PCSK9 Inhibition During the Inflammatory Stage of SARS-CoV-2 Infection.

BACKGROUND: The intensity of inflammation during COVID-19 is related to adverse outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in low-density lipoprotein receptor homeostasis, with potential influence on vascular inflammation and on COVID-19 inflammatory response. OBJECTIVES: The goal of this study was to investigate the impact of PCSK9 inhibition vs placebo on clinical and laboratory outcomes in patients with severe COVID-19. METHODS: In this double-blind, placebo-controlled, multicenter pilot trial, 60 patients hospitalized for severe COVID-19, with ground-glass opacity pneumonia and arterial partial oxygen pressure to fraction of inspired oxygen ratio ≤300 mm Hg, were randomized 1:1 to receive a single 140-mg subcutaneous injection of evolocumab or placebo. The primary endpoint was death or need for intubation at 30 days. The main secondary endpoint was change in circulating interleukin (IL)-6 at 7 and 30 days from baseline. RESULTS: Patients randomized to receive the PCSK9 inhibitor had lower rates of death or need for intubation within 30 days vs placebo (23.3% vs 53.3%, risk difference: -30%; 95% CI: -53.40% to -6.59%). Serum IL-6 across time was lower with the PCSK9 inhibitor than with placebo (30-day decline: -56% vs -21%). Patients with baseline IL-6 above the median had lower mortality with PCSK9 inhibition vs placebo (risk difference: -37.50%; 95% CI: -68.20% to -6.70%). CONCLUSIONS: PCSK9 inhibition compared with placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in severe COVID-19. Patients with more intense inflammation at randomization had better survival with PCSK9 inhibition vs placebo, indicating that inflammatory intensity may drive therapeutic benefits. (Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19 [IMPACT-SIRIO 5]; NCT04941105).

A new approach to ticagrelor-based de-escalation of antiplatelet therapy after acute coronary syndrome. A rationale for a randomized, double-blind, placebo-controlled, investigator-initiated, multicenter clinical study.

The risk of ischemic events gradually decreases after acute coronary syndrome (ACS), reaching a stable level after 1 month, while the risk of bleeding remains steady during the whole period of dual antiplatelet treatment (DAPT). Several de-escalation strategies of antiplatelet treatment aiming to enhance safety of DAPT without depriving it of its efficacy have been evaluated so far. We hypothesized that reduction of the ticagrelor maintenance dose 1 month after ACS and its continuation until 12 months after ACS may improve adherence to antiplatelet treatment due to better tolerability compared with the standard dose of ticagrelor. Moreover, improved safety of treatment and preserved anti-ischemic benefit may also be expected with additional acetylsalicylic acid (ASA) withdrawal. To evaluate these hypotheses, we designed the Evaluating Safety and Efficacy of Two Ticagrelor-based De-escalation Antiplatelet Strategies in Acute Coronary Syndrome - a randomized clinical trial (ELECTRA-SIRIO 2), to assess the influence of ticagrelor dose reduction with or without continuation of ASA versus DAPT with standard dose ticagrelor in reducing clinically relevant bleeding and maintaining anti-ischemic efficacy in ACS patients. The study was designed as a phase III, randomized, multicenter, double-blind, investigator-initiated clinical study with a 12-month follow-up (ClinicalTrials.gov Identifier: NCT04718025; EudraCT number: 2020-005130-15).

Prolonged antithrombotic therapy in patients after acute coronary syndrome: A critical appraisal of current European Society of Cardiology guidelines.

The increased risk of non-cardiovascular death in patients receiving clopidogrel or prasugrel in comparison with the placebo group in the Dual Antiplatelet Therapy (DAPT) trial in contrast to the decreased risk of cardiovascular death and all-cause death seen in patients treated with low-dose ticagrelor in the EU label population of the PEGASUS-TIMI 54 trial, resulted in inclusion in the 2020 ESC NSTE-ACS guidelines the recommendation for use of clopidogrel or prasugrel only if the patient is not eligible for treatment with ticagrelor. The prevalence of the primary outcome composed of cardiovascular death, stroke, or myocardial infarction was lower in the low-dose rivaroxaban and acetylsalicylic acid (ASA) group than in the ASA-alone group in the COMPASS trial. Moreover, all-cause mortality and cardiovascular mortality rates were lower in the rivaroxaban-plus-ASA group. Comparison of the PEGASUS-TIMI 54 and COMPASS trial patient characteristics clearly shows that each of these treatment strategies should be addressed at different groups of patients. A greater benefit in post-acute coronary syndrome (ACS) patients with a high risk of ischemic events and without high bleeding risk may be expected with ASA and ticagrelor 60 mg b.i.d. when the therapy is continued without interruption or with short interruption only after ACS. On the other hand, ASA and rivaroxaban 2.5 mg b.i.d. seems to be a better option when indications for dual antithrombotic therapy (DATT) appear after a longer time from ACS (more than 2 years) and/or from cessation of DAPT (more than 1 year) and in patients with multiple vascular bed atherosclerosis. Thus, both options of DATTs complement each other rather than compete, as can be presumed from the recommendations. However, a direct comparison between these strategies should be tested in future clinical trials.

[Collaborative synergy in the management of diabetic patients with acute coronary syndrome]. / Sinergia collaborativa nella gestione del paziente diabetico con recente sindrome coronarica acuta.

BACKGROUND: An increasing amount of evidence confirms that abnormalities in glucose metabolism are associated with cardiovascular morbidity and mortality in acute coronary syndromes (ACS). The in-hospital management of hyperglycemic diabetic patients with ACS is complex, and the traditional clinical-organizational approaches show a high degree of heterogeneity nationwide in Italy. METHODS: The current survey (March 2016-January 2017), carried out through the Delphi method, was focused on some management issues to verify the modalities/possibilities of resolution in daily clinical practice. In addition to the 12 members of the Board, who defined the web-based questionnaire and coordinated the various stages of the process, 66 specialists, cardiologists or diabetologists, were involved in 6 Italian Regions (Lombardy, Tuscany, Lazio, Friuli-Venezia Giulia, Puglia and Sicily). Three iterative rounds of evaluation of the 24 statements included in the questionnaire were scheduled. For each statement, the median evaluation value and the degree of convergence of the Panel of specialists were determined. RESULTS AND CONCLUSIONS: The final analysis reveals two key aspects with a broad convergence of opinions: (i) the need, since admission to hospital, of a close collaboration between cardiologists and diabetologists in the assistance of high-risk patients; and (ii) the opportunity of a specific diagnostic therapeutic care pathway extended to post-discharge management, where the role of the general practitioner should be adequately emphasized.

Long-Term Contrast Echocardiography and Clinical Follow-Up after Percutaneous Closure of Patent Foramen Ovale Using Two Different Atrial Septal Occluder Devices.

INTRODUCTION: Percutaneous patent foramen ovale (PFO) closure by means of a septal occluder device (SOD) is a well-known therapeutic strategy for the secondary prevention of paradoxical embolic neurological events. The aim of this study was to provide long-term echocardiographic and clinical follow-up data on patients who had undergone percutaneous PFO closure with 2 different SOD. METHODS: We selected 2 groups of patients treated with 2 different SOD: Group A: 52 patients with an Amplatzer(®) PFO Occluder and Group B: 49 patients with a Figulla Flex(®) device. All patients underwent follow-up Bubble Test Transthoracic Echocardiography (BTTE) and clinical examination. The results were compared with those recently reported in a group of patients with similar characteristics, but that had been treated conservatively, which acted as a control group. RESULTS: The mean follow-up after PFO closure was 53 months. The Amplatzer(®) PFO Occluder and the Figulla Flex were used in 52 (51.5%) and 49 (48.5%) of patients, respectively. We found no significant difference in the rate of effective PFO closure between the devices: Amplatzer 91.4%, Figulla 93.9% (P = 0.71). One patient (1.0%) suffered a recurrent neurologic event. BTTE was positive (BTTE+) in 8 patients (8%), 5 with an Amplatzer, and 3 with a Figulla device (P = 0.516). Only 1 patient with BTTE+ had a recurrent TIA (12.5%). No significant relationship was found between device dimensions and BTTE+ (P = 0.062). In the control group (163 patients), the recurrence of neurologic events was 9.2% (15 events), that was significantly higher in respect to the patients who had undergone percutaneous closure of the PFO. CONCLUSIONS: Percutaneous PFO closure was associated with a remarkably low risk of recurrent embolic neurological events, and no long-term device-related major complications. No statistically significant difference emerged between the 2 different SODs regarding BTTE positivity. Long-term follow-up showed that the recurrence of neurological events has been significantly higher in the group treated in a conservative way.

The prognostic role of troponin I elevation after elective percutaneous coronary intervention.

OBJECTIVES: To assess the prognostic role of isolated troponin I (TnI) elevation after elective percutaneous coronary intervention (PCI) in patients with stable coronary artery disease. BACKGROUND: The prognostic role of minor troponin elevation after PCI is controversial. METHODS: A total of 1532 consecutive patients who underwent elective PCI were included. Follow-up data were obtained for 1432 of 1532 (93.4%) patients. The events taken into account in the follow-up included total mortality, cardiac death, hospitalization for acute myocardial infarction and/or unstable angina. RESULTS: The following variables were identified as predictive of major adverse cardiac events (MACE) by univariate analysis: age 75 years at least (P = 0.012), ejection fraction less than 50% (P = 0.001), prior myocardial infarction (P = 0.031) and TnI 1.0 ng/ml at least after PCI (P = 0.04). The Cox-regression model identified the TnI elevation after PCI, the older age and the ejection fraction as independent predictors of MACE during follow-up (TnI: P = 0.042; older age: P = 0.001; ejection fraction: P = 0.003). In a subgroup of patients with preserved ejection fraction, the incidence of MACE was significantly higher in those with TnI of at least 1.0 ng/ml at least than in the ones with TnI less than 1.0 ng/ml, with the highest incidence among the older cohort. The multivariate analysis confirmed the TnI elevation 1.0 ng/ml at least after PCI and the older age as predictors of MACE. CONCLUSION: This study documented that in clinically stable patients, minor TnI elevations after elective PCI are independent predictors of MACE during follow-up, as are older age and reduced ejection fraction. Additionally, TnI elevation was a predictor of MACE during follow-up in a subset of patients with preserved ejection fraction. The combination of TnI elevation and older age confers the highest risk of MACE.

Neutrophil gelatinase-associated lipocalin predicts worsening of renal function in acute heart failure: methodological and clinical issues.

BACKGROUND: Worsening of renal function (WRF) in acute heart failure (AHF) strongly predicts adverse clinical outcome. Plasma neutrophil gelatinase-associated lipocalin (NGAL) has been proposed as an earlier biomarker of tubular damage, but important methodological issues remain unsolved, particularly in AHF. METHODS AND RESULTS: In 30 consecutive patients admitted for AHF, 108 serum NGAL (Alere system) measurements were performed at entry and in the first days of recovery, and reproducibility within the same blood samples was very high (r = 0.98). NGAL at entry was related to kidney function [r = 0.51 vs. creatinine (Cr) and r = -0.49 vs. estimated glomerular filtration rate (eGFR), both P < 0.001], and weakly with hemoglobin (r = -0.36, P < 0.05) and C-reactive protein (CRP) (r = 0.26, P < 0.05). During hospitalization, WRF occurred in 26.7% of the patients. Baseline NGAL was only slightly higher in patients who developed WRF as compared to those who did not (151 ±â€Š90 vs. 119 ±â€Š75 ng/ml, NS), but it increased significantly in the following days, always preceding WRF occurrence (max. previous 24 h, average 95%, range 25-200%). The area under the Receiver Operating Characteristic (ROC) curve (AUC-ROC) was 0.69 for pathological NGAL at entry and 0.91 for delta NGAL changes during the first days. CONCLUSIONS: In patients with AHF, serum NGAL measurement is highly reproducible and at entry it is related to baseline Cr and eGFR, but does not predict WRF during subsequent hospitalization. On the contrary, serial measurements of NGAL in the first days of hospitalization can accurately predict WRF.

Adaptive servo ventilation reduces central sleep apnea in chronic heart failure patients: beneficial effects on autonomic modulation of heart rate.

AIM: Adaptive servo ventilation (ASV) is a method of ventilator support aimed to treat central sleep apnea (CSA). We investigated the effects of an acute use of ASV in chronic heart failure (CHF) patients with CSA and the potential influence on sympathetic nerve activity. METHODS: Patients were studied with ambulatory cardio-respiratory 24 Holter (Somtè) recording of air flow, ECG and oxygen saturation. Comparison before and after ASV treatment was made for apnea index (AI), apnea-hypopnea index (AHI), pulse oxygen saturation, desaturation related to apnea, heart rate (HR) and heart rate variability (HRV). RESULTS: Seventeen patients were enrolled. At baseline, apnea index and apnea-hypopnea index were, respectively, 16.92 ±â€Š7.8 and 41.37 ±â€Š17.5. During ASV, they significantly decreased to 0.06 ±â€Š0.0 (P < 0.001) and 2.84 ±â€Š1.1 (P < 0.001). The mean and minimal oxygen saturation (%) increased from 94 ±â€Š1 and 86.5 ±â€Š4 to 95 ±â€Š2 (P = 0.04) and 91 ±â€Š2 (P = 0.008). Mean HR decreased from 68 ±â€Š10 to 62 ±â€Š7 beats/min (P < 0.003). In 11 out of 17 patients, HRV was calculated, documenting a significant improvement of the standard deviation of the average of NN - normal sinus to normal sinus (SDANN), standard deviation of NN intervals (SDNN) and SDNN index (respectively, 71.5 ±â€Š31.1 vs. 80.4 ±â€Š36.1, P = 0.008; 99.7 ±â€Š31.3 vs. 112.7 ±â€Š37.5, P = 0.003; 57.8 ±â€Š20.7 vs. 69.3 ±â€Š30.8, P = 0.03). CONCLUSION: The acute use of ASV is effective on CSA by increasing oxygen saturation and reducing HR. Moreover, the significant improvement of HRV highlights ASV's benefit in moderating the sympathetic adrenergic tone.

[Drug-eluting stents in non-coronary arteries]. / Gli stent medicati nei distretti arteriosi non coronarici.

According to the available literature, drug-eluting stents (DES) are used mainly in coronary arteries. However, DES are used in non-coronary districts as well. The indication for DES implantation in non-coronary arteries is the same as that in the coronary circulation that is to prevent restenosis. Although data from both controlled studies and observational reports do exist, the use of DES in the non-coronary circulation is very limited and is not comparable with that for the treatment of coronary artery disease. The most important factors one has to consider before DES implantation in non-coronary arteries are histologic features, blood flow characteristics and compressive extrinsic forces. Further studies on larger populations are warranted to define the ideal combination stent/drug and the clinical indications for the correct use of DES in non-coronary vascular districts.

Stress-induced QTc-interval shortening as an ancillary marker of ischemia in patients with complete left bundle branch block.

BACKGROUND: In patients with left bundle branch block (LBBB), ischemia-induced repolarization changes associated with QTc-interval shortening may be recorded during coronary angioplasty. We aimed to assess whether these repolarization changes may be predictive of severe coronary artery disease in patients with LBBB. METHODS: Fifty noninfarcted LBBB patients underwent dipyridamole stress test and coronary angiography for chest pain. To localize the site of ischemia, we considered four groups of conventional ECG leads (V1-V2-V3; V4-V5-V6; aVL-I; III-aVF-II), exploring the anteroseptal, lateral, high-lateral, and inferior left ventricular walls. ST-T changes and QTc intervals were estimated at rest and peak stress, lead by lead, in each group of leads and the fractional percentage difference between rest-stress QTc intervals ([DELTA]QTc) was calculated. A [DELTA]QTc greater than -10% was used to define significant QTc-interval shortening. Coronary stenosis of more than 70% and more than 90% were considered 'significant' and 'severe'. RESULTS: According to dipyridamole stress test response, two groups were identified: group I (35 patients) with dipyridamole-induced ischemia and group II (15 patients) without dipyridamole-induced ischemia. The wall motion score index at peak stress (compared with resting wall motion score index) was significantly higher in group I (1.98 +/- 0.13 vs. 1.28 +/- 0.08, P < 0.0001) than in group II (1.36 +/- 0.18 vs. 1.25 +/- 0.08, P = 0.296). The patients of group I showed a significant QTc-interval shortening ([DELTA]QTc = -16.9 +/- 3.9%), whereas this did not happen in patients of group II ([DELTA]QTc = +8.8 +/- 2.4%, P < 0.0001). The patients of group I also had a more severe stenosis in the vessel related to the stress-induced dyssynergic area (I = 90.5 +/- 9.5 vs. II = 34.3 +/- 31.1%; P < 0.0001). CONCLUSION: In patients with LBBB, stress-induced pseudonormalization pattern, associated with QTc-interval shortening, allows the identification of cardiac areas supplied by severely stenosed coronary arteries.

Multislice computed tomography for the evaluation of coronary bypass grafts and native coronary arteries: comparison with traditional angiography.

BACKGROUND: Multislice computed tomography (CT) is a promising new noninvasive technique for the detection of atherosclerotic disease within a vessel's wall. The present study was designed to assess the diagnostic accuracy of 64-slice CT in detecting graft disease and in the evaluation of native vessels distally to the grafts. METHODS: Forty consecutive patients with previous coronary artery bypass underwent both invasive coronary angiography and 64-slice CT. The CT data were acquired over 7-12 s period during a single-breath hold using the Smartprep technique. Images were reconstructed using the retrospective modality on a synchronized ECG in a time frame of between 40 and 80% of the R-R interval. RESULTS: A total of 118 grafts were investigated (80 vein and 38 arterial conduits). At CT, 31/38 arterial grafts were classified as patent and free from significant lesions, whereas seven appeared diseased (five complete occlusion and two significant stenoses along the body of the graft). Out of 80 vein grafts, 52 appeared free of disease and 28 diseased (23 total occlusion and five critical stenosis). An absolute concordance between CT and angiographic findings was documented for all arterial and venous grafts (100% diagnostic concordance). The accuracy of 64-slice CT in the assessment of distal run-off arteries was 90%. CONCLUSION: The 64-slice CT detected with very high accuracy the presence of diseased arterial and vein grafts. Moreover, an optimal diagnostic accuracy was also documented in the appraisal of native vessels distal to the graft anastomoses. On the basis of these results, 64-slice CT can be proposed for the study of patients after coronary artery bypass and may represent an effective screening technique to select those patients with indications of new revascularization.

Baroreflex sensitivity predicts long-term cardiovascular mortality after myocardial infarction even in patients with preserved left ventricular function.

OBJECTIVES: This study sought to assess the long-term predictive power of depressed baroreflex sensitivity (BRS) among post-myocardial infarction (MI) patients with preserved left ventricular function. BACKGROUND: Risk stratification after MI is primarily performed by identifying patients with depressed left ventricular ejection fraction (LVEF) because of their greater mortality. Autonomic markers can help refining risk stratification. Depressed BRS (<3 ms/mm Hg) correlated with cardiovascular mortality in 1,284 post-MI patients during a 21-month follow-up in the multicenter ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) study, but had no significant predictive power in patients with LVEF >35% or above age 65 years. METHODS: Two hundred forty-four consecutive post-MI patients (age 59 +/- 10 years) with LVEF >35% (average 54 +/- 8%) were enrolled. They underwent a complete assessment, including BRS 4 weeks after MI. RESULTS: During a 5-year mean follow-up, 14 (5.7%) patients died of cardiovascular causes. Multivariate analysis identified BRS (p = 0.0001), but not LVEF and age, as predictive of cardiovascular mortality. The relative risk (95% confidence interval [CI]) for depressed BRS was 11.4 (95% CI 3.3 to 39.0) for the overall population, 19.6 (95% CI 4.1 to 94.8) for patients

Protective role of chronic statin therapy in reducing myocardial damage during percutaneous coronary intervention.

OBJECTIVE: Percutaneous coronary intervention (PCI) is frequently associated with troponin I (TnI) elevation. Experimental studies suggest that statins may reduce ischaemia-reperfusion myocardial injury. The study objective was to verify whether chronic treatment with statins might reduce the occurrence and the extent of periprocedural myocardial damage in patients undergoing PCI. METHODS: Five hundred and fifty-two consecutive patients undergoing PCI were included: 279 were not on statins before PCI, 273 were on statins. TnI levels >or= 0.3 ng/ml were considered indicative of myocardial injury. RESULTS: Statin-treated patients had a higher prevalence of hyperlipidaemia, previous myocardial infarction, and revascularization procedures. Coronary angiography also documented a higher prevalence of multivessel disease. No difference between the two groups was observed regarding the PCI-treated vessel, type of lesions, use of stents and of anti-IIb/IIIa inhibitors. Patients on statins showed the lowest incidence of TnI >or= 0.3 ng/ml (29 vs. 48%, P = 0.00001) and of creatine kinase-MB elevation (7 vs. 12%, P = 0.04). The mean peak TnI levels were significantly lower in patients on statins (1.07 +/- 3.8 vs. 2.73 +/- 12.3, P = 0.00006). Multivariate analysis identified preprocedural statin therapy as the only independent negative predictor of postprocedural abnormal TnI levels (odds ratio = 0.52; 95% confidence intervals 0.34-0.79; P = 0.003). CONCLUSIONS: This study shows that chronic therapy with statins reduces the incidence of periprocedural myocardial damage after PCI. The beneficial effect of statins was independent of either the most important clinical and angiographic characteristics or the use of other cardiovascular drugs including beta-blockers. These data support the specific cardioprotective role of statins.

Exercise-induced increase in baroreflex sensitivity predicts improved prognosis after myocardial infarction.

BACKGROUND: Despite the rational expectation for a survival benefit produced by exercise training among post-myocardial infarction (MI) patients, direct evidence remains elusive. Clinically, changes in autonomic balance toward lower vagal activity have consistently been associated with increased mortality risk; conversely, among both control and post-MI dogs, exercise training improved vagal reflexes and prevented sudden death. Accordingly, we tested the hypothesis that exercise training, if accompanied by a shift toward increased vagal activity of an autonomic marker such as baroreflex sensitivity (BRS), could reduce mortality in post-MI patients. METHODS AND RESULTS: Ninety-five consecutive male patients surviving a first uncomplicated MI were randomly assigned to a 4-week endurance training period or to no training. Age (51+/-8 versus 52+/-8 years), site of MI (anterior 41% versus 43%), left ventricular ejection fraction (52+/-13 versus 51+/-14%), and BRS (7.9+/-5.4 versus 7.9+/-3.4 ms/mm Hg) did not differ between the two groups. After 4 weeks, BRS improved by 26% (P=0.04) in trained patients, whereas it did not change in nontrained patients. During a 10-year follow-up, cardiac mortality among the 16 trained patients who had an exercise-induced increase in BRS >or = 3 ms/mm Hg (responders) was strikingly lower compared with that of the trained patients without such a BRS increase (nonresponders) and that of the nontrained patients (0 of 16 versus 18 of 79 [23%], P=0.04). Cardiac mortality was also lower among responders irrespective of training (4% versus 24%, P=0.04). CONCLUSIONS: Post-MI exercise training can favorably modify long-term survival, provided that it is associated with a clear shift of the autonomic balance toward an increase in vagal activity.