Pre-existing endothelial cell activation predicts vasoplegia after mitral valve surgery†

OBJECTIVES: Post-cardiac surgery vasoplegia is a common complication of cardiac surgery, characterized by profound loss of systemic vascular resistance. This results in severe hypotension, high cardiac output and metabolic acidosis reflecting inadequate tissue perfusion. The pathophysiological mechanisms underlying this syndrome remain unknown. We hypothesized that this vasoplegia reflects endothelial dysfunction, either as pre-existing condition or as a consequence of the surgical procedure. METHODS: To examine these mechanisms, six established and distinct markers of endothelial cell activation were measured pre- and perioperatively in patients undergoing mitral valve surgery. Arterial (radial artery) and myocardial venous blood samples (coronary sinus) were collected simultaneously over the reperfused heart at various time points during the first hour after reperfusion. Additional samples were collected at baseline (brachial vein) and 1 day post-reperfusion (radial artery). Post-cardiac surgery vasoplegia was defined as a mean arterial blood pressure of <60 mmHg, with a cardiac index of ≥2.2 l/min/m(2) treated with continuous intravenous administration of norepinephrine. RESULTS: No myocardial release of endothelial cell activation markers was observed upon reperfusion in patients with vasoplegia (n = 15; mean age 71 years, 73% male). In contrast, in patients without vasoplegia (n = 24; mean age 64 years, 54% male), reperfusion was characterized by a myocardial release of three endothelial cell activation markers. Myocardial von Willebrand Factor propeptide, osteoprotegerin and interleukin-8 were increased 107% (P < 0.001), 106% (P = 0.02) and 116% (P = 0.009), respectively, compared with arterial levels upon reperfusion. Similar systemic levels of all markers were found upon reperfusion in both groups, except for 120% increased soluble P-selectin (sP-selectin) levels in vasoplegia patients (P = 0.03). Remarkably, postoperative vasoplegia was identified with baseline von Willebrand Factor propeptide levels with a cut-off value of 11.9 nM as well as with baseline sP-selectin levels with a cut-off value of 64.4 ng/ml. CONCLUSIONS: Pre-existing endothelial cell activation, reflected by higher baseline von Willebrand Factor propeptide and sP-selectin levels, is a predisposing factor for post-cardiac surgery vasoplegia. The pre-existing endothelial cell activation may have resulted in desensibilization of endothelium in patients who develop vasoplegic syndrome, resulting in no myocardial release of endothelial cell activation markers upon reperfusion

Heart failure determines the myocardial inflammatory response to injury

Aims: Systemic complications after cardiac surgery are common in heart failure patients. However, the pathophysiological mechanisms, such as a different local inflammatory response of failing hearts, remain in question. This study examines whether failing hearts respond differently to cardioplegic arrest and reperfusion compared with non-failing hearts (controls). Methods and results: The inflammatory response was evaluated in samples collected simultaneously from the radial artery and coronary sinus, and myocardial tissue in 62 patients undergoing cardiac surgery. No myocardial release of inflammatory mediators was observed upon reperfusion in controls (n ¼ 19). In contrast, in patients with heart failure, reperfusion was characterized by a myocardial release of several cytokines. Myocardial interleukin-6 was 115% increased in non-is-chaemic heart failure (n ¼ 18, P ¼ 0.002) as compared with a 117% increase in patients with ischaemic heart failure (n ¼ 25, P ¼ 0.01). Furthermore, a myocardial release of monocyte chemoattractant protein-1 was observedin both patient groups: a 109% (P ¼ 0.001) and 114% (P ¼ 0.01) increase in patients with non-ischaemic heart failure and ischaemic heart failure, respectively. Post-operative myocardial damage, expression of inflammatory mediators, and p65-nuclear factor-kB activity were similar in all patient groups. Inflammatory cell content was increased in early ischaemic myocardial tissue in both heart failure groups compared with controls. Conclusion: Heart failure patients show a clear myocardial inflammatory response upon reperfusion, probably explained by degranulation of infiltrated inflammatory cells. Results in controls indicate that they better withstand cardioplegic arrest and reperfusion without an explicit myocardial inflammatory response

No indications for platelet activation in acute clinical myocardial or renal ischemia/reperfusion injury

The pathophysiology of ischemia/reperfusion (I/R) injury is complex and poorly understood. Animal studies imply platelet activation as an initiator of the inflammatory response upon reperfusion. However, it remains unclear whether and how these results translate to clinical I/R. This study evaluates putative platelet activation in the context of two forms of clinical I/R (heart valve surgery with aortic-cross clamping, n = 39 and kidney transplantation, n = 34). The technique of sequential selective arteriovenous (AV) measurements over the reperfused organs was applied to exclude the influence of systemic changes occurring during surgery while simultaneously maximizing sensitivity. Platelet activation and degranulation was evaluated by assessing the expression levels of established markers, i.e. RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), ss-thromboglobulin (ss-TG), platelet-derived growth factor (PDGF)-BB and CXCL8 (known as interleukin-8), and by employing an in-vitro assay that specifically tests for platelet excitability. Moreover, a histological analysis was performed by means of CD41 staining. Results show stable RANTES, ss-TG, PDGF-BB and CXCL8 AV-concentrations within the first half hour over the reperfused organs, suggesting that myocardial and renal I/R are not associated with platelet activation. Results from the platelet excitability assay were in line with these findings and indicated reduced and stable platelet excitability following renal and myocardial reperfusion, respectively. Histological analysis yield evidence of platelet marginalization in the reperfused organs. In conclusion, results from this study do not support a role for platelet activation in early phases of clinical I/R injury

Oxidative damage in clinical ischemia/reperfusion injury: a reappraisal

Ischemia/reperfusion (I/R) injury is a common clinical problem. Although the pathophysiological mechanisms underlying I/R injury are unclear, oxidative damage is considered a key factor in the initiation of I/R injury. Findings from preclinical studies consistently show that quenching reactive oxygen and nitrogen species (RONS), thus limiting oxidative damage, alleviates I/R injury. Results from clinical intervention studies on the other hand are largely inconclusive. In this study, we systematically evaluated the release of established biomarkers of oxidative and nitrosative damage during planned I/R of the kidney and heart in a wide range of clinical conditions. Sequential arteriovenous concentration differences allowed specific measurements over the reperfused organ in time. None of the biomarkers of oxidative and nitrosative damage (i.e., malondialdehyde, 15(S)-8-iso-prostaglandin F2α, nitrite, nitrate, and nitrotyrosine) were released upon reperfusion. Cumulative urinary measurements confirmed plasma findings. As of these negative findings, we tested for oxidative stress during I/R and found activation of the nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of oxidative stress signaling. This comprehensive, clinical study evaluates the role of RONS in I/R injury in two different human organs (kidney and heart). Results show oxidative stress, but do not provide evidence for oxidative damage during early reperfusion, thereby challenging the prevailing paradigm on RONS-mediated I/R injury. Findings from this study suggest that the contribution of oxidative damage to human I/R may be less than commonly thought and propose a re-evaluation of the mechanism of I/

Galectin-3 and left ventricular reverse remodelling after surgical mitral valve repair

<p>Mitral valve repair in patients with functional mitral regurgitation (FMR) has been associated with beneficial left ventricular (LV) reverse remodelling. Recently, galectin-3 emerged as a marker of myocardial inflammation and fibrosis which may influence LV remodelling after surgery. The aim of the current study was to evaluate the association between pre-operative galectin-3 levels and LV reverse remodelling in heart failure patients with significant FMR who underwent mitral valve repair.</p><p>In total, 42 heart failure patients (66 10 years, 69 male) were evaluated. Plasma galectin-3 levels were assessed pre-operatively. Two-dimensional echocardiographic parameters were measured at baseline, and at 6 and 12 months after surgery. LV reverse remodelling was defined as a decrease in LV end-systolic volume 15 at 6 months follow-up. In total, 57 of the patients showed LV reverse remodelling. Patients with LV reverse remodelling showed significantly lower pre-operative galectin-3 levels (17.5 5.6 vs. 23.7 9.9 ng/mL, P 0.009) compared with patients without LV reverse remodelling. In addition, patients with galectin-3 18.2 ng/mL had a six-fold higher probability of showing LV reverse remodelling after surgery as compared with patients with levels 18.2 ng/mL (odds ratio 6.58, 95 confidence interval 1.3233.33, P 0.02).</p><p>High pre-operative plasma galectin-3 is independently associated with the absence of LV reverse remodelling after mitral valve repair. Galectin-3 may be useful to identify heart failure patients who will need additional treatment to obtain beneficial LV reverse remodelling.</p>