Interleukin-1 and Eosinophils in Heart Failure

Background. Anakinra, an IL-1 inhibitor, temporarily increases eosinophil blood levels in patients with acute myocardial infarction and reduces heart failure (HF) events. Anakinra is also frequently associated with injection site reactions (ISR), and eosinophils have been shown to play a role. Whether anakinra is associated with changes in eosinophils in patients with HF and whether these changes are linked to a different response in terms of cardiorespiratory fitness (CRF) is unknown. Moreover, whether ISR represents an eosinophilic response to anakinra and is associated with a different response to treatment in patients with HF also remains unclear. Aim. This study aims to explore the effect of anakinra on changes in eosinophils in patients with HF, and their correlation with CRF. Methods. We measured eosinophils in 64 patients with HF (50% females), 55 [51–63] years of age, before and after treatment, and, in a subset of 41 patients, also after treatment cessation. We also evaluated CRF by measuring peak oxygen consumption (peak VO2) with a treadmill test. Results. Treatment with anakinra led to a significant and transient increase in eosinophils, from 0.2 [0.1–0.3] to 0.3 [0.1–0.4] x103 cells/µL (p<0.001), and from 0.3 [0.2–0.5] to 0.2 [0.1–0.3] x103 cells/µL, with suspension (p<0.001). Changes in eosinophils correlated with the changes in peak VO2 (Spearman's Rho= +0.228, p=0.020) and predicted peak VO2 (Rho= +0.265, p=0.014). Patients experiencing ISR (n=8, 13%) had higher levels of eosinophils (0.5 [0.4–0.6] vs. 0.2 [0.1–0.4] x103 cells/µL, p=0.023), and a greater increase in peak VO2 (3.0 [0.9–4.3] vs. 0.3 [-0.6–1.8] mLO2·kg-1·min-1, p=0.015). Conclusion. Patients with HF treated with anakinra experience a transient increase in eosinophils, which is associated with ISR and greater improvement in peak VO2.(1)Background. Anakinra, an IL-1 inhibitor, temporarily increases eosinophil blood levels in patients with acute myocardial infarction and reduces heart failure (HF) events. Anakinra is also frequently associated with injection site reactions (ISR), and eosinophils have been shown to play a role. Whether anakinra is associated with changes in eosinophils in patients with HF and whether these changes are linked to a different response in terms of cardiorespiratory fitness (CRF) is unknown. Moreover, whether ISR represents an eosinophilic response to anakinra and is associated with a different response to treatment in patients with HF also remains unclear. Aim. This study aims to explore the effect of anakinra on changes in eosinophils in patients with HF, and their correlation with CRF. Methods. We measured eosinophils in 64 patients with HF (50% females), 55 [51–63] years of age, before and after treatment, and, in a subset of 41 patients, also after treatment cessation. We also evaluated CRF by measuring peak oxygen consumption (peak VO2) with a treadmill test. Results. Treatment with anakinra led to a significant and transient increase in eosinophils, from 0.2 [0.1–0.3] to 0.3 [0.1–0.4] x103 cells/µL (p<0.001), and from 0.3 [0.2–0.5] to 0.2 [0.1–0.3] x103 cells/µL, with suspension (p<0.001). Changes in eosinophils correlated with the changes in peak VO2 (Spearman's Rho= +0.228, p=0.020) and predicted peak VO2 (Rho= +0.265, p=0.014). Patients experiencing ISR (n=8, 13%) had higher levels of eosinophils (0.5 [0.4–0.6] vs. 0.2 [0.1–0.4] x103 cells/µL, p=0.023), and a greater increase in peak VO2 (3.0 [0.9–4.3] vs. 0.3 [-0.6–1.8] mLO2·kg-1·min-1, p=0.015). Conclusion. Patients with HF treated with anakinra experience a transient increase in eosinophils, which is associated with ISR and greater improvement in peak VO2.(1

Hypertension and Arrhythmias: A Clinical Overview of the Pathophysiology-Driven Management of Cardiac Arrhythmias in Hypertensive Patients

Because of demographic aging, the prevalence of arterial hypertension (HTN) and cardiac arrhythmias, namely atrial fibrillation (AF), is progressively increasing. Not only are these clinical entities strongly connected, but, acting with a synergistic effect, their association may cause a worse clinical outcome in patients already at risk of ischemic and/or haemorrhagic stroke and, consequently, disability and death. Despite the well-known association between HTN and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. Although several trials reported the overall clinical benefit of renin-angiotensin-aldosterone inhibitors in reducing incident AF in HTN, the role of this class of drugs is greatly reduced when AF diagnosis is already established, thus hinting at the urgent need for primary prevention measures to reduce AF occurrence in these patients. Through a thorough review of the available literature in the field, we investigated the basic mechanisms through which HTN is believed to promote AF, summarising the evidence supporting a pathophysiology-driven approach to prevent this arrhythmia in hypertensive patients, including those suffering from primary aldosteronism, a non-negligible and under-recognised cause of secondary HTN. Finally, in the hazy scenario of AF screening in hypertensive patients, we reviewed which patients should be screened, by which modality, and who should be offered oral anticoagulation for stroke prevention

High density lipoprotein cholesterol increasing therapy: the unmet cardiovascular need

Despite aggressive strategies are now available to reduce LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. Several preclinical and clinical studies have shown that drug therapy ultimately leads to a regression of the angiographic lesions but also results in a reduction in cardiovascular events. The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein (CEPT) inhibitors, torcetrapib and dalcetrapib, has led to considerable doubt about the value of the current strategy to raise high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These clinical results, as well as animal studies, have revealed the complexity of HDL metabolism, assessing a more important role of functional quality compared to circulating quantity of HDL. As a result, HDL-based therapeutic interventions that maintain or enhance HDL functionality, such as improving its main property, the reverse cholesterol transport, require closer investigation. In this review, we will discuss HDL metabolism and function, clinical-trial data available for HDL-raising agents, and potential strategies for future HDL-based therapies

Active fixation coronary sinus lead in a patient with persistence of left superior vena cava

n/

Association Between Circulating CD4+ T Cell Methylation Signatures of Network-Oriented SOCS3 Gene and Hemodynamics in Patients Suffering Pulmonary Arterial Hypertension

Pathogenic DNA methylation changes may be involved in pulmonary arterial hypertension (PAH) onset and its progression, but there is no data on potential associations with patient-derived hemodynamic parameters. The reduced representation bisulfite sequencing (RRBS) platform identified N= 631 differentially methylated CpG sites which annotated to N= 408 genes (DMGs) in circulating CD4(+) T cells isolated from PAH patients vs. healthy controls (CTRLs). A promoter-restricted network analysis established the PAH subnetwork that included 5 hub DMGs (SOCS3, GNAS, ITGAL, NCOR2, NFIC) and 5 non-hub DMGs (NR4A2, GRM2, PGK1, STMN1, LIMS2). The functional analysis revealed that the SOCS3 gene was the most recurrent among the top ten significant pathways enriching the PAH subnetwork, including the growth hormone receptor and the interleukin-6 signaling. Correlation analysis showed that the promoter methylation levels of each network-oriented DMG were associated individually with hemodynamic parameters. In particular, SOCS3 hypomethylation was negatively associated with right atrial pressure (RAP) and positively associated with cardiac index (CI) (vertical bar r vertical bar &gt;= 0.6). A significant upregulation of the SOCS3, ITGAL, NFIC, NCOR2, and PGK1 mRNA levels (qRT-PCR) in peripheral blood mononuclear cells from PAH patients vs. CTRLs was found (P &lt;= 0.05). By immunoblotting, a significant upregulation of the SOCS3 protein was confirmed in PAH patients vs. CTRLs (P &lt; 0.01). This is the first network-oriented study which integrates circulating CD4(+) T cell DNA methylation signatures, hemodynamic parameters, and validation experiments in PAH patients at first diagnosis or early follow-up. Our data suggests that SOCS3 gene might be involved in PAH pathogenesis and serve as potential prognostic biomarker

589 External validation of the increased wall thickness score for the diagnosis of cardiac amyloidosis

Abstract Aims This study aimed to validate the increased wall thickness (IWT) score, a multiparametric echocardiographic score to facilitate diagnosis of cardiac amyloidosis (CA), in an independent population of patients with increased LV wall thickness suspicious for CA. Methods and results Between January 2019 and December 2020, 152 consecutive patients with increased LV wall thickness suspicious for CA were included. For all patient, the multiparametric echocardiographic score (IWT score) was calculated. To validate the diagnostic accuracy of an IWT score ≥8 to predict the diagnosis of CA, sensibility (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy (PA) were calculated. Among the 152 patients included in the study, 50 (33%) were diagnosed as CA, 25 (16%) had severe aortic stenosis, 25 (16%) had hypertensive remodelling, and 52 (34%) had hypertrophic cardiomyopathy. Among the 50 and 102 patients with and without CA, 19 (38%) and 1 (1%) showed an IWT score ≥8, respectively. Overall, the diagnostic accuracy of an IWT score ≥8 for the diagnosis of CA in our population was the following: Se 38% (95% CI: 25–53%); Sp 99% (95% CI: 95–100%); PPV 95% (95% CI: 72–99%); NPV 77% (95% CI: 73–80%); PA 79% (95% CI: 72–85%). Conclusions This study reports the first external validation of the IWT score for the diagnosis of CA in patients with increased LV wall thickness. A score ≥8 showed a high Sp, PPV and PA, suggesting that the IWT score can be used to identify CA patients in those with increased LV wall thickness

Exercise promotes angiogenesis and improves beta-adrenergic receptor signalling in the post-ischaemic failing rat heart.

We investigated whether exercise training could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodelling of the post-myocardial infarction (MI) failing heart. We also explored the contribution of ameliorated beta-adrenergic receptor signalling and function on the overall improvement of cardiac contractility reserve induced by exercise.Adult Wistar male rats were randomly assigned to one of four experimental groups. Sham-operated and post-MI heart failure (HF) rats were housed under sedentary conditions or assigned to 10-weeks of a treadmill exercise protocol. At 4 weeks after MI, sedentary HF rats showed LV eccentric hypertrophy, marked increase of LV diameters associated with severely impaired fractional shortening (14 +/- 5\%), increased LV end diastolic pressure (20.9 +/- 2.6 mmHg), and pulmonary congestion. In addition, cardiac contractile responses to adrenergic stimulation were significantly blunted. In trained HF rats, exercise was able to (i) reactivate the cardiac vascular endothelial growth factor pathway with a concurrent enhancement of myocardial angiogenesis, (ii) significantly increase myocardial perfusion and coronary reserve, (iii) reduce cardiac diameters, and (iv) improve LV contractility in response to adrenergic stimulation. This latter finding was also associated with a significant improvement of cardiac beta-adrenergic receptor downregulation and desensitization.Our data indicate that exercise favourably affects angiogenesis and improves LV remodelling and contractility reserve in a rat model of severe chronic HF

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts

High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control

Role of continuous glucose monitoring in diabetic patients at high cardiovascular risk. an expert-based multidisciplinary delphi consensus

Background: Continuous glucose monitoring (CGM) shows in more detail the glycaemic pattern of diabetic subjects and provides several new parameters (“glucometrics”) to assess patients’ glycaemia and consensually guide treatment. A better control of glucose levels might result in improvement of clinical outcome and reduce disease complications. This study aimed to gather an expert consensus on the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk or with heart disease. Methods: A list of 22 statements concerning type of patients who can benefit from CGM, prognostic impact of CGM in diabetic patients with heart disease, CGM use during acute cardiovascular events and educational issues of CGM were developed. Using a two-round Delphi methodology, the survey was distributed online to 42 Italian experts (21 diabetologists and 21 cardiologists) who rated their level of agreement with each statement on a 5-point Likert scale. Consensus was predefined as more than 66% of the panel agreeing/disagreeing with any given statement. Results: Forty experts (95%) answered the survey. Every statement achieved a positive consensus. In particular, the panel expressed the feeling that CGM can be prognostically relevant for every diabetic patient (70%) and that is clinically useful also in the management of those with type 2 diabetes not treated with insulin (87.5%). The assessment of time in range (TIR), glycaemic variability (GV) and hypoglycaemic/hyperglycaemic episodes were considered relevant in the management of diabetic patients with heart disease (92.5% for TIR, 95% for GV, 97.5% for time spent in hypoglycaemia) and can improve the prognosis of those with ischaemic heart disease (100% for hypoglycaemia, 90% for hyperglycaemia) or with heart failure (87.5% for hypoglycaemia, 85% for TIR, 87.5% for GV). The experts retained that CGM can be used and can impact the short- and long-term prognosis during an acute cardiovascular event. Lastly, CGM has a recognized educational role for diabetic subjects. Conclusions: According to this Delphi consensus, the clinical and prognostic use of CGM in diabetic patients at high cardiovascular risk is promising and deserves dedicated studies to confirm the experts’ feeling