Understanding the heart-brain axis response in COVID-19 patients: A suggestive perspective for therapeutic development

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches

Paraoxonase-1 Is Not a Major Determinant of Stent Thrombosis in a Taiwanese Population

BACKGROUND: Clopidogrel is a prodrug that undergoes in vivo bioactivation to show its antiplatelet effects. Recent studies have shown that cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogrel bioactivation. Here, we aim to determine the effects of genetic polymorphisms of CYP (CYP 2C19*2, CYP 2C19*3, and CYP 2C19*17), ABCB1 (ABCB1 3435C>T, ABCB1 129T>C, and ABCB1 2677G>T/A), and PON1 (PON1 Q192R, PON1 L55M, and PON1 108C>T) on the development of stent thrombosis (ST) in patients receiving clopidogrel after percutaneous coronary intervention (PCI). METHODS AND RESULTS: We evaluated the incidence of ST (0.64%) in 4964 patients who were recruited in the CAPTAIN registry (Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions). The presence of genetic polymorphisms was assessed in 20 subjects who developed ST after aspirin and clopidogrel therapy and in 40 age- and sex-matched control subjects who did not develop ST, which was documented after 9 months of angiographic follow-up. ST was acute in 5 subjects, subacute in 7, late in 7, and very late in 1. The presence of CYP 2C19*2 allele was significantly associated with ST (adjusted odds ratio [ORadj]: 4.20, 95% confidence interval [CI], 1.263-9.544; P = 0.031). However, genetic variations in PON1 and ABCB1 showed no significant association with ST. CONCLUSION: We conclude that in a Taiwanese population, PON1 Q192R genotype is not associated with ST development after PCI. However, the presence of CYP 2C19*2 allele is a risk factor for ST development after PCI

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Granger causality analysis of geophysical, geodetic and geochemical observations during volcanic unrest: A case study in the campi flegrei caldera (Italy)

The recent signs of reawakening at Campi Flegrei caldera (Southern Italy) received a great deal of attention due to the issues related to the volcanic risk management in a densely populated area. This paper explores relations between ground deformations, seismicity and geochemical time series in the time span 2004–2016. The aim is to unravel primary processes of unrest and the related indicators which may change in time. Data structure and interactions among variables were examined applying the clustering analysis, the correlations and the Granger causality test. The hierarchical agglomerative clustering detected two sub-periods which were further investigated. In both sub-period causal links were observed between variables while correlations did not appear and vice versa. Thus, well established formal approaches are required to study causal relations. Granger test results indicate that during 2004–2011 the awakening unrest could be mainly ascribed to hydrothermal system pressure fluctuations, probably induced by deep-rooted fluids injection, and that ground deformation together with CO2 /H2 O appears the most suitable geo-indicators. The 2011–2016 sub-period is characterized by enhanced dynamical connectivity. Granger test results suggest that the unrest is driven by a more localized and shallower thermohydromechanical engine. CO/CO2, He/CH4 and ground deformation velocity are mutually interacting appearing the most suitable geo-indicators

A perturbative approach for modeling short-term fluid-driven ground deformation episodes on volcanoes: a case study in the Campi Flegrei caldera (Italy)

Ground deformation in volcanic areas is linked to various, often interconnected processes such as magma intrusion, pressurized fluid migration, and thermal expansion effects. The presence of active and extended hydrothermal systems plays a key role and affects the deformation phenomenon in complex ways. In this study, we propose a generalized conceptual and mathematical model, which allows retrieving the flow rate of fluid injection in a volcanic hydrothermal system, assuming a ground deformation dataset as input. The basic assumption is that short‐term ground uplift episodes (with characteristic periods of less than 5 years) depend on the injection of volcanic fluids into the hydrothermal system. Then, assuming a deformation field shape independent of time and a linear time‐invariant relation between the amount of injected fluid and the resulting ground deformation, we define a Green's function as the product of spatial and temporal components. The case study is a 3D elastic model with permeability and porosity for the Campi Flegrei caldera (CFc), Italy. By Green's function, a 2 km‐long source at 2.4 km depth, which matches the InSAR deformation, is localized and the amount of injected volcanic fluid in the last 20 years of high‐frequency deformation episodes estimated. In conclusion, we find a good agreement between the measured and estimated temporal deformation patterns and, principally, that fluids injection rates can be retrieved from the deformation field at volcanoes

Evidence of thermal-driven processes triggering the 2005–2014 unrest at Campi Flegrei caldera

An accelerating process of ground deformation that began 10 years ago is currently affecting the Campi Flegrei caldera. The deformation pattern is here explained with the overlapping of two processes: short time pulses that are caused by injection of magmatic fluids into the hydrothermal system; and a long time process of heating of the rock. The short pulses are highlighted by comparison of the residuals of ground deformation (fitted with an accelerating polynomial function) with the fumarolic CO2/CH4 and He/CH4 ratios (which are good geochemical indicators of the arrival of magmatic gases). The two independent datasets show the same sequence of five peaks, with a delay of ∼200 days of the geochemical signal with respect to the geodetic signal. The heating of the hydrothermal system, which parallels the long-period accelerating curve, is inferred by temperature–pressure gas geoindicators. Referring to a recent interpretation that relates variations in the fumarolic inert gas species to open system magma degassing, we infer that the heating is caused by enrichment in water of the magmatic fluids and by an increment in their flux. Heating of the rock caused by magmatic fluids can be a central factor in triggering unrest at calderas