Prevention of coronary microvascular obstruction by addressing ischemia reperfusion injury-part a

Most recently, substantial research efforts were directed to the treatment and prevention of coronary microvascular obstruction (CMVO) by targeting various mechanisms involved in its multifactorial pathophysiology. Among other strategies, antiplatelets and vasodilators were tested in order to reduce thrombus burden and coronary vasospasm potentially resulting in enhanced myocardial perfusion. Furthermore, the impact of intensified statin therapy was evaluated in numerous investigations. Although most of these studies failed to convincingly prove beneficial effects regarding CMVO, especially antiplatelets and statins are indispensable cornerstones of post-infarction medical therapy. This chapter discusses the scientific evidence and guideline recommendations for the use of antiplatelets, statins, and vasodilators in patients with myocardial infarction with a particular focus on their efficacy to treat or prevent CMVO

Randomised trials and meta-analyses of double vs triple antithrombotic therapy for atrial fibrillation-ACS/PCI: A critical appraisal

•The optimal antithrombotic regimen to be used in patients with AF and PCI or ACS is still debated.•Each of the six randomised controlled trials comparing double to triple therapy has limitations.•None was powered to assess differences between treatment arms in ischaemic event rates.•The contrasting results regarding ischaemic events within published meta-analyses can be explained by heterogeneity, incompleteness and varying definitions of stent thrombosis.•The overall reduced bleeding rates, but increased early definite and probable stent thrombosis rates with double versus triple antithrombotic therapy encourage consideration of triple therapy during the first weeks from PCI followed by double therapy

Indication, from Pioneer 10/11, Galileo, and Ulysses Data, of an Apparent Anomalous, Weak, Long-Range Acceleration

Radio metric data from the Pioneer 10/11, Galileo, and Ulysses spacecraft indicate an apparent anomalous, constant, acceleration acting on the spacecraft with a magnitude $\sim 8.5\times 10^{-8}$ cm/s$^2$, directed towards the Sun. Two independent codes and physical strategies have been used to analyze the data. A number of potential causes have been ruled out. We discuss future kinematic tests and possible origins of the signal.Comment: Revtex, 4 pages and 1 figure. Minor changes for publicatio

Association between dosing and combination use of medications and outcomes in heart failure with reduced ejection fraction: data from the Swedish Heart Failure Registry.

AIMS: To assess the association between combination, dose and use of current guideline-recommended target doses (TD) of renin-angiotensin system inhibitors (RASi), angiotensin receptor-neprilysin inhibitors (ARNi) and β-blockers, and outcomes in a large and unselected contemporary cohort of patients with heart failure (HF) and reduced ejection fraction. METHODS AND RESULTS: Overall, 17 809 outpatients registered in the Swedish Heart Failure Registry (SwedeHF) from May 2000 to December 2018, with ejection fraction <40% and duration of HF ≥90 days were selected. Primary outcome was a composite of time to cardiovascular death and first HF hospitalization. Compared with no use of RASi or ARNi, the adjusted hazard ratio (HR) (95% confidence interval [CI]) was 0.83 (0.76-0.91) with <50% of TD, 0.78 (0.71-0.86) with 50%-99%, and 0.73 (0.67-0.80) with ≥100% of TD. Compared with no use of β-blockers, the adjusted HR (95% CI) was 0.86 (0.76-0.91), 0.81 (0.74-0.89) and 0.74 (0.68-0.82) with <50%, 50%-99% and ≥100% of TD, respectively. Patients receiving both an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB)/ARNi and a β-blocker at 50%-99% of TD had a lower adjusted risk of the primary outcome compared with patients only receiving one drug, i.e. ACEi/ARB/ARNi or β-blocker, even if this was at ≥100% of TD. CONCLUSION: Heart failure with reduced ejection fraction patients using higher doses of RASi or ARNi and β-blockers had lower risk of cardiovascular death or HF hospitalization. Use of two drug classes at 50%-99% of TD dose was associated with lower risk than one drug class at 100% of TD

Long-term clinical impact of permanent pacemaker implantation in patients undergoing transcatheter aortic valve implantation: a systematic review and meta-analysis

AIMS: The aims of this study is to assess by an updated meta-analysis the clinical outcomes related to permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) at long-term (≥12 months) follow-up (LTF). METHODS AND RESULTS: A comprehensive literature research was performed on PubMed and EMBASE. The primary endpoint was all-cause death. Secondary endpoints were rehospitalization for heart failure, stroke, and myocardial infarction. A subgroup analysis was performed according to the Society of Thoracic Surgeon-Predicted Risk of Mortality (STS-PROM) score. This study is registered with PROSPERO (CRD42021243301). A total of 51 069 patients undergoing TAVI from 31 observational studies were included. The mean duration of follow-up was 22 months. At LTF, PPI post-TAVI was associated with a higher risk of all-cause death [risk ratio (RR) 1.18, 95% confidence interval (CI) 1.10-1.25; P &lt; 0.001] and rehospitalization for heart failure (RR 1.32, 95% CI 1.13-1.52; P &lt; 0.001). In contrast, the risks of stroke and myocardial infarction were not affected. Among the 20 studies that reported procedural risk, the association between PPI and all-cause death risk at LTF was statistically significant only in studies enrolling patients with high STS-PROM score (RR 1.25, 95% CI 1.12-1.40), although there was a similar tendency of the results in those at medium and low risk. CONCLUSION: Patients necessitating PPI after TAVI have a higher long-term risk of all-cause death and rehospitalization for heart failure as compared to those who do not receive PPI

Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is an increasingly studied entity accounting for 50% of all diagnosed heart failure and that has claimed its own dignity being markedly different from heart failure with reduced EF in terms of etiology and natural history (Graziani et al., 2018). Recently, a growing body of evidence points the finger toward microvascular dysfunction as the major determinant of the pathological cascade that justifies clinical manifestations (Crea et al., 2017). The high burden of comorbidities such as metabolic syndrome, hypertension, atrial fibrillation, chronic kidney disease, obstructive sleep apnea, and similar, could lead to a systemic inflammatory state that impacts the physiology of the endothelium and the perivascular environment, engaging complex molecular pathways that ultimately converge to myocardial fibrosis, stiffening, and dysfunction (Paulus and Tschope, 2013). These changes could even self-perpetrate with a positive feedback where hypoxia and locally released inflammatory cytokines trigger interstitial fibrosis and hypertrophy (Ohanyan et al., 2018). Identifying microvascular dysfunction both as the cause and the maintenance mechanism of this condition has opened the field to explore specific pharmacological targets like nitric oxide (NO) pathway, sarcomeric titin, transforming growth factor beta (TGF-β) pathway, immunomodulators or adenosine receptors, trying to tackle the endothelial impairment that lies in the background of this syndrome (Graziani et al., 2018;Lam et al., 2018). Yet, many questions remain, and the new data collected still lack a translation to improved treatment strategies. To further elaborate on this tangled and exponentially growing topic, we will review the evidence favoring a microvasculature-driven etiology of this condition, its clinical correlations, the proposed diagnostic workup, and the available/hypothesized therapeutic options to address microvascular dysfunction in the failing heart

Perilipin 2 levels are increased in patients with in-stent neoatherosclerosis: A clue to mechanisms of accelerated plaque formation after drug-eluting stent implantation

Background: Perilipin 2 (PLIN2) is a protein that potentially facilitates atherogenesis in native coronary arteries or arteries with an implanted drug-eluting stent (DES). The aim of the study was to determine PLIN2 protein levels in peripheral monocytes of enrolled subjects and compare them between patients with native coronary artery disease (CAD) and those with an in-stent restenosis (ISR) due to neoatherosclerosis occurring >1 year after DES implantation. Methods: Forty-two patients were prospectively enrolled in the study in 3:1 fashion and underwent coronary catheterization. Both groups were angiographically matched for CAD burden with respect to the number of diseased vessels. Neoatherosclerosis was determined by intracoronary optical coherence tomography (OCT) among patients with ISR. Results: Patients with ISR due to neoatherosclerosis had significantly higher PLIN2 protein levels in peripheral blood monocytes compared to patients with native CAD (342.47 ± 75.63[SE] versus 119.51 ± 20.95, p < 0.001). PLIN2 protein levels did not significantly differ between unstable and stable disease phenotype (125.59 ± 131.02 vs. 146.14 ± 111.87, p = 0.109). Conclusions: In this explorative study, PLIN2 protein levels are significantly increased in patients with neoatherosclerosis, irrespective of clinical presentation, implicating that it might play a pathogenetic role in accelerated atherosclerosis after DES implantation. Further larger clinical studies are warranted to confirm these initial findings