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Objectives: We assessed the relationship between exposure to air pollutants and mechanisms of coronary instability evaluated by optical coherence tomography (OCT) in patients with acute coronary syndrome (ACS). Background: Air pollution is an emerging key player in determining the residual risk of coronary events. However, pathophysiological mechanisms linking air pollution and coronary events have been not adequately investigated. Methods: Patients with ACS undergoing OCT imaging were retrospectively selected. Mechanism of culprit lesion instability was classified as plaque rupture (PR) or intact fibrous cap (IFC) by OCT, and the presence of macrophage infiltrates (MØI) and thin-cap fibroatheroma (TCFA) at the culprit site was also assessed. Based on each case's home address, exposure to several pollutants was evaluated, including particulate matter 2.5 (PM2.5), PM10, and carbon monoxide (CO). Only patients with >2 years of available data on air pollution exposure prior to ACS were enrolled. Results: We included 126 patients (median age: 67.0 years of age; IQR: 55.5-76.0; 97 male patients [77.0%]). Sixty-six patients (52.4%) had PR as the mechanism of plaque instability. Patients with PR were exposed to significantly higher PM2.5 levels than to IFC, and PM2.5 was independently associated with PR (odds ratio: 1.194; 95% CI: 1.036 to 1.377; P = 0.015). Moreover, exposure to higher levels of PM2.5 was independently associated with the presence of TCFA and of MØI at the culprit site. Interestingly, PM2.5, PM10, and CO levels were positively and significantly correlated with serum levels of C-reactive protein. Conclusions: We provide novel insights into the missing link between air pollution and increased risk of coronary events. In particular, exposure to higher concentrations of air pollutants is associated with the presence of vulnerable plaque features and with plaque rupture as a mechanism of coronary instability. An enhanced systemic and plaque inflammatory act

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Endothelial dysfunction (EnD) is a hallmark feature of coronary artery disease (CAD), representing the key early step of atherosclerotic plaque development and progression. Percutaneous coronary intervention (PCI) is performed daily worldwide to treat symptomatic CAD, however a consistent proportion of patients remain symptomatic for angina despite otherwise successful revascularization. EnD plays a central role in the mechanisms of post-PCI angina, as it is strictly associated with both structural and functional abnormalities in the coronary arteries that may persist, or even accentuate, following PCI. The assessment of endothelial function in patients undergoing PCI might help to identify those patients at higher risk of future cardiovascular events and recurrent/persistent angina who might therefore benefit more from an intensive treatment. In this review, we address the role of EnD in determining angina after PCI, discussing its pathophysiological mechanisms, diagnostic approaches and therapeutic perspectives.

Over the last several decades, clinicians and clinical scientists have had growing interest in heart failure (HF) diagnosis and treatment. While HF with reduced ejection fraction (EF) is a well-known clinical entity with several therapeutic strategies proven to be successful, HF with preserved ejection fraction is a more heterogenous syndrome with a prevalence that has increased in the last two decades, without effective therapeutic strategies. Great strides have been made in the detection of predisposing risk factors and pathological mechanisms; however, pharmacological therapies have shown to be ineffective in reducing cardiovascular mortality in the HF with preserved EF (HFpEF) population, opening the way to the necessity of developing new precision medicine based approaches. On the other hand, novel therapies and device interventions still require refinements with the ultimate goal of offering new clinically treatments for the HFpEF population. The aim of the present review is to provide insights into the HFpEF pathophysiology, diagnostic pathways and the latest updates on treatment strategies and their potential future application in routine clinical practice.

Coronary microvascular dysfunction (CMD) encompasses several pathogenetic mechanisms involving coronary microcirculation and plays a major role in determining myocardial ischemia in patients with angina without obstructive coronary artery disease, as well as in several other conditions, including obstructive coronary artery disease, nonischemic cardiomyopathies, takotsubo syndrome, and heart failure, especially the phenotype associated with preserved ejection fraction. Unfortunately, despite the identified pathophysiological and prognostic role of CMD in several conditions, to date, there is no specific treatment for CMD. Due to the emerging role of CMD as common denominator in different clinical phenotypes, additional research in this area is warranted to provide personalized treatments in this “garden variety” of patients. The purpose of this review is to describe the pathophysiological mechanisms of CMD and its mechanistic and prognostic role across different cardiovascular diseases. We will also discuss diagnostic modalities and the potential therapeutic strategies resulting from recent clinical studies.

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Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor highly expressed in coronary plaques, particularly in macrophages, and in activated platelets. Thus, a possible role in the pathogenesis of acute coronary syndrome (ACS) has been suggested. We evaluated systemic BDNF levels according to the different clinical presentations of ACS. Moreover, we assessed the relationship between BDNF levels and the presence of optical coherence tomography (OCT)-defined macrophage infiltrates (MØI) and healed plaques along the culprit vessel. We enrolled consecutive patients presenting with ST-elevation myocardial infarction (STEMI) or non-ST-elevation (NSTE)-ACS. Serum BDNF levels were assessed by enzyme-linked immunosorbent assay. Plaque characteristics of the culprit vessel were assessed by OCT. Among 126 ACS patients (median age 68.00, interquartile range [IQR] 59.75–75.25 years, male 74.6%, 71 (56.3%) were NSTE-ACS and 55 (43.7%) were STEMI. BDNF levels were higher in STEMI patients compared to NSTE-ACS. OCT assessment was performed in 53 (42.1%) patients. Patients with MØI (n = 27) had higher BDNF levels compared to patients without MØI. Furthermore, patients with healed plaques (n = 13) had lower BDNF levels than patients without healed plaques. At multivariate regression analysis BDNF levels independently predicted the presence of MØI (odds ratio [OR] = 2.856; 95% confidence interval [CI] [1.151–7.090], P = 0.024) and the absence of healed plaques (OR = 0.438, 95% CI [0.185–0.992], P= 0.050). Among ACS patients, BDNF levels were higher in patients with STEMI. Moreover, BDNF levels were independently associated with MØI and with the absence of healed plaques along the culprit vessel, suggesting a possible role of BDNF in promoting plaque inflammation, destabilization and occlusive thrombosis.

AIMS: Killip classification is a simple and fast clinical tool for risk stratification of patients presenting with acute coronary syndrome (ACS). However, the clinical features and predictors of high Killip class at admission, and its prognostic impact in patients presenting with anterior ST elevation MI (STEMI) as first clinical cardiovascular event are still poorly known. The aim of this study was to identify the predictors of high Killip class and its impact on in-hospital and follow-up outcomes. METHODS: We prospectively enrolled patients with unheralded anterior STEMI because of proximal or mid left anterior descending (LAD) artery categorized according to Killip classification. Patients' characteristics, in-hospital complications and major adverse cardiovascular events (MACEs; composite of all-cause death, heart failure hospitalization and new-onset ACS) at follow-up were collected. RESULTS: We enrolled 147 patients [age 66.16±13.33, 113 male patients (76.9%)]. Killip class III--IV occurred in 22 (15%) patients. The median duration of follow-up was 12 [6--15.1] months. At multivariate analysis age [hazard ratio 1.137, 95% CI (1.068--1.209), P < 0.001], prehospital cardiac arrest [hazard ratio 12.145, 95% CI (1.710--86.254), P = 0.013] and proximal LAD lesion [hazard ratio 5.066, 95% CI (1.400--18.334), P = 0.013] were predictive of Killip class III--IV at admission. At multivariate analysis, Killip class III--IV was an independent predictor of in-hospital mortality [hazard ratio 7.790, 95% CI (1.024--59.276], P = 0.047 and of MACEs [hazard ratio 4.155 (1.558--11.082), P = 0.004) at follow-up. CONCLUSION: Killip classification performed at the time of admission is a simple and useful clinical marker of a high risk of early and late adverse cardiovascular events.

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Takotsubo syndrome (TS) is an acute and reversible form of myocardial stunning preceded by emotional or physical stress, not explained by an obstruction of an epicardial coronary artery as in acute coronary syndrome. Over the last decades, TS is receiving growing attention, leading to an increase in awareness and diagnostic rate. Chest pain and dyspnea are the most common presenting symptoms; however, nonspecific presentations make the diagnosis challenging for clinicians. Here, we present the case of a 76-year-old female who experienced two completely asymptomatic episodes of TS 20 years apart.

Novel Oral Anticoagulants (NOACs) have been considered for treating cancer-related venous thromboembolism (VTE), but safety issues have been raised. We performed a systematic review and pairwise meta-analysis of the efficacy and safety of NOACs versus low molecular weight heparin (LMWH) in this setting. Four randomized controlled trials were included, providing data on 2894 patients. Compared to LMWH, NOACs were associated with a significantly lower risk of VTE recurrence and were not associated with an increased risk of major bleedings (MB). NOACs were non inferior to LMWH for a composite outcome of VTE recurrence and MB, pulmonary embolism recurrence and all-cause mortality; however, NOACs were associated with an increased risk of clinically relevant nonmajor bleedings (CRNMB) and gastrointestinal MB. In conclusion, in patients with cancer-related VTE, NOACs are effective and safe in reducing VTE recurrence compared to LMWH. An increased risk of CNRMB and GI MB should nonetheless be considered.

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor highly expressed in coronary plaques, particularly in macrophages, and in activated platelets. Thus, a possible role in the pathogenesis of acute coronary syndrome (ACS) has been suggested. We evaluated systemic BDNF levels according to the different clinical presentations of ACS. Moreover, we assessed the relationship between BDNF levels and the presence of optical coherence tomography (OCT)-defined macrophage infiltrates (MØI) and healed plaques along the culprit vessel. We enrolled consecutive patients presenting with ST-elevation myocardial infarction (STEMI) or non-ST-elevation (NSTE)-ACS. Serum BDNF levels were assessed by enzyme-linked immunosorbent assay. Plaque characteristics of the culprit vessel were assessed by OCT. Among 126 ACS patients (median age 68.00, interquartile range [IQR] 59.75–75.25 years, male 74.6%, 71 (56.3%) were NSTE-ACS and 55 (43.7%) were STEMI. BDNF levels were higher in STEMI patients compared to NSTE-ACS. OCT assessment was performed in 53 (42.1%) patients. Patients with MØI (n = 27) had higher BDNF levels compared to patients without MØI. Furthermore, patients with healed plaques (n = 13) had lower BDNF levels than patients without healed plaques. At multivariate regression analysis BDNF levels independently predicted the presence of MØI (odds ratio [OR] = 2.856; 95% confidence interval [CI] [1.151–7.090], P = 0.024) and the absence of healed plaques (OR = 0.438, 95% CI [0.185–0.992], P= 0.050). Among ACS patients, BDNF levels were higher in patients with STEMI. Moreover, BDNF levels were independently associated with MØI and with the absence of healed plaques along the culprit vessel, suggesting a possible role of BDNF in promoting plaque inflammation, destabilization and occlusive thrombosis.

Primary percutaneous coronary intervention (PCI) represents the reperfusion strategy of choice for patients presenting with ST-segment elevation myocardial infarction. However, despite the restoration of epicardial flow, primary PCI may not determine an effective reperfusion of myocardial tissue due to the occurrence of microvascular obstruction. This phenomenon also known as “no-reflow” may occur in 30-60% of patients treated with primary PCI. Of importance, no-reflow attenuates the benefit of reperfusion therapy and is associated with a poor clinical outcome in terms of adverse ventricular remodeling, heart failure and mortality. The pathophysiology of no-reflow is complex and multiple players may be involved. Indeed, distal embolization, ischemia-reperfusion injury and an individual predisposition to microvascular dysfunction synergically interact to determine the occurrence of no-reflow. In this review, we will analyze the pathophysiological mechanisms, the diagnostic tools and the main therapeutic targets of no-reflow, with particular attention to the most recent acquisitions in this field.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged in Wuhan, Hubei-China, as responsible for the coronavirus disease 2019 (COVID-19) and then spread rapidly worldwide. While most individuals remain asymptomatic or develop only mild symptoms, approximately 5% develop severe forms of COVID-19 characterized by acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) that usually require intensive-care support and often yield a poor prognosis. Summary: The pathophysiology of COVID-19 is far from being completely understood, and the lack of effective treatments leads to a sense of urgency to develop new therapeutic strategies based on pathophysiological assumptions. The exaggerated cytokine release in response to viral infection, a condition known as cytokine release syndrome (CRS) or cytokine storm, is emerging as the mechanism leading to ARDS and MOF in COVID-19, thus endorsing the hypothesis that properly timed anti-inflammatory therapeutic strategies could improve patients' clinical outcomes and prognosis. Key Messages: The objective of this article is to explore and comment on the potential role of the promising immunomodulatory therapies using pharmacological and nonpharmacological approaches to overcome the dysregulated proinflammatory response in COVID-19.

Background: Coronary vasomotor dysfunction represents an important mechanism responsible for myocardial ischaemia in patients with non-obstructive coronary artery disease (CAD). The use of invasive provocative tests allows identifying patients with epicardial or microvascular spasm. Of note, clinical characteristics associated with the occurrence of epicardial or microvascular spasm have still not completely clarified. Methods and results: We prospectively enrolled consecutive patients undergoing coronary angiography for suspected myocardial ischaemia/necrosis with evidence of non-obstructive CAD and undergoing intracoronary provocative test for suspected vasomotor dysfunction. Patients with a positive provocative test were enrolled. Clinical, echocardiographic and angiographic characteristics of patients were evaluated according to the pattern of vasomotor dysfunction (epicardial vs. microvascular spasm). We included 120 patients [68 patients with stable angina and 52 patients with myocardial infarction and non-obstructive coronary arteries (MINOCA)]. In particular, 77 (64.2%) patients had a provocative test positive for epicardial spasm and 43 (35.8%) patients for microvascular spasm. Patients with epicardial spasm were more frequently males, smokers, had higher rates of diffuse coronary atherosclerosis at angiography and more frequently presented with MINOCA. On the other hand, patients with microvascular spasm presented more frequently diastolic dysfunction. At multivariate logistic regression analysis male sex, smoking, and diffuse coronary atherosclerosis were independent predictors for the occurrence of epicardial spasm. Conclusions: Our study showed that specific clinical features are associated with different responses to intracoronary provocative test. Epicardial spasm is more frequent in males and in MINOCA patients, whereas microvascular spasm is more frequent in patients with stable angina and is associated with diastolic dysfunction.

Objective: Patients with Takotsubo syndrome (TTS) present an acute microvascular dysfunction that leads to an impaired myocardial perfusion and, in more severe forms, an impaired epicardial flow. However, clinical relevance of a delayed coronary flow, the coronary slow flow (CSF), has never been investigated. We studied the prognostic value of CSF occurring in the acute phase of TTS. Methods: This cohort study prospectively evaluated patients with a diagnosis of TTS. CSF was defined as angiographically non-obstructive coronary arteries with thrombolysis in myocardial infarction-2 flow. The incidence of overall mortality and major adverse cardiovascular events (MACEs), defined as the composite of TTS recurrence, cardiac rehospitalisation, cerebrovascular events and mortality, was assessed at follow-up. Results: We enrolled 101 patients (mean age 71.0±11.1 years, 86 (85.1%) female); CSF occurred in 18 (17.8%) patients. At admission, patients with CSF presented more frequently with Killip class III/IV, moderate-to-severe left ventricle systolic dysfunction and right ventricle dysfunction. During the index admission, patients with CSF had a higher rate of intrahospital complications (12 (66.7%) vs 28 (33.7%), p=0.01). At long-term follow-up, patients with CSF had a significantly higher occurrence of overall mortality (9 (50%) vs 19 (22.9%), p=0.011), mainly due to non-cardiac causes (89.3%), and a higher rate of MACE (10 (55.5%) vs 27 (32.5%), p=0.06). At multivariable Cox regression, CSF was independently associated with death from any causes. Conclusions: Patients with TTS presenting with CSF have a worse clinical presentation with a higher rate of intrahospital complications and a poor long-term clinical outcome.