Aortic stiffness as a marker of cardiac function and myocardial strain in patients undergoing aortic valve replacement

Background: Cardiac function and myocardial strain are affected by cardiac afterload, which is in part due to the stiffness of the aortic wall. In this study, we hypothesize that aortic pulse wave velocity (PWV) as a marker of aortic stiffness correlates with conventional clinical and biochemical markers of cardiac function and perioperative myocardial strain in aortic valve replacement (AVR). Methods: Patients undergoing AVR for aortic stenosis between June 2010 and August 2012 were recruited for inclusion in this study. PWV, NYHA class and left ventricular (LV) function were assessed pre-operatively. PWV was analysed both as a continuous and dichotomous variable according to age-standardized reference values. B-type natriuretic peptide (BNP) was measured pre-operatively, and at 3 h and 18-24 h after cardiopulmonary bypass (CPB). NYHA class, leg edema, and LV function were recorded at follow-up (409 ± 159 days). Results: Fifty-six patients (16 females) with a mean age of 71 ± 8.4 years were included, with 50 (89%) patients completing follow-up. The NYHA class of PWV-norm patients was significantly lower than PWV-high patients both pre- and post-operatively. Multiple logistic regression also highlighted PWV-cut off as an independent predictor of NYHA class pre- and post-operatively (OR 8.3, 95%CI [2.27,33.33] and OR 14.44, 95%CI [1.49,139.31] respectively). No significant relationship was observed between PWV and either LV function or plasma BNP. Conclusion: In patients undergoing AVR for aortic stenosis, PWV is independently related to pre- and post-operative NYHA class but not to LV function or BNP. These findings provisionally support the use of perioperative PWV as a non-invasive marker of clinical functional status, which when used in conjunction with biomarkers of myocardial strain such as BNP, may provide a holistic functional assessment of patients undergoing aortic valve surgery. However, in order for PWV assessment to be translated into clinical practice and utilised as more than simply a research tool, further validation is required in the form of larger prospective studies specifically designed to assess the relationship between PWV and these functional clinical outcomes

The role of the Toll-like receptors in systemic inflammatory response to cardiac surgery

Background: Cardiac surgery with cardiopulmonary bypass (CPB) can lead to a spectrum of post-operative complications as a result of activation of systemic inflammatory responses. Cellular injury can lead to the release of damage-associated molecular patterns (DAMPs) such as mitochondria DNA (mtDNA), which act as a ligand activating leukocytes and endothelial cells via innate immunity receptors such as Toll-like receptor 9 (TLR9). However, the contributions of DAMPs to inflammatory responses to CPB are unknown. Aim: This study is to identify the DAMPs and associated receptors that drive systemic inflammatory responses to surgery, which may lead to the identification of novel anti-inflammatory interventions such as TLR antagonists with subsequent translation of our findings to the clinical field. Additionally, Post-operative atrial fibrillation (POAF) is frequent complication in cardiac surgery, which may contribute to the inflammatory response. We aimed to identify a possible predictor for POAF, which may lead to its prevention or early management. Methods: Sixty-six patients undergoing CABG were recruited, 44 with on-pump and 22 with off-pump CABG (OPCAB) to compare the effect of CPB. To identify the effect of ischemic heart disease (IHD) on the mtDNA release. We recruited a separate group of 22 patients undergoing aortic valve replacement (AVR) with normal coronary angiogram. Blood samples were taken at different time-points to CPB. Quantitative PCR was generated to quantify mtDNA concentration (Chapter 3). Pro-inflammatory biomarkers such as interleukines, interferons, MAP kinases , NF-κB and other biomarkers were assessed by PCR array (Chapter 5). Both mtDNA and the proinflmmatory biomarker were preoperatively compared to assess of the development of POAF (Chapter 6). Additionally, we used different animal models experiments, to establish the effect of surgery and CPB on TLR9 signalling and to test the effect of blocking TLR9. Specifically, we performed sternotomy in mouse and rat models respectively and performed sternotomy with CPB in the pig model (Chapter 4). Results: mtDNA was significantly higher in patients with IHD than those without (p0.05). Blocking the TLR9 in mice has significantly reduced the production of proinflammatory cytokine (IL-6). INF-α and mtDNA were the only independent predictors for POAF development. Conclusion: Elevation in circulating mtDNA level is related to the extent of the IHD. CPB can influence the release of circulating mtDNA and proinflammatory cytokines production via signalling the TLR9, which may contribute to the initiation of a sterile systemic inflammatory response. The mtDNA and INF- α were independent predictors for development of POAF, which are in agreement with the inflammatory theory that relates the inflammation to the POAF development.Open Acces

Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass

ObjectivesSystemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood.MethodsA porcine model was established to study the signaling pathways that promote systemic inflammation in response to cardiac surgery with cardiopulmonary bypass under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to cardiopulmonary bypass was also studied. Intracellular staining and flow cytometry were performed to measure phosphorylation of p38 mitogen-activated protein kinase and the transcription factor nuclear factor-κB in granulocytes and mononuclear cells.ResultsSurgery with cardiopulmonary bypass for 1 to 2 hours enhanced phosphorylation of p38 (2.5-fold) and nuclear factor-κB (1.6-fold) in circulating mononuclear cells. Cardiopulmonary bypass also modified granulocytes by activating nuclear factor-κB (1.6-fold), whereas p38 was not altered. Histologic analyses revealed that cardiopulmonary bypass promoted acute tubular necrosis. Pretreatment of animals with sulforaphane reduced p38 (90% reduction) and nuclear factor-κB (50% reduction) phosphorylation in leukocytes and protected kidneys from injury.ConclusionsSystemic inflammatory responses after cardiopulmonary bypass were associated with activation of p38 and nuclear factor-κB pathways in circulating leukocytes. Inflammatory responses to cardiopulmonary bypass can be reduced by sulforaphane, which reduced leukocyte activation and protected against renal injury

Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass

Objectives: Systemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood. Methods: A porcine model was established to study the signaling pathways that promote systemic inflammation in response to cardiac surgery with cardiopulmonary bypass under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to cardiopulmonary bypass was also studied. Intracellular staining and flow cytometry were performed to measure phosphorylation of p38 mitogen-activated protein kinase and the transcription factor nuclear factor-kB in granulocytes and mononuclear cells. Results: Surgery with cardiopulmonary bypass for 1 to 2 hours enhanced phosphorylation of p38 (2.5-fold) and nuclear factor-kB (1.6-fold) in circulating mononuclear cells. Cardiopulmonary bypass also modified granulocytes by activating nuclear factor-kB (1.6-fold), whereas p38 was not altered. Histologic analyses revealed that cardiopulmonary bypass promoted acute tubular necrosis. Pretreatment of animals with sulforaphane reduced p38 (90% reduction) and nuclear factor-kB (50% reduction) phosphorylation in leukocytes and protected kidneys from injury. Conclusions: Systemic inflammatory responses after cardiopulmonary bypass were associated with activation of p38 and nuclear factor-kB pathways in circulating leukocytes. Inflammatory responses to cardiopulmonary bypass can be reduced by sulforaphane, which reduced leukocyte activation and protected against renal injury. (J Thorac Cardiovasc Surg 2014;148:690-7

Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass

ObjectivesSystemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood.MethodsA porcine model was established to study the signaling pathways that promote systemic inflammation in response to cardiac surgery with cardiopulmonary bypass under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to cardiopulmonary bypass was also studied. Intracellular staining and flow cytometry were performed to measure phosphorylation of p38 mitogen-activated protein kinase and the transcription factor nuclear factor-κB in granulocytes and mononuclear cells.ResultsSurgery with cardiopulmonary bypass for 1 to 2 hours enhanced phosphorylation of p38 (2.5-fold) and nuclear factor-κB (1.6-fold) in circulating mononuclear cells. Cardiopulmonary bypass also modified granulocytes by activating nuclear factor-κB (1.6-fold), whereas p38 was not altered. Histologic analyses revealed that cardiopulmonary bypass promoted acute tubular necrosis. Pretreatment of animals with sulforaphane reduced p38 (90% reduction) and nuclear factor-κB (50% reduction) phosphorylation in leukocytes and protected kidneys from injury.ConclusionsSystemic inflammatory responses after cardiopulmonary bypass were associated with activation of p38 and nuclear factor-κB pathways in circulating leukocytes. Inflammatory responses to cardiopulmonary bypass can be reduced by sulforaphane, which reduced leukocyte activation and protected against renal injury