Effect of remote ischaemic preconditioning in cardiac dysfunction and end-organ injury following cardiac surgery with cardiopulmonary bypass in children: A translational approach investigating clinical outcome and myocardial molecular biology

Congenital heart disease (CHD) is the most common birth defect, causing an important rate of morbidity and mortality. Treatment of CHD requires surgical correction in a significant percentage of cases which exposes patients to cardiac and end organ injury. Cardiac surgical procedures often require the utilisation of cardiopulmonary bypass (CPB), a system that replaces heart and lungs function by diverting circulation into an external circuit. The use of CPB can initiate potent inflammatory responses, in addition a proportion of procedures require a period of aortic cross clamp during which the heart is rendered ischaemic and is exposed to injury. High O2 concentrations are used during cardiac procedures and when circulation is re-established to the heart which had adjusted metabolically to ischaemia, further injury is caused in a process known as ischaemic reperfusion injury (IRI). Several strategies are in place in order to protect the heart during surgery, however injury is still caused, having detrimental effects in patients at short and long term. Remote ischaemic preconditioning (RIPC) is a technique proposed as a potential cardioprotective measure. It consists of exposing a remote tissue bed to brief episodes of ischaemia prior to surgery in order to activate protective pathways that would act during CPB, ischaemia and reperfusion. This study aimed to assess RIPC in paediatric patients requiring CHD surgical correction with a translational approach, integrating clinical outcome, marker analysis, cardiac function parameters and molecular mechanisms within the cardiac tissue. A prospective, single blinded, randomized, controlled trial was conducted applying a RIPC protocol to randomised patients through episodes of limb ischaemia on the day before surgery which was repeated right before the surgery started, after anaesthesia induction. Blood samples were obtained before surgery and at three post-operative time points from venous lines, additional pre and post-bypass blood samples were obtained from the right atrium. Myocardial tissue was resected during the ischaemic period of surgery. Echocardiographic images were obtained before the surgery started after anaesthetic induction and the day after surgery, images were stored for later off line analysis. PICU surveillance data was collected including ventilation parameters, inotrope use, standard laboratory analysis and six hourly blood gas analysis. Pre and post-operative quantitation of markers in blood specimens included cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), inflammatory mediators including interleukins IL-6, IL-8, IL-10, tumour necrosis factor (TNF-α), and the adhesion molecules ICAM-1 and VCAM-1; the renal marker Cystatin C and the cardiovascular markers asymmetric dymethylarginine (ADMA) and symmetric dymethylarginine (SDMA). Nitric oxide (NO) metabolites and cyclic guanosine monophosphate (cGMP) were measured before and after bypass. Myocardial tissue was processed at baseline and after incubation at hyperoxic concentration during four hours in order to mimic surgical conditions. Expression of genes involved in IRI and RIPC pathways was analysed including heat shock proteins (HSPs), toll like receptors (TLRs), transcription factors nuclear factor κ-B (NF- κ-B) and hypoxia inducible factor 1 (HIF-1). The participation of hydrogen sulfide enzymatic genes, apelin and its receptor were explored. There was no significant difference according to group allocation in any of the echocardiographic parameters. There was a tendency for higher cTnI values and inotropic score in control patients post-operatively, however this was not statistically significant. BNP presented no significant difference according to group allocation. Inflammatory parameters tended to be higher in the control group, however only TNF- α was significantly higher. There was no difference in levels of Cystatin C, NO metabolites, cGMP, ADMA or SDMA. RIPC patients required shorter PICU stay, all other clinical and laboratory analysis presented no difference related to the intervention. Gene expression analysis revealed interesting patterns before and after incubation. HSP-60 presented a lower expression at baseline in tissue corresponding to RIPC patients, no other differences were found. This study provided with valuable descriptive information on previously known and newly explored parameters in the study population. Demographic characteristics and the presence of cyanosis before surgery influenced patterns of activity in several parameters, numerous indicators were linked to the degree of injury suffered by the myocardium. RIPC did not reduce markers of cardiac injury or improved echocardiographic parameters and it did not have an effect on end organ function; some effects were seen in inflammatory responses and gene expression analysis. Nevertheless, an important clinical outcome indicator, PICU length of stay was reduced suggesting benefit from the intervention. Larger studies with more statistical power could determine if the tendency of lower injury and inflammatory markers linked to RIPC is real. The present results mostly support findings of larger multicentre trials which have reported no cardiac benefit from RIPC in paediatric cardiac surgery.

Cognitive impairment in heart failure

The clinical syndrome of heart failure is one of the leading causes of hospitalisation and mortality in older adults. Due to ageing of the general population and improved survival from cardiac disease the prevalence of heart failure is rising. Despite the fact that the majority of patients with heart failure are aged over 65 years old, many with multiple co-morbidities, the association between cognitive impairment and heart failure has received relatively little research interest compared to other aspects of cardiac disease. The presence of concomitant cognitive impairment has implications for the management of patients with heart failure in the community. There are many evidence based pharmacological therapies used in heart failure management which obviously rely on patient education regarding compliance. Also central to the treatment of heart failure is patient self-monitoring for signs indicative of clinical deterioration which may prompt them to seek medical assistance or initiate a therapeutic intervention e.g. taking additional diuretic. Adherence and self-management may be jeopardised by cognitive impairment. Formal diagnosis of cognitive impairment requires evidence of abnormalities on neuropsychological testing (typically a result ≥1.5 standard deviation below the age-standardised mean) in at least one cognitive domain. Cognitive impairment is associated with an increased risk of dementia and people with mild cognitive impairment develop dementia at a rate of 10-15% per year, compared with a rate of 1-2% per year in healthy controls.1 Cognitive impairment has been reported in a variety of cardiovascular disorders. It is well documented among patients with hypertension, atrial fibrillation and coronary artery disease, especially after coronary artery bypass grafting. This background is relevant to the study of patients with heart failure as many, if not most, have a history of one or more of these co-morbidities. A systematic review of the literature to date has shown a wide variation in the reported prevalence of cognitive impairment in heart failure. This range in variation probably reflects small study sample sizes, differences in the heart failure populations studied (inpatients versus outpatients), neuropsychological tests employed and threshold values used to define cognitive impairment. The main aim of this study was to identify the prevalence of cognitive impairment in a representative sample of heart failure patients and to examine whether this association was due to heart failure per se rather than the common cardiovascular co-morbidities that often accompany it such as atherosclerosis and atrial fibrillation. Of the 817 potential participants screened, 344 were included in this study. The study cohort included 196 patients with HF, 61 patients with ischaemic heart disease and no HF and 87 healthy control participants. The HF cohort consisted of 70 patients with HF and coronary artery disease in sinus rhythm, 51 patients with no coronary artery disease in sinus rhythm and 75 patients with HF and atrial fibrillation. All patients with HF had evidence of HF-REF with a LVEF <45% on transthoracic echocardiography. The majority of the cohort was male and elderly. HF patients with AF were more likely to have multiple co-morbidities. Patients recruited from cardiac rehabilitation clinics had proven coronary artery disease, no clinical HF and a LVEF >55%. The ischaemic heart disease group were relatively well matched to healthy controls who had no previous diagnosis of any chronic illness, prescribed no regular medication and also had a LVEF >55%. All participants underwent the same baseline investigations and there were no obvious differences in baseline demographics between each of the cohorts. All 344 participants attended for 2 study visits. Baseline investigations including physiological measurements, electrocardiography, echocardiography and laboratory testing were all completed at the initial screening visit. Participants were then invited to attend their second study visit within 10 days of the screening visit. 342 participants completed all neuropsychological assessments (2 participants failed to complete 1 questionnaire). A full comprehensive battery of neuropsychological assessment tools were administered in the 90 minute study visit. These included three global cognitive screening assessment tools (mini mental state examination, Montreal cognitive assessment tool and the repeatable battery for the assessment of neuropsychological status) and additional measures of executive function (an area we believe has been understudied to date). In total there were 9 cognitive tests performed. These were generally well tolerated. Data were also collected using quality of life questionnaires and health status measures. In addition to this, carers of the study participant were asked to complete a measure of caregiver strain and an informant questionnaire on cognitive decline. The prevalence of cognitive impairment varied significantly depending on the neuropsychological assessment tool used and cut-off value used to define cognitive impairment. Despite this, all assessment tools showed the same pattern of results with those patients with heart failure and atrial fibrillation having poorer cognitive performance than those with heart failure in sinus rhythm. Cognitive impairment was also more common in patients with cardiac disease (either coronary artery disease or heart failure) than age-, sex- and education-matched healthy controls, even after adjustment for common vascular risk factors.