Publications by authors named "Francesca Perego"

32 Publications

Lack of association between heart period variability asymmetry and respiratory sinus arrhythmia in healthy and chronic heart failure individuals.

PLoS One 2021 16;16(2):e0247145. Epub 2021 Feb 16.

Department of Cardiothoracic, Vascular Anesthesia and Intensive Care, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.

Temporal asymmetry is a peculiar aspect of heart period (HP) variability (HPV). HPV asymmetry (HPVA) is reduced with aging and pathology, but its origin is not fully elucidated. Given the impact of respiration on HPV resulting in the respiratory sinus arrhythmia (RSA) and the asymmetric shape of the respiratory pattern, a possible link between HPVA and RSA might be expected. In this study we tested the hypothesis that HPVA is significantly associated with RSA and asymmetry of the respiratory rhythm. We studied 42 middle-aged healthy (H) subjects, and 56 chronic heart failure (CHF) patients of whom 26 assigned to the New York Heart Association (NYHA) class II (CHF-II) and 30 to NYHA class III (CHF-III). Electrocardiogram and lung volume were monitored for 8 minutes during spontaneous breathing (SB) and controlled breathing (CB) at 15 breaths/minute. The ratio of inspiratory (INSP) to expiratory (EXP) phases, namely the I/E ratio, and RSA were calculated. HPVA was estimated as the percentage of negative HP variations, traditionally measured via the Porta's index (PI). Departures of PI from 50% indicated HPVA and its significance was tested via surrogate data. We found that RSA increased during CB and I/E ratio was smaller than 1 in all groups and experimental conditions. In H subjects the PI was about 50% during SB and it increased significantly during CB. In both CHF-II and CHF-III groups the PI was about 50% during SB and remained unmodified during CB. The PI was uncorrelated with RSA and I/E ratio regardless of the experimental condition and group. Pooling together data of different experimental conditions did not affect conclusions. Therefore, we conclude that the HPVA cannot be explained by RSA and/or I/E ratio, thus representing a peculiar feature of the cardiac control that can be aroused in middle-aged H individuals via CB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247145PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886158PMC
February 2021

A case of highly disabling orthostatic hypotension: when an integrated cardiac rehabilitation approach makes the difference.

G Ital Med Lav Ergon 2020 06;42(2):121-123

IRCCS, Istituti Clinici Scientifici Maugeri, Milano, Italy.

Summary: Orthostatic hypotension (OH) is a disabling condition accompanying several diseases. It has increased morbidity and mortality, and limited chances of treatment. We report a case of a patient with stable ischemic heart disease and severe OH unresponsive to usual care. A baseline 75° head-up tilt test (HUT) was positive for symptomatic OH, i.e. pre-syncope with a systolic arterial pressure drop of 35 mmHg. On top of optimal treatment, ivabradine was started. Symptoms improved within 24 hours. At a repeated HUT, the patient could tolerate the up-right position up to 25 minutes. He was able to undergo an individualized training program with further amelioration of quality of life. Thereafter, titration of ACE inhibitors became possible. Lasting benefits were present at a 6-month follow-up. To our knowledge, this is the first reported case of successful use of ivabradine to integrate cardiac rehabilitation for management of a highly disabling OH.
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June 2020

Pediatric angioedema: Essential features and preliminary results from the Hereditary Angioedema Global Registry in Italy.

Pediatr Allergy Immunol 2020 02;31 Suppl 24:22-24

ASST Fatebenefratelli Sacco, Milano, Italy.

Isolated angioedema, which is a localized, non-pitting, and transient swelling of the subcutaneous or submucosal tissue not associated with pruritus, urticaria, or anaphylaxis, may be classified, based on genetic pattern and mediators, respectively, as acquired or hereditary and histamine- or non-histamine-induced. The pediatric population with C1-INH-HAE (Hereditary angioedema due to C1-inhibitor deficiency) is mostly symptomatic. The frequency of symptoms in such a population compared to adults seems to be lower, but we need more prospective data to conclude on this point. The HGR (Hereditary angioedema global registry), which collects symptoms in real time, will probably provide such information. In terms of treatments, pediatric patients are significantly disadvantaged due to the few studies aimed at registering treatment for this population.
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http://dx.doi.org/10.1111/pai.13170DOI Listing
February 2020

Lanadelumab Injection Treatment For The Prevention Of Hereditary Angioedema (HAE): Design, Development And Place In Therapy.

Drug Des Devel Ther 2019 22;13:3635-3646. Epub 2019 Oct 22.

Department of Cure Subacute, Istituti Clinici Scientifici Maugeri, IRCCS, Milan, Italy.

Despite the efficacy of the on-demand treatment for the control of acute attacks of Hereditary Angioedema due to C1-Inhibitor Deficiency (C1-INH-HAE), the number and severity of attacks and the impairment in the quality of life of the affected patients have led to the development of a new monoclonal antibody, lanadelumab, directly addressed to the blockage of bradykinin, the principal mediator of vasodilation during angioedema attacks. It is indicated for the prophylactic treatment, it is easy to administer, highly effective and with known limited side effects. The current review summarizes the development of the drug, its clinical background and its perspectives.
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http://dx.doi.org/10.2147/DDDT.S192475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815761PMC
March 2020

Opioid Utilization and Perception of Pain Control in Hospitalized Patients: A Cross-Sectional Study of 11 Sites in 8 Countries.

J Hosp Med 2019 12 24;14(12):737-745. Epub 2019 Jul 24.

Department of Medicine, University of Colorado School of Medicine., Aurora, Colorado.

Background: Hospitalized patients are frequently treated with opioids for pain control, and receipt of opioids at hospital discharge may increase the risk of future chronic opioid use.

Objective: To compare inpatient analgesic prescribing patterns and patients' perception of pain control in the United States and non-US hospitals.

Design: Cross-sectional observational study.

Setting: Four hospitals in the US and seven in seven other countries.

Participants: Medical inpatients reporting pain.

Measurements: Opioid analgesics dispensed during the first 24-36 hours of hospitalization and at discharge; assessments and beliefs about pain.

Results: We acquired completed surveys for 981 patients, 503 of 719 patients in the US and 478 of 590 patients in other countries. After adjusting for confounding factors, we found that more US patients were given opioids during their hospitalization compared with patients in other countries, regardless of whether they did or did not report taking opioids prior to admission (92% vs 70% and 71% vs 41%, respectively; P < .05), and similar trends were seen for opioids prescribed at discharge. Patient satisfaction, beliefs, and expectations about pain control differed between patients in the US and other sites.

Limitations: Limited number of sites and patients/country.

Conclusions: In the hospitals we sampled, our data suggest that physicians in the US may prescribe opioids more frequently during patients' hospitalizations and at discharge than their colleagues in other countries, and patients have different beliefs and expectations about pain control. Efforts to curb the opioid epidemic likely need to include addressing inpatient analgesic prescribing practices and patients' expectations regarding pain control.
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http://dx.doi.org/10.12788/jhm.3256DOI Listing
December 2019

Current and emerging biologics for the treatment of hereditary angioedema.

Expert Opin Biol Ther 2019 06 26;19(6):517-526. Epub 2019 Mar 26.

b Department of Biomedical and Clinical Sciences Luigi Sacco , University of Milan , Milan , Italy.

Introduction: Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is a rare disease with unpredictable, self-limiting and localized swelling episodes involving the cutaneous and subcutaneous tissues. In the last decade, the spectrum of the possibilities to control the disease has considerably changed with the development of biologic therapies making necessary a careful evaluation of the differences among current and emerging treatments to properly optimize the management of patients.

Areas Covered: This review serves to summarize the literature regarding the use of biologics for the treatment of C1-INH-HAE. Medications already available on the market and new drugs in different phases of development are addressed.

Expert Opinion: The advent of biologic therapies dramatically improved the lives of patients with C1-INH-HAE although further improvement is still needed. Whether this is cost/effective will be answered in the next years when we will see if these major advances will benefit the majority of the patients.
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http://dx.doi.org/10.1080/14712598.2019.1595581DOI Listing
June 2019

Costs and effects of on-demand treatment of hereditary angioedema in Italy: a prospective cohort study of 167 patients.

BMJ Open 2018 07 30;8(7):e022291. Epub 2018 Jul 30.

Department of Biomedical and Clinical Sciences, "Luigi Sacco" University Hospital, University of Milan, Milan, Italy.

Objectives: To explore treatment behaviours in a cohort of Italian patients with hereditary angioedema due to complement C1-inhibitor deficiency (C1-INH-HAE), and to estimate how effects and costs of treating attacks in routine practice differed across available on-demand treatments.

Design: Cost analyses and survival analyses using attack-level data collected prospectively for 1 year.

Setting: National reference centre for C1-INH-HAE.

Participants: 167 patients with proved diagnosis of C1-INH-HAE, who reported data on angioedema attacks, including severity, localisation and duration, treatment received, and use of other healthcare services.

Interventions: Attacks were treated with either icatibant, plasma-derived C1-INH (pdC1-INH) or just supportive care.

Main Outcome Measures: Treatment efficacy in reducing attack duration and the direct costs of acute attacks.

Results: Overall, 133 of 167 patients (79.6%) reported 1508 attacks during the study period, with mean incidence of 11 attacks per patient per year. Only 78.9% of attacks were treated in contrast to current guidelines. Both icatibant and pdC1-INH significantly reduced attack duration compared with no treatment (median times from onset 7, 10 and 47 hours, respectively), but remission rates with icatibant were 31% faster compared with pdC1-INH (HR 1.31, 95% CI 1.14 to 1.51). However, observed treatment behaviours suggest patterns of suboptimal dosing for pdC1-INH. The average cost per attack was €1183 (SD €789) resulting in €1.58 million healthcare costs during the observation period (€11 912 per patient per year). Icatibant was 54% more expensive than pdC1-INH, whereas age, sex and prophylactic treatment were not associated to higher or lower costs.

Conclusions: Both icatibant and pdC1-INH significantly reduced attack duration compared with no treatment, however, icatibant was more effective but also more expensive. Treatment behaviours and suboptimal dosing of pdC1-INH may account for the differences, but further research is needed to define their role.
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http://dx.doi.org/10.1136/bmjopen-2018-022291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067408PMC
July 2018

Recurrent Retroperitoneal Angioedema.

J Allergy Clin Immunol Pract 2018 Jul - Aug;6(4):1384-1385. Epub 2018 May 3.

Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, ASST Fatebenefratelli-Sacco, Milan, Italy.

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http://dx.doi.org/10.1016/j.jaip.2018.04.019DOI Listing
November 2019

Hereditary angioedema: Assessing the hypothesis for underlying autonomic dysfunction.

PLoS One 2017 6;12(11):e0187110. Epub 2017 Nov 6.

Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.

Background: Attacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1-INH-HAE)are often triggered by stressful events/hormonal changes.

Objective: Our study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation.

Methods: Twenty-three HAE patients (6 males, mean age 47.5±11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3±10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10') and 75-degrees-head-up tilt (10'). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively.

Results: HAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls. At rest HAE patients showed higher noradrenaline values (301.4±132.9 pg/ml vs 210.5±89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 ± 7.5% after T vs 47.1 ± 7.8% at R, p = 0.01).

Conclusions: Our data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187110PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673184PMC
November 2017

Hemispheric language organization after congenital left brain lesions: A comparison between functional transcranial Doppler and functional MRI.

J Neuropsychol 2019 03 31;13(1):46-66. Epub 2017 May 31.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy.

This study investigated whether functional transcranial Doppler ultrasound (fTCD) is a suitable tool for studying hemispheric lateralization of language in patients with pre-perinatal left hemisphere (LH) lesions and right hemiparesis. Eighteen left-hemisphere-damaged children and young adults and 18 healthy controls were assessed by fTCD and fMRI to evaluate hemispheric activation during two language tasks: a fTCD animation description task and a fMRI covert rhyme generation task. Lateralization indices (LIs), measured by the two methods, differed significantly between the two groups, for a clear LH dominance in healthy participants and a prevalent activation of right hemisphere in more than 80% of brain-damaged patients. Distribution of participants in terms of left, right, and bilateral lateralization was highly concordant between fTCD and fMRI values. Moreover, right hemisphere language dominance in patients with left hemispheric lesions was significantly associated with severity of cortical and subcortical damage in LH. This study suggests that fTCD is an easily applicable tool that might be a valid alternative to fMRI for large-scale studies of patients with congenital brain lesions.
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http://dx.doi.org/10.1111/jnp.12128DOI Listing
March 2019

Diagnosis, Course, and Management of Angioedema in Patients With Acquired C1-Inhibitor Deficiency.

J Allergy Clin Immunol Pract 2017 Sep - Oct;5(5):1307-1313. Epub 2017 Mar 9.

Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy; ASST Fatebenefratelli Sacco, Milan, Italy.

Background: Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease with no prevalence data or approved therapies.

Objective: To report data on patients with C1-INH-AAE followed at Angioedema Center, Milan (from 1976 to 2015).

Methods: Diagnostic criteria included history of recurrent angioedema without wheals; decreased C1-INH antigen levels and/or functional activity of C1-INH and C4 antigen less than 50% of normal; late symptom onset (>40 years); no family history of angioedema and C1-INH deficiency.

Results: In total, 77 patients (58% females; median age, 70 years) were diagnosed with C1-INH-AAE and 675 patients with hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) (1 patient with C1-INH-AAE/8.8 patients with C1-INH-HAE). Median age at diagnosis was 64 years. Median time between symptom onset and diagnosis was 2 years. Sixteen patients (21%) died since diagnosis, including 1 because of laryngeal edema. Angioedema of the face was most common (N = 63 [82%]), followed by abdomen (N = 51 [66%]), peripheries (N = 50 [65%]), and oral mucosa and/or glottis (N = 42 [55%]). Forty-eight of 71 patients (68%) had autoantibodies to C1-INH. In total, 56 patients (70%) used on-demand treatment for angioedema including intravenous pdC1-INH 2000 U (Berinert, CSL Behring, Marburg, Germany) (N = 49) and/or subcutaneous icatibant 30 mg (Firazyr, Shire; Milano, Italy) (N = 27). Eventually, 8 of 49 patients receiving pdC1-INH became nonresponsive; all had autoantibodies. Thirty-four patients received long-term prophylaxis with tranexamic acid (effective in 29) and 20 with androgens (effective in 8).

Conclusions: The incidence of C1-INH-AAE was 1 for every 8.8 patients with C1-INH-HAE. Thirty percent of the deaths were related to the disease. Treatments approved for C1-INH-HAE are effective in C1-INH-AAE, although with minimal differences.
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http://dx.doi.org/10.1016/j.jaip.2016.12.032DOI Listing
May 2018

Angioedema Phenotypes: Disease Expression and Classification.

Clin Rev Allergy Immunol 2016 Oct;51(2):162-9

Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Luigi Sacco Hospital, Milan, Italy.

Due to marked heterogeneity of clinical presentations, comprehensive knowledge of angioedema phenotypes is crucial for correct diagnosis and choosing the appropriate therapeutic approach. One of the ways to a meaningful clinical distinction can be made between forms of angioedema occurring "with or without wheals." Angioedema with wheals (rash) is a hallmark of urticaria, either acute or chronic, spontaneous or inducible. Angioedema without wheals may still be manifested in about 10 % of patients with urticaria, but it may also occur as a separate entity. Several classifications of angioedema as part of urticaria were published over time, while a latest one, released in 2014 (HAWK group consensus, see below), provided a classification of all forms of "angioedema without wheals" distinct from urticaria, which will be the focus of the present review. At this time, the HAWK consensus classification is the best in terms of covering the pathophysiology, mediators involved, angioedema triggers, and clinical expression. According to this classification, three types of hereditary angioedema (genetic C1-INH deficiency, normal C1-INH with factor XII mutations, and unknown origin) and four types of acquired angioedema (C1-INH deficiency, related to ACE inhibitors intake, idiopathic histaminergic, and idiopathic non-histaminergic) are presented. We will review the distinctive clinical features of each phenotype in details.
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http://dx.doi.org/10.1007/s12016-016-8541-zDOI Listing
October 2016

Is dual RAAS blockade useful in diabetic nephropathy?

Intern Emerg Med 2014 Aug 21;9(5):589-91. Epub 2014 May 21.

Division of Medicine, Department of Biomedical and Clinical Sciences "L. Sacco", L. Sacco Hospital, University of Milan, via GB Grassi, 74, 20157, Milan, Italy,

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http://dx.doi.org/10.1007/s11739-014-1075-6DOI Listing
August 2014

Effects of high-amount-high-intensity exercise on in vivo platelet activation: modulation by lipid peroxidation and AGE/RAGE axis.

Thromb Haemost 2013 Dec 12;110(6):1232-40. Epub 2013 Sep 12.

Giovanni Davì, Center of Excellence on Aging, "G. D'Annunzio" University Foundation, Via Colle dell'Ara, 66013 Chieti, Italy, Tel.: +39 0871 541312, Fax: +39 0871 541261, E-mail:

Physical activity is associated with cardiovascular risk reduction, but the effects of exercise on platelet activation remain controversial. We investigated the effects of regular high-amount, high intensity aerobic exercise on in vivo thromboxane (TX)-dependent platelet activation and plasma levels of platelet-derived proteins, CD40L and P-selectin, and whether platelet variables changes may be related to changes in high-density lipoprotein (HDL) and in the extent of oxidative stress and oxidative stress-related inflammation, as reflected by urinary isoprostane excretion and endogenous soluble receptor for advanced glycation end-products (esRAGE), respectively. Urinary excretion of 11-dehydro-TXB₂ and 8-iso-prostaglandin (PG)F(2α) and plasma levels of P-selectin, CD40L and esRAGE were measured before and after a eight-week standardised aerobic high-amount-high-intensity training program in 22 sedentary subjects with low-to-intermediate risk. Exercise training had a clear beneficial effect on HDL cholesterol (+10%, p=0.027) and triglyceride (-27%, p=0.008) concentration. In addition, a significant (p<0.0001) decrease in urinary 11-dehydro-TXB₂ (26%), 8-iso-PGF(2α) (21%), plasma P-selectin (27%), CD40L (35%) and a 61% increase in esRAGE were observed. Multiple regression analysis revealed that urinary 8-iso-PGF(2α) [beta=0.33, SEM=0.116, p=0.027] and esRAGE (beta=-0.30, SEM=31.3, p=0.046) were the only significant predictors of urinary 11-dehydro-TXB₂ excretion rate over the training period. In conclusion, regular high-amount-high-intensity exercise training has broad beneficial effects on platelet activation markers, paralleled and possibly associated with changes in the lipoprotein profile and in markers of lipid peroxidation and AGE/RAGE axis. Our findings may help explaining why a similar amount of exercise exerts significant benefits in preventing cardiovascular events.
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http://dx.doi.org/10.1160/TH13-04-0295DOI Listing
December 2013

Is coronary CT angiography useful in diagnosing acute coronary syndromes in the Emergency Department?

Intern Emerg Med 2013 Jun 27;8(4):345-6. Epub 2013 Mar 27.

Clinica Medica, Medicina 4, Humanitas Clinical and Research Center, Via Manzoni, 56, Rozzano, Milan, 20089, Italy.

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http://dx.doi.org/10.1007/s11739-013-0931-0DOI Listing
June 2013

Aspirin for the primary prevention of cardiovascular diseases.

Intern Emerg Med 2012 Aug 6;7(4):375-9. Epub 2012 Jun 6.

Scuola di Specializzazione in Igiene e Medicina Preventiva, Università degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.1007/s11739-012-0791-zDOI Listing
August 2012

Why meta-analyses on the same topic lead to different conclusions?

Intern Emerg Med 2012 Aug 25;7(4):381-3. Epub 2012 May 25.

Dipartimento di Medicina, Medicina Interna III, Università degli Studi di Milano, Ospedale L. Sacco, Milan, Italy.

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http://dx.doi.org/10.1007/s11739-012-0792-yDOI Listing
August 2012

Does a lower diagnostic threshold of sensitive plasma troponin I assay improve clinical outcomes of patients with chest pain?

Intern Emerg Med 2011 Dec 1;6(6):559-60. Epub 2011 Nov 1.

Medicina III, Luigi Sacco Hospital, University of Milan, via G.B. Grassi 74, 20154 Milan, Italy.

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http://dx.doi.org/10.1007/s11739-011-0718-0DOI Listing
December 2011

Influence of climate on emergency department visits for syncope: role of air temperature variability.

PLoS One 2011 27;6(7):e22719. Epub 2011 Jul 27.

Emergency Department, Vimercate Hospital, Vimercate, Milan, Italy.

Background: Syncope is a clinical event characterized by a transient loss of consciousness, estimated to affect 6.2/1000 person-years, resulting in remarkable health care and social costs. Human pathophysiology suggests that heat may promote syncope during standing. We tested the hypothesis that the increase of air temperatures from January to July would be accompanied by an increased rate of syncope resulting in a higher frequency of Emergency Department (ED) visits. We also evaluated the role of maximal temperature variability in affecting ED visits for syncope.

Methodology/principal Findings: We included 770 of 2775 consecutive subjects who were seen for syncope at four EDs between January and July 2004. This period was subdivided into three epochs of similar length: 23 January-31 March, 1 April-31 May and 1 June-31 July. Spectral techniques were used to analyze oscillatory components of day by day maximal temperature and syncope variability and assess their linear relationship. There was no correlation between daily maximum temperatures and number of syncope. ED visits for syncope were lower in June and July when maximal temperature variability declined although the maximal temperatures themselves were higher. Frequency analysis of day by day maximal temperature variability showed a major non-random fluctuation characterized by a ∼23-day period and two minor oscillations with ∼3- and ∼7-day periods. This latter oscillation was correlated with a similar ∼7-day fluctuation in ED visits for syncope.

Conclusions/significance: We conclude that ED visits for syncope were not predicted by daily maximal temperature but were associated with increased temperature variability. A ∼7-day rhythm characterized both maximal temperatures and ED visits for syncope variability suggesting that climate changes may have a significant effect on the mode of syncope occurrence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022719PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144938PMC
December 2011

Target organ damage in a population at intermediate cardiovascular risk, with adjunctive major risk factors: CArdiovascular PREvention Sacco Study (CAPRESS).

Intern Emerg Med 2011 Aug 17;6(4):337-47. Epub 2010 Dec 17.

Department of Internal Medicine, Luigi Sacco Hospital, University of Milan, via G.B. Grassi 74, 20157, Milan, Italy.

The objective of the study is to assess the prevalence of target organ damage (TOD) at carotid, cardiac, renal and peripheral vascular levels in a population at intermediate cardiovascular risk, with adjunctive major risk factors (AMRF). From March 2007 to July 2009 we examined 979 subjects at intermediate cardiovascular risk, as indicated by the Italian algorithm "Progetto Cuore"; the patients were aged 40-69 years, sensitized by one or more AMRF such as family history for cardiovascular disease (CVD), being overweight or obese, and smoking habit (more than 10 cigarettes/day). We measured common carotid intima-media thickness (cc-IMT) and plaque at any level, left ventricular mass index (LVMI), urine albumin/creatinine ratio (UACR), and ankle-brachial index (ABI). The prevalence of at least one TOD was 63% (617 subjects), cc-IMT was high in 48.2% (472), UACR abnormal in 14.1% (138), LVMI high in 12.6% (117) and ABI pathological in 9.1% (89). In those with carotid damage 423 had a plaque, amounting to 43.2% of the total population. Of note, carotid damage was present in all subjects with 3 TODs, and in 92% of subjects with 2 TODs. A multivariate logistic regression model including conventional factors and AMRF indicated that age 50-69 years, systolic blood pressure, relevant smoking and CV risk score ≥15 were independently and significantly associated with at least one TOD, and at least, with carotid damage. Among the AMRF, peripheral arterial disease was associated with relevant smoking, with an odds ratio (OR) of 3 [confidence interval (CI) 1.80-4.97, p < 0.0001]; overweight and obesity both had selective associations with cardiac damage with OR 2.75 (CI 1.2-6.3, p < 0.01) and OR 3.89 (CI 1.61-9.73, p < 0.01). A substantial proportion of people at intermediate risk, with at least one AMRF have at least one TOD, a major predictor of cardiovascular outcomes.
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http://dx.doi.org/10.1007/s11739-010-0501-7DOI Listing
August 2011

San Francisco Syncope Rule, Osservatorio Epidemiologico sulla Sincope nel Lazio risk score, and clinical judgment in the assessment of short-term outcome of syncope.

Am J Emerg Med 2010 May 28;28(4):432-9. Epub 2010 Jan 28.

Unità Sincopi, Medicina Interna II, Ospedale L. Sacco, Università degli Studi di Milano, 20157 Milano, Italy.

Objective: The study aimed to compare the efficacy of the Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) risk score, San Francisco Syncope Rule, and clinical judgment in assessing the short-term prognosis of syncope.

Methods: We studied 488 patients consecutively seen for syncope at the emergency department of 2 general hospitals between January and July 2004. Sensitivity, specificity, predictive values, and likelihood ratios for short-term (within 10 days) severe outcomes were computed for each decision rule and clinical judgment. Severe outcomes comprised death, major therapeutic procedures, and early readmission to hospital.

Results: Clinical judgment had a sensitivity of 77%, a specificity of 69%, and would have admitted less patients (34%, P < .05 vs decision rules). The OESIL risk score was characterized by a sensitivity of 88% and a specificity of 60% (admission 43%). San Francisco Syncope Rule sensitivity was 81% and specificity was 63% (admission 40%). According to both clinical rules, no discharged patient would have died. With combined OESIL risk score and clinical judgment, the probability of adverse events was 0.7% for patients with both low risk scores, whereas that for both high risk scores was roughly 16%.

Conclusion: Because of a relatively low sensitivity, both risk scores were partially lacking in recognizing patients with short-term high-risk syncope. However, the application of the decision rules would have identified all patients who subsequently died, and OESIL risk score and clinical judgment combined seem to improve the decision-making process concerning the identification of high-risk patients who deserve admission.
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http://dx.doi.org/10.1016/j.ajem.2008.12.039DOI Listing
May 2010

Short- and long-term prognosis of syncope, risk factors, and role of hospital admission: results from the STePS (Short-Term Prognosis of Syncope) study.

J Am Coll Cardiol 2008 Jan;51(3):276-83

Syncope Unit, Internal Medicine II, L. Sacco Hospital, University of Milan, Milan, Italy.

Objective: We sought to assess short- and long-term prognosis of syncope and associated risk factors.

Background: Syncope is a common clinical event, but our knowledge of its short-term outcome is largely incomplete. Further, it is unknown whether hospital admission might positively affect a patient's syncope prognosis.

Methods: We screened 2,775 consecutive subjects who presented for syncope at 4 emergency departments between January and July 2004. Short- and long-term severe outcomes (i.e., death and major therapeutic procedures) and related risk factors were compared in all enrolled patients arrayed according to hospital admission or discharge.

Results: A total of 676 subjects were included in the study. Forty-one subjects (6.1%) experienced severe outcomes (5 deaths, 0.7%; 36 major therapeutic procedures, 5.4%) in the 10 days after presentation. An abnormal electrocardiogram, concomitant trauma, absence of symptoms of impending syncope, and male gender were associated with short-term unfavorable outcomes. Long-term severe outcomes were 9.3% (40 deaths, 6.0%; 22 major therapeutic procedures, 3.3%), and their occurrence was correlated with an age >65 years, history of neoplasms, cerebrovascular diseases, structural heart diseases, and ventricular arrhythmias. Short-term major therapeutic procedures were more common (p < 0.05) in subjects who had been admitted to hospital (13.3%) than in discharged (1.6%), whereas mortality was similar. One-year mortality was greater (p < 0.05) in admitted (14.7%) than in discharged (1.8%) patients.

Conclusions: Risk factors for short- and long-term adverse outcomes after syncope differed. Hospital admission favorably influenced syncope short term prognosis. Instead, 1-year mortality was unaffected by hospital admission and related to comorbidity.
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http://dx.doi.org/10.1016/j.jacc.2007.08.059DOI Listing
January 2008

Early abnormalities of vascular and cardiac autonomic control in Parkinson's disease without orthostatic hypotension.

Hypertension 2007 Jan 13;49(1):120-6. Epub 2006 Nov 13.

Medicina Interna II, Ospedale L. Sacco, Università degli Studi di Milano, Milan, Italy.

Cardiac autonomic abnormalities have been described in Parkinson's disease. Little is known about possible alterations of vascular sympathetic regulatory activity in patients without orthostatic hypotension or symptoms of orthostatic intolerance. Nineteen patients with Parkinson's disease without orthostatic hypotension (PD), 21 with orthostatic hypotension (PDOH), and 20 healthy controls underwent ECG, beat-to-beat arterial pressure, and respiration recordings while recumbent and during a 75 degrees head-up tilt. Spectrum analysis of RR interval and systolic arterial pressure (SAP) variability provided indices of cardiac sympathovagal interaction (low frequency [LF]/high frequency [HF]) to the sinoatrial node and sympathetic vasomotor control (LF(SAP)). Arterial baroreceptor mechanisms were assessed by the spontaneous sequences technique and bivariate spectrum analysis (alpha index). Plasma catecholamines provided the neurohormonal profile. At rest, hemodynamics and spectral markers of autonomic function were similar in PD and control subjects. Norepinephrine was lower in PD and PDOH than in control subjects. In PDOH, SAP was higher, whereas LF/HF ratio and LF(SAP) were lower compared with control subjects. During tilt, SAP was unchanged in PD; however, similar to PDOH, the increase of heart rate, LF/HF ratio, and LF(SAP) was blunted compared with control subjects. Baroreflex indices were unmodified in PD and PDOH compared with control subjects. Initial alterations in both cardiac and vascular sympathetic modulatory activity were found in PD and revealed by a gravitational stimulus. Prompt recognition of sympathetic abnormalities might result in earlier therapeutic intervention, reduced orthostatic intolerance, and increased quality of life.
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http://dx.doi.org/10.1161/01.HYP.0000250939.71343.7cDOI Listing
January 2007

Abnormalities of cardiovascular neural control and reduced orthostatic tolerance in patients with primary fibromyalgia.

J Rheumatol 2005 Sep;32(9):1787-93

Department of Internal Medicine II, Ospedale L. Sacco, Università degli Studi di Milano, Milano, Italy.

Objective: Fibromyalgia (FM) is a syndrome characterized by widespread musculoskeletal pain. Symptoms of orthostatic intolerance may also be present, suggesting underlying abnormalities of cardiovascular neural regulation. We tested the hypothesis that FM is characterized by sympathetic overactivity and alterations in cardiovascular autonomic response to gravitational stimulus.

Methods: Sixteen patients with primary FM and 16 healthy controls underwent electrocardiography examination, finger blood pressure, respiration, and muscle sympathetic nerve activity (MSNA) recordings at rest and during stepwise tilt test, up to 75 degrees . The autonomic profile was assessed by MSNA, plasma catecholamine, and spectral indices of cardiac sympathetic (LFRR in normalized units, NU) and vagal (HFRR both in absolute and NU) modulation and of sympathetic vasomotor control (LFSAP) computed by spectrum analysis of RR and systolic arterial pressure (SAP) variability. Arterial baroreflex function was evaluated by the SAP/RR spontaneous-sequences technique, the index a, and the gain of MSNA/diastolic pressure relationship during stepwise tilt test.

Results: At rest, patients showed higher values of heart rate, MSNA, LFRR NU, LF/HF, LFSAP, and reduced HFRR than controls. During tilt test, lack of increase of MSNA, less decrease of HFRR, and excessive rate (44%) of syncope were found in patients, suggesting reduced capability to enhance the sympathetic activity to vessels and withdraw the vagal modulation to sino-atrial node. Baroreflex function was similar in both groups.

Conclusion: Patients with FM have an overall enhancement of cardiovascular sympathetic activity while recumbent. Lack of increased sympathetic discharge to vessels and decreased cardiac vagal activity characterize their autonomic profile during tilt test, and might account for the excessive rate of syncope.
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September 2005

Sympathetic overactivity in active ulcerative colitis: effects of clonidine.

Am J Physiol Regul Integr Comp Physiol 2006 Jan 25;290(1):R224-32. Epub 2005 Aug 25.

Unità Sincopi e Disturbi della Postura, Medicina Interna II, Ospedale L. Sacco, Università di Milano, Via G.B. Grassi 74, 20157 Milano, Italy.

Previous reports suggest that inflammatory bowel diseases may be accompanied by abnormalities in the neural autonomic profile. We tested the hypotheses that 1) an exaggerated sympathetic activity characterizes active ulcerative colitis (UC) and 2) a reduction of sympathetic activity by clonidine would be associated with clinical changes of UC. In 23 patients with UC and 20 controls, muscle sympathetic nerve activity (MSNA), ECG, blood pressure, and respiration were continuously recorded, and plasma catecholamine was evaluated both at rest and during a 75 degrees head-up tilt. Autonomic profile was assessed by MSNA, norepinephrine, epinephrine, spectral markers of low-frequency (LF) cardiac sympathetic (LF(RR); normalized units) and high-frequency (HF) parasympathetic (HF(RR); normalized units) modulation and sympathetic vasomotor control (LF systolic arterial pressure; LF(SAP)), obtained by spectrum analysis of the R-R interval and systolic pressure variability. Among UC patients, 16 agreed to be randomly assigned to 8-wk transdermal clonidine (15 mg/wk, 9 subjects), or placebo (7 patients). An autonomic profile, Disease Activity Index (DAI), and endoscopic pattern were compared before and after clonidine/placebo. At rest, MSNA, heart rate (HR), LF(RR), LF/HF, and LF(SAP) were higher and HF(RR) was lower in patients than in controls. Tilt decreased HF(RR) and increased MSNA and LF(RR) less in patients than in controls. Clonidine decreased HR, MSNA, epinephrine, LF(RR), and increased HF(RR), whereas placebo had no effects. Changes of the autonomic profile after clonidine were associated with reduction of DAI score. An overall increase of sympathetic activity characterized active UC. Normalization of the autonomic profile by clonidine was accompanied by an improvement of the disease.
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http://dx.doi.org/10.1152/ajpregu.00442.2005DOI Listing
January 2006