Cell Surface Platelet Tissue Factor Expression: Regulation by P2Y12 and Link to Residual Platelet Reactivity.

BACKGROUND: ADP-induced platelet activation leads to cell surface expression of several proteins, including TF (tissue factor). The role of ADP receptors in platelet TF modulation is still unknown. We aimed to assess the (1) involvement of P2Y1 and P2Y12 receptors in ADP-induced TF exposure; (2) modulation of TFpos-platelets in anti-P2Y12-treated patients with coronary artery disease. Based on the obtained results, we revisited the intracellular localization of TF in platelets. METHODS: The effects of P2Y1 or P2Y12 antagonists on ADP-induced TF expression and activity were analyzed in vitro by flow cytometry and thrombin generation assay in blood from healthy subjects, P2Y12-/-, and patients with gray platelet syndrome. Ex vivo, P2Y12 inhibition of TF expression by clopidogrel/prasugrel/ticagrelor, assessed by VASP (vasodilator-stimulated phosphoprotein) platelet reactivity index, was investigated in coronary artery disease (n=238). Inhibition of open canalicular system externalization and electron microscopy (TEM) were used for TF localization. RESULTS: In blood from healthy subjects, stimulated in vitro by ADP, the percentage of TFpos-platelets (17.3±5.5%) was significantly reduced in a concentration-dependent manner by P2Y12 inhibition only (-81.7±9.5% with 100 nM AR-C69931MX). In coronary artery disease, inhibition of P2Y12 is paralleled by reduction of ADP-induced platelet TF expression (VASP platelet reactivity index: 17.9±11%, 20.9±11.3%, 40.3±13%; TFpos-platelets: 10.5±4.8%, 9.8±5.9%, 13.6±6.3%, in prasugrel/ticagrelor/clopidogrel-treated patients, respectively). Despite this, 15% of clopidogrel good responders had a level of TFpos-platelets similar to the poor-responder group. Indeed, a stronger P2Y12 inhibition (130-fold) is required to inhibit TF than VASP. Thus, a VASP platelet reactivity index <20% (as in prasugrel/ticagrelor-treated patients) identifies patients with TFpos-platelets <20% (92% sensitivity). Finally, colchicine impaired in vitro ADP-induced TF expression but not α-granule release, suggesting that TF is open canalicular system stored as confirmed by TEM and platelet analysis of patients with gray platelet syndrome. CONCLUSIONS: Data show that TF expression is regulated by P2Y12 and not P2Y1; P2Y12 antagonists downregulate the percentage of TFpos-platelets. In clopidogrel good-responder patients, assessment of TFpos-platelets highlights those with residual platelet reactivity. TF is stored in open canalicular system, and its membrane exposure upon activation is prevented by colchicine.

Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

BACKGROUND: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. METHODS: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM. RESULTS: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). CONCLUSIONS: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

Cardiopulmonary exercise testing and heart failure: a tale born from oxygen uptake.

Since 50 years, cardiopulmonary exercise testing (CPET) plays a central role in heart failure (HF) assessment. Oxygen uptake (VO2) is one of the main HF prognostic indicators, then paralleled by ventilation to carbon dioxide (VE/VCO2) relationship slope. Also anaerobic threshold retains a strong prognostic power in severe HF, especially if expressed as a percent of maximal VO2 predicted value. Moving beyond its absolute value, a modern approach is to consider the percentage of predicted value for peak VO2 and VE/VCO2 slope, thus allowing a better comparison between genders, ages, and races. Several VO2 equations have been adopted to predict peak VO2, built considering different populations. A step forward was made possible by the introduction of reliable non-invasive methods able to calculate cardiac output during exercise: the inert gas rebreathing method and the thoracic electrical bioimpedance. These techniques made possible to calculate the artero-venous oxygen content differences (ΔC(a-v)O2), a value related to haemoglobin concentration, pO2, muscle perfusion, and oxygen extraction. The role of haemoglobin, frequently neglected, is however essential being anaemia a frequent HF comorbidity. Finally, peak VO2 is traditionally obtained in a laboratory setting while performing a standardized physical effort. Recently, different wearable ergo-spirometers have been developed to allow an accurate metabolic data collection during different activities that better reproduce HF patients' everyday life. The evaluation of exercise performance is now part of the holistic approach to the HF syndrome, with the inclusion of CPET data into multiparametric prognostic scores, such as the MECKI score.

Dysregulation of Iron Metabolism-Linked Genes at Myocardial Tissue and Cell Levels in Dilated Cardiomyopathy.

In heart failure, the biological and clinical connection between abnormal iron homeostasis, myocardial function, and prognosis is known; however, the expression profiles of iron-linked genes both at myocardial tissue and single-cell level are not well defined. Through publicly available bulk and single-nucleus RNA sequencing (RNA-seq) datasets of left ventricle samples from adult non-failed (NF) and dilated cardiomyopathy (DCM) subjects, we aim to evaluate the altered iron metabolism in a diseased condition, at the whole cardiac tissue and single-cell level. From the bulk RNA-seq data, we found 223 iron-linked genes expressed at the myocardial tissue level and 44 differentially expressed between DCM and NF subjects. At the single-cell level, at least 18 iron-linked expressed genes were significantly regulated in DCM when compared to NF subjects. Specifically, the iron metabolism in DCM cardiomyocytes is altered at several levels, including: (1) imbalance of Fe3+ internalization (SCARA5 down-regulation) and reduction of internal conversion from Fe3+ to Fe2+ (STEAP3 down-regulation), (2) increase of iron consumption to produce hemoglobin (HBA1/2 up-regulation), (3) higher heme synthesis and externalization (ALAS2 and ABCG2 up-regulation), (4) lower cleavage of heme to Fe2+, biliverdin and carbon monoxide (HMOX2 down-regulation), and (5) positive regulation of hepcidin (BMP6 up-regulation).

Why Levosimendan Improves the Clinical Condition of Patients With Advanced Heart Failure: A Holistic Approach.

BACKGROUND: In advanced heart failure (HF), levosimendan increases peak oxygen uptake (VO2). We investigated whether peak VO2 increase is linked to cardiovascular, respiratory, or muscular performance changes. METHODS AND RESULTS: Twenty patients hospitalized for advanced HF underwent, before and shortly after levosimendan infusion, 2 different cardiopulmonary exercise tests: (a) a personalized ramp protocol with repeated arterial blood gas analysis and standard spirometry including alveolar-capillary gas diffusion measurements at rest and at peak exercise, and (b) a step incremental workload cardiopulmonary exercise testing with continuous near-infrared spectroscopy analysis and cardiac output assessment by bioelectrical impedance analysis.Levosimendan significantly decreased natriuretic peptides, improved peak VO2 (11.3 [interquartile range 10.1-12.8] to 12.6 [10.2-14.4] mL/kg/min, P < .01) and decreased minute ventilation to carbon dioxide production relationship slope (47.7 ± 10.7 to 43.4 ± 8.1, P < .01). In parallel, spirometry showed only a minor increase in forced expiratory volume, whereas the peak exercise dead space ventilation was unchanged. However, during exercise, a smaller edema formation was observed after levosimendan infusion, as inferable from the changes in diffusion components, that is, the membrane diffusion and capillary volume. The end-tidal pressure of CO2 during the isocapnic buffering period increased after levosimendan (from 28 ± 3 mm Hg to 31 ± 2 mm Hg, P < .01). During exercise, cardiac output increased in parallel with VO2. After levosimendan, the total and oxygenated tissue hemoglobin, but not deoxygenated hemoglobin, increased in all exercise phases. CONCLUSIONS: In advanced HF, levosimendan increases peak VO2, decreases the formation of exercise-induced lung edema, increases ventilation efficiency owing to a decrease of reflex hyperventilation, and increases cardiac output and muscular oxygen delivery and extraction.

A case of myopericarditis recurrence after third dose of BNT162b2 vaccine against SARS-CoV-2 in a young subject: link or causality?

The rate of post-vaccine myocarditis is being studied from the beginning of the massive vaccination campaign against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a direct cause-effect relationship has been described, in most cases, the vaccine pathophysiological role is doubtful. Moreover, it is not quite as clear as having had a previous myocarditis could be a risk factor for a post-vaccine disease relapse. A 27-year-old man presented to the emergency department for palpitations and pericardial chest pain radiated to the upper left limb, on the 4th day after the third dose of BNT162b2 vaccine. He experienced a previous myocarditis 3 years before, with full recovery and no other comorbidities. Electrocardiogram showed normal atrioventricular conduction, incomplete right bundle branch block, and diffuse ST-segment elevation. A cardiac echo showed lateral wall hypokinesis with preserved ejection fraction. Troponin-T was elevated (160 ng/L), chest X-ray was normal, and the SARS-CoV-2 molecular buffer was negative. High-dose anti-inflammatory therapy with ibuprofen and colchicine was started; in the 3rd day high-sensitivity Troponin I reached a peak of 23000 ng/L. No heart failure or arrhythmias were observed. A cardiac magnetic resonance was performed showing normal biventricular systolic function and abnormal tissue characterization suggestive for acute non-ischaemic myocardial injury (increased native T1 and T2 values, increased signal intensity at T2-weighted images and late gadolinium enhancement, all findings with matched subepicardial distribution) at the level of mid to apical septal, anterior, and anterolateral walls. A left ventricular electroanatomic voltage mapping was negative (both unipolar and bipolar), while the endomyocardial biopsy showed a picture consistent with active myocarditis. The patient was discharged in good clinical condition, on bisoprolol 1.25 mg, ramipril 2.5 mg, ibuprofen 600 mg three times a day, colchicine 0.5 mg twice a day. We presented the case of a young man with history of previous myocarditis, admitted with a non-complicated acute myopericarditis relapse occurred 4 days after SARS-CoV-2 vaccination (3rd dose). Despite the observed very low incidence of cardiac complications following BNT162b2 administration, and the lack of a clear proof of a direct cause-effect relationship, we think that in our patient this link can be more than likely. In the probable need for additional SARS-CoV-2 vaccine doses in the next future, studies addressing the risk-benefit balance of this subset of patient are warranted. We described a multidisciplinary management of a case of myocarditis recurrence after the third dose of SARS-CoV-2 BNT162b2 vaccine.

"You can leave your mask on": effects on cardiopulmonary parameters of different airway protective masks at rest and during maximal exercise.

During the COVID-19 pandemic, the use of protective masks has been essential to reduce contagions. However, public opinion is that there is an associated subjective shortness of breath. We evaluated cardiorespiratory parameters at rest and during maximal exertion to highlight any differences with the use of protective masks.12 healthy subjects performed three identical cardiopulmonary exercise tests, one without wearing a protective mask, one wearing a surgical mask and one with a filtering face piece particles class 2 (FFP2) mask. Dyspnoea was assessed using the Borg scale. Standard pulmonary function tests were also performed.All the subjects (40.8±12.4 years; six male) completed the protocol with no adverse events. Spirometry showed a progressive reduction of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) from no mask to surgical to FFP2 (FEV1: 3.94±0.91 L, 3.23±0.81 L, 2.94±0.98 L; FVC: 4.70±1.21 L, 3.77±1.02 L, 3.52±1.21 L; p<0.001). Rest ventilation, O2 uptake (V˙ O2 ) and CO2 production (V˙ CO2 ) were progressively lower, with a reduction in respiratory rate. At peak exercise, subjects had a progressively higher Borg scale when wearing surgical and FFP2 masks. Accordingly, at peak exercise, V˙ O2 (31.0±23.4 mL·kg-1·min-1, 27.5±6.9 mL·kg-1·min-1, 28.2±8.8 mL·kg-1·min-1; p=0.001), ventilation (92±26 L, 76±22 L, 72±21 L; p=0.003), respiratory rate (42±8 breaths·min-1, 38±5 breaths·min-1, 37±4 breaths·min-1; p=0.04) and tidal volume (2.28±0.72 L, 2.05±0.60 L, 1.96±0.65 L; p=0.001) were gradually lower. There was no significant difference in oxygen saturation.Protective masks are associated with significant but modest worsening of spirometry and cardiorespiratory parameters at rest and peak exercise. The effect is driven by a ventilation reduction due to increased airflow resistance. However, because exercise ventilatory limitation is far from being reached, their use is safe even during maximal exercise, with a slight reduction in performance.

G-CSF for Extensive STEMI.

RATIONALE: In the exploratory Phase II STEM-AMI (Stem Cells Mobilization in Acute Myocardial Infarction) trial, we reported that early administration of G-CSF (granulocyte colony-stimulating factor), in patients with anterior ST-segment-elevation myocardial infarction and left ventricular (LV) dysfunction after successful percutaneous coronary intervention, had the potential to significantly attenuate LV adverse remodeling in the long-term. OBJECTIVE: The STEM-AMI OUTCOME CMR (Stem Cells Mobilization in Acute Myocardial Infarction Outcome Cardiac Magnetic Resonance) Substudy was adequately powered to evaluate, in a population showing LV ejection fraction ≤45% after percutaneous coronary intervention for extensive ST-segment-elevation myocardial infarction, the effects of early administration of G-CSF in terms of LV remodeling and function, infarct size assessed by late gadolinium enhancement, and myocardial strain. METHODS AND RESULTS: Within the Italian, multicenter, prospective, randomized, Phase III STEM-AMI OUTCOME trial, 161 ST-segment-elevation myocardial infarction patients were enrolled in the CMR Substudy and assigned to standard of care (SOC) plus G-CSF or SOC alone. In 119 patients (61 G-CSF and 58 SOC, respectively), CMR was available at baseline and 6-month follow-up. Paired imaging data were independently analyzed by 2 blinded experts in a core CMR lab. The 2 groups were similar for clinical characteristics, cardiovascular risk factors, and pharmacological treatment, except for a trend towards a larger infarct size and longer symptom-to-balloon time in G-CSF patients. ANCOVA showed that the improvement of LV ejection fraction from baseline to 6 months was 5.1% higher in G-CSF patients versus SOC (P=0.01); concurrently, there was a significant between-group difference of 6.7 mL/m2 in the change of indexed LV end-systolic volume in favor of G-CSF group (P=0.02). Indexed late gadolinium enhancement significantly decreased in G-CSF group only (P=0.04). Moreover, over time improvement of global longitudinal strain was 2.4% higher in G-CSF patients versus SOC (P=0.04). Global circumferential strain significantly improved in G-CSF group only (P=0.006). CONCLUSIONS: Early administration of G-CSF exerted a beneficial effect on top of SOC in patients with LV dysfunction after extensive ST-segment-elevation myocardial infarction in terms of global systolic function, adverse remodeling, scar size, and myocardial strain. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01969890.

Can the in-hospital mortality gap between STEMI patients with and without diabetes mellitus be reduced? The cardio-renal hypothesis.

BACKGROUND AND AIMS: Diabetes mellitus (DM) is a frequent comorbidity in ST-elevation-myocardial infarction (STEMI) patients and carries a higher risk of in-hospital mortality. We recently demonstrated that the higher in-hospital mortality of STEMI patients with DM, when compared to that of patients without DM, is mainly associated with their more frequent cardiac and renal dysfunction. These exploratory results prompted us to hypothesize that this higher risk in DM patients is mediated by their lower cardio-renal functional reserve. METHODS AND RESULTS: We included 5152 STEMI patients treated with primary angioplasty. By using an advanced statistical methodology (path analysis), able to clarify the putative causal paths between variables of interest, we reported that the higher in-hospital mortality of STEMI patients with DM is possibly caused by its adverse impact on cardio-renal function. CONCLUSION: This statistical approach allows to reinforce the well-known notion that DM is associated with an increased in-hospital mortality risk in STEMI and sheds lights on the causal relationship among DM, cardio-renal dysfunction, and higher in-hospital mortality. Whether the mortality gap between DM and non-DM patients with STEMI can be reduced by pharmacological strategies combining cardio-renal protective effects is an intriguing question that deserves an answer in the future.

Diabetes Mellitus and Acute Myocardial Infarction: Impact on Short and Long-Term Mortality.

Diabetes mellitus (DM) is an important risk factor for acute myocardial infarction (AMI) and a frequent co-morbidity in patients hospitalized with AMI, being present in about 30% of cases. Although current treatment of AMI has considerably improved survival in both patients with and without DM, the presence of DM still doubles the case fatality rate during both the acute phase of AMI and at long-term follow-up. This higher mortality risk of DM patients strongly indicates a particular need for better treatment options in these patients and suggests that intensive medical treatment, prolonged surveillance, and stringent control of other risk factors should be carefully pursued and maintained for as long as possible in them.In this review, we will focus on the close association between DM and in-hospital and long-term mortality in AMI patients. We will also aim at providing current evidence on the mechanisms underlying this association and on emerging therapeutic strategies, which may reduce the traditional mortality gap that still differentiates AMI patients with DM from those without.

Exercise Dynamic of Patients with Chronic Heart Failure and Reduced Ejection Fraction.

PURPOSE OF REVIEW: Exercise causes various dynamic changes in all body parts either in healthy subject or in heart failure (HF) patients. The present review of current knowledge about HF patients with reduced ejection fraction focuses on dynamic changes along a "metabo-hemodynamic" perspective. RECENT FINDINGS: Studies on the dynamic changes occurring during exercise span many years. Thanks to the availability of advanced methods, it is nowadays possible to properly characterize respiratory, hemodynamic, and muscular function adjustments and their mismatch with the pulmonary and systemic circulations. Exercise is a dynamic event that involves several body functions. In HF patients, it is important to know at what level the limitation takes place in order to better manage these patients and to optimize therapeutic strategies.

Plasma Exosome Profile in ST-Elevation Myocardial Infarction Patients with and without Out-of-Hospital Cardiac Arrest.

The identification of new biomarkers allowing an early and more accurate characterization of patients with ST-segment elevation myocardial infarction (STEMI) is still needed, and exosomes represent an attractive diagnostic tool in this context. However, the characterization of their protein cargo in relation to cardiovascular clinical manifestation is still lacking. To this end, 35 STEMI patients (17 experiencing resuscitated out-of-hospital cardiac arrest (OHCA-STEMI) and 18 uncomplicated) and 32 patients with chronic coronary syndrome (CCS) were enrolled. Plasma exosomes were characterized by the nanoparticle tracking analysis and Western blotting. Exosomes from STEMI patients displayed a higher concentration and size and a greater expression of platelet (GPIIb) and vascular endothelial (VE-cadherin) markers, but a similar amount of cardiac troponin compared to CCS. In addition, a difference in exosome expression of acute-phase proteins (ceruloplasmin, transthyretin and fibronectin) between STEMI and CCS patients was found. GPIIb and brain-associated marker PLP1 accurately discriminated between OHCA and uncomplicated STEMI. In conclusion, the exosome profile of STEMI patients has peculiar features that differentiate it from that of CCS patients, reflecting the pathophysiological mechanisms involved in STEMI. Additionally, the exosome expression of brain- and platelet-specific markers might allow the identification of patients experiencing ischemic brain injury in STEMI.

Prognostic impact of admission high-sensitivity C-reactive protein in acute myocardial infarction patients with and without diabetes mellitus.

BACKGROUND: High-sensitivity C-reactive protein (hs-CRP) elevation frequently occurs in acute myocardial infarction (AMI) and is associated with adverse outcomes. Since diabetes mellitus (DM) is characterized by an underlying chronic inflammation, hs-CRP may have a different prognostic power in AMI patients with and without DM. METHODS: We prospectively included 2064 AMI patients; hs-CRP was measured at hospital admission. Patients were grouped according to hs-CRP quartiles and DM status. The primary endpoint was a composite of in-hospital mortality, cardiogenic shock, and acute pulmonary edema. Two-year all-cause mortality was the secondary endpoint. RESULTS: Twenty-six percent (n = 548) of patients had DM and they had higher hs-CRP levels than non-DM patients (5.32 vs. 3.24 mg/L; P < 0.0001). The primary endpoint incidence in the overall population (7%, 9%, 13%, 22%; P for trend < 0.0001), in DM (14%, 9%, 21%, 27%; P = 0.0001), and non-DM (5%, 8%, 10%, 19%; P < 0.0001) patients increased in parallel with hs-CRP quartiles. The adjusted risk of the primary endpoint increased in parallel with hs-CRP quartiles in DM and non-DM patients but this relationship was less evident in DM patients. In the overall population, the adjusted OR of the primary endpoint associated with an hs-CRP value ≥ 2 mg/L was 2.10 (95% CI 1.46-3.00). For the same risk, hs-CRP was 7 and 2 mg/L in patients with and without DM. A similar behavior was observed for the secondary endpoint when the HR associated with an hs-CRP value ≥ 2 mg/L found in the overall population was 2.25 (95% CI 1.57-3.22). For the same risk, hs-CRP was 8 and 1.5 mg/L in DM and non-DM patients. CONCLUSIONS: This study shows that hs-CRP predicts in-hospital outcome and two-year mortality in AMI patients with and without DM. However, in DM patients, the same risk of developing events as in non-DM patients is associated to higher hs-CRP levels.

Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry.

BACKGROUND: There is controversy about the outcome of patients with acute myocarditis (AM), and data are lacking on how patients admitted with suspected AM are managed. We report characteristics, in-hospital management, and long-term outcome of patients with AM based on a retrospective multicenter registry from 19 Italian hospitals. METHODS: A total of 684 patients with suspected AM and recent onset of symptoms (<30 days) were screened between May 2001 and February 2017. Patients >70 years of age and those >50 years of age without coronary angiography were excluded. The final study population comprised 443 patients (median age, 34 years; 19.4% female) with AM diagnosed by either endomyocardial biopsy or increased troponin plus edema and late gadolinium enhancement at cardiac magnetic resonance. RESULTS: At presentation, 118 patients (26.6%) had left ventricular ejection fraction <50%, sustained ventricular arrhythmias, or a low cardiac output syndrome, whereas 325 (73.4%) had no such complications. Endomyocardial biopsy was performed in 56 of 443 (12.6%), and a baseline cardiac magnetic resonance was performed in 415 of 443 (93.7%). Cardiac mortality plus heart transplantation rates at 1 and 5 years were 3.0% and 4.1%. Cardiac mortality plus heart transplantation rates were 11.3% and 14.7% in patients with complicated presentation and 0% in uncomplicated cases (log-rank P<0.0001). Major AM-related cardiac events after the acute phase (postdischarge death and heart transplantation, sustained ventricular arrhythmias treated with electric shock or ablation, symptomatic heart failure needing device implantation) occurred in 2.8% at the 5-year follow-up, with a higher incidence in patients with complicated forms (10.8% versus 0% in uncomplicated AM; log-rank P<0.0001). ß-Adrenoceptor blockers were the most frequently used medications both in complicated (61.9%) and in uncomplicated forms (53.8%; P=0.18). After a median time of 196 days, 200 patients had follow-up cardiac magnetic resonance, and 8 of 55 (14.5%) with complications at presentation had left ventricular ejection fraction <50% compared with 1 of 145 (0.7%) of those with uncomplicated presentation. CONCLUSIONS: In this contemporary study, overall serious adverse events after AM were lower than previously reported. However, patients with left ventricular ejection fraction <50%, ventricular arrhythmias, or low cardiac output syndrome at presentation were at higher risk compared with uncomplicated cases that had a benign prognosis and low risk of subsequent left ventricular systolic dysfunction.

Extended dual antiplatelet therapy after acute myocardial infarction. Current evidence and future perspectives.

Patients with acute myocardial infarction (AMI) are at increased risk of recurrent ischemic events after hospital discharge, despite optimal medical therapy. Current practice guidelines strongly encourage the early assessment of the residual ischemic risk in post-AMI patients, in order to identify those who may benefit from a prolonged dual antiplatelet therapy. To this end, some scoring systems have been proposed. However, most scores were developed for patients with stable coronary artery disease undergoing percutaneous coronary intervention. Moreover, nearly all failed to be implemented in everyday clinical practice, probably because of the perceived complexity due to the large number of incorporated variables. Therefore, the identification of the ideal AMI patient who can benefit from a prolonged (beyond 1 year after the index event) dual antiplatelet therapy remains to be clarified, especially when the bleeding risk associated with such therapy is considered. In this review, we summarize the current evidence on the prolonged use of dual antiplatelet therapy after AMI, with a special focus on recent advances regarding the identification of high-risk patients who may derive a favorable net clinical benefit from such a therapeutic strategy.

Physiology of exercise and heart failure treatments: cardiopulmonary exercise testing as a tool for choosing the optimal therapeutic strategy.

In the last decades, the pharmacological treatment of heart failure (HF) become more complex due to the availability of new highly effective drugs. Although the cardiovascular effects of HF therapies have been extensively described, less known are their effects on cardiopulmonary function considered as a whole, both at rest and in response to exercise. This is a 'holistic' approach to disease treatment that can be accurately evaluated by a cardiopulmonary exercise test. The aim of this paper is to assess the main differences in the effects of different drugs [angiotensin-converting enzyme (ACE)-inhibitors, Angiotensin II receptor blockers, ß-blockers, Angiotensin receptor-neprilysin inhibitors, renal sodium-glucose co-transporter 2 inhibitors, iron supplementation] on cardiopulmonary function in patients with HF, both at rest and during exercise, and to understand how these differences can be taken into account when choosing the most appropriate treatment protocol for each individual patient leading to a precision medicine approach.

What's behind your eosinophilic myocarditis? A case of Churg-Strauss syndrome diagnosed during acute heart failure.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem disorder; cardiac involvement may include eosinophilic myocarditis. A 67-year-old woman presented with 1-week history of dyspnoea and orthopnoea. She had a history of adult-onset asthma and peripheral eosinophilia. The investigations showed T-wave inversion on lateral leads, peripheral eosinophilia, elevated troponin and BNP values, and severe biventricular systolic dysfunction with diffuse hypokinesia and apical akinesia. Computed tomography excluded coronary disease and showed bilateral basal ground-glass opacities, air-space consolidation, and bilateral reticular-nodular pattern. Cardiac magnetic resonance findings were compatible with active myocardial inflammation. An endomyocardial biopsy (EMB) confirmed the diagnosis of eosinophilic myocarditis, and a therapy with oral corticosteroids and heart failure medications was started.

Is red distribution width a valid tool to predict impaired iron transport in heart failure?

Background: Impaired iron transport (IIT) is a form of iron deficiency (ID) defined as transferrin saturation (TSAT) < 20% irrespective of serum ferritin levels. It is frequently observed in heart failure (HF) where it negatively affects prognosis irrespective of anaemia. Objectives: In this retrospective study we searched for a surrogate biomarker of IIT. Methods: We tested the predictive power of red distribution width (RDW), mean corpuscular volume (MCV) and mean corpuscular haemoglobin concentration (MCHC) to detect IIT in 797 non-anaemic HF patients. Results: At ROC analysis, RDW provided the best AUC (0.6928). An RDW cut-off value of 14.2% identified patients with IIT, with positive and negative predictive values of 48 and 80%, respectively. Comparison between the true and false negative groups showed that estimated glomerular filtration rate (eGFR) was significantly higher (p = 0.0092) in the true negative vs. false negative group. Therefore, we divided the study population according to eGFR value: 109 patients with eGFR ≥ 90 ml/min/1.73 m2, 318 patients with eGFR 60-89 ml/min/1.73 m2, 308 patients with eGFR 30-59 ml/min/1.73 m2 and 62 patients with eGFR < 30 ml/min/1.73 m2. In the first group, positive and negative predictive values were 48 and 81% respectively, 51 and 85% in the second group, 48 and 73% in the third group and 43 and 67% in the fourth group. Conclusion: RDW may be seen as a reliable marker to exclude IIT in non-anaemic HF patients with eGFR ≥60 ml/min/1.73 m2.

The importance of re-evaluating the risk score in heart failure patients: An analysis from the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database.

BACKGROUND: The role of risk scores in heart failure (HF) management has been highlighted by international guidelines. In contrast with HF, which is intrinsically a dynamic and unstable syndrome, all its prognostic studies have been based on a single evaluation. We investigated whether time-related changes of a well-recognized risk score, the MECKI score, added prognostic value. MECKI score is based on peak VO2, VE/VCO2 slope, Na+, LVEF, MDRD and Hb. METHODS: A multi-centre retrospective study was conducted involving 660 patients who performed MECKI re-evaluation at least 6 months apart. Based on the difference between II and I evaluation of MECKI values (MECKI II - MECKI I = ∆ MECKI) the study population was divided in 2 groups: those presenting a score reduction (∆ MECKI <0, i.e. clinical improvement), vs. patients presenting an increase (∆ MECKI >0, clinical deterioration). RESULTS: The prognostic value of MECKI score is confirmed also when re-assessed during follow-up. The group with improved MECKI (366 patients) showed a better prognosis compared to patients with worsened MECKI (294 patients) (p < 0.0001). At 1st evaluation, the two groups differentiated by LVEF, VE/VCO2 slope and blood Na+ concentration, while at 2nd evaluation they differentiated in all 6 parameters considered in the score. The patients who improved MECKI score, improved in all components of the score but hemoglobin, while patients who worsened the score, worsened all parameters. CONCLUSIONS: This study shows that re-assessment of MECKI score identifies HF subjects at higher risk and that score improvement or deterioration regards several MECKI score generating parameters confirming the holistic background of HF.

International validation of the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score in heart failure.

AIMS: Current European heart failure (HF) guidelines suggest the use of risk score: among them, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score has demonstrated to be one of the most accurate. However, the risk scores are still poorly implemented in clinical practice, also due to the lack of strong evidence regarding their external validation in different populations. Thus, the current study was designed as an external validation test of the MECKI score in an international multicentre setting. METHODS AND RESULTS: The study cohort consisted of patients diagnosed with HF with reduced ejection fraction (HFrEF) across international centres (not Italian), retrospectively recruited. Collected data included demographics, HF aetiology, laboratory testing, electrocardiogram (ECG), echocardiographic findings, and cardiopulmonary exercise testing (CPET) results as described in the original MECKI score publication. A total of 1042 patients across 8 international centres (7 European and 1 Asian) were included and followed up from 1998 till 2019. Patients were divided according to the calculated MECKI scores into three subgroups: (i) MECKI score <10%, (ii) 10-20%, and (iii) ≥ 20%. Survival analysis comparison among the three MECKI score subgroups showed a worse prognosis in patients with higher MECKI score value: median event-free survival times were 4396 days for MECKI score <10%, 3457 days for 10-20%, and 1022 days for ≥20% (P < 0.0001). Receiver operating characteristic (ROC) curves and area under the ROC curves (AUC) were like those reported in the original internal validation studies. CONCLUSION: In patients diagnosed with HFrEF, the power of the MECKI score was confirmed in terms of prognosis and risk stratification, supporting its implementation as advised by the HF guidelines.

In patients diagnosed with heart failure with reduced ejection fraction, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) risk score underwent an external validation. The MECKI score prognostic power was confirmed in a large population of patients from Europe and Asia. These data support MECKI score implementation, as advised by the 2021 European heart failure guidelines.