hemodilution). The mean arterial blood pressure (MAP), rectal temperature, arterial blood gases (ABGs), and chemistry (radiometer) were measured under each condition. Blue and red light enabled measurement of PkO2 in the superficial renal cortex and deeper cortical and medullary tissue, respectively. RESULTS: PkO2 was higher in the superficial renal cortex (~ 60 mmHg, blue light) relative to the deeper renal cortex and outer medulla (~ 45 mmHg, red light). Hyperoxia resulted in a proportional increase in PkO2 values while hemodilution decreased microvascular PkO2 in a linear manner in both superficial and deeper regions of the kidney. In both cases (blue and red light), PkO2 correlated with CaO2 but not with MAP. CONCLUSION: The observed linear relationship between CaO2 and PkO2 shows the biological function of the kidney as a quantitative sensor of anemic hypoxia and hyperoxia. A better understanding of the impact of changes in PkO2 may inform clinical practices to improve renal oxygen delivery and prevent acute kidney injury.

RéSUMé: OBJECTIF: Les reins jouent un rôle physiologique central en tant que détecteurs d'oxygène. Cependant, le mécanisme direct de ce rôle n'est pas complètement compris. Nous avons mesuré la pression partielle d'oxygène microvasculaire rénal (PkO2) afin de déterminer l'impact de conditions pertinentes d'un point de vue clinique qui modifient de façon aiguë la PkO2, y compris l'hyperoxie et l'hémodilution. MéTHODE: Nous avons utilisé l'excitation à deux longueurs d'onde (spectres rouge et bleu) de la sonde phosphorescente, sensible à l'oxygène, intravasculaire Oxyphor PdG4 afin de mesurer la PO2 dans le tissu rénal de rats sous anesthésie (isoflurane 2 %, n = 6) dans deux conditions de contenu en oxygène du sang artériel (CaO2) altéré : 1) hyperoxie (fraction d'oxygène inspiré 21 %, 30 % et 50 %) et 2) anémie par hémodilution aiguë (valeurs de base, hémodilution aiguë 25 % et 50 %). La tension artérielle moyenne (TAM), la température rectale, les gaz sanguins artériels et la chimie (radiomètre) ont été mesurés dans chacune des conditions. Les lumières bleue et rouge ont permis de mesurer la PkO2 dans le cortex rénal superficiel et les tissus cortical et médullaire plus profonds, respectivement. RéSULTATS: La PkO2 était plus élevée dans le cortex rénal superficiel (~ 60 mmHg, lumière bleue) comparativement au cortex rénal plus profond et à la zone médullaire extérieure (~ 45 mmHg, lumière rouge). L'hyperoxie a entraîné une augmentation proportionnelle des valeurs de PkO2, alors que l'hémodilution a diminué la PkO2 microvasculaire de façon linéaire tant dans les régions rénales superficielles que plus profondes. Dans les deux cas (lumières bleue et rouge), la PkO2 était corrélée au CaO2 mais pas à la TAM. CONCLUSION: La relation linéaire observée entre le CaO2 et la PkO2 montre la fonction biologique du rein en tant que détecteur quantitatif de l'hypoxie anémique et de l'hyperoxie. Une meilleure compréhension de l'impact des changements de la PkO2 pourrait guider les pratiques cliniques afin d'améliorer la distribution d'oxygène aux reins et prévenir l'insuffisance rénale aiguë.

Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction.

BACKGROUND AND AIMS: Sodium-glucose linked cotransporter-2 (SGLT2) inhibitors reduce the likelihood of hospitalization for heart failure and cardiovascular death in both diabetic and non-diabetic individuals with reduced ejection fraction heart failure. Because SGLT2 inhibitors lead to volume contraction with reductions in both preload and afterload, these load-dependent factors are thought to be major contributors to the cardioprotective effects of the drug class. Beyond these effects, we hypothesized that SGLT2 inhibitors may also improve intrinsic cardiac function, independent of loading conditions. METHODS: Pressure-volume (P-V) relationship analysis was used to elucidate changes in intrinsic cardiac function, independent of alterations in loading conditions in animals with experimental myocardial infarction, a well-established model of HFrEF. Ten-week old, non-diabetic Fischer F344 rats underwent ligation of the left anterior descending (LAD) coronary artery to induce myocardial infarction (MI) of the left ventricle (LV). Following confirmation of infarct size with echocardiography 1-week post MI, animals were randomized to receive vehicle, or the SGLT2 inhibitor, empagliflozin. Cardiac function was assessed by conductance catheterization just prior to termination 6 weeks later. RESULTS: The circumferential extent of MI in animals that were subsequently randomized to vehicle or empagliflozin groups was similar. Empagliflozin did not affect fractional shortening (FS) as assessed by echocardiography. In contrast, load-insensitive measures of cardiac function were substantially improved with empagliflozin. Load-independent measures of cardiac contractility, preload recruitable stroke work (PRSW) and end-systolic pressure volume relationship (ESPVR) were higher in rats that had received empagliflozin. Consistent with enhanced cardiac performance in the heart failure setting, systolic blood pressure (SBP) was higher in rats that had received empagliflozin despite its diuretic effects. A trend to improved diastolic function, as evidenced by reduction in left ventricular end-diastolic pressure (LVEDP) was also seen with empagliflozin. MI animals treated with vehicle demonstrated myocyte hypertrophy, interstitial fibrosis and evidence for changes in key calcium handling proteins (all p < 0.05) that were not affected by empagliflozin therapy. CONCLUSION: Empagliflozin therapy improves cardiac function independent of loading conditions. These findings suggest that its salutary effects are, at least in part, due to actions beyond a direct effect of reduced preload and afterload.