Elisa Maria Fiorelli

Acute particulate matter affects cardiovascular autonomic modulation and IFN-γ methylation in healthy volunteers

Aims: Air particulate matter (PM) is associated with increased cardiovascular morbidity and mortality. Altered autonomic functions play a key role in PM‐induced cardiovascular disease. However, previous studies have not address the impact of PM on sympathetic and parasympathetic control of heart function, independently, and using controlled conditions, i.e., increasing titration of PM of known composition, in absence of other potential confounding factors. To fill this gap, here we used symbolic analysis that is capable of detecting non‐mutual changes of the two autonomic branches, thus considering them as independent, and concentrations of PM as they could be measured at peak levels in Milan during a polluted winter day. Methods and results: In this randomized, cross‐over study, we enrolled 12 healthy subjects who underwent two random sessions: inhalation of filtered air mixture or inhalation of filtered air containing particulate mixture (PM 10, PM 2.5, PM 1.0 and PM 0.5 &mgr;m). ECG and respiration for autonomic analysis and blood sample for DNA Methylation were collected at baseline (T1), after air exposure (T2) and after 2 h (T3). Spectral and symbolic analysis of heart rate variability (HRV) were performed for autonomic control of cardiac function, while alterations in DNA methylation of candidate genes were used to index pro‐inflammatory modifications. In the PM expose group, autonomic analysis revealed a significant decrease of 2UV%, index of parasympathetic modulation (14% vs 9%, p = 0.0309), while DNA analysis showed a significant increase of interferon &ggr; (IFN‐ &ggr;) methylation, from T1 to T3. In a mixed model using T1, T2 and T3, fine and ultrafine PM fractions showed significant associations with IFN‐ &ggr; methylation and parasympathetic modulation. Conclusions: Our study shows, for the first time, that in healthy subjects, acute exposure to PM affects parasympathetic control of heart function and it increases methylation of a pro‐inflammatory gene (i.e. methylation of interferon &ggr;). Thus, our study suggests that, even in absence of other co‐factors and in otherwise healthy individuals, PM per se is sufficient to trigger parasympathetic dysautonomia, independently from changes in sympathetic control, and inflammation, in a dose‐dependent manner. HIGHLIGHTSIn healthy subjects, acute exposure to PM affects vagal autonomic control of the heart.PM exposure increases methylation of a pro‐inflammatory gene, i.e. methylation of interferon &ggr; (IFN‐ &ggr;).PM per se is able to trigger autonomic deregulation and inflammation in a dose‐dependent manner.

Edoxaban for the treatment of cancer associated venous thromboembolism as an alternative to low-molecular-weight-heparin

Cancer is a well-known risk factor for venous thromboembolism (VTE), both due to the presence of cancer and to cancer-related interventions. Evidence on what is the best anticoagulation strategy in cancer-associated VTE both in the acute phase and long term is limited. Guidelines recommend treatment with low-molecular-weight-heparin (LMWH) basing the evidence mainly on a single trial that shows that dalteparin is more effective than oral anticoagulation with vitamin K antagonists (VKA) in reducing VTE recurrence with a comparable risk of bleeding [1]. A Cochrane systematic review published in 2014 confirms a reduction of recurrent VTE in patients treated with LMWH compared to VKA (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.32–0.71, moderate quality of evidence) with no difference in survival and bleeding [2]. A more recent trial comparing full-dose tinzaparin with warfarin for 6 months shows that treatment with full-dose tinzaparin is not associated with a significant reduction of VTE recurrence, overall mortality and major bleeding, but is associated with a lower rate of clinically relevant non major (CRNM) bleeding [3]. Evidence on direct oral anticoagulants (DOAC) is still limited, and is mainly derived from subgroup analysis of randomized trials enrolling both patients with cancer and without cancer [4]. Based on current evidence, guidelines do not recommend their use. Decision on treatment duration is often made on a caseby-case basis, evaluating the risk–benefit ratio of prolonging an anticoagulant treatment after 3-6 months of therapy. However, as patients with cancer are often allocated to longterm treatment, an oral option would be attractive.

Bedside focused cardiac ultrasound in the evaluation of systolic dysfunction.

The assessment of left ventricular systolic function (LVSF) plays a crucial role in the diagnosis, management and risk stratification of many cardiac diseases, such as myocarditis, acute coronary syndrome (ACS) and heart failure (HF). Transthoracic echocardiographic (TTE) imaging is the method of choice to evaluate LVSF because of its high accuracy, safety, and low cost; however, formal TTE may not be always immediately available [1]. History, physical examination, chest X-ray study, serum chemistries and electrocardiography have poor accuracy in identifying impaired LVSF [1, 2]. The delay in performing a TTE may be harmful in unstable patients: shock, dyspnoea and chest pain are the main symptoms requiring a bedside echocardiography in the medical emergency setting. Distinguishing patients with impaired LVSF is of pivotal importance to identify the correct therapeutic strategy as is true on medical wards, particularly when approaching patients with decompensated HF or volume-depleted patients. Moreover, early recognition of impaired LVSF permits an avoidance of harmful therapies. Bedside cardiac ultrasound consists of a focused approach, mainly used to reveal ‘presence’ or ‘absence’ of significant abnormalities. The assessment of LVSF can be performed by clinicians at the bedside with any portable device. Although bedside cardiac ultrasound does not replace in any case a comprehensive TTE, it can be part of the first clinical evaluation increasing diagnostic accuracy when added to traditional clinical assessment [1, 2].

Primary PCI is associated with different cardiac autonomic patterns in relation to the site of myocardial infarction.

AIM Reflex alterations of cardiac autonomic modulation have been described after acute myocardial infarction (AMI). The non-homogeneous autonomic innervation of the heart gives reason of different patterns of autonomic modulation depending upon the site of AMI. Conflicting data are available on cardiac autonomic modifications after primary percutaneous coronary intervention (pPCI). We evaluated cardiac autonomic changes in patients with ST-elevation myocardial infarction (STEMI) after pPCI, either within 24h after revascularization (T0) and at clinical stability (T1, 6±2days), taking into account the site of infarction. METHODS AND RESULTS We enrolled 33 consecutive patients with STEMI treated with pPCI (25 males, mean age 61±12.1yr); 15 had an anterior wall STEMI (ANT) and 18 had an inferior wall STEMI (INF). ECG and respiration were recorded at T0 and at T1. Cardiac autonomic modulation was evaluated by means of symbolic analysis of heart rate variability. At T0, At T0, 0V% (marker of sympathetic modulation) was higher in INF compared to ANT [31% (18-43) vs 18% (7-32), p=0.014]. Moreover, ANT had a higher 2LV%, index of vagal modulation, compared to INF [8% (7-15) vs 5% (2-8), p=0.006]. CONCLUSION After pPCI, these preliminary results suggest that patients with INF were characterized by a sympathetic predominance, while ANT by a predominant vagal modulation. Our data suggest that pPCI can be associated with specific autonomic patterns, which are different for ANT and INF STEMI, according to the different autonomic innervation. Future ad hoc studies are needed to confirm these preliminary observations.

Does the Absence of Comorbidities Really Identify Low-Risk Syncope Patients?

We read with great interest the article by Ruwald et al. ([1][1]) on the prognosis among healthy individuals discharged with syncope as the primary diagnosis. However, we wonder whether the subjects enrolled in the study can be effectively considered low-risk patients. Syncope is, most of the time,

Nothing as it seems

Dr. Tobaldini: An 82-year-old woman was brought by her daughter to the Emergency Department (ED) because she was found on the ground, confused, with right ocular deviation, dysarthria, left hemisoma hyposthenia, attention and executive functions’ deficit. The past medical history was significant for Lewy bodies dementia and systemic hypertension. Her medications included quetiapina, selegina, zolpidem, escitalopram, acetylsalicylic acid, atenolol, enalapril and amlodipina. On admission to ED, the patient was confused and apyretic; blood pressure was 235/135 mmHg, SatO2 97 % in ambient air, heart rate 95 beats/min, respiratory rate 26/min and plasma glucose 101 mg/dl. General physical examination revealed pulmonary bibasilar crackles. Neurological examination showed a left sided inattention, right ocular deviation, left partial vision paralysis, deficiency of the VII left cranial nerve, left hemisoma hyposthenia, positive Babinsky reflex on the left side, deep pain stimulus extinction on the left side; the NIH Stroke Scale (NIHSS) score was 11. Laboratory blood tests, ECG and a chest X-ray study were normal; the first brain CT-scan performed showed a past lacunar ischemia of the left thalamic region but it was negative for acute lesions. In the ED, the patient was treated with captopril and urapidil for blood pressure control; due to the patient’s agitation, iv delorazepam was administered. The patient was admitted to internal medicine service. The patient was sleepy but arousable, the physical examination remained unchanged.

Indomethacin prevents post-ERCP pancreatitis in selected high-risk patients

BackgroundPancreatitis is one of the major complications of cholan-giopancreatography (ERCP). It occurs in 1–10 % ofpatients but the incidence may reach 25 % in high-riskpatient populations. Generally post-ERCP pancreatitis(PEP) is mild, but moderate or severe pancreatitis (pan-creas necrosis, pseudocyst formation, need of surgicalintervention, long hospitalization) may arise in 0.5 % ofcases [1, 2].The most common risk factors for this complication areboth patient-related and procedure-related: younger age,female gender, prior ERCP-induced pancreatitis, sphincterof Oddi dysfunction, pancreas divisum, difficulty of can-nulation, biliary sphincterotomy or pancreatic opacification[3]. Although some randomized clinical trials (RCTs) haveshown a potential benefit of gabexate mesilate andsomatostatin in preventing post-ERCP pancreatitis, thereare few data to recommend the use of these drugs; more-over, they require continuous infusion and are quiteexpensive [4, 5].A few RCTs have demonstrated a potential role ofnonsteroidal anti-inflammatory drugs (NSAIDs) as pre-vention for post-ERCP pancreatitis, but before introducingthese prophylactic strategies in clinical practice, morestudies are needed [6, 7].SummaryElmunzer et al. conducted a multicenter, randomized,placebo-controlled, double-blind clinical trial comparingthe use of a single dose of rectal indomethacin versusplacebo for the prevention of post-ERCP pancreatitis inhigh-risk patients. Patients were considered eligible, if theymet at least one major criteria: (clinical suspicion ofsphincter of Oddi dysfunction, a history of PEP, pancreaticsphincterectomy, precut sphincterectomy, more than eightcannulation attempts, pneumatic dilatation of an intactbiliary sphincter or ampullectomy) or two or more minorcriteria (age less than 50 and female gender, a history ofrecurrent pancreatitis, three or more injections of contrastagent into the pancreatic duct, excessive injection of con-trast agent resulting in opacification of pancreatic acini, orthe acquisition of a cytologic specimen from the pancreaticduct using a brush). The main exclusion criteria were:active pancreatitis, contraindication to the use of NSAIDs(creatinine level [1.4 mg per deciliter, or active pepticulcer disease), pre-existing therapy with NSAIDs (exceptfor cardioprotective aspirin), and low risk of post procedurepancreatitis (chronic calcific pancreatitis, biliary stentexchange). After ERCP had been performed, a total of 602patients were randomized to receive either 100 mg of rectalindomethacin or a placebo immediately after the proce-dure. The primary outcome was the development of PEPdefined as new-onset upper abdominal pain associated withan elevation of pancreatic enzymes C3 URL, and hospi-talization for at least two nights. The secondary outcomewas the development of moderate or severe post-ERCPpancreatitis. Patients who were discharged after anuneventful procedure were contacted by telephone after5 days, and again after 30 days to assess for delayedadverse events, and to determine the severity of post-ERCP

Is perioperative bridging anticoagulation useful in patients with atrial fibrillation

Temporary interruption of oral anticoagulation (OAC) for elective surgery or other elective invasive procedures is often required in patients with atrial fibrillation (AF) [1]. Several guidelines recommend stopping vitamin K antagonist (VKA) 5 days before procedures, and suggest bridging anticoagulation during VKA interruption in patients at high risk of thromboembolism [2, 3]. However, evidence on this issue is lacking, and guidelines recommendations regarding the need for bridging anticoagulation are based primarily on observational studies [1, 4]. Indeed, although heparin bridging therapy is commonly used in clinical practice, its efficacy and safety remain a controversial issue.

New blood pressure goals for patients with increased cardiovascular risk.

Hypertension is one of the leading causes of morbidity and mortality worldwide. The overall prevalence of hypertension is around 30–45 % of the general population, and increases with aging [1]. Hypertension is a major risk factor for cardiovascular events, chronic kidney disease, peripheral vascular disease, cognitive decline, and premature death. There is strong evidence about the benefit of antihypertensive drug treatment in reducing important outcomes, however, which target systolic and diastolic blood pressure level goals should be sought is still debated. European hypertension guidelines recommend a target systolic blood pressure (SBP) level lower than 140 mmHg; an higher target SBP (lower than 150 mmHg) is recommended in patients older than 80 years old [1], while American guidelines recommend the latter target SBP in patients older than 60 years old. All the guidelines agree in the maintenance of a target SBP level lower than 140 mmHg in patients with diabetes. This target is supported by the results of the ACCORD study [2], which does not show any benefit in targeting an SBP lower than 120 mmHg as compared with a threshold of 140 mmHg in patients with diabetes. Conversely, a recent systematic review and meta-analysis [3] shows a benefit of a more intensive treatment as compared with standard treatment in high-risk patients with or without diabetes. Summary

Efficacy of antibiotics and non-steroidal anti-inflammatory drugs in non-complicated acute bronchitis

Acute bronchitis is defined as an acute self-limiting respiratory tract infection, occurring in a patient without chronic lung disease, in which cough, which may or may not be productive, is the predominant feature. The process affects 5 % of adults annually, and it accounts for a large number of the infections attended by family physicians [1]. Acute bronchitis is mainly a viral infection, and the role of bacteria in this condition continues to be controversial. Despite the limited evidence to support the use of antibiotics for acute bronchitis, the majority of patients are still treated with antibiotics [2]. Little evidence is available about the role of non-steroidal anti-inflammatory drugs, antitussive agents or other over-the-counter medicines.