Atrial Fibrillation and Diabetes Mellitus: Dangerous Liaisons or Innocent Bystanders?

Atrial fibrillation (AF) is the most common arrhythmia in adults and diabetes mellitus (DM) is a major risk factor for cardiovascular diseases. However, the relationship between both pathologies has not been fully documented and new evidence supports the existence of direct and independent links. In the myocardium, a combination of structural, electrical, and autonomic remodeling may lead to AF. Importantly, patients with AF and DM showed more dramatic alterations than those with AF or DM alone, particularly in mitochondrial respiration and atrial remodeling, which alters conductivity, thrombogenesis, and contractile function. In AF and DM, elevations of cytosolic Ca2⁺ and accumulation of extra cellular matrix (ECM) proteins at the interstitium can promote delayed afterdepolarizations. The DM-associated low-grade inflammation and deposition/infiltration of epicardial adipose tissue (EAT) enforce abnormalities in Ca2+ handling and in excitation-contraction coupling, leading to atrial myopathy. This atrial enlargement and the reduction in passive emptying volume and fraction can be key for AF maintenance and re-entry. Moreover, the stored EAT can prolong action of potential durations and progression from paroxysmal to persistent AF. In this way, DM may increase the risk of thrombogenesis as a consequence of increased glycation and oxidation of fibrinogen and plasminogen, impairing plasmin conversion and resistance to fibrinolysis. Additionally, the DM-associated autonomic remodeling may also initiate AF and its re-entry. Finally, further evidence of DM influence on AF development and maintenance are based on the anti-arrhythmogenic effects of certain anti-diabetic drugs like SGLT2 inhibitors. Therefore, AF and DM may share molecular alterations related to Ca2+ mobility, mitochondrial function and ECM composition that induce atrial remodeling and defects in autonomic stimulation and conductivity. Likely, some specific therapies could work against the associated cardiac damage to AF and/or DM.

Cardiovascular Damage in COVID-19: Therapeutic Approaches Targeting the Renin-Angiotensin-Aldosterone System.

Coronavirus disease 2019 (COVID-19) is usually more severe and associated with worst outcomes in individuals with pre-existing cardiovascular pathologies, including hypertension or atherothrombosis. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can differentially infect multiple tissues (i.e., lung, vessel, heart, liver) in different stages of disease, and in an age- and sex-dependent manner. In particular, cardiovascular (CV) cells (e.g., endothelial cells, cardiomyocytes) could be directly infected and indirectly disturbed by systemic alterations, leading to hyperinflammatory, apoptotic, thrombotic, and vasoconstrictive responses. Until now, hundreds of clinical trials are testing antivirals and immunomodulators to decrease SARS-CoV-2 infection or related systemic anomalies. However, new therapies targeting the CV system might reduce the severity and lethality of disease. In this line, activation of the non-canonical pathway of the renin-angiotensin-aldosterone system (RAAS) could improve CV homeostasis under COVID-19. In particular, treatments with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) may help to reduce hyperinflammation and viral propagation, while infusion of soluble ACE2 may trap plasma viral particles and increase cardioprotective Ang-(1-9) and Ang-(1-7) peptides. The association of specific ACE2 polymorphisms with increased susceptibility of infection and related CV pathologies suggests potential genetic therapies. Moreover, specific agonists of Ang-(1-7) receptor could counter-regulate the hypertensive, hyperinflammatory, and hypercoagulable responses. Interestingly, sex hormones could also regulate all these RAAS components. Therefore, while waiting for an efficient vaccine, we suggest further investigations on the non-canonical RAAS pathway to reduce cardiovascular damage and mortality in COVID-19 patients.

Covariate adjusted reanalysis of the I-Preserve trial.

BACKGROUND: The CHARM-Preserved trial suggested that the renin-angiotensin system (RAS) inhibitor candesartan might have been beneficial in heart failure with preserved ejection fraction (HFpEF); however, this hypothesis was not supported by the findings of I-Preserve with irbesartan. AIMS: To re-analyse the results of I-Preserve, adjusting for imbalances in baseline variables that may have influenced the trial outcomes. METHODS: Cox proportional hazards models with covariate adjustment for baseline variables, including age, sex, medical history, physiological and laboratory variables. RESULTS: In I-Preserve, 763 (37.0%) participants in the placebo group and 742 (35.9%) in the irbesartan group experienced the primary composite outcome (death from any cause or hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). The prespecified analysis of this outcome, stratifying for the use of ACEi at baseline, gave a hazard ratio (HR) of 0.95 (95% confidence interval, 0.86-1.05); p = 0.35. Adjusting the effect of treatment for key prognostic baseline variables, gave a HR of 0.89 (0.80-0.99); p = 0.033. Similar findings were observed for the composite of cardiovascular death or HF hospitalization. CONCLUSION: Adjusting for imbalances in baseline variables that influence outcomes (or the response to therapy or both) can improve the power around the estimate of the effect of treatment and may alter its statistical significance. Along with the CHARM-Preserved results, these findings suggest that angiotensin-receptor blockers may have a modest effect in HFpEF.

Acute Community-Acquired Bacterial Meningitis: Update on Clinical Presentation and Prognostic factors.

The epidemiology of community-acquired bacterial meningitis (CABM) in adults has changed significantly in the past several years. Despite substantial improvement in patient care, CABM remains a major cause of morbidity and mortality. Thus, new prognostic factors could help improve patient stratification. We conducted a multicenter retrospective study to determine the clinical pattern of CABM in an urban area of Western Europe and to identify potential predictors of unfavorable prognosis and complicated course. Over a period of 6-8 years, 79 adult CABM cases were treated at three tertiary hospitals. A Glasgow Outcome Scale (GOS) score of ≤4 was defined as unfavorable outcome. Predictors of unfavorable prognosis or complicated course were identified through logistic-regression analysis. S. pneumoniae was the most frequent pathogen (34%). 82% of patients exhibited at least two of five signs, including fever, neck stiffness, altered mental status, headache and nausea. Almost 50% presented focal neurological deficits; the overall mortality rate was 15%. In the multivariate analysis, risk factors for an unfavorable outcome included a GCS score of ≤13, female sex, and etiology by L. monocytogenes and gram-negative bacilli. However, risk factors for systemic complications were a GCS score of ≤13 and reduced platelet count, whereas C-Reactive Protein (CRP) increase was associated with a higher rate of neurological complications. Patients with non-pneumococcal CABM were more prone to an unfavorable outcome, probably because of underutilization of empiric ampicillin in patients at risk of listeriosis and because the suspicion of pneumococcal infection was facilitated by the existence of otitis and the higher yield of Gram's stain. Patients presenting a GCS of ≤13, thrombocytopenia and/or increased CRP, may benefit from more aggressive care to avoid in-hospital complications and neurological sequelae.