An update on the mechanisms of Takotsubo syndrome: "At the end an acute coronary syndrome".

Takotsubo syndrome (TTS) is an acute reversible form of myocardial dysfunction, often preceded by a physical or emotional stressful event, that acts as a trigger. Despite, recent advances in the comprehension of the mechanisms leading to TTS, its pathophysiology is far from being completely understood. However, several studies seem to suggest that an acute coronary microvascular dysfunction may represent a crucial pathogenic mechanism involved in TTS occurrence. In this article, we aim to review the complex pathophysiology of TTS and the possible different mechanisms underlying this clinical condition, focusing on the role of coronary microvascular dysfunction and the remaining knowledge's gaps in the field.

Predicting the response to acetylcholine in ischemia or infarction with non-obstructive coronary arteries: The ABCD score.

BACKGROUND AND AIMS: Acetylcholine (ACh) provocation testing can detect vasomotor disorders in patients with ischemia and non-obstructed coronary arteries (INOCA) or myocardial infarction and non-obstructed coronary arteries (MINOCA). We aimed to derive and validate a simple risk score to predict a positive ACh test response. METHODS: We prospectively enrolled consecutive INOCA and MINOCA patients undergoing ACh provocation testing. Patients were split in two cohorts (derivation and validation) according to time of enrolment. The score was derived in 386 patients (derivation cohort) and then validated in 165 patients (validation cohort). RESULTS: 551 patients were enrolled, 371 (67.3%) INOCA and 180 (32.7%) MINOCA. ACh test was positive in 288 (52.3%) patients. MINOCA, myocardial bridge (MB), C-reactive protein (CRP) and dyslipidaemia were independent predictors of a positive ACh test in the derivation cohort. The ABCD (Acute presentation, Bridge, CRP, Dyslipidaemia) score was derived: 2 points were assigned to MINOCA, 3 to MB, 1 to elevated CRP and 1 to dyslipidaemia. The ABCD score accurately identified patients with a positive ACh test response with an AUC of 0.703 (CI 95% 0.652-0.754,p < 0.001) in the derivation cohort, and 0.705 (CI 95% 0.626-0.784, p < 0.001) in the validation cohort. In the whole population, an ABCD score ≥4 portended 94.3% risk of a positive ACh test and all patients with an ABCD score ≥6 presented a positive test. CONCLUSIONS: The ABCD score could avoid the need of ACh provocation testing in patients with a high score, reducing procedural risks, time, and costs, and allowing the implementation of a tailored treatment strategy. These results are hypothesis generating and further research involving larger cohorts and multicentre trials is needed to validate and refine the ABCD score.

Exposome in ischaemic heart disease: beyond traditional risk factors.

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.

Coronary physiology thresholds associated with microvascular obstruction in myocardial infarction.

OBJECTIVES: To ascertain whether invasive assessment of coronary physiology soon after recanalisation of the culprit artery by primary percutaneous coronary intervention is associated with the development of microvascular obstruction by cardiac magnetic resonance in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Between November 2020 and December 2021, 102 consecutive patients were prospectively enrolled in five tertiary centres in Italy. Coronary flow reserve (CFR) and index of microvascular resistance (IMR) were measured in the culprit vessel soon after successful primary percutaneous coronary intervention. Optimal cut-off points of IMR and CFR to predict the presence of microvascular obstruction were estimated, stratifying the population accordingly in four groups. A comparison with previously proposed stratification models was carried out. RESULTS: IMR>31 units and CFR≤1.25 yielded the best accuracy. Patients with IMR>31 and CFR≤1.25 exhibited higher microvascular obstruction prevalence (83% vs 38%, p<0.001) and lower left ventricular ejection fraction (45±9% vs 52±9%, p=0.043) compared with those with IMR≤31 and CFR>1.25, and lower left ventricular ejection fraction compared with patients with CFR≤1.25 and IMR≤31 (45±9% vs 54±7%, p=0.025). Infarct size and area at risk were larger in the former, compared with other groups. CONCLUSIONS: IMR and CFR are associated with the presence of microvascular obstruction in STEMI. Patients with an IMR>31 units and a CFR≤1.25 have higher prevalence of microvascular obstruction, lower left ventricular ejection fraction, larger infarct size and area at risk. TRIAL REGISTRATION NUMBER: NCT04677257.

Short-term air pollution exposure and mechanisms of plaque instability in acute coronary syndromes: An optical coherence tomography study.

BACKGROUND AND AIMS: Air pollution is emerging as an important risk factor for acute coronary syndrome (ACS). In this study, we investigated the association between short-term air pollution exposure and mechanisms of coronary plaque instability evaluated by optical coherence tomography (OCT) imaging in ACS patients. 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. Based on each case's home address, the mean daily exposures to several pollutants, including particulate matter 2.5 (PM2.5), on the same day of ACS and in the immediate days (up to 6 days) prior to the index ACS, were collected. RESULTS: 139 ACS patients were included [69 (49.6%) had PR and 70 (50.4%) IFC]. Patients with PR, compared to those with IFC, had higher PM2.5 exposure levels on the same day of ACS, without differences in the immediate 6 days before index ACS. At multivariate analysis, PM2.5 exposure on the same day of ACS was the only independent predictor of PR [OR = 1.912 per SD (8.6 µg/m3), CI95 % (1.087-3.364), p = 0.025]. Patients with PR presented a steady increase in PM2.5 daily exposure levels in the days preceding the occurrence of ACS, with a peak the day of ACS (p for trend = 0.042) CONCLUSIONS: This study demonstrates for the first time that a higher short-term PM2.5 exposure, on the same day of ACS, is associated with an increased risk of PR as a pathobiological mechanism of coronary plaque instability.

Coronary microvascular obstruction and dysfunction in patients with acute myocardial infarction.

Despite prompt epicardial recanalization in patients presenting with ST-segment elevation myocardial infarction (STEMI), coronary microvascular obstruction and dysfunction (CMVO) is still fairly common and is associated with poor prognosis. Various pharmacological and mechanical strategies to treat CMVO have been proposed, but the positive results reported in preclinical and small proof-of-concept studies have not translated into benefits in large clinical trials conducted in the modern treatment setting of patients with STEMI. Therefore, the optimal management of these patients remains a topic of debate. In this Review, we appraise the pathophysiological mechanisms of CMVO, explore the evidence and provide future perspectives on strategies to be implemented to reduce the incidence of CMVO and improve prognosis in patients with STEMI.

Prognostic value of combined fractional flow reserve and pressure-bounded coronary flow reserve: outcomes in FFR and Pb-CFR assessment.

BACKGROUND: Coronary flow reserve (CFR) has an emerging role to predict outcome in patients with and without flow-limiting stenoses. However, the role of its surrogate pressure bounded-CFR (Pb-CFR) is controversial. We investigated the usefulness of combined use of fractional flow reserve (FFR) and Pb-CFR to predict outcomes. METHODS: This is a sub-study of the PROPHET-FFR Trial, including patients with chronic coronary syndrome and functionally tested coronary lesions. Patients were divided into four groups based on positive or negative FFR (cut-off 0.80) and preserved (lower boundary ≥2) or reduced (upper boundary <2) Pb-CFR: Group1 FFR≤0.80/ Pb-CFR <2; Group 2 FFR≤0.80/Pb-CFR≥2; Group 3 FFR >0.80/Pb-CFR<2; Group 4 FFR>0.80/Pb-CFR≥2. Lesions with positive FFR were treated with PCI. Primary endpoint was the rate of major adverse cardiac events (MACEs), defined as a composite of death from any cause, myocardial infarction, target vessel revascularization, unplanned cardiac hospitalization at 36-months. RESULTS: A total of 609 patients and 816 lesions were available for the analysis. At Kaplan-Meier analysis MACEs rate was significantly different between groups (36.7% Group 1, 27.4% Group 2, 19.2% Group 3, 22.6% Group 4, P=0.019) and more prevalent in groups with FFR≤0.80 irrespective of Pb-CFR. In case of discrepancy, no difference in MACEs were observed between groups stratified by Pb-CFR. FFR≤0.80 was associated with an increased MACEs rate (30.2% vs. 21.5%, P<0.01) while Pb-CFR<2 was not (24.5% vs. 24.2% Pb-CFR≥2 P=0.67). CONCLUSIONS: FFR confirms its ability to predict outcomes in patients with intermediate coronary stenoses. Pb-CFR does not add any relevant prognostic information.

Pathophysiology of coronary microvascular dysfunction.

The term "coronary microvascular dysfunction" (CMD) encompasses several pathogenetic mechanisms resulting in functional and/or structural changes in the coronary microcirculation. CMD often determines angina and myocardial ischemia in a broad spectrum of cardiovascular diseases, including patients with ischemia with non-obstructive coronary arteries or ischemia with obstructive coronary artery disease, infarction with non-obstructive coronary arteries, cardiomyopathies, the Takotsubo syndrome and heart failure, especially heart failure with preserved ejection fraction. In this article, we provide updated evidence regarding the pathophysiological mechanisms underlying CMD across the different cardiovascular diseases, aiming to pave the way for further research and the development of novel strategies for a precision medicine approach.

Microvascular Complications Are Associated With Coronary Collateralization in Type 2 Diabetes and Chronic Occlusion.

CONTEXT: Coronary collateral (CC) vessel development appears to be protective with regard to adverse cardiovascular events and survival in patients with coronary chronic total occlusion (CTO). The influence of type 2 diabetes mellitus (T2DM) on CC growth has been controversial. In particular, the role of diabetic microvascular complications (DMC) in determining coronary collateralization has not been elucidated. OBJECTIVE: To investigate whether patients with DMC presented differences in CC vessel presence and grading as compared with patients without DMC. METHODS: We conducted a single-center observational study, including consecutive T2DM patients, without previous cardiovascular history, undergoing a clinically indicated coronary angiography for chronic coronary syndrome (CCS) and angiographic evidence of at least one CTO. Patients were subdivided into 2 study groups according to the presence/absence of at least one DMC (neuropathy, nephropathy, or retinopathy). The presence and grading of angiographically visible CC development from the patent vessels to the occluded artery were assessed using the Rentrop classification. RESULTS: We enrolled 157 patients (mean age 68.6 ± 9.8 years; 120 [76.4%] men). Patients with DMC (75 [47.8%]) had a higher prevalence of CC (69 [92.0%] vs 62 [75.6%], P = .006) and high-grade CC (55 [73.3%] vs 39 [47.6%], P = .001) compared with those without, and we found a positive association between the number of DMC in each patient and the prevalence of high-grade CC. CONCLUSION: Among T2DM patients with coronary CTO, the presence of DMC was associated with a high CC development.

De-escalation strategies in patients with acute coronary syndrome: a step towards precision medicine.

INTRODUCTION: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is a cornerstone in the treatment of patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Current international guidelines recommend the use of 12 months of DAPT with newer P2Y12 inhibitors (i.e. ticagrelor or prasugrel) as first-line therapy in this setting. However, intense and prolonged DAPT regimens are associated with an increased risk of bleeding, with relevant prognostic implications. Recently, a strategy of de-escalation of P2Y12 inhibitors has been proposed as an alternative to conventional DAPT to mitigate the risk of bleeding while preserving ischemic protection after ACS. AREAS COVERED: In this review, we summarize the available evidence on guided and unguided strategies for P2Y12 inhibitor de-escalation in patients with ACS undergoing PCI. EXPERT OPINION: Among patients with ACS, guided and unguided de-escalation strategies are safe and effective for secondary cardiovascular prevention. Although the implementation of genetic and platelet function tests is of interest for treatment personalization, the routine use of guided de-escalation strategies seems impractical. In this context, unguided de-escalation approaches appear more attractive, convenient, and suitable for contemporary practice.

Culprit plaque morphology determines inflammatory risk and clinical outcomes in acute coronary syndrome.

AIMS: Rupture of the fibrous cap (RFC) and erosion of an intact fibrous cap (IFC) are the two predominant mechanisms causing acute coronary syndromes (ACS). It is uncertain whether clinical outcomes are different following RFC-ACS vs. IFC-ACS and whether this is affected by a specific inflammatory response. The prospective, translational OPTIcal-COherence Tomography in Acute Coronary Syndrome study programme investigates the impact of the culprit lesion phenotype on inflammatory profiles and prognosis in ACS patients. METHODS AND RESULTS: This analysis included 398 consecutive ACS patients, of which 62% had RFC-ACS and 25% had IFC-ACS. The primary endpoint was a composite of cardiac death, recurrent ACS, hospitalization for unstable angina, and target vessel revascularization at 2 years [major adverse cardiovascular events (MACE+)]. Inflammatory profiling was performed at baseline and after 90 days. Patients with IFC-ACS had lower rates of MACE+ than those with RFC-ACS (14.3% vs. 26.7%, P = 0.02). In 368-plex proteomic analyses, patients with IFC-ACS showed lower inflammatory proteome expression compared with those with RFC-ACS, including interleukin-6 and proteins associated with the response to interleukin-1ß. Circulating plasma levels of interleukin-1ß decreased from baseline to 3 months following IFC-ACS (P < 0.001) but remained stable following RFC-ACS (P = 0.25). Interleukin-6 levels decreased in patients with RFC-ACS free of MACE+ (P = 0.01) but persisted high in those with MACE+. CONCLUSION: This study demonstrates a distinct inflammatory response and a lower risk of MACE+ following IFC-ACS. These findings advance our understanding of inflammatory cascades associated with different mechanisms of plaque disruption and provide hypothesis generating data for personalized anti-inflammatory therapeutic allocation to ACS patients, a strategy that merits evaluation in future clinical trials.

MINOCA Associated with a Myocardial Bridge: Pathogenesis, Diagnosis and Treatment.

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.

Is spontaneous coronary artery dissection (SCAD) related to local anatomy and hemodynamics? An exploratory study.

AIMS: Spontaneous coronary artery dissection (SCAD) is an increasingly diagnosed cause of myocardial infarction with unclear pathophysiology. The aim of the study was to test if vascular segments site of SCAD present distinctive local anatomy and hemodynamic profiles. METHODS: Coronary arteries with spontaneously healed SCAD (confirmed by follow-up angiography) underwent three-dimensional reconstruction, morphometric analysis with definition of vessel local curvature and torsion, and computational fluid dynamics (CFD) simulations with derivation of time-averaged wall shear stress (TAWSS) and topological shear variation index (TSVI). The (reconstructed) healed proximal SCAD segment was visually inspected for co-localization with curvature, torsion, and CFD-derived quantities hot spots. RESULTS: Thirteen vessels with healed SCAD underwent the morpho-functional analysis. Median time between baseline and follow-up coronary angiograms was 57 (interquartile range [IQR] 45-95) days. In seven cases (53.8%), SCAD was classified as type 2b and occurred in the left anterior descending artery or near a bifurcation. In all cases (100%), at least one hot spot co-localized within the healed proximal SCAD segment, in 9 cases (69.2%) ≥ 3 hot spots were identified. Healed SCAD in proximity of a coronary bifurcation presented lower TAWSS peak values (6.65 [IQR 6.20-13.20] vs. 3.81 [2.53-5.17] Pa, p = 0.008) and hosted less frequently TSVI hot spots (100% vs. 57.1%, p = 0.034). CONCLUSION: Vascular segments of healed SCAD were characterized by high curvature/torsion and WSS profiles reflecting increased local flow disturbances. Hence, a pathophysiological role of the interaction between vessel anatomy and shear forces in SCAD is hypothesized.

Impact of acute and persistent stent malapposition after percutaneous coronary intervention on adverse cardiovascular outcomes.

INTRODUCTION: The association of coronary stent malapposition (SM) and adverse clinical outcomes after percutaneous coronary intervention (PCI) remains unclear. We aimed to perform a systematic review and meta-analysis of randomized and observational studies to assess the association between acute and persistent SM detected using intravascular ultrasound (IVUS) or optical coherence tomography (OCT) and adverse cardiovascular outcomes. EVIDENCE ACQUISITION: Available studies were identified through a systematic search of PubMed, reference lists of relevant articles, and Medline. Main efficacy outcomes of interest were: device-oriented composite endpoint (DoCE, including cardiac death, myocardial infarction [MI], target lesion revascularization [TLR], and stent thrombosis [ST]), major safety events (MSE, including cardiac death, MI and ST), TLR, and ST. A sensitivity analysis regarding the impact of major malapposition was also performed. EVIDENCE SYNTHESIS: A total of 9 studies enrolling 6497 patients were included in the meta-analysis. After a mean follow-up of 24±14 months, overall acute and/or persistent malapposition was not significantly associated with the occurrence of all the outcomes of interest, including DoCE (risk ratio [RR] 1.00, 95% confidence interval [CI, 0.79-1.26], P=0.99), MSE (RR 1.42, 95%CI [0.81-2.50], P=0.22), TLR (RR 0.84, 95%CI [0.59-1.19], P=0.33), and ST (RR 1.16, 95%CI [0.48-2.85], P=0.74). In the sensitivity analysis, we found a significant increase of MSE in patients with major malapposition (RR 2.97, 95%CI [1.51-5.87], P=0.001). CONCLUSIONS: Acute and persistent SM were not overall associated with adverse cardiovascular clinical outcomes at follow-up. However, major malapposition was associated with an increased risk of major safety events, including cardiac death, MI and ST. These findings should be taken into account during stent implantation and PCI optimization.