Discussion
hypertrophic, T2D, myocardial interstitial oedema, renal failure, cardiac dysfunction, CHF, heart failure, glucosuria, muscle inversion
CHF, RENAL FAILURE, HEART FAILURE, HYPERTROPHIC
Randomised clinical trials conducted with empagliflozin or dapagliflozin in patients with CHF have demonstrated protective effects of SGLT2 inhibitors concerning development of heart failure, incident heart failure hospitalisations, all-cause mortality and renal failure [These results are in accordance with the results of a small exploratory analysis showing a significant reduction in skin sodium content with no reduction in muscle sodium and muscle water content in patients with T2D after 6 weeks treatment with dapagliflozin [With the current MRI technique, we are not able to accurately differentiate between intracellular and extracellular interstitial sodium ion signals and thus to separate whether the observed decrease in skin sodium content is indicative of reduced micro-oedema or/and reduced water-independent bound sodium or both (and this is most likely the case in our opinion). The muscle inversion recovery Indirect signs of our trial, supporting the fact that the measured change in skin sodium content is related to the non-osmotic sodium, are the absence of a correlation between change in skin sodium content and change in muscle water content as well as in 24-h urine volume excretion, 24-h urine sodium excretion and 24-h urine glucose excretion. However, a close relationship between change in skin sodium content and change in muscle sodium content was observed after 1 and 3 months treatment with empagliflozin, indicating a parallel line in the changes. Possible explanations for the lack of significant difference in change in muscle sodium content are either smaller and more heterogenous changes in the muscle than in the skin or the short follow-up. Further, there is a relation between change in muscle sodium content and muscle water content that persisted after 3 months. These observations may reflect the glycoaminoglycan bound sodium in the tissue. Others have shown that in patients on haemodialysis, sodium content in muscle (Increased tissue sodium content may lead, in addition to micro-oedema, to cardiac as well as vascular effects, which ultimately lead to CHF. In experimental and in vivo studies, increased tissue sodium content (high sodium concentration in the extracellular fluid) lead to increased hypertrophic signalling, e.g. induced directly hypertrophic responses in myocardial myoblasts and vascular smooth muscle cells of neonatal rats [It has been demonstrated that patients with CHF have myocardial interstitial oedema, which causes systolic and diastolic cardiac dysfunction and increased stiffness of the left ventricle [We showed reduced office BP and improved metabolic control, findings well described in our previous studies [The broad known mode of action of SGLT2 inhibitors is enhanced glucosuria and natriuresis. Initially at 1 month, a significant increase in 24 h urinary sodium excretion was observed, as already by others, which was although no longer evident at 3 months and may explain in part the rapid onset of reduced incidence of heart failure hospitalisation observed in the prospective endpoint trial [We think that the changes in bone marrow sodium content mirror the changes observed in the skin and constitute a finding of unclear significance. Furthermore, the measurement of bone marrow sodium content lacks validation against a gold standard method as shown for skin and muscle sodium content [Several limitations should be pointed out. This was a single-center trial with an overall small sample size. However, this trial was not designed to be a clinical outcome trial, but a mechanistic trial. The chosen sample size was based on power calculation according to the data of our previous trial [