Mission & Aims

The Istituto di Ricerche Farmacologiche “Mario Negri” (IRFMN) is a not-for-profit biomedical research organization. It was founded in 1961 and started work in Milan, Italy, in 1963. There are now research units in Bergamo and near Chieti, Italy. The Institute‘s research programs span from the molecular level to the whole human being, and the findings help build up the basis for developing new therapeutic approaches and drugs, and making existing ones more effective. The main research themes are the battle against cardiovascular diseases, cancer, nervous and mental illnesses, kidney and rare diseases and the toxic effects of environmental contaminants, mother and child‘s health.

The Laboratory of Cardiopulmonary Pathophysiology is within the Department of Cardiovascular Research at IRFMN. The areas of interest of the Department of Cardiovascular Research include the experimental, clinical, genetic, epidemiological aspects of cardiovascular diseases (acute myocardial infarction, heart failure, cardiac arrest and cardiopulmonary resuscitation, cardiac arrhythmias, diabetes) as well as the clinical and epidemiological investigation of cardiovascular prevention, hypertension and stroke. The activity in clinical research includes the clinical assessment of therapeutic strategies and of phenotypic and genetic biomarkers of cardiovascular risk with large scale clinical trials in the field of acute coronary syndromes, heart failure and atrial fibrillation and the genetic epidemiology of myocardial infarction and heart failure.

The Department of Cardiovascular research of the Mario Negri Institute for Pharmacological Research has a recognized expertise in several fields:

  1. design, management, coordination and monitoring of large-scale, national and international, phases II and III, randomized clinical trials (i.e. GISSI trials);
  2. design and coordination of biological substudies and biobanking facilities in large-scale clinical studies; clinical evaluation of genotypic and phenotypic biomarkers;
  3. statistical expertise in the planning and analysis of clinical trials, genetics of association studies, and biomarkers;
  4. design and management of experimental studies in small and large animals in the field of myocardial infarction and cardiac arrest.



Relevant Publications

  • Ristagno G, Mauri T, Cesana G, Li Y, Finzi A, Fumagalli F, Rossi G, Grieco N, Migliori M, Andreassi A, Latini R, Fornari C, Pesenti A; Azienda Regionale Emergenza Urgenza (AREU) Research Group. Amplitude Spectrum Area to Guide Defibrillation: A Validation on 1617 Ventricular Fibrillation Patients. Circulation 2015;131(5):478-87 Link: https://www.ncbi.nlm.nih.gov/pubmed/25466976

Summary: This study sought to validate the ability of amplitude spectrum area (AMSA) to predict defibrillation success and long-term survival in a large population of out-of-hospital cardiac arrests. ECGs recorded by automated external defibrillators from different manufacturers were obtained from patients with cardiac arrests occurring in 8 city areas. A database, including 2447 defibrillations from 1050 patients, was used as the derivation group, and an additional database, including 1381 defibrillations from 567 patients, served as validation. A 2-second ECG window before defibrillation was analyzed, and AMSA was calculated. Among the 2447 defibrillations of the derivation database, 26.2% were successful. AMSA was significantly higher before a successful defibrillation than a failing one (13 ± 5 versus 6.8 ± 3.5 mV-Hz) and was an independent predictor of defibrillation success (odds ratio, 1.33; 95% confidence interval, 1.20-1.37) and sustained return of spontaneous circulation (odds ratio, 1.22; 95% confidence interval, 1.17-1.26). Area under the receiver operating characteristic curve for defibrillation success prediction was 0.86 (95% confidence interval, 0.85-0.88). AMSA was also significantly associated with long-term survival. The following AMSA thresholds were identified: 15.5 mV-Hz for defibrillation success and 6.5 mV-Hz for defibrillation failure. In the validation database, AMSA ≥ 15.5 mV-Hz had a positive predictive value of 84%, whereas AMSA ≤ 6.5 mV-Hz had a negative predictive value of 98%. In this large derivation-validation study, AMSA was validated as an accurate predictor of defibrillation success. AMSA also appeared as a predictor of long-term survival.

  • Ristagno G, Latini R, Vaahersalo J, Masson S, Kurola J, Varpula T, Lucchetti J, Fracasso C, Guiso G, Montanelli A, Barlera S, Gobbi M, Tiainen M, Pettilä V, Skrifvars MB; FINNRESUSCI Investigators. Early Activation of the Kynurenine Pathway Predicts Early Death and Long-term Outcome in Patients Resuscitated From Out-of-Hospital Cardiac Arrest. J Am Heart Assoc. 2014 Aug 4;3(4). pii: e001094 Link: https://www.ncbi.nlm.nih.gov/pubmed/25092787

Summary: The kynurenine pathway (KP) is the major route of tryptophan (TRP) catabolism and is activated by inflammation and after cardiac arrest in animals. We hypothesized that the KP activation level correlates with severity of post-cardiac arrest shock, early death, and long-term outcome. Plasma was obtained from 245 patients enrolled in a prospective multicenter observational study in 21 intensive care units in Finland. Time to return of spontaneous circulation, lowest systolic arterial pressure, and bicarbonate during the first 24 hours were collected. A cerebral performance category of 3 to 5 defined 12-month poor outcome. Plasma TRP and KP metabolites, kynurenine (KYN), kynurenic acid, 3-hydroxyanthranilic acid, and the ratio of KYN to TRP were measured by liquid chromatography and mass spectrometry. All KP metabolites at intensive care unit admission were significantly higher in cardiac arrest patients with a nonshockable rhythm compared to those with a shockable rhythm, and kynurenic acid and 3-hydroxyanthranilic acid correlated with time to return of spontaneous circulation. Patients with higher levels of KYN, KYN to TRP, kynurenic acid, and 3-hydroxyanthranilic acid had lower 24-hour systolic arterial pressure and bicarbonate. All KP metabolites and the ratio of KYN to TRP, but not TRP, were significantly higher in patients who died in the intensive care unit in comparison to those who survived. Multivariable logistic regression showed that high kynurenic acid (odds ratio: 1.004; 95% confidence interval: 1.001 to 1.008; P=0.014), and 3-hydroxyanthranilic acid (odds ratio: 1.011; 95% confidence interval: 1.001 to 1.022; P=0.03) were independently associated with 12-month poor outcome and significantly improved risk reclassification.

  • Ristagno G, Li Y, Fumagalli F, Finzi A, Quan W. Amplitude spectrum area to guide resuscitation – A retrospective analysis during out-of-hospital cardiopulmonary resuscitation in 609 patients with ventricular fibrillation cardiac arrest. Resuscitation 2013; 84(12):1697-703 Link: https://www.ncbi.nlm.nih.gov/pubmed/24005007

Summary: The capability of amplitude spectrum area (AMSA) to predict the success of defibrillation (DF) was retrospectively evaluated in a large database of out-of-hospital cardiac arrests. Electrocardiographic data, including 1260 DFs, were obtained from 609 cardiac arrest patients due to ventricular fibrillation. AMSA sensitivity, specificity, accuracy, and positive and negative predictive values (PPV, NPV) for predicting DF success were calculated, together with receiver operating characteristic (ROC) curves. In 303 patients with chest compression (CC) depth data collected with an accelerometer, changes in AMSA were analyzed in relationship to CC depth. AMSA was significantly higher prior to a successful DF than prior to an unsuccessful DF (15.6±0.6 vs. 7.97±0.2mV-Hz, p<0.0001). Intersection of sensitivity, specificity and accuracy curves identified a threshold AMSA of 10mV-Hz to predict DF success with a balanced sensitivity, specificity and accuracy of almost 80%. Higher AMSA thresholds were associated with further increases in accuracy, specificity and PPV. AMSA of 17mV-Hz predicted DF success in two third of instances (PPV of 67%). Low AMSA, instead, predicted unsuccessful DFs with high sensitivity and NPV >97%. Area under the ROC curve was 0.84. CC depth affected AMSA value. When depth was <1.75in., AMSA decreased for consecutive DFs, while it increased when the depth was >1.75in. (p<0.05).