Assessing the immune phenotype of cardiac syndrome x: a prospective study of biomarkers

Cardiac Syndrome X (CSX), the presence of angina pectoris with objective signs of myocardial ischaemia despite angiographically normal epicardial coronary arteries, appears to be due to coronary microvascular dysfunction and is known to be associated with an elevation of several inflammatory biomarkers, suggesting a possible role for inflammation in its pathogenesis. We aimed to further characterise this relationship by prospectively analysing a wide variety of molecular biomarkers in a cohort of CSX patients thereby charting the changes in biomarkers throughout the natural history of CSX from its initial diagnosis to eventual disease quiescence. We found that CSX patients, when compared to healthy controls, have a persistent low-grade systemic inflammatory response characterised by an elevation of Tumour Necrosis Factor and Interferon-gamma, regardless of the presence of contemporaneous signs or symptoms of disease activity. Interleukin-6 and C-reactive Protein (CRP) are only elevated when patients have clinical evidence of disease activity and may be state markers in CSX. Moreover, CRP levels appear to correlate with signals of disease severity such as the time taken to develop symptoms during exercise stress testing. We have also demonstrated that the enzyme Indoleamine-2,3- dioxygenase is upregulated in active disease thus providing a possible explanation for the increased burden of psychological disease encountered in CSX. Analysis of the microRNA transcriptome showed that miR-143 is significantly under-expressed in CSX patients. This could allow phenotype switching in vascular smooth muscle cells with the resultant vascular remodelling causing reduced vessel responsiveness to local rheological stimuli and reduced luminal diameter with consequent increased microvascular resistance during times of increased myocardial oxygen demand, thereby limiting maximal hyperaemia during exercise. Our findings corroborate many previous hypotheses regarding the role of inflammation in CSX, generate new insights into possible pathogenic mechanisms and offer new therapeutic targets for the future management of this important cardiological condition.

The impact of first pregnancy and delivery on pelvic floor dysfunction

Background: The first childbirth has the greatest impact on a woman’s pelvic floor when major changes occur. The aim of this study was to comprehensively describe pelvic floor dysfunction (PFD) in young nulliparous women, and its correlation with postnatal pathology. Methods: A prospective study was performed at Cork University Maternity Hospital, Ireland. Initially 1484 nulliparous women completed the validated Australian Pelvic Floor Questionnaire at 15 weeks’ gestation and repeatedly at one year postnatally (N=872). In the second phase, at least one year postnatally, 202 participants without subsequent pregnancies attended the clinical follow up which included: pelvic organ prolapse quantification, a 3D-Transperineal ultrasound scan and collagen level assessment. Results: A high pre-pregnancy prevalence of various types of PFD was detected, which in the majority of cases persisted postnatally and included multiple types of PFD. The first birth had a negative impact on severity of pre-pregnancy symptoms in <15% of cases. Apart from prolapse, vaginal delivery, including instrumental delivery did not increase the risk of PFD symptoms, where as Caesarean section was protective for all types of PFD. The first birth had a bigger impact on pre-existing symptoms of overactive bladder compared to stress urinary incontinence. Pelvic organ prolapse is extremely prevalent in young primiparous women, however usually it is low grade and asymptomatic. Congenital factors and high collagen type III levels play an important role in the aetiology of pelvic organs prolapse. Levator ani trauma is present in one in three women after the first pregnancy and delivery. Conclusion: The main damage to the pelvic floor most likely occurs due to an undiagnosed congenital intrinsic weakness of the pelvic floor structures. PFD is highly associated with first childbirth, however it seems that pregnancy and delivery are contributing factors only which unmask the congenital intrinsic weakness of the pelvic floor support.