Mechanisms of coronary ischaemia in women: Are we any closer to deciphering the code?

Increasing interest continues to focus on cardiovascular risk in women. Community perceptions typically highlight the role of heart disease as a major driver of morbidity and mortality in men. However, this contrasts with the evidence demonstrating that cardiovascular disease remains the leading cause of death for both men and women in most nations. In fact, women are three times more likely to die from heart disease than breast cancer, yet the significance of this observation does not translate into population approaches to disease prevention and treatment. As a result, women typically present later with clinical syndromes and are less likely to receive evidence-based therapies than their male counterparts.1 This disparity in terms of access to established interventions is often justified by the clear underrepresentation of women in clinical trials; however, this simply exposes many patients to unacceptably higher risks of recurrent ischaemic events. In parallel, there are considerable questions regarding potential gender differences in disease pathophysiology. It is well established that the clinical manifestation of cardiovascular disease typically starts later in life in women, attributed to the protective effects of oestrogen. Mechanistic studies have suggested a higher prevalence of non-obstructive disease and microvascular dysfunction.1 The direct correlation between these observations and clinical outcomes remains uncertain. As a result, there remains considerable work required to provide a more definitive characterisation of the factors driving cardiovascular risk in women. This will permit the development of more effective approaches to prevention, risk prediction and treatment. There also continues to be significant research interest in understanding what factors underscore ischaemic-type presentations in patients with non-obstructive disease.2 This research area has received substantial interest for several decades, providing the rationale for the use of a number of diagnoses in this setting, including syndrome X, slow flow syndrome, microvascular dysfunction, Takotsubo’s cardiomyopathy, vascular spasm and myocardial infarction with non-obstructive coronary arteries. While each of these entities involves distinct features, which underlie their definitions, they all fundamentally involve patients whose clinical presentations can not be explained by conventional oculostenotic paradigms. However, a provocative question should be postulated: do all of these patients have a coronary syndrome? It is clear that a number of patients will have some alternative form of coronary pathology. Vascular spasm is real, can easily be demonstrated at the time of coronary angiography and responds well to treatment with anti-spasm agents. Diagnostic criteria for Takotsubo’s cardiomyopathy have also become well accepted, although the appropriate medical therapy for these patients has not been subject to large scale clinical trials. The ability to image the vessel wall, as opposed to the lumen, has the potential to reveal much more about vascular disease in these patients. Intravascular ultrasound has established the presence of substantial plaque and expansive vascular remodeling, even when the degree of luminal obstruction is modest. Optical coherence tomography illustrates with superior resolution the superficial phenotype of atherosclerotic plaque. This technique, for example, has demonstrated a greater prevalence of plaque erosion in women with ischaemic syndromes – the therapeutic implications of which are unknown.3 More recent observations from non-invasive imaging with computed tomography and the administration of radioactive isotopes have also demonstrated the presence of substantial periarterial inflammation in a number of patients with non-obstructive disease on angiography and vasospasm.4 It is also likely that some of these patients will not have a coronary syndrome at all. Accordingly, more work is required as opposed to erroneously assigning a coronary diagnosis when it does not exist. The therapeutic, economic and social implications of applying such a diagnosis can be profound. In the current issue of the journal, Nielsen and colleagues5 present provocative observations in a cohort of women with ischaemic symptoms and non-obstructive disease on coronary angiography. In this substudy of the iPOWER study, the investigators measured soluble markers of collagen formation and breakdown, demonstrating phenotypic differences compared with asymptomatic controls. These same patients demonstrated evidence of cardiac fibrosis on cardiac magnetic resonance imaging. The potential mechanistic link suggests that episodes of cardiac ischaemia may promote fibrotic change, which may itself underlie adverse cardiovascular outcomes observed in these patients. While the study is small and there are major differences between the groups, which themselves may contribute to the observed collagen differences reported, the findings propose the provocative question: do these changes help to discriminate those patients with significant coronary pathology from those without, even when the coronary angiogram is unhelpful? The implications of such a finding have the potential to promote a sea change in our approach to the investigation of patients with underwhelming angiography findings. Larger validation studies that control for differences in other factors that may promote fibrosis are required. Clinical trials are then needed to determine if the use of either of these blood-based biomarkers or cardiac imaging can triage patients to different therapies. Whether those therapies target specific coronary pathologies or prevent the development of cardiac fibrosis also remains unknown. The ability to demonstrate that such an intervention results in cost-effective improvements in cardiovascular outcomes would permit translation of theoretical dysfunction of the coronary vasculature to clinical syndromes that can be prevented and potentially reversed. It is a small step towards a big advance; however, the time has come to decide how best to tackle these issues. The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. The author(s) received no financial support for the research, authorship and/or publication of this article.