TAPSE/sPAP prognostic value for In-Hospital Adverse Events in Patients Hospitalized for Acute Coronary Syndrome.

AIMS: Although several studies have shown that the right ventricular to pulmonary artery (RV-PA) coupling, assessed by the ratio between tricuspid annular plane systolic excursion and systolic pulmonary artery pressure (TAPSE/sPAP) using echocardiography, is strongly associated with cardiovascular events, its prognostic value is not established in acute coronary syndrome (ACS). We aimed to assess the in-hospital prognostic value of TAPSE/sPAP among patients hospitalized for ACS in a retrospective analysis from the prospective ADDICT-ICCU study. METHODS AND RESULTS: 481 consecutive patients hospitalized in intensive cardiac care unit (mean age 65±13 years, 73% of male, 46% STEMI) for ACS (either ST-elevation [STEMI] or non-ST-elevation [NSTEMI] myocardial infarction) with TAPSE/sPAP available were included in this prospective French multicentric study (39 centers). The primary outcome was in-hospital major adverse cardiovascular events (MACEs) defined as all-cause death, resuscitated cardiac arrest or cardiogenic shock and occurred in 33 (7%) patients. ROC-curve analysis identified 0.55 mm/mmHg as the best TAPSE/sPAP cut-off to predict in-hospital MACEs. TAPSE/sPAP <0.55 was associated with in-hospital MACEs, even after adjustment with comorbidities (OR:19.1, 95%CI[7.78-54.8]), clinical severity including left ventricular ejection fraction (OR:14.4, 95%CI[5.70-41.7]) and propensity-matched population analysis (OR:22.8, 95%CI[7.83-97.2], all p<0.001). After adjustment, TAPSE/sPAP <0.55 showed the best improvement in model discrimination and reclassification above traditional prognosticators (C-statistic improvement: 0.16; global chi-square improvement: 52.8; LR-test p<0.001) with similar results for both STEMI and NSTEMI subgroups. CONCLUSION: A low RV-PA coupling defined as TAPSE/sPAP ratio <0.55 was independently associated with in-hospital MACEs and provided incremental prognostic value over traditional prognosticators in patients hospitalized for ACS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05063097.

Oxidation-reduction imaging of myoglobin reveals two-phase oxidation in the reperfused myocardium.

Myocardial infarction (MI) is a serious acute cardiovascular syndrome that causes myocardial injury due to blood flow obstruction to a specific myocardial area. Under ischemic-reperfusion settings, a burst of reactive oxygen species is generated, leading to redox imbalance that could be attributed to several molecules, including myoglobin. Myoglobin is dynamic and exhibits various oxidation-reduction states that have been an early subject of attention in the food industry, specifically for meat consumers. However, rarely if ever have the myoglobin optical properties been used to measure the severity of MI. In the current study, we develop a novel imaging pipeline that integrates tissue clearing, confocal and light sheet fluorescence microscopy, combined with imaging analysis, and processing tools to investigate and characterize the oxidation-reduction states of myoglobin in the ischemic area of the cleared myocardium post-MI. Using spectral imaging, we have characterized the endogenous fluorescence of the myocardium and demonstrated that it is partly composed by fluorescence of myoglobin. Under ischemia-reperfusion experimental settings, we report that the infarcted myocardium spectral signature is similar to that of oxidized myoglobin signal that peaks 3 h post-reperfusion and decreases with cardioprotection. The infarct size assessed by oxidation-reduction imaging at 3 h post-reperfusion was correlated to the one estimated with late gadolinium enhancement MRI at 24 h post-reperfusion. In conclusion, this original work suggests that the redox state of myoglobin can be used as a promising imaging biomarker for characterizing and estimating the size of the MI during early phases of reperfusion.

Colchicine in acute myocardial infarction: cardiovascular events at 1-year follow up.

OBJECTIVE: In the COVERT-MI randomised placebo-controlled trial, oral administration of high-dose colchicine at the time of reperfusion and for 5 days in acute ST-elevated myocardial infarction did not reduce infarct size but was associated with a significant increase in left ventricular thrombus (LVT) in comparison to placebo. We aimed to assess the 1-year clinical outcomes of the study population. METHODS: This study is a follow-up analysis of the COVERT-MI study on prespecified secondary clinical endpoints at 1 year. The primary endpoint of this study was a composite of major adverse cardiovascular events (MACEs), including all-cause death, acute coronary syndromes, heart failure events, ischaemic strokes, sustained ventricular arrhythmias and acute kidney injury at 1-year follow-up. The quality of life (QOL) and the drug therapy prescription were also assessed. RESULTS: At 1 year, 192 patients (101 patients in the colchicine group, 91 in the placebo group) were followed up. Seventy-six (39.6%) MACEs were reported in the study population. There was no significant difference regarding the number of MACEs between groups: 36 (35.6%) in the colchicine group and 40 (44.1%) in the placebo group (p=0.3). There were no differences in the occurrence of ischaemic strokes between the colchicine group and the control group (3 (3%) vs 2 (2.2%), respectively, p=0.99). There was a trend towards fewer heart failure events in the colchicine group compared with the placebo group (12 (11.9%) vs 18 (19.8%), p=0.20). There was no significant difference in QOL scores at 1 year (75.8±15.7 vs 72.7±16.2 respectively, p=0.18). CONCLUSIONS: There was no significant difference between the colchicine and placebo groups at 1 year regarding MACEs, especially concerning deaths or ischaemic strokes. No excess of ischaemic adverse events was observed despite the initial increase in LVT in the colchicine group. TRIAL REGISTRATION NUMBER: NCT0315681.

Thrombus burden management during primary coronary bifurcation intervention: a new experimental bench model.

BACKGROUND: Management of thrombus burden during primary percutaneous coronary intervention (pPCI) is a key-point, given the high risk of stent malapposition and/or thrombus embolization. These issues are especially important if pPCI involves a coronary bifurcation. Herein, a new experimental bifurcation bench model to analyze thrombus burden behavior was developed. METHODS: On a fractal left main bifurcation bench model, we generated standardized thrombus with human blood and tissue factor. Three provisional pPCI strategies were compared (n = 10/group): 1) balloon-expandable stent (BES), 2) BES completed by proximal optimizing technique (POT), and 3) nitinol self-apposing stent (SAS). The embolized distal thrombus after stent implantation was weighed. Stent apposition and thrombus trapped by the stent were quantified on 2D-OCT. To analyze final stent apposition, a new OCT acquisition was performed after pharmacological thrombolysis. RESULTS: Trapped thrombus was significantly greater with isolated BES than SAS or BES+POT (18.8 ± 5.8% vs. 10.3 ± 3.3% and 6.2 ± 2.1%, respectively; p < 0.05), and greater with SAS than BES+POT (p < 0.05). Isolated BES and SAS tended show less embolized thrombus than BES+POT (5.93 ± 4.32 mg and 5.05 ± 4.56 mg vs. 7.01 ± 4.32 mg, respectively; p = NS). Conversely, SAS and BES+POT ensured perfect final global apposition (0.4 ± 0.6% and 1.3 ± 1.3%, respectively, p = NS) compared to isolated BES (74.0 ± 7.6%, p < 0.05). CONCLUSIONS: This first experimental bench model of pPCI in a bifurcation quantified thrombus trapping and embolization. BES provided the best thrombus trapping, while SAS and BES+POT achieved better final stent apposition. These factors should be taken into account in selecting revascularization strategy.

One year results of coronary bifurcation revascularization with the re-POT provisional sequential technique. The CABRIOLET registry.

BACKGROUND: Re-POT (proximal optimization technique (POT)) is a simple provisional sequential technique for percutaneous coronary bifurcation revascularization with better arterial geometry respect compared to classical techniques. Re-POT has demonstrated excellent mechanical and short-term clinical results. The multicenter CABRIOLET registry (NCT03550196) evaluate the long-term clinical benefit of the re-POT sequence in non-selected patients. METHODS: All consecutive patients presenting a coronary bifurcation lesion for which provisional stenting was indicated were included in 5 european centers. Re-POT strategy was systematically attempted. The primary endpoint was target lesion failure (TLF), comprising cardiac death, myocardial infarction, stent thrombosis and target lesion revascularization (TLR) at 12 months' follow-up. The secondary endpoints were the individual components of the primary endpoint, all-cause death, target vessel failure (TVF) and target vessel revascularization (TVR). Complex bifurcation was defined as Medina 0.1.1 or 1.1.1. RESULTS: A total of 500 patients aged 67.7 ± 11.7 years, 78.4% male, were included from 2015 to 2019, 174 of whom (34.8%) were considered having complex bifurcation lesions. Bifurcations involved the left main in 35.2% of cases. The full re-POT sequence was systematically performed in all cases. At 1 year, TLF was 2.0% (1.7% in complex vs. 2.1% in non-complex bifurcation; p = NS), and TLR was 1.6%, (1.1% vs. 1.8% respectively; p = NS). TVF and TVR rates were 3.2% and 2.8%. On multivariate analysis, only multivessel disease was predictive of TLF at 1 year (OR = 1.66 (1.09-2.53), p = 0.02). CONCLUSIONS: In this large prospective all-comer registry, provisional stenting with re-POT technique appeared safe and effective at 1 year, without anatomical bifurcation restriction.

Beta-blocker management in patients admitted for acute heart failure and reduced ejection fraction: a review and expert consensus opinion.

The role of the beta-adrenergic signaling pathway in heart failure (HF) is pivotal. Early blockade of this pathway with beta-blocker (BB) therapy is recommended as the first-line medication for patients with HF and reduced ejection fraction (HFrEF). Conversely, in patients with severe acute HF (AHF), including those with resolved cardiogenic shock (CS), BB initiation can be hazardous. There are very few data on the management of BB in these situations. The present expert consensus aims to review all published data on the use of BB in patients with severe decompensated AHF, with or without hemodynamic compromise, and proposes an expert-recommended practical algorithm for the prescription and monitoring of BB therapy in critical settings.

A bibliometric analysis: Ca2+ fluxes and inflammatory phenotyping by flow cytometry in peripheral blood mononuclear cells.

Background: The immune system, composed of organs, tissues, cells, and proteins, is the key to protecting the body from external biological attacks and inflammation. The latter occurs in several pathologies, such as cancers, type 1 diabetes, and human immunodeficiency virus infection. Immunophenotyping by flow cytometry is the method of choice for diagnosing these pathologies. Under inflammatory conditions, the peripheral blood mononuclear cells (PBMCs) are partially activated and generate intracellular pathways involving Ca2+-dependent signaling cascades leading to transcription factor expression. Ca2+ signaling is typically studied by microscopy in cell lines but can present some limitations to explore human PBMCs, where flow cytometry can be a good alternative. Objective: In this review, we dived into the research field of inflammation and Ca2+ signaling in PBMCs. We aimed to investigate the structure and evolution of this field in a physio-pathological context, and then we focused our review on flow cytometry analysis of Ca2+ fluxes in PBMCs. Methods: From 1984 to 2022, 3865 articles on inflammation and Ca2+ signaling in PBMCs were published, according to The Clarivate Web of Science (WOS) database used in this review. A bibliometric study was designed for this collection and consisted of a co-citation and bibliographic coupling analysis. Results: The co-citation analysis was performed on 133 articles: 4 clusters highlighted the global context of Ca2+ homeostasis, including chemical probe development, identification of the leading players in Ca2+ signaling, and the link with chemokine production in immune cell function. Next, the bibliographic coupling analysis combined 998 articles in 8 clusters. This analysis outlined the mechanisms of PBMC activation, from signal integration to cellular response. Further explorations of the bibliographic coupling network, focusing on flow cytometry, revealed 21 articles measuring cytosolic Ca2+ in PBMCs, with only 5 since 2016. This final query showed that Ca2+ signaling analysis in human PBMCs using flow cytometry is still underdeveloped and investigates mainly the cytosolic Ca2+ compartment. Conclusion: Our review uncovers remaining knowledge gaps of intracellular players involved in Ca2+ signaling in PBMCs, such as reticulum and mitochondria, and presents flow cytometry as a solid option to supplement gold-standard microscopy studies.

Human peripheral blood mononuclear cells display a temporal evolving inflammatory profile after myocardial infarction and modify myocardial fibroblasts phenotype.

Pathophysiological response after acute myocardial infarction (AMI) is described as a three-stage model involving temporal phenotypic modifications of both immune cells and fibroblasts: a primary inflammatory phase, followed by a reparative phase and a fibrous scar maturation phase. Purinergic receptors, particularly the P2Y11 receptor, have been reported to be involved in the regulation of inflammation after ischemia and could act for the resolution of inflammation after AMI. For the first time, we characterized the immuno-inflammatory and P2Y11 expression profiles of peripheral blood mononuclear cells (PBMC) from AMI patients and analyzed the consequences of presenting these cells to cardiac fibroblasts in vitro. PBMC from 178 patients were collected at various times after reperfused ST-segment elevation AMI, from H0 to M12. Expression level of P2RY11 and genes involved in tolerogenic profile of dendritic cells and T cell polarization were evaluated by RT-PCR. P2Y11 protein expression was assessed by flow cytometry. PBMC and human cardiac fibroblasts (HCF) were cocultured and α-SMA/vimentin ratio was analyzed by flow cytometry. Within the first 48 h after AMI, expression levels of HMOX1, STAT3 and CD4 increased while IDO1 and TBX21/GATA3 ratio decreased. Concomitantly, the expression of P2RY11 increased in both T and B cells. In vitro, PBMC collected at H48 after AMI induced an increase in α-SMA/vimentin ratio in HCF. Our results suggest that human PBMC display an evolving inflammatory profile with reparative characteristics the first two days after AMI and secrete soluble mediators leading to the fibroblastic proteins modification, thus participating to myocardial fibrosis.

Specific inflammatory profile of acute ischemic stroke patients with left atrial enlargement.

Background: The inflammatory process underlying atrial myopathy may affect the inflammatory response activated in acute ischemic stroke (AIS). Objectives: We aimed to assess whether left atrial enlargement (LAE) as a marker of atrial myopathy is associated with a different profile of circulating inflammatory markers in AIS patients. Methods: HIBISCUS-STROKE is a cohort study including anterior circulation AIS patients treated with mechanical thrombectomy following MRI. Ten circulating inflammatory markers were measured at admission and 6, 24, and 48 h after admission. LAE was defined as a left atrial volume index (LAVi) ≥34 ml/m2. A multiple logistic regression model was performed to detect an independent association between the area under the curve (AUC) of these markers and LAE. Results: We included 143 patients. Of them, 85 (59.4%) had LAE. On univariable analysis, we found that patients with LAE had higher soluble form suppression of tumorigenicity 2 (sST2), soluble tumor necrosis factor receptor I (sTNFR1), and vascular cellular adhesion molecule-1 (VCAM-1) AUC, were older, mostly female, had a higher National Institutes of Health Stroke Scale (NIHSS) score and blood glucose level at admission, had more often hypertension, and a cardioembolic source of AIS, such as atrial fibrillation, while they were less frequently current smokers and had a lower rate of tandem occlusion than patients without LAE. On multivariable analysis, we found that among circulating inflammatory markers, only high VCAM-1 (OR: 9.13, 95% CI: 3.21-25.9) and sST2 (OR: 3.40, 95% CI: 1.68-6.86) AUC remained associated with LAE. Conclusions: High VCAM-1 and sST2 levels within the first 48 h are associated with LAE in AIS patients.

Prevalence and impact of recreational drug use in patients with acute cardiovascular events.

OBJECTIVE: While recreational drug use is a risk factor for cardiovascular events, its exact prevalence and prognostic impact in patients admitted for these events are not established. We aimed to assess the prevalence of recreational drug use and its association with in-hospital major adverse events (MAEs) in patients admitted to intensive cardiac care units (ICCU). METHODS: In the Addiction in Intensive Cardiac Care Units (ADDICT-ICCU) study, systematic screening for recreational drugs was performed by prospective urinary testing all patients admitted to ICCU in 39 French centres from 7 to 22 April 2021. The primary outcome was prevalence of recreational drug detection. In-hospital MAEs were defined by death, resuscitated cardiac arrest, or haemodynamic shock. RESULTS: Of 1499 consecutive patients (63±15 years, 70% male), 161 (11%) had a positive test for recreational drugs (cannabis 9.1%, opioids 2.1%, cocaine 1.7%, amphetamines 0.7%, 3,4-methylenedioxymethamphetamine (MDMA) 0.6%). Only 57% of these patients declared recreational drug use. Patients who used recreational drugs exhibited a higher MAE rate than others (13% vs 3%, respectively, p<0.001). Recreational drugs were associated with a higher rate of in-hospital MAEs after adjustment for comorbidities (OR 8.84, 95% CI 4.68 to 16.7, p<0.001). After adjustment, cannabis, cocaine, and MDMA, assessed separately, were independently associated with in-hospital MAEs. Multiple drug detection was frequent (28% of positive patients) and associated with an even higher incidence of MAEs (OR 12.7, 95% CI 4.80 to 35.6, p<0.001). CONCLUSION: The prevalence of recreational drug use in patients hospitalised in ICCU was 11%. Recreational drug detection was independently associated with worse in-hospital outcomes. CLINICAL TRIAL REGISTRATION: NCT05063097.

SERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases.

Despite advances in cardioprotection, new therapeutic strategies capable of preventing ischemia-reperfusion injury of patients are still needed. Here, we discover that sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA2) phosphorylation at serine 663 is a clinical and pathophysiological event of cardiac function. Indeed, the phosphorylation level of SERCA2 at serine 663 is increased in ischemic hearts of patients and mouse. Analyses on different human cell lines indicate that preventing serine 663 phosphorylation significantly increases SERCA2 activity and protects against cell death, by counteracting cytosolic and mitochondrial Ca2+ overload. By identifying the phosphorylation level of SERCA2 at serine 663 as an essential regulator of SERCA2 activity, Ca2+ homeostasis and infarct size, these data contribute to a more comprehensive understanding of the excitation/contraction coupling of cardiomyocytes and establish the pathophysiological role and the therapeutic potential of SERCA2 modulation in acute myocardial infarction, based on the hotspot phosphorylation level of SERCA2 at serine 663 residue.

Prognostic impact of precipitated cardiac decompensation in symptomatic heart failure with reduced ejection fraction and severe secondary mitral regurgitation.

BACKGROUND: Our aim was to assess the distribution of primary (with no trigger) and secondary (with a decompensation trigger) heart failure events in a severe heart failure population and their association with 2-year all-cause mortality in the Mitra.Fr study. METHODS: We included 304 patients with symptomatic heart failure, and severe mitral regurgitation and guideline directed medical therapy randomized to medical therapy alone or medical therapy with percutaneous mitral valve repair. According to the follow-up, we defined 3 categories of events: follow-up without any heart failure event, at least 1 decompensation starting with a primary heart failure decompensation or starting with a precipitated secondary heart failure event. The primary outcome was 2-years all-cause mortality. RESULTS: A total of 179 patients (59 %) had at least 1 heart failure decompensation within 24-months of follow-up. 129 heart failure decompensations (72%) were a first primary heart failure and 50 (28%) were a first secondary decompensation. Finally, 30 patients had both types of decompensations but these were not taken into account for the comparison of primary and secondary decompensations. Primary decompensations were 3-times more frequent than secondary decompensations, but the mean number of heart failure decompensations was similar in the "Primary heart failure group" compared to the "Secondary heart failure group": (1.94 ± 1.39 vs 1.80 ± 1.07 respectively; P = .480). Compared to patients without heart failure decompensation, patients with "Only primary decompensation" or with "Only secondary decompensation" had a significantly increased risk of death (HR = 4.87, 95% CI [2.86, 8.32] and 2.68 95%CI [1.64, 4.37] respectively). All-cause mortality, was not significantly different between these 2 type of decompensations (HR = 1.82, 95% CI [0.93, 3.58]; P = .082), but each additional heart failure recurrence was associated with a significant increase in mortality risk (HR = 1.27, 95% CI [1.08; 1.50]; P = .005). CONCLUSIONS: In heart failure with reduced ejection fraction and severe secondary mitral regurgitation patients, primary heart failure decompensations were 3-times more frequent compared to precipitated decompensations with a nonsignificant trend in increased risk of all-cause mortality. Our results fail to support the differentiation between primary and secondary decompensations as they seem to portend the same outcome impact.

Pheochromocytoma-induced cardiogenic shock: A multicentre analysis of clinical profiles, management and outcomes.

OBJECTIVE: There is still uncertainty about the management of patients with pheochromocytoma-induced cardiogenic shock (PICS). This study aims to investigate the clinical presentation, management, and outcome of patients with PICS. METHODS: We collected, retrospectively, the data of 18 patients without previously known pheochromocytoma admitted to 8 European hospitals with a diagnosis of PICS. RESULTS: Among the 18 patients with a median age of 50 years (Q1-Q3: 40-61), 50% were men. The main clinical features at presentation were pulmonary congestion (83%) and cyclic fluctuation of hypertension peaks and hypotension (72%). Echocardiography showed a median left ventricular ejection fraction (LVEF) of 25% (Q1-Q3: 15-33.5) with an atypical- Takotsubo (TTS) pattern in 50%. Inotropes/vasopressors were started in all patients and temporary mechanical circulatory support (t-MCS) was required in 11 (61%) patients. All patients underwent surgical removal of the pheochromocytoma; 4 patients (22%) were operated on while under t-MCS. The median LVEF was estimated at 55% at discharge. Only one patient required heart transplantation (5.5%), and all patients were alive at a median follow-up of 679 days. CONCLUSIONS: PICS should be suspected in case of a CS with severe cyclic blood pressure fluctuation and rapid hemodynamic deterioration, associated with increased inflammatory markers or in case of TTS progressing to CS, particularly if an atypical TTS echocardiographic pattern is revealed. T-MCS should be considered in the most severe cases. The main challenge is to stabilize the patient, with medical therapy or with t-MCS, since it remains a reversible cause of CS with a low mortality rate.

Impact of Neuroeffector Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia.

Background Cardiac adrenergic receptor gene polymorphisms have the potential to influence risk of developing ventricular fibrillation (VF) during ST-segment-elevation myocardial infarction, but no previous study has comprehensively investigated those most likely to alter norepinephrine release, signal transduction, or biased signaling. Methods and Results In a case-control study, we recruited 953 patients with ST-segment-elevation myocardial infarction without previous cardiac history, 477 with primary VF, and 476 controls without VF, and genotyped them for ADRB1 Arg389Gly and Ser49Gly, ADRB2 Gln27Glu and Gly16Arg, and ADRA2C Ins322-325Del. Within each minor allele-containing genotype, haplotype, or 2-genotype combination, patients with incident VF were compared with non-VF controls by odds ratios (OR) of variant frequencies referenced against major allele homozygotes. Of 156 investigated genetic constructs, 19 (12.2%) exhibited significantly (P<0.05) reduced association with incident VF, and none was associated with increased VF risk except for ADRB1 Gly389 homozygotes in the subset of patients not receiving ß-blockers. ADRB1 Gly49 carriers (prevalence 23.0%) had an OR (95% CI) of 0.70 (0.49-0.98), and the ADRA2C 322-325 deletion (Del) carriers (prevalence 13.5%) had an OR of 0.61 (0.39-0.94). When present in genotype combinations (8 each), both ADRB1 Gly49 carriers (OR, 0.67 [0.56-0.80]) and ADRA2C Del carriers (OR, 0.57 [0.45- 0.71]) were associated with reduced VF risk. Conclusions In ST-segment-elevation myocardial infarction, the adrenergic receptor minor alleles ADRB1 Gly49, whose encoded receptor undergoes enhanced agonist-mediated internalization and ß-arrestin interactions leading to cardioprotective biased signaling, and ADRA2C Del322-325, whose receptor causes disinhibition of norepinephrine release, are associated with a lower incidence of VF. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT00859300.