Pathogenic pathways and therapeutic targets of inflammation in heart diseases: A focus on Interleukin-1.

BACKGROUND: An exuberant and dysregulated inflammatory response contributes to the development and progression of cardiovascular diseases (CVDs). METHODS: This narrative review includes original articles and reviews published over the past 20 years and found through PubMed. The following search terms (or combination of terms) were considered: "acute pericarditis," "recurrent pericarditis," "myocarditis," "cardiac sarcoidosis," "atherosclerosis," "acute myocardial infarction," "inflammation," "NLRP3 inflammasome," "Interleukin-1" and "treatment." RESULTS: Recent evidence supports the role of inflammation across a wide spectrum of CVDs including myocarditis, pericarditis, inflammatory cardiomyopathies (i.e. cardiac sarcoidosis) as well as atherosclerotic CVD and heart failure. Interleukins (ILs) are the signalling mediators of the inflammatory response. The NACHT, leucine-rich repeat and pyrin-domain containing protein 3 (NLRP3) inflammasome play a key role in producing IL-1ß, the prototypical pro-inflammatory cytokine involved in CVDs. Other pro-inflammatory cytokines (e.g. tumour necrosis factor) have been implicated in cardiac sarcoidosis. As a proof of this, IL-1 blockade has been proven efficacious in pericarditis and chronic coronary syndrome. CONCLUSION: Tailored strategies aiming at quenching the inflammatory response have emerged as promising to treat CVDs. In this review article, we summarize recent evidence regarding the role of inflammation across a broad spectrum of CVDs. We also review novel evidence regarding targeted therapeutic strategies.

Novel Therapeutic Insights Into the Treatment of Pericarditis: Targeting the Innate Immune System.

ABSTRACT: Acute pericarditis is characterized by pericardial inflammation that can be treated with anti-inflammatory drugs. A considerable percentage of patients develops recurrent pericarditis with several relapses. In developed countries, the idiopathic form is the most frequent and has a high risk of recurrences. Two pathophysiological mechanisms have been described for idiopathic recurrent pericarditis: autoimmune and autoinflammatory. The autoimmune mechanism is more frequently encountered in patients with rheumatologic disorders, especially systemic lupus erythematosus. The innate immune system plays a central role in the pathophysiology of pericarditis, especially in the autoinflammatory phenotype. Current evidence highlights the central role played by interleukin 1 and NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) in idiopathic recurrent pericarditis. Accordingly, interleukin 1 blockers have been approved for the treatment of this condition. Neutrophils are likely to be important in such setting; however, their role has only been partially investigated. In the present review, we have collected the current knowledge on the role of innate immune system in pericarditis pathophysiology and how this can be used to provide targeted treatments for patients with recurrent pericarditis.

An Overview of Cannabidiol as a Multifunctional Drug: Pharmacokinetics and Cellular Effects.

Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive review delves into the complex pharmacokinetics of CBD, including factors such as bioavailability, distribution, safety profile, and dosage recommendations, which contribute to the compound's pharmacological profile. CBD's role as a pharmacological inhibitor is explored, encompassing interactions with the endocannabinoid system and ion channels. The compound's anti-inflammatory effects, influencing the Interferon-beta and NF-κB, position it as a versatile candidate for immune system regulation and interventions in inflammatory processes. The historical context of Cannabis Sativa's use for recreational and medicinal purposes adds depth to the discussion, emphasizing CBD's emergence as a pivotal phytocannabinoid. As research continues, CBD's integration into clinical practice holds promise for revolutionizing treatment approaches and enhancing patient outcomes. The evolution in CBD research encourages ongoing exploration, offering the prospect of unlocking new therapeutic utility.

Comparison of Safety and Biological Efficacy of Anakinra (Kineret) Dispensed in Polycarbonate Plastic versus Borosilicate Glass Syringes: A Patient-Level Analysis of VCUART2 and VCUART3 Clinical Trials.

Anakinra is a recombinant human interleukin-1 receptor antagonist approved for the treatment of inflammatory diseases. Kineret is available as a solution prepared in a borosilicate glass syringe. For implementing a placebo-controlled double-blind randomized clinical trial, anakinra is commonly transferred into plastic syringes. However, there is limited data on anakinra's stability in polycarbonate syringes. We described the results of our previous studies on the use of anakinra in glass (VCUART3) versus plastic syringes (VCUART2) compared with placebo. These studies were conducted in patients with ST-segment elevation myocardial infarction (STEMI), and we assessed the anti-inflammatory effects of anakinra versus placebo by comparing the area under the curve for high-sensitivity cardiac reactive protein (AUC-CRP) levels during the first 14 days of STEMI, its clinical effects on heart failure (HF) hospitalization, cardiovascular death, or new diagnosis of HF as well as adverse events profile between groups. The levels of AUC-CRP were 75 (50-255 mg·day/l) for anakinra in plastic syringes versus 255 (116-592 mg·day/l) in placebo and 60 (24-139 mg·day/l) and 86 (43-123 mg·day/l) for anakinra once and twice daily in glass syringes, respectively, compared with placebo 214 (131-394 mg·day/l). The rate of adverse events was also comparable between groups. There were no differences in the rate of HF hospitalization or cardiovascular death in patients who received anakinra in plastic or glass syringes. Fewer cases of new-onset heart failure occurred in patients receiving anakinra in plastic or glass syringes compared with placebo. Anakinra stored in plastic (polycarbonate) syringes provides comparable biologic and clinical effect to glass (borosilicate) syringes. SIGNIFICANCE STATEMENT: Anakinra (Kineret) 100 mg administered subcutaneously in patients with ST-segment elevation myocardial infarction (STEMI) for a duration of up to 14 days appears to have comparable safety and biological efficacy signals when delivered in prefilled glass or transferred into plastic polycarbonate syringes. This may have important implications for the feasibility of designing clinical trials in STEMI and other clinical conditions.

Novel Pathophysiological, Diagnostic and Therapeutic Concepts in Acute and Recurrent Pericarditis.

Acute pericarditis is the most frequent pericardial disease characterized by inflammation of the pericardial layers resulting in pain, dyspnea and fatigue. Often limited to an isolated event, up to 30% of patients experience one or more recurrences. There is limited knowledge about the pathophysiology of this disease, possibly due to the limited availability of animal models. More recently, following seminal clinical trials with colchicine and interleukin-1 (IL-1) blockers and a novel murine model of acute pericarditis using zymosan A, it has become clear that the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome/IL-1 ß axis plays a central role in driving acute pericardial inflammation and in sustaining this process during recurrences. Diagnostic management of pericarditis has been implemented with multimodality imaging including echocardiography, cardiac computed tomography, and cardiac magnetic resonance. These imaging modalities provide essential diagnostic and pathogenetic information, and are able to characterize pericardial inflammation, allowing to refine risk stratification and personalize treatment. Recent acquisitions yield relevant implications with regard to the therapeutic management of acute and recurrent pericarditis. Non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are cornerstone therapies either for acute and recurrent pericarditis. However, the benefits of targeted agents, such as anakinra - a recombinant human IL-1 receptor antagonist - and rilonacept - an IL-1 α /IL-1 ß trap, are being increasingly recognized. To this end, phenotyping patients with pericarditis and addressing such therapies to those presenting with auto-inflammatory features (elevated C-reactive protein, sustained pericardial and systemic inflammation, multiple recurrences) is of utmost importance to identify patients who might be more likely to benefit from NLRP3 inflammasome/IL-1 ß pathway blockade.

Molecular and Cellular Mechanisms of Action of Cannabidiol.

Cannabidiol (CBD) is the primary non-psychoactive chemical from Cannabis Sativa, a plant used for centuries for both recreational and medicinal purposes. CBD lacks the psychotropic effects of Δ9-tetrahydrocannabinol (Δ9-THC) and has shown great therapeutic potential. CBD exerts a wide spectrum of effects at a molecular, cellular, and organ level, affecting inflammation, oxidative damage, cell survival, pain, vasodilation, and excitability, among others, modifying many physiological and pathophysiological processes. There is evidence that CBD may be effective in treating several human disorders, like anxiety, chronic pain, psychiatric pathologies, cardiovascular diseases, and even cancer. Multiple cellular and pre-clinical studies using animal models of disease and several human trials have shown that CBD has an overall safe profile. In this review article, we summarize the pharmacokinetics data, the putative mechanisms of action of CBD, and the physiological effects reported in pre-clinical studies to give a comprehensive list of the findings and major effects attributed to this compound.

Catheter ablation of atrial tachycardias after mitral valve surgery: A systematic review and meta-analysis.

INTRODUCTION: Data regarding catheter ablation (CA) of atrial tachycardias (ATs) occurring after mitral valve surgery (MVS) are scarce. The aim of this study was to assess the safety and efficacy of CA of ATs in this surgical population through a systematic review of the literature and meta-analysis. METHODS: A systematic search on PubMed/MEDLINE, EMBASE, and Web of Science was performed considering patients undergoing CA for ATs occurring after MVS. Periprocedural thromboembolic and hemorrhagic complications were assessed. The acute success and maintenance of sinus rhythm (SR) at a mid (<24 months) and long-term follow-up (FU) after CA were investigated along with the burden of arrhythmic recurrence at FU. RESULTS: Fourteen studies for a total of 227 patients were considered. Three-dimensional (3D) mapping systems were used in all studies. Only two major bleedings were recorded with a pooled estimate of periprocedural major complications of 0%. The acute success after CA was 95% with a clear improvement over time. Although maintenance of SR was 71% at a midterm FU, long-term efficacy was as low as 47% due to an increased burden of atrial fibrillation (AF) recurrence despite multiple procedures/patient. CONCLUSION: In this meta-analysis, CA of postsurgical ATs after MVS proved safe and effective but with still a significant burden of AF recurrence at more than 24 months of FU due to a progressive atrial substrate deterioration. The improvement of procedural success over time might suggest a learning curve in optimizing the use of 3D mapping systems.

Genetics of Hypertension: From Monogenic Analysis to GETomics.

Arterial hypertension is the most frequent cardiovascular risk factor all over the world, and it is one of the leading drivers of the risk of cardiovascular events and death. It is a complex trait influenced by heritable and environmental factors. To date, the World Health Organization estimates that 1.28 billion adults aged 30-79 years worldwide have arterial hypertension (defined by European guidelines as office systolic blood pressure ≥ 140 mmHg or office diastolic blood pressure ≥ 90 mmHg), and 7.1 million die from this disease. The molecular genetic basis of primary arterial hypertension is the subject of intense research and has recently yielded remarkable progress. In this review, we will discuss the genetics of arterial hypertension. Recent studies have identified over 900 independent loci associated with blood pressure regulation across the genome. Comprehending these mechanisms not only could shed light on the pathogenesis of the disease but also hold the potential for assessing the risk of developing arterial hypertension in the future. In addition, these findings may pave the way for novel drug development and personalized therapeutic strategies.

Sex-related differences in non-ischemic myocardial injury in the emergency department: A real-world perspective.

BACKGROUND: Myocardial injury is associated with adverse outcomes. No data are reported about sex differences in incidence and factors associated with myocardial injury in an emergency department (ED) setting from a real-world perspective. We aimed to assess whether sex plays a major role in the diagnosis of myocardial injury in the ED. METHODS: In this subanalysis of a retrospective study, patients presenting at the ED with at least one high-sensitivity cardiac troponin T (hs-cTnT) value and without acute coronary syndromes diagnosis were compared. RESULTS: 31,383 patients were admitted to the ED, 4660 had one hs-cTnT value, and 3937 were enrolled: 1943 females (49.4%) and 1994 males (50.6%). The diagnosis of myocardial injury was higher among men (36.8% vs. 32.9%, p < 0.01). Male sex was independently associated with myocardial injury. An older age, an elevated NT-proB-type Natriuretic Peptide and a lower estimated glomerular filtrate rate were independently associated with myocardial injury in both sexes. CONCLUSIONS: In the ED, from a real-world perspective, myocardial injury occurred more frequently in males, and it was associated with older age and the presence of cardiac, lung, and kidney disease but not higher hs-cTnT values.

Early reduction in cardiorespiratory fitness and diastolic reserve following radiation therapy for lung cancer.

BACKGROUND: Contemporary radiotherapy for the treatment of lung cancer is effective in targeting tumor tissue while limiting heart exposure, yet cardiac toxicity still occurs, often becoming clinically apparent years later. Cardiorespiratory fitness (CRF) is an independent predictor of cardiovascular, cancer-related, and overall mortality and may serve as a sensitive measure of subclinical cardiac toxicity following anti-cancer treatments. Prior work has demonstrated a significant relationship between reduced CRF and impaired left-ventricular (LV) diastolic reserve in cancer survivors following thoracic radiotherapy. The purpose of this study was to assess early longitudinal changes in CRF and cardiac function in patients with lung cancer following radiotherapy. METHODS: Ten patients (69 [61-76] years, 70% female) with lung cancer without known cardiovascular disease scheduled to receive radiotherapy involving a clinically-relevant heart dose (≥ 5 Gy to > 10% of heart volume) were evaluated prior to and following treatment. Changes in CRF (peak oxygen consumption [VO2peak], oxygen uptake efficiency slope [OUES]), cardiac function (LV ejection fraction [LVEF], rest and exercise diastolic function [diastolic functional reserve index (DFRI)]), cardiac biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity C-reactive protein [hsCRP]), and health-related quality of life (HRQOL; Functional Assessment of Cancer Therapy-General-7 [FACT-G7]) were measured. RESULTS: The VO2peak was reduced at baseline (1.245 [0.882-1.605] L·min- 1; 70 [62-86] %-predicted) and significantly declined (1.095 [0.810-1.448] L·min- 1, P = 0.047; 62 [56-76] %-predicted, P = 0.005) at 6.0 [3.0-6.0] months post-radiotherapy. Similarly, a significant decline in the OUES was observed (1.63 [1.27-1.88] to 1.57 [1.12-1.75], P = 0.032). Systolic cardiac function was normal at baseline and did not change following radiotherapy (LVEF; 62 [56-65]% to 66 [57-68]%, P = 0.475). The DFRI significantly declined following radiotherapy (34.9 [22.7-41.6] vs. 12.8 [3.1-35.9]). The hsCRP increased significantly from 4.4 [1.4-5.8] to 6.1 [3.7-20.7] g/L, P = 0.047 with a trend towards higher levels of NT-proBNP (65 [49-125] to 121 [88-191] pg/mL, P = 0.110). Health-related quality of life significantly decreased (FACT-G7; 21.5 [18.8-25] to 15.5 [11.5-20]; P = 0.021) post-radiotherapy. CONCLUSIONS: Patients with lung cancer receiving radiotherapy with a clinically-significant heart dose experience reductions in CRF (VO2peak, OUES) as early as six months following treatment with concurrent reductions in diastolic reserve (DFRI), HRQOL, and increases in cardiac biomarkers (NT-proBNP, hsCRP).

Innate and adaptive immunity in acute myocarditis.

Acute myocarditis is an acute inflammatory cardiomyopathy associated with cardiac damage triggered by a virus or a pathological immune activation. It may present with a wide range of clinical presentations, ranging from mild symptoms to severe forms like fulminant myocarditis, characterized by hemodynamic compromise and cardiogenic shock. The immune system plays a central role in the pathogenesis of myocarditis. In fact, while its function is primarily protective, aberrant responses can be detrimental. In this context, both innate and adaptive immunity play pivotal roles; notably, the innate system offers a non-specific and immediate defense, while the adaptive provides specialized protection with immunological memory. However, dysregulation in these systems can misidentify cardiac tissue, triggering autoimmune reactions and possibly leading to significant cardiac tissue damage. This review highlights the importance of innate and adaptive immune responses in the progression and treatment of acute myocarditis.

Impact of C-reactive protein levels and role of anakinra in patients with ST-elevation myocardial infarction.

BACKGROUND: Interleukin-1 blockade with anakinra reduces C-reactive protein (CRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). The effectiveness of anakinra according to the degree of systemic inflammation in STEMI has not been addressed. METHODS: We analyzed 139 patients from three Virginia Commonwealth University Anakinra Response Trial randomized clinical trials to assess whether CRP levels predicted HF hospitalization or death in patients with STEMI, and if CRP levels influenced the effects of treatment with anakinra. RESULTS: CRP cut-off levels for prediction of the composite of death or HF hospitalization for CRP at admission, 3 and 14 days were, respectively 6.45 mg/L (100% of sensitivity and 66.1% specificity), 26 mg/L (100% of sensitivity and 78% specificity) and 9.56 mg/L (100% of sensitivity and 80% specificity). More patients with elevated CRP levels died or had a HF hospitalization (5/47 [11%] vs 0/82 [0%], p = 0.004 for CRP at admission; 5/32 [15.6%] vs 0/92 [0%], p < 0.001 for day 3 and 5/26 [19%] vs 0/89 [0%], p < 0.001 for day 14). A greater number of patients treated with anakinra had low CRP levels at 3 and 14 days compared to placebo (Odds Ratio 0.11 [95% IC 0.04-0.28], p < 0.0001 and OR 0.35 [95% CI 0.14-0.86], p = 0.02, respectively). Anakinra significantly prevented death or HF hospitalization in patients with high inflammatory burden (p = 0.04 for admission, p = 0.24 for day 3, and p = 0.05 for day 14). CONCLUSION: Patients with elevated CRP had higher incidence of HF hospitalization or death. Anakinra reduced the number of patients with elevated CRP levels and prevented death or HF hospitalization in patients with elevated CRP levels.

Life-Threatening Arrhythmias in Patients With Takotsubo Syndrome: Insights Into Pathophysiology and Treatment Innovations.

Takotsubo syndrome (TTS) is a reversible form of acute myocardial injury due to a neurocardiogenic mechanism associated with a relevant risk for life-threatening ventricular arrhythmias, occurring in up to 25% of all patients and including both ventricular arrhythmias (especially) in the context of QT prolongation and atrial tachy- or bradyarrhythmias. The pathogenetic mechanisms of TTS-related arrhythmic complications are not completely understood, and there are no randomized clinical trials addressing the pharmacologic and nonpharmacologic management in this specific setting. In this narrative review, the authors provide an overview of the pathogenesis and the therapeutic management of arrhythmic complications in patients with TTS, along with the future perspectives and the remaining knowledge gaps in this field.

Response to interleukin-1 blockade with anakinra in women and men with ST-segment elevation myocardial infarction.

BACKGROUND: Interleukin-1 blockade with anakinra reduces high-sensitivity C-reactive protein (hsCRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). Sex-based differences in STEMI patients have been reported, but no data are available regarding response to anakinra. METHODS: We analyzed the systemic inflammation and composite end-point of new-onset HF or death in women and men with STEMI treated with anakinra from three different Virginia Commonwealth University Anakinra Response Trial (VCUART) randomized clinical trials. RESULTS: We analyzed 139 patients, 29 (21%) were women while 110 (79%) were men. Baseline hsCRP was higher in women compared to men (8.9 [5.2-13.5] vs. 4.2 [2.1-7.7] mg/L, P<0.001). Eighty-four patients were treated with anakinra (22 [75%] women and 62 [56%] men). The area under the curve of hsCRP (hsCRP-AUC) after 14 days was numerically lower in patients receiving anakinra versus placebo both in men (86 [37-130] vs. 223 [119-374] mg day/L) and in women (73 [46-313] vs. 242 [102-988] mg day/L) (P<0.001 for multiple groups, P for interaction 0.22). The incidence of the composite endpoint was also numerically lower in the anakinra group compared to placebo, both in men (4 [6.4%] vs. 14 [29.1%]) and in women (3 [13.6%] vs. 2 [28.5%]) (P=0.019 for multiple groups, P for interaction 0.44). There were no statistically significant differences between women and men in hsCRP-AUC and death or HF events when comparing separately the anakinra and placebo groups (all P>0.05). CONCLUSIONS: Women were underrepresented in the VCUART trials, they appeared to have higher hsCRP levels at time of presentation, yet to benefit similar to men by treatment with anakinra in STEMI.

mRNA Metabolism and Hypertension.

Hypertension is the most frequent cardiovascular risk factor all over the world. It remains a leading contributor to the risk of cardiovascular events and death. In the year 2015, about 1.5 billion of adult people worldwide had hypertension (as defined by office systolic blood pressure ≥ 140 mmHg or office diastolic blood pressure ≥ 90 mmHg). Moreover, the number of hypertensive patients with age ranging from 30 to 79 years doubled in the last 30 years (from 317 million men and 331 million women in the year 1990 to 652 million men and 626 million women in 2019) despite stable age-standardized prevalence worldwide. Despite such impressive growth, the proportion of controlled hypertension is very low. A better understanding of the pathogenesis of hypertension may contribute to the development of innovative therapeutic strategies. In this context, alterations of the messenger RNA metabolism have been recently evaluated as contributors to the pathogenesis of hypertension, and pharmacological modulation of RNA metabolism is under investigation as potential and novel therapeutic armamentarium in hypertension.

IL-1 blockade in cardiovascular disease: an appraisal of the evidence across different inflammatory paradigms.

Pre-clinical and clinical studies suggest a role for inflammation in the pathophysiology of cardiovascular (CV) diseases. The NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome is activated during tissue injury and releases interleukin-1ß (IL-1ß). We describe three paradigms in which the NLRP3 inflammasome and IL-1ß contribute to CV diseases. During acute myocardial infarction (AMI), necrotic cell debris, including IL-1α, induce NLRP3 inflammasome activation and further damage the myocardium contributing to heart failure (HF) (acute injury paradigm). In chronic HF, IL-1ß is induced by persistent myocardial overload and injury, neurohumoral activation and systemic comorbidities favoring infiltration and activation of immune cells into the myocardium, microvascular inflammation, and a pro-fibrotic response (chronic inflammation paradigm). In recurrent pericarditis, an autoinflammatory response triggered by cell injury and maintained by the NLRP3 inflammasome/IL-1ß axis is present (autoinflammatory disease paradigm). Anakinra, recombinant IL-1 receptor antagonist, inhibits the acute inflammatory response in patients with ST elevation myocardial infarction (STEMI) and acute HF. Canakinumab, IL-1ß antibody, blunts systemic inflammation and prevents complications of atherosclerosis in stable patients with prior AMI. In chronic HF, anakinra reduces systemic inflammation and improves cardiorespiratory fitness. In recurrent pericarditis, anakinra and rilonacept, a soluble IL-1 receptor chimeric fusion protein blocking IL-1α and IL-1ß, treat and prevent acute flares. In conclusion, the NLRP3 inflammasome and IL-1 contribute to the pathophysiology of CV diseases, and IL-1 blockade is beneficial with different roles in the acute injury, chronic inflammation and autoinflammatory disease paradigms. Further research is needed to guide the optimal use of IL-1 blockers in clinical practice.

What Else Is Needed to Improve Survival from Out-of-Hospital Cardiac Arrest to Hospital Admission? Data from a Prospective Registry for the Years 2020-2023 in the Italian Province of Varese.

Around the world, data on out-of-hospital cardiac arrest (OHCA) are heterogeneous in terms of outcomes and reporting, and not all registries follow the Utstein recommendations for uniform OHCA data collection. This study reports data on OHCA occurring in recent years in a limited territory to analyze, in a homogenous setting, the circumstances and interventions affecting survival to hospital admission. OHCA data from the province of Varese for the years 2020-2022 were extracted from a prospective registry. For survival to hospital admission, the impact of pandemic waves and variables known to affect survival was evaluated both in the overall population and in the subgroup of patients in whom cardiopulmonary resuscitation (CPR) was initiated or continued by the emergency medical service (EMS). Overall, 3263 OHCAs occurred mainly at home (88%), with a time to intervention of 13.7 min, which was significantly longer during lockdown (15.7 min). Bystanders performed CPR in 22% of the cases and used automatic external defibrillator (AED) in 2.2% of the cases. Overall survival to hospital admission was 7.7%. In the multivariate analysis, in the general population, occurrence near a public building (OR 1.92), the presence of witnesses (OR 2.65), and a shockable rhythm (OR 7.04) were independent predictors of survival to hospital admission, whereas age (OR 0.97) and occurrence during a pandemic wave (OR 0.62) were associated with significantly worse survival to hospital admission. In the group of patients who received CPR, AED shock by bystanders was the only independent predictor of survival (OR 3.14) to hospital admission. Among other factors, early defibrillation was of crucial importance to improve survival to hospital admission in possibly rescuable patients. The occurrence of OHCA during pandemic waves was associated with longer intervention time and worse survival to hospital admission.

Interleukin-1 blockade in heart failure: an on-treatment and off-treatment cardiorespiratory fitness analysis.

AIMS: Interleukin-1 (IL-1) blockade may improve exercise capacity in patients with heart failure (HF) patients. The extent of the improvement and its persistence beyond discontinuation of IL-1 blockade is unknown. METHODS AND RESULTS: The primary objective was to determine changes in cardiorespiratory fitness and cardiac function on-treatment with IL-1 blocker, anakinra, and off-treatment, after treatment cessation. We performed cardiopulmonary exercise testing, Doppler echocardiography, and biomarkers in 73 patients with HF, 37 (51%) females, 52 (71%) Black-African-American, before and after treatment with anakinra 100 mg daily. In a subset of 46 patients, testing was also repeated after treatment cessation. Quality of life was assessed in each patient using standardized questionnaires. Data are presented as median and interquartile range. Treatment with anakinra for 4 [2-12] weeks was associated with a significant improvement in high-sensitivity C-reactive protein (from 6.2 [3.3-15.4] to 1.4 [0.8-3.4] mg/L, P < 0.001), peak oxygen consumption (VO2peak , from 13.9 [11.6-16.6] to 15.2 [12.9-17.4] mL/kg/min, P < 0.001). Ventilatory efficiency, exercise time, Doppler-derived signs and biomarkers of elevated intracardiac pressures, and quality-of-life measures also improved with anakinra. In the 46 patients in whom off-treatment data were available 12 [4-12] weeks later, many of the favourable changes seen with anakinra were largely reversed (from 1.5 [1.0-3.4] to 5.9 [1.8-13.1], P = 0.001 for C-reactive protein, and from 16.2 [14.0-18.4] to 14.9 [11.5-17.8] mL/kg/min, P = 0.017, for VO2peak ). CONCLUSIONS: These data validate IL-1 as an active and dynamic modulator of cardiac function and cardiorespiratory fitness in HF.