BIOmarkers and PLAtelet Function Assessment in Myocardial Ischemia and Non Obstructive Coronary Arteries Study: The BIOplatINO Study

Background

Ischemic heart diseases (IHD) still represent the leading cause of disability and mortality worldwide, with IHD and obstructive coronary artery disease (OCAD) (defined as any coronary artery stenosis ≥50%) often used as synonymous or interchangeable terms. However, a significant proportion of patients (up to 50% and particularly women) undergoing coronary angiography (CAG) because of angina and/or evidence of myocardial ischemia do not have OCAD. The term "ischemia with non-obstructive coronary artery disease" (INOCA) identifies this significant proportion of patients presenting with signs and symptoms of myocardial ischemia (e.g., angina pectoris) with normal or near-normal coronary arteries at angiography. Even if initially believed a benign condition, it is now well-established that INOCA patients are at increased risk for cardiovascular events (including acute coronary syndrome, heart failure hospitalization, stroke and repeated cardiovascular procedures). Vasomotion disorders, including microvascular angina (MVA) and/or vasospastic angina (VSA), may be particularly relevant in the pathogenesis of INOCA. Indeed, coronary vasomotion disorders can cause a relative supply-demand mismatch of myocardial blood flow and nutrients relative to their requirements, inducing myocardial ischemia that may be transient, recurrent, and/or chronic. MVA is the clinical manifestation of myocardial ischemia caused by coronary microvascular dysfunction (CMD). In this clinical entity, myocardial ischemia may result from structural remodeling of the microvasculature leading to fixed reduced microcirculatory conductance (impaired vasodilatation) and/or vasomotor disorders affecting the coronary arterioles and causing dynamic arteriolar obstruction in the presence of endothelial dysfunction and local inflammation (microvascular spasm). VSA is the clinical manifestation of myocardial ischemia caused by dynamic epicardial coronary obstruction due to epicardial artery spasm. Key subgroups of patients (endotypes) within the heterogeneous population of INOCA may be distinguished by distinct mechanisms and/or responses to medical therapy (i.e.: MVA, VSA, both MVA and VSA or none). This distinction is of mainstay importance, as the Coronary Microvascular Angina (CorMicA) trial demonstrated that a strategy of adjunctive invasive testing for disorders of coronary function linked with stratified medical therapy led to improvements in patient outcomes, including a reduction in angina severity and better quality of life. However, the specific endotype is rarely correctly diagnosed in clinical practice and, therefore, no tailored therapy is prescribed for these patients. Consequently, INOCA patients often experience recurrent angina, with hospital readmission, repeated CAG and a significant impact on quality of life and healthcare-related costs.

Platelets play pivotal roles in thrombosis and subsequent ischemic complications in patients with OCAD, and platelet activation and dysfunction have been reported also in INOCA patients. Indeed, platelets dense bodies contain adenine nucleotides (adenosine diphosphate [ADP] and adenosine triphosphate [ATP]) and serotonin which induce platelet aggregation, vasoconstriction and production of cytokines and modulators of inflammation. Moreover, healthy vascular endothelium produces potent platelet inhibitors such as nitric oxide, prostacyclin, and natural ADPase. Therefore, an imbalance in platelet activation and endothelial function, along with platelet-mediated vascular inflammation, may be relevant to the pathogenesis of INOCA. Given these diagnostic shortcomings in this evolving area of clinical research, the assessment of different circulating plasma biomarkers along with platelet function tests and their correlation with specific underlying pathophysiological mechanisms may help to identify new diagnostic and stratification tools for INOCA patients.

Hypothesis and significance

Diagnosing the precise cause, in particular, the identification of the specific endotype, is of mainstay importance in INOCA patients, given that a tailored therapy demonstrated to have a significant impact on cardiovascular and quality-of-life outcomes. Thus, the investigators hypothesized that distinct signatures of circulating biomarkers and/or platelet function may be associated with a specific endotype of INOCA. Therefore, identifying these specific signatures may help in the diagnosis of these patients as well as pave the way for the identification of specific pathophysiologic pathways and the development of future therapies. In addition, the investigators hypothesized that such specific signatures may be associated with different clinical courses at follow-up, and therefore they may help in the prognostic stratification of INOCA patients.