Ischaemic heart disease represents the leading cause of morbidity and mortality, typically induced by the detrimental effects of risk factors on the cardiovascular system. Although preventive interventions tackling conventional risk factors have helped to reduce the incidence of ischaemic heart disease, it remains a major cause of death worldwide. Thus, attention is now shifting to non-traditional risk factors in the built, natural, and social environments that collectively contribute substantially to the disease burden and perpetuate residual risk. Of importance, these complex factors interact non-linearly and in unpredictable ways to often enhance the detrimental effects attributable to a single or collection of these factors. For this reason, a new paradigm called the ‘exposome’ has recently been introduced by epidemiologists in order to define the totality of exposure to these new risk factors. The purpose of this review is to outline how these emerging risk factors may interact and contribute to the occurrence of ischaemic heart disease, with a particular attention on the impact of long-term exposure to different environmental pollutants, socioeconomic and psychological factors, along with infectious diseases such as influenza and COVID-19. Moreover, potential mitigation strategies for both individuals and communities will be discussed.

Myocardial bridging (MB) is the most frequent congenital coronary anomaly characterized by a segment of an epicardial coronary artery that passes through the myocardium. MB is an important cause of myocardial ischemia and is also emerging as a possible cause of myocardial infarction with non-obstructed coronary arteries (MINOCA). There are multiple mechanisms underlying MINOCA in patients with MB (i.e., MB-mediated increased risk of epicardial or microvascular coronary spasm, atherosclerotic plaque disruption and spontaneous coronary artery dissection). The identification of the exact pathogenetic mechanism is crucial in order to establish a patient-tailored therapy. This review provides the most up-to-date evidence regarding the pathophysiology of MINOCA in patients with MB. Moreover, it focuses on the available diagnostic tools that could be implemented at the time of coronary angiography to achieve a pathophysiologic diagnosis. Finally, it focuses on the therapeutic implications associated with the different pathogenetic mechanisms of MINOCA in patients with MB.

Background: Cardiovascular sequelae after COVID-19 are frequent. However, the predictors for their occurrence are still unknown. In this study, we aimed to assess whether myocardial injury during COVID-19 hospitalization is associated to CV sequelae and death after hospital discharge. Methods: In this prospective observational study, consecutive patients who were admitted for COVID-19 in a metropolitan COVID-19 hub in Italy, between March 2021 and January 2022, with a ≥ 1 assessment of high sensitivity cardiac troponin I (hs-cTnI) were included in the study, if they were alive at hospital discharge. Myocardial injury was defined as elevation hs-cTnI > 99th percentile of the upper reference limit. The incidence of all-cause mortality and major adverse cardiovascular and cerebrovascular events (MACCE, including cardiovascular death, admission for acute or chronic coronary syndrome, hospitalization for heart failure, and stroke/transient ischemic attack) at follow-up were the primary outcomes. Arrhythmias, inflammatory heart diseases, and/or thrombotic disorders were analyzed as well. Results: Among the 701 COVID-19 survivors (mean age 66.4 ± 14.4 years, 40.2% female), myocardial injury occurred in 75 (10.7%) patients. At a median follow-up of 270 days (IQR 165, 380), all-cause mortality (21.3% vs. 6.1%, p < 0.001), MACCE (25.3% vs. 4.5%, p < 0.001), arrhythmias (9.3% vs. 5.0%, p = 0.034), and inflammatory heart disease (8.0% vs. 1.1%, p < 0.001) were more frequent in patients with myocardial injury compared to those without. At multivariate analysis, myocardial injury (HR 1.95 [95% CI:1.05–3.61]), age (HR 1.09 [95% CI:1.06–1.12]), and chronic kidney disease (HR 2.63 [95% CI:1.33–5.21]) were independent predictors of death. Myocardial injury (HR 3.92 [95% CI:2.07–7.42]), age (HR 1.05 [95% CI:1.02–1.08]), and diabetes (HR 2.35 [95% CI:1.25–4.43]) were independent predictors of MACCE. Conclusion: In COVID-19 survivors, myocardial injury during the hospital stay portends a higher risk of mortality and cardiovascular sequelae and could be considered for the risk stratification of COVID-19 sequelae in patients who are successfully discharged.

The functional capacity of the immune cells is strongly dependent on their metabolic state and inflammatory responses are characterized by a greater use of glucose in immune cells. This study is aimed to establish the role of glucose metabolism and its players [glucose transporter 1 (GLUT-1) and pyruvate kinase isozyme M2 (PKM2)] in the dysregulation of adaptive immunity and inflammation observed in patients with non-ST-segment elevation myocardial infarction (NSTEMI). We enrolled 248 patients allocated to three groups: NSTEMI patients, chronic coronary syndromes (CCS) patients, healthy subjects (HSs). NSTEMI patients showed higher expression of GLUT-1 and an enhanced glucose uptake in T cells when compared with CCS patients (P < 0.0001; P = 0.0101, respectively) and HSs (P = 0.0071; P = 0.0122, respectively). PKM2 had a prevalent nuclear localization in T lymphocytes in NSTEMI (P = 0.0005 for nuclear vs. cytoplasm localization), while in CCS and HS, it was equally distributed in both compartments. In addition, the nuclear fraction of PKM2 was significantly higher in NSTEMI compared with HS (P = 0.0023). In NSTEMI patients, treatment with Shikonin and Fasentin, which inhibits PKM2 enzyme activity and GLUT-1-mediated glucose internalization, respectively, led to a significant reduction in GLUT-1 expression along with the down-regulation of pro-inflammatory cytokine expression. NSTEMI patients exhibit dysregulation of the GLUT-1/PKM2 metabolic loop characterized by nuclear translocation of PKM2, where it acts as a transcription regulator of pro-inflammatory genes. This detrimental loop might represent a new therapeutic target for personalized medicine. GLUT-1/PKM2 metabolic loop and inflammatory pathways. PKM2 plays a central role in the modulation of the metabolic and inflammatory state. Our data showed aberrant localization of PKM2, in patients with NSTEMI, promoting enhanced GLUT-1 expression and glucose metabolism that shifts adaptive immunity towards a pro-inflammatory profile. The functional effects of the disruption of the metabolic loop GLUT-1/PKM2, through treatment with SKN and FSN in NSTEMI patients, led to a reduction of the pro-inflammatory profile and a modulation of the factors involved in lipid metabolism, contributing to the re-establishment of a physiological phenotype. Conversely, the treatment of HS with OLI, an inhibitor of oxidative phosphorylation, promotes GLUT-1 enhancement and a PKM2 dependent pro-inflammatory profile (not shown). Therefore, the evaluation of the immuno-metabolic profile could help to stratify NSTEMI patients and allow the identification of new therapeutic targets in the perspective of a personalized medicine approach [Created with BioRender.com]. ApoA1, apolipoprotein A1; CHI3L1, chitinase-3 like-1; FSN, fasentin; GLUT-1, glucose transporter 1; IL-6, interleukin 6; MPO, myeloperoxidase; PDGF, platelet-derived growth factor; PKM2, pyruvate kinase isozyme M2; RBP4, retinol-binding protein 4; SKN, shikonin.

Type 2 diabetes mellitus (DM) represents, with its macro and microvascular complications, one of the most critical healthcare issues for the next decades. Remarkably, in the context of regulatory approval trials, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) proved a reduced incidence of major adverse cardiovascular events (MACEs), i.e., cardiovascular death and heart failure (HF) hospitalizations. The cardioprotective abilities of these new anti-diabetic drugs seem to run beyond mere glycemic control, and a growing body of evidence disclosed a wide range of pleiotropic effects. The connection between diabetes and meta-inflammation seems to be the key to understanding how to knock down residual cardiovascular risk, especially in this high-risk population. The aim of this review is to explore the link between meta-inflammation and diabetes, the role of newer glucose-lowering medications in this field, and the possible connection with their unexpected cardiovascular benefits.

Up to 4 million patients with signs of myocardial ischemia have no obstructive coronary artery disease (CAD). The absence of precise guidelines for diagnosis and treatment in non-obstructive CAD encourages the scientific community to fill the gap knowledge, to provide non-invasive and less expensive diagnostic tools. The aim of our study was to explore the biological profile of Ischemia with Non-Obstructive Coronary Arteries (INOCA) patients with microvascular dysfunction compared to patients presenting with obstructive chronic coronary syndrome (ObCCS) in order to find specific hallmarks of each clinical condition. We performed a gene expression array from peripheral blood mononuclear cells (PBMCs) isolated from INOCA (n = 18) and ObCCS (n = 20) patients. Our results showed a significantly reduced gene expression of molecules involved in cell adhesion, signaling, vascular motion, and inflammation in INOCA as compared to the ObCCS group. In detail, we found lower expression of Platelet and Endothelial Cell Adhesion Molecule 1 (CD31, p < 0.0001), Intercellular Adhesion Molecule-1 (ICAM1, p = 0.0004), Tumor Necrosis Factor (TNF p = 0.0003), Transferrin Receptor (TFRC, p = 0.002), and Vascular Endothelial Growth Factor A (VEGFA, p = 0.0006) in the INOCA group compared with ObCCS. Meanwhile, we observed an increased expression of Hyaluronidase (HYAL2, p < 0.0001) in INOCA patients in comparison to ObCCS. The distinct expression of molecular biomarkers might allow an early and non-invasive differential diagnosis between ObCCS and INOCA, improving clinical management and treatment options, in the era of personalized medicine.