Baseline neutrophil-to-lymphocyte ratio and efficacy of SGLT2 inhibition with empagliflozin on cardiac remodelling

Aims: The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and plays a critical role in the assessment and prognosis in patients with heart failure. The EMPA-HEART CardioLink-6 trial demonstrated that patients with type 2 diabetes (T2D) and coronary artery disease (CAD) treated with a sodium-glucose transport protein 2 inhibitor for 6 months experienced regression in left ventricular mass. Given this, we evaluated the relationship of baseline NLR and cardiac reverse remodelling in the entire cohort of this trial. Methods and results: A total of 97 individuals were randomized to receive empagliflozin (10 mg/day) or placebo for 6 months. The primary outcome of the trial was change in left ventricular mass indexed to body surface area (LVMi) from baseline to 6 months as measured by cardiac magnetic resonance imaging. In our analysis, the cohort was stratified above and below an NLR level of 2. To assess the treatment effect on the 6 month change in NLR, we used a linear model adjusting for baseline differences in NLR [analysis of covariance (ANCOVA)] that included an interaction term between the baseline NLR and treatment. To assess the treatment effect on the 6 month change in LVMi in each of the subgroups divided by baseline NLR, we used an ANCOVA adjusting for baseline differences in LVMi that included an interaction term between the subgroups and treatment. The results of the regression models were summarized as adjusted differences with two-sided 95% confidence intervals (CIs). Patients who exhibited an elevated baseline NLR demonstrated higher LVMi and left ventricular end-diastolic volume indexed to body surface area than those with a lower NLR. In patients with an NLR Conclusions: Empagliflozin treatment is associated with consistent reductions in LVMi in patients with T2D and CAD independent of baseline NLR.</p

Upregulation of Krebs cycle and anaerobic glycolysis activity early after onset of liver ischemia

<div><p>The liver is a highly vascularized organ receiving a dual input of oxygenated blood from the hepatic artery and portal vein. The impact of decreased blood flow on glucose metabolism and how hepatocytes could adapt to this restrictive environment are still unclear. Using the left portal vein ligation (LPVL) rat model, we found that cellular injury was delayed after the onset of liver ischemia. We hypothesized that a metabolic adaptation by hepatocytes to maintain energy homeostasis could account for this lag phase. Liver glucose metabolism was characterized by ¹³C- and ¹H-NMR spectroscopy and analysis of high-energy metabolites. ALT levels and caspase 3 activity in LPVL animals remained normal during the first 12 h following surgery (<i>P</i><0.05). Ischemia rapidly led to decreased intrahepatic tissue oxygen tension and blood flow (<i>P</i><0.05) and increased expression of Hypoxia-inducible factor 1-alpha. Intrahepatic glucose uptake, ATP/ADP ratio and energy charge level remained stable for up to 12 h after ligation. Entry of glucose in the Krebs cycle was impaired with lowered incorporation of ¹³C from [U^-13C]glucose into glutamate and succinate from 0.25 to 12 h after LPVL. However, total hepatic succinate and glutamate increased 6 and 12 h after ischemia (<i>P</i><0.05). Glycolysis was initially reduced (<i>P</i><0.05) but reached maximum ¹³C-lactate (<i>P</i><0.001) and ¹³C-alanine (<i>P</i><0.01) enrichments 12 h after LPVL. In conclusion, early liver homeostasis stems from an inherent ability of ischemic hepatocytes to metabolically adapt through increased Krebs cycle and glycolysis activity to preserve bioenergetics and cell viability. This metabolic plasticity of hepatocytes could be harnessed to develop novel metabolic strategies to prevent ischemic liver damage.</p></div

ATP/ADP ratio and energy charge levels in the left lateral lobe of sham and LPVL-treated rats.

<p>Hepatic (A) AMP, (B) ADP, (C) ATP, (D) ATP/ADP ratio and (E) energy charge of sham and LPVL-operated rats over a period ranging from 0.25 to 12 h following ischemia. Values are expressed as the mean ± SEM of 3–8 animals.</p

Time course of total and ¹³C-enriched hepatic lactate and alanine in the ligated lobe following LPVL.

<p>Unlabeled levels of hepatic (A) lactate and (B) alanine of sham-operated rats (open white squares) and LPVL-treated (filled grey squares) rats. ¹³C-enrichment of metabolites: lactate (A) and alanine (B) in sham (white patterned squares) and LPVL-treated (black patterned squares) rats. Values are expressed as the mean ± SEM of 3–5 animals per group. (**<i>P</i><0.01, ***<i>P</i><0.001 when total lactate and alanine levels were compared in (A-B)).</p

Time course of total and ¹³C glucose levels during hypoxia.

<p>(A) Total levels of hepatic glucose of sham-operated (filled white circles) and LPVL-treated (filled grey circles) rats. (B) Levels of ¹³C glucose in sham (filled white circles) versus LPVL-treated (filled grey circles) rats. [U^-13C] glucose was infused for 45 min after the indicated times. (C) Representative microphotographs of Hypoxia inducible factor 1-α (HIF 1-α) staining of the left liver lobe of LPVL-treated animals 12h after ischemia. Slides were stained with Mayer’s Hematoxylin and mouse-anti-HIF-1α. Values are expressed as the mean ± SEM of 3–10 animals per group.</p

Time course of total and ¹³C-enriched hepatic glutamate and succinate in the ligated lobe following LPVL.

<p>Unlabeled levels of hepatic (A) glutamate and (B) succinate of sham-operated rats (open white squares) and LPVL-treated (filled grey squares) rats. ¹³C-enrichment of the metabolites: (A) glutamate and (B) succinate in sham (white patterned squares) and LPVL-treated (black patterned squares) rats. Values are expressed as the mean ± SEM of 3–6 animals per group. (*<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001 when total glutamate and succinate levels were compared in (A-B)).</p

Delayed hepatocyte injury after induction of ischemia.

<p>(A) Evaluation of ALT serum levels and (B) quantification of caspase 3 activity in sham and LPVL-treated rats over a period of up to 48 h following induction of ischemia. (C) Representative microphotographs of HPS staining of the left liver lobe of LPVL-operated rats over a period ranging from 6 to 48 h following ischemia. Liver injury was assessed by the histological evaluation of necrosis. Values are ±SEM of 3–8 different animals. (*<i>P</i><0.05, ***<i>P</i><0.001).</p

The impact of statins on postdischarge atrial fibrillation after cardiac surgery: secondary analysis from a randomized trial

Background Whether statins reliably reduce the risk of postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery remains controversial. We sought to determine the impact of statin use on new-onset postdischarge POAF in the Post-Surgical Enhanced Monitoring for Cardiac Arrhythmias and Atrial Fibrillation (SEARCH-AF) CardioLink-1 randomized controlled trial. Methods We randomized 336 patients with risk factors for stroke (CHA2DS2-VASc score ≥ 2) and no history of preoperative atrial fibrillation (AF) to 30-day continuous cardiac rhythm monitoring after discharge from cardiac surgery with a wearable, patched-based device or to usual care. The primary endpoint was the occurrence of cumulative AF and/or atrial flutter lasting for ≥ 6 minutes detected by continuous monitoring, or AF and/or atrial flutter documented by a 12-lead electrocardiogram within 30 days of randomization. Results The 260 patients (77.4%) discharged on statins were more likely to be male (P = 0.018) and to have lower CHA2DS2-VASc scores (P = 0.011). Patients treated with statins at discharge had a 2-fold lower rate of POAF than those who were not treated with statins in the entire cohort (18.4% vs 8.1%, log-rank P = 0.0076). On multivariable Cox regression including the CHA2DS2-VASc score adjustment, statin use was associated with a lower risk of POAF (hazard ratio 0.43, 95% confidence interval: 0.25-0.98, P = 0.043). Use of statins at a higher intensity was associated with lower risk of POAF, suggestive of a dose–response effect (log-rank Ptrend = 0.0082). Conclusions The use of statins was associated with a reduction in postdischarge POAF risk among patients undergoing cardiac surgery. The routine use of high-intensity statin to prevent subacute POAF after discharge deserves further study.</p