CXCR4 plays a crucial role in endogenous remodeling processes after MI, contributing to inflammatory/progenitor cell recruitment and neovascularization, whereas its deficiency limits infarct size and causes adaptation to hypoxic stress. This should be carefully scrutinized when devising therapeutic strategies involving the CXCL12/CXCR4 axis.

Cell transplantation has recently emerged as a novel therapy for ischemic heart disease. The presented study investigated the effect of intramyocardial transfer of human endothelial progenitor cells (EPCs) and stromal-cell derived factor-1alpha (SDF-1alpha) on left ventricular function in a chronic setting after myocardial infarction in cyclosporine treated rats. BrdU-labeled EPCs (10(6)), 10 microg SDF-1alpha, EPCs+SDF-1alpha or placebo medium were injected directly into the border infarct zone 4 weeks after acute myocardial infarction. Eight weeks after transplantation, echocardiography identified significantly improved fractional shortening after EPC or EPCs+SDF-1alpha injection as compared with injection of placebo medium. Investigating isolated hearts revealed a significant increase in left ventricular developing pressure after transplantation of SDF-1alpha or EPCs+SDF-1alpha. Furthermore, coronary flow rates were significantly elevated, especially after transplantation of EPCs+SDF-1alpha (under catecholamine stress 24.2 +/- 1.55 ml/min vs. 13.1 +/- 1 ml/min in the control) correlating with increased density of CD31+ vessel structures in the EPC as well as EPCs+SDF-1alpha groups, thus defining a higher rate of neovascularization. Notably, SDF-1alpha injected hearts showed only a trend towards improvement in coronary flow. BrdU+ signals were detected in infarct areas, partially integrating into vascular networks. The rate of apoptotic cells as well as the amount of inflammatory cells was significantly elevated in the placebo control group. In conclusion, transplantation of EPCs as well as EPCs+SDF-1alpha associated with improvement in cardiac function after infarction, which was attributable to enhanced neovascularization and decreased inflammation. These results imply a combined benefit of EPCs+SDF-1alpha in the treatment of myocardial infarction.

Fibroblast growth factor−23 (FGF23) is a mainly osteocytic hormone which increases renal phosphate excretion and reduces calcitriol synthesis. These renal actions are mediated via alpha-klotho as the obligate co-receptor. Beyond these canonical “mineral metabolism” actions, FGF23 has been identified as an independent marker for cardiovascular risk in various patient populations. Previous research has linked elevated FGF23 predominantly to left-ventricular dysfunction and consecutive morbidity and mortality. Moreover, some experimental data suggest FGF23 as a direct and causal stimulator for cardiac hypertrophy via specific myocardial FGF23-receptor activation, independent from alpha-klotho. This hypothesis offers fascinating prospects in terms of therapeutic interventions, specifically in patients with chronic kidney disease (CKD) in whom the FGF23 system is strongly stimulated and in whom left-ventricular dysfunction is a major disease burden. However, novel data challenges the previous stand-alone hypothesis about a one-way road which guides unidirectionally skeletal FGF23 toward cardiotoxic effects. In fact, recent data point toward local myocardial production and release of FGF23 in cases where (acute) myocardial damage occurs. The effects of this local production and the physiological meaning are under current examination. Moreover, epidemiologic studies suggest that high FGF-23 may follow, rather than induce, myocardial disease in certain conditions. In summary, while FGF23 is an interesting link between mineral metabolism and cardiac function underlining the meaning of the bone-heart axis, more research is needed before therapeutic interventions may be considered.

Background In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function. Methods In this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment. Results Baseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p < 0.001) as well as urinary volume (1740 ± 601 mL/24 h to 2112 ± 837 mL/24 h; p = 0.011) already after one day compared to placebo. Treatment with empagliflozin had no effect on the primary endpoint of systemic vascular resistance index, nor on cardiac index, stroke volume index or pulse rate at any time point. In addition, echocardiography showed no difference in left ventricular systolic function as assessed by left ventricular ejections fraction and strain analysis. However, empagliflozin significantly improved left ventricular filling pressure as assessed by a reduction of early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/eʹ) which became significant at day 1 of treatment (baseline: 9.2 ± 2.6; day 1: 8.5 ± 2.2; p = 0.005) and remained apparent throughout the study. This was primarily attributable to reduced early mitral inflow velocity E (baseline: 0.8 ± 0.2 m/s; day 1: 0.73 ± 0.2 m/sec; p = 0.003). Conclusions Empagliflozin treatment of patients with T2D has no significant effect on hemodynamic parameters after 1 or 3 days, nor after 3 months, but leads to rapid and sustained significant improvement of diastolic function. Trial registration EudraCT Number: 2016-000172-19; date of registration: 2017-02-20 (clinicaltrialregister.eu)