Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide, presenting with acute and chronic coronary syndromes. Although coronary atherosclerosis is a major cause of IHD, many patients with angina or myocardial ischemia do not have obstructive coronary heart disease and impairment of the coronary microcirculation has been increasingly implicated as a relevant cause of IHD. Therefore, coronary microvascular dysfunction (CMD) refers to a term covering a wide spectrum of structural and functional alterations which affect the coronary microcirculation leading to myocardial ischemia and angina. The advent of non-invasive and invasive functional tests has exponentially broadened the ability to recognize CMD and delineate related clinical and biochemical features. Despite major advances in diagnosing and stratifying this condition, therapeutic strategies remain limited and poorly defined. In this review, we will provide an overview of the pathophysiology and the diagnostic evaluation of CMD across the spectrum of cardiovascular diseases. Furthermore, we will discuss the novel therapeutic strategies available for these patients in the perspective of a personalised medicine approach.

Nowadays, current guidelines on acute coronary syndrome (ACS) provide recommendations mainly based on the clinical presentation. However, greater attention is being directed to the specific pathophysiology underlying ACS, considering that plaque destabilization and rupture leading to luminal thrombotic obstruction is not the only pathway involved, albeit the most recognized. In this review, we discuss how intracoronary imaging and biomarkers allow the identification of specific ACS endotypes, leading to the recognition of different prognostic implications, tailored management strategies, and new potential therapeutic targets. Furthermore, different strategies can be applied on a personalized basis regarding antithrombotic therapy, non-culprit lesion revascularization, and microvascular obstruction (MVO). With respect to myocardial infarction with non-obstructive coronary arteries (MINOCA), we will present a precision medicine approach, suggested by current guidelines as the mainstay of the diagnostic process and with relevant therapeutic implications. Moreover, we aim at illustrating the clinical implications of targeted strategies for ACS secondary prevention, which may lower residual risk in selected patients.

Background: Intracoronary provocation testing with acetylcholine (ACh) is helpful to diagnose and risk‐stratify patients with ischemia with nonobstructed coronary arteries (NOCA) and myocardial infarction with NOCA. This study explored potential sex‐related disparities on the prognostic significance of ACh provocative testing. Methods: Consecutive patients with ischemia with NOCA and those with myocardial infarction with NOCA who underwent ACh provocation testing were enrolled. The primary end point was the incidence of major adverse cardiovascular and cerebrovascular events at follow‐up. Co‐primary end points were angina recurrence and quality of life assessed by 12‐month Seattle Angina Questionnaire (SAQ) summary score. Results: A total of 519 patients (mean age, 61.4±12.1 years; 275 [53.0%] women and 244 [47%] men) were enrolled: 346 (66.7%) with ischemia with NOCA and 173 (33.3%) with myocardial infarction with NOCA. A positive ACh test was observed in 274 (52.8%) patients, with a lower prevalence of epicardial spasm (82 [56.2%] versus 106 [82.8%]) and a higher prevalence of microvascular spasm (64 [43.8%] versus 22 [17.2%]) in women compared with men ( P >0.001). After a median 22‐month follow‐up, major adverse cardiovascular and cerebrovascular events occurred in 53 (10.2%) patients, without significant sex differences ( P >0.05). Men with a positive ACh test had a significantly higher rate of major adverse cardiovascular and cerebrovascular events (22 [17.2%] versus 5 [4.3%], P =0.002) compared with those with a negative test; no difference was observed in women ( P >0.05) ( P for interaction=0.003). Women with a positive test experienced a higher rate of angina recurrence (61 [41.8%] versus 32 [24.8%], P =0.005) and a lower SAQ summary score (82 [interquartile range, 72–90] versus 86 [interquartile range, 78–100], P 0.05). Conclusions: This study revealed the importance of recognizing sex‐specific differences in the prognostic value of ACh testing for proper management of coronary vasomotor disorders.

Acetylsalicylic acid (ASA) represents a cornerstone of antiplatelet therapy for the treatment of atherosclerotic coronary artery disease (CAD). ASA is in fact indicated in case of an acute coronary syndrome or after a percutaneous coronary intervention with stent implantation. Aspirin hypersensitivity is frequently reported by patients, and this challenging situation requires a careful evaluation of the true nature of the presumed sensitivity and of its mechanisms, as well as to differentiate it from a more frequent (and more easily manageable) aspirin intolerance. Two main strategies are available to allow ASA administration for patients with CAD and suspected ASA hypersensitivity: a low-dose ASA challenge, aimed at assessing the tolerability of ASA at the antiplatelet dose of 100 mg, and desensitization, a therapeutic procedure which aims to induce tolerance to ASA. For those patients who cannot undergo ASA challenge and desensitization due to previous serious adverse reactions, or for those in whom desensitization was unsuccessful, a number of further alternative strategies are available, even if these have not been validated and approved by guidelines. The aim of this state-of-the-art review is therefore to summarize the established evidence regarding pathophysiology, clinical presentation, diagnosis, and management of aspirin hypersensitivity and to provide a practical guide for cardiologists (and clinicians) who have to face the not uncommon situation of a patient with concomitant coronary artery disease and aspirin hypersensitivity.

Vulnerable coronary plaques are the primary substrate for acute coronary syndromes, representing a significant challenge in cardiovascular care. This review examines the pivotal role of intracoronary imaging, specifically intravascular ultrasound (IVUS) and optical coherence tomography (OCT), in the detection and management of these high-risk lesions. We detail the technical principles of these modalities and their unique capabilities in characterizing plaque morphology, from identifying thin-cap fibroatheromas (TCFA) to differentiating mechanisms of plaque rupture and erosion. The article further synthesizes evidence on how imaging-guided strategies—ranging from intensive medical therapy to emerging interventional approaches like preventive stenting—can stabilize vulnerable plaques and improve patient outcomes. Finally, we explore future directions, including the integration of artificial intelligence and hybrid imaging technologies, which promise to refine risk stratification and personalize the treatment of coronary artery disease.

Vasospastic angina and microvascular angina are increasingly recognized as important causes of myocardial ischemia in patients with angina or myocardial infarction and non-obstructive coronary arteries (ANOCA/MINOCA). Unlike obstructive coronary artery disease, these conditions result from dynamic alterations in epicardial and/or microvascular tone that are not detected by standard coronary angiography. Intracoronary acetylcholine (ACh) provocation testing enables direct assessment of coronary vasomotor function by evaluating both endothelial integrity and smooth muscle reactivity. Moreover, ACh can identify epicardial spasm, microvascular spasm, or impaired endothelium-dependent vasodilation, thereby providing precise characterization of the underlying pathophysiological mechanism. When performed using standardized protocols, ACh testing has shown a high diagnostic yield and a reassuring safety profile. In addition to the associated diagnostic relevance, the ACh response carries prognostic significance, as abnormal findings are associated with a higher risk of recurrent angina and adverse cardiovascular events. Furthermore, randomized data demonstrated that treatment tailored to invasive coronary function testing improves symptoms and quality of life. This review summarizes the pathophysiological background, practical aspects, safety, and clinical value of ACh provocation testing, underscoring its central role in a more personalized approach to patients with ANOCA/MINOCA.