Remote postconditioning consisted of 1 min isc/1 min rep protects the ischemic rabbit heart in vivo, independently of the site of the remote artery. This intervention seems to confer a stronger protection than the classic postconditioning.
Despite current optimal treatment, the morbidity and mortality of coronary heart disease remain significant worldwide and open the way for the development of novel cardioprotective therapies. In the last two decades, a remarkable scientific effort has focused on the limitation of infarct size. Important input from experimental studies has led the way in this direction. However, clinical and preclinical results using various cardioprotective strategies to attenuate reperfusion injury have generally not been applicable for every day clinical practice. Protection of the ischemic myocardium is known to occur as a result of ischemic preconditioning (PC), in which repetitive brief periods of ischemia protect the heart from a subsequent prolong ischemic insult. Although PC is a powerful form of protection, it is of limited clinical application for obvious ethical and practical reasons. Another endogenous form of cardioprotection, similar to PC but applicable at the time of reperfusion, termed postconditioning (PostC), has been recently described. Short series of repetitive cycles of brief reperfusion and re-occlusion of the coronary artery applied at the onset of reperfusion, reduce the infarct size and coronary artery endothelial dysfunction. At present, pharmacological PC and PostC are possible alternative methods that may substitute pharmaceutical treatments the short ischemic insults. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. We summarize the recent research efforts on novel therapeutic strategies and on the design of new compounds, based on the accumulated knowledge of the ligands, receptors and intracellular signaling pathways of PC and PostC.
The aim of this study was to assess the effectiveness of chronic medical treatment with oral propranolol and its influence on heart rate variability in patients with vasovagal syndrome. A spectral frequency domain analysis was used for the estimation of heart rate variability characteristics. Thirty-six patients, mean age 49 +/- 17 years, with a history of recurrent syncope and positive tilt testing were involved in the study. All patients received oral propranolol (five patients also had a dual chamber inhibited DDI pacemaker implanted) for a mean time 12 +/- 6 months. One patient complained of syncope during this follow-up. The tilt test repeated in 29 patients during follow-up was negative in 28. In 20 patients treatment was discontinued for 4 days and a new tilt test was then performed. Eleven of these 20 patients (55%) had a positive test (P < 0.001 compared with the group in which treatment was continued). In the group of 11 patients in whom the tilt test became positive again after medical treatment had been withdrawn (mean age 43 +/- 20 years) and in 11 asymptomatic controls (mean age 52 +/- 19 years), with no history of syncope and negative tilt testing, the heart rate variability was assessed. The increase in the low frequency component from rest to the maximum value of heart rate variability during tilt testing was higher in the vasovagal group than in the controls (2.6 +/- 1.2 vs 1.5 +/- 0.7 P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Background
Empagliflozin (EMPA), Dapagliflozin (DAPA) and Ertugliflozin (ERTU) are selective sodium glucose co-transporter 2 inhibitors (SGLT2i) acting against type 2 diabetes mellitus.
Purpose
Due to differences in clinical trial outcomes, we aimed to 1) compare the cardioprotective effects of selective SGLT2i in terms of infarct size (IS) reduction and 2) reveal the mechanism of cardioprotection in non-diabetic mice.
Methods
C57BL/6 mice were randomized and orally received EMPA (10mg/kg/day), DAPA (9.0mg/kg/day), ERTU (9.7mg/kg/day) or vehicle for 7 days. IS was measured after 30' ischemia (I), and 120' reperfusion (R). EMPA, DAPA and ERTU were given at equivalent stoichiometrically doses (ESD). Body weight and fasting blood glucose (FBG) levels were determined at baseline and at the end of the treatment. On the 7th day, mice were housed in metabolic cages for 24 hours. Urine volume (UV), food and water uptake and 24h-glucose levels were determined to examine the extend of SGLT-2 inhibition by the drugs. In a second series, the ischemic myocardium was taken (10'R), shotgun proteomics were performed and several cardioprotective pathways were evaluated. In a third series, the dominant pathways were evaluated through molecular analyses and mitochondrial functionality. The causal relationships in the mechanism of protection, was established by inhibiting the concomitant cardioprotective pathways. Static, the specific STAT-3 inhibitor and wortmannin (a PI3K inhibitor) were administered and IS was measured upon 30'I/120' R.
Results
EMPA and DAPA but not ERTU reduced IS at this dose. Body weight and FBG levels were not affected by the treatments. EMPA, DAPA and ERTU lead to significant increase in UV and urinary glucose levels compared to the control group independently of the water and food intake. There was no significant difference in the parameters among the different SGLT-2i indicating that the chosen doses are sufficient to produce the same pharmacological SGLT-2 inhibition in mice. Proteomics revealed mitochondrial metabolism and NF-kB signaling as significant. Only EMPA preserved mitochondrial functionality in complex I & II linked oxidative phosphorylation. NF-kB, RISK and STAT-3 activation and the downstream reduction in apoptosis were evident in EMPA and DAPA groups coinciding with IS reduction. Static and wortmannin significantly attenuated IS reduction both in EMPA and DAPA groups indicating that STAT-3 and PI3K activation are the leading mechanisms of cardioprotection. Among several upstream mediators, fibroblast growth factor 2 (FGF-2) and caveolin-3 were increased in EMPA and DAPA groups.
Conclusions
Short term EMPA, DAPA and ERTU at the chosen ESD inhibit SGLT-2i in a similar extent but only EMPA and DAPA reduce IS. Our study reveals drug specific effects on cardioprotection against I/R injury. Cardioprotection afforded by EMPA and DAPA are STAT-3 and PI3K dependent and associated with increased FGF-2 and Cav-3 expression.
Funding Acknowledgement
Type of funding sources: None.
The response of the contralateral arteries was investigated during balloon angioplasty of the left anterior descending artery. Thirty patients were studied. Coronary arteriograms were obtained at baseline, during maximal balloon inflation and at the end of the procedure. Luminal diameter was measured by a quantitative coronary arteriography analysis system. During balloon inflation the luminal diameter of the proximal segment of the right coronary artery increased by 2.4 +/- 6% (P < 0.05), and that of the left circumflex artery increased by 0.6 +/- 6% (P = ns). Both returned to near baseline values after angioplasty. In patients with increased collaterals during balloon inflation the left circumflex proximal segment increased more significantly than in patients with unchanged collaterals. The luminal diameter of the distal segment of the right coronary artery increased by 9 +/- 8% (P < 0.001) and that of the left circumflex artery by 8 +/- 11% (P < 0.01) during balloon inflation, returning to near baseline values after angioplasty. Thus, vasodilation of the contralateral arteries during balloon inflation at the time of coronary angioplasty occurs mainly in the distal segments, and appears to be related to an increase in collateral filling.
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