5. MAIN ONGOING RESEARCH ACTIVITIES AND PROJECTS
- 5.1. Experimental Research
Cardiac Remodelling after myocardial infarction (AMI)
AMI causes progressive changes in left ventricular shape and structure, called remodelling, which eventually lead to heart failure. The effects of drugs (e.g. ACE-inhibitors, angiotensin receptor antagonists, nitrates, beta-blockers) on left ventricular remodelling are studied in an experimental model of AMI in the rat.
Reference persons: R. Latini
Ageing and Cardiac Remodelling
Ageing impairs the cardiovascular adaptations to hemodynamic stress. Studies are aimed at investigating the specific response of the senescent heart to hormonal or mechanical stress in terms of gene expression, heart structure and function and pharmacological interventions.
Reference persons: R. Latini, S. Masson
Dopaminergic agonist in rats with heart failure and renovascular hypertension
The effects of an agonist of dopamine type II receptors, CHF-1024, are studied in rat models of post-AMI congestive heart failure and renovascular hypertension induced by abdominal aortic coarctation. The drug should modulate neuroendocrine responses to these stresses (e.g. increased secretion of catecholamines and aldosterone), which have a role in the development of heart failure and ventricular remodelling.
Reference persons: R. Latini, S. Masson
Testing new agents modulating cytokine activity in heart ischemia/reperfusion
During ischemia/reperfusion migration of polymorphonuclear cells occurs mainly over the first 24-48 hours; PMN migration seems to be positively correlated to necrotic damage, possibly mediated by release by PMN of lytic enzymes and cytokines. While antiinflammatory agents have been shown to decrease ischemic damage in the experimental animal, the effects in humans with myocardial infarction were not encouraging. Therefore, a more specific strategy based on inhibition of individual cytokines like IL-8 for example, might be attempted. The aim is to decrease ischemia/reperfusion damage without depressing reparatory processes leading to collagen deposition in place of dead myocytes. After in vitro screening, new agents are tested first in a model of subcutaneous air bubble in mouse, then in our model of ischemia/reperfusion in the rat. In order to study longterm consequences of treatments, open chest rats are ventilated by tracheal intubation, tube is pulled out as soon as reperfusion is started and the animal can be weaned from the ventilator.
In collaboration with the Department of Immunology and Cell Biology (S. Sozzani, M. Romano).
Reference persons: L. Calvillo, R. Latini
Cardiotoxicity of doxorubicin-taxol association
Taxol has shown to improve therapeutic efficacy of doxorubicin in breast and ovarian cancer, but little is known on cardiac effects of the combination of the two agents. While doxorubicin is a well known cardiotoxic drug, it is not known whether cardiomyocytes die only for necrosis or also for apoptosis (as it has been shown in primary cultures in vitro). In vivo experiments in the mouse are performed in order to answer these two questions. Mice are repeatedly treated with iv doxorubicin and/or taxol and their hearts are studied by light and electron microscopy.
In collaboration with the Department of Oncology (M. D'Incalci, T. Colombo)
Reference persons: S. Chimenti, R. Latini
Acute phase protein, PTX3, in myocardial infarction
PTX3, a protein of the pentraxin family, is found to peak 6-12 hours after AMI in humans. Research is aimed at finding the site of PTX3 production in mouse heart with experimental AMI by immunoistochemical methods. Moreover, the relation between PTX3 plasma concentrations in AMI patients and their prognosis will be investigated.
In collaboration with the Department of Immunologly and Cell Biology (G. Peri, A. Mantovani).
Reference persons: R. Latini
- 5.2. Clinical Pharmacology
Therapeutic Drug Monitoring
Antiarrhythmic drug concentrations are measured in the plasma of patients. This monitoring service is offered to cardiologists in selected cases upon request, and to document patient compliance in clinical trials.
Plasma concentrations of other cardiovascular drugs are measured in biological fluids with special reference to pharmacokinetic and bioequivalence studies.
Reference persons: R. Bernasconi, R. Latini
The results of the GISSI-3 trial indicate some potentiation of the lisinopril beneficial effects by the addition of nitroglycerin. The possibility of an interaction between ACE-inhibitors and nitrates is studied both in the GISSI-3 data base (sub-analysis) and in an ad hoc trial, DRAMI (Delapril and Remodelling in Acute Myocardial Infarction), scheduled to close recruitment by March 1999.
Reference persons: R. Latini, A.P. Maggioni, L. Staszewsky
Drug utilization studies
Analysis of drug prescription patterns in patients with cardiovascular diseases to monitor the trends of therapeutic choices according to different variables (clinical, pharmacological, economic). These analyses are conducted within different trials (GISSI, PPP) during the in- hospital phase, after discharge and in primary care settings.
Reference persons: F. Avanzini, C. Roncaglioni
- 5.3. Controlled Clinical Studies
Core laboratory for the assay of neurohormones in heart failure
The relevance of some endogenous molecules (norepinephrine, brain natriuretic peptide, aldosterone, endothelin, renin) for the diagnosis and prognosis of patients with heart failure, and the technical difficulty in reliably assaying them in plasma are the rationale for creating a reference Laboratory. This lab offers assays of neurohormones to clinical centers enrolling patients in clinical trials or in observational studies. At present, the core lab is involved in an international mortality trial (Val-HeFT) and in an observational study (ANMCO data base) on heart failure.
Reference persons: R. Latini, S. Masson.
Echocardiographic core laboratory
Echocardiography is the non invasive technique more widely used for assessing heart size and function in clinical practice and in trials. In order to standardize measurements to allow high quality data a central laboratory has been created, which reads echo exams performed peripherally and gives advice on how to improve echo execution to participating centers.
Echo exams are digitized and analyzed by the use of an ad-hoc made software.
The echo core lab is now involved in 2 clinical trials: a mortality trial (Val-HeFT) in heart failure and a smaller trial in myocardial infarction (DRAMI).
Reference persons: L. Staszewsky, A. Volpi
- 5.4. Large Scale Clinical Trials
A secondary prevention study started in late 1993, with a two-step protocol: an early randomization (R1) according to a factorial design to antioxidant (Vit. E) and unsaturated fatty acid (n-3) treatment; a subsequent (after 6 months) randomization (R2) to cholesterol lowering (with pravastatin) for patients with total cholesterol = 250 mg/dl. A total of 11,372 patients have been randomized to R1; 4,271 patients have been randomized to R2. This second step of the trial was prematurely terminated following the suggestion of the Ethical Committee, on the basis of the already available evidences on the benefit of statins in post-MI patients. The analysis of the database for the main results and the many epidemiological aspects, ha started early 1999.
Reference persons: R. Marchioli, G. Tognoni, M.G. Franzosi, A.P. Maggioni
Peripheral artery diseases
Following the experience of the large-scale trial on the role of prostanoids on chronic critical limb ischemia (1,500 patients in 67 centers), the attention has been re-focussed on the broader problem of peripheral artery disease(s), with a specific emphasis on the epidemiology as well as on the burden and the quality of related care in the context of hospital vs. primary care.
Reference persons: M.C. Roncaglioni
OASIS (Organization to Assess Strategies for Ischemic Syndromes)
The OASIS is a multinational network of nearly 500 Cardiological Centers in more than 20 countries, aimed at assessing new therapeutic strategies in patients with acute coronary syndromes, coordinated by the Canadian Cardiovascular Collaboration (CCC), McMaster University, Hamilton. The first large-scale trial recruited more than 10,000 patients to evaluate whether recombinant hirudin is superior to heparin in preventing cardiovascular mortality, new non-fatal myocardial infarction or refractory angina in patients with unstable angina or AMI without ST elevation. In a subset of approximately 3,600 patients, the effect of warfarin versus standard therapy on cardiovascular death, AMI, and stroke was also assessed.
Two new trials in the acute coronary syndromes are now ongoing: the OASIS-3 study, which will assess whether a prolonged treatment with a direct thrombin inhibitor (PEG-hirudin) given subcutaneously is increasing efficacy and decreasing rebound with respect to heparin in approximately 8,500 patients with unstable angina or AMI not requiring thrombolysis; the OASIS-4 study, which will evaluate the efficacy of a long-term treatment with clopidogrel versus placebo in addition to aspirin for the reduction of ischemic events (MI, stroke, CV deaths) in 9,500 patients with unstable angina or AMI without ST elevation.
Reference persons: M.G. Franzosi, E. Bonfanti, E. Gardinale,
A.P. Maggioni, G. Tognoni
PPP (Progetto di Prevenzione Primaria)
Patients with at least one cardiovascular risk factor have been recruited in a large network of general practices to be randomized into a factorial design including antioxidant (Vit. E) and low-dose aspirin treatment, to assess their preventive effects on major cardiovascular events over a minimum of 3-year period. The trial has included ~ 5,000 patients and the closure of the follow-up was Dec. 1998, and the analysis of the results has started early 1999.
Reference persons: F. Avanzini, V. Bertele', I. Pangrazzi,M.C. Roncaglioni
STARC II (Studio Trapidil e Aspirina nella Restenosi Coronarica)
Patients undergoing coronary angioplasty are randomized to receive aspirin or aspirin plus trapidil (a new antiplatelet agent, inhibitor of the platelet derived growth factor) in order to reduce clinical events strictly related to the restenosis phenomenon: death, reinfarction and need for repeated revascularization procedures (estimated sample size: 1,200 patients). An angiographic substudy will be conducted as an integral part of STARC II study, to quantitatively assess restenosis (estimated sample size: 350 patients).
The study is scheduled to terminate its randomization phase by the end of 1998 and the follow-up by the end of 2001.
Reference persons: A.P. Maggioni, F.Turazza, R. Latini
A multicenter multinational large scale mortality trial to evaluate the benefit risk profile of valsartan (a AT1 receptor antagonist) vs. placebo in patients with symptomatic congestive heart failure already optimally treated with available drugs.
The study is coordinated by the Veteran Affairs in US and by this department for all non-US countries. The main end-point of the study is total mortality. The planned sample size is 5,000 patients. The randomization phase should be completed by the end of 1998. The follow-up period is planned by the end of year 2000.
Reference persons: R. Latini, A.P. Maggioni, G. Tognoni
- 5.5 Clinical Epidemiology
The systematic analysis of the ECG database of GISSI studies allows to assess prognostic significance of established and novel ECG indexes for prognostic stratification of post-AMI patients.
Reference persons: R. Latini, A.P. Maggioni
The large databases of the concluded and ongoing intervention studies shall be used for epidemiologic analyses.
The following projects and working groups are activated:
Reference persons: V. Bertele', M.C. Roncaglioni
|GISSI-3 ||Reference persons: M.G.Franzosi, A.P. Maggioni|
Reference persons: R. Marchioli, A.P.Maggioni, G. Tognoni
Reference persons: F. Avanzini, M.C. Roncaglioni
- 5.6. Genetic Epidemiology
The PROCARDIS Research Programme is a genome-wide strategy to identify susceptibility loci in precocious coronary artery disease (CAD). The objective of this study is to recruit at least 2,000 affected sibling pairs and families with precocious CAD through a European collaborative network, and to apply molecular genetic screening techniques to identify chromosomal regions which are linked to the susceptibilty of early onset CAD.
Reference persons: M.G. Franzosi, G. Tognoni
- 5.7. Health Care Research and Pharmacoeconomics
Epidemiological surveillance intervention strategies for the management of CV risk factors
This area includes a series of studies on the transferability of guidelines and on the optimization of interventions mainly with prospective "outcome" oriented designs and pharmacoeconomic analyses in the fields of: hypertension, secondary prevention, comorbid conditions, post-menopausal women.
Reference persons: C. Alli, F. Avanzini, M.G. Franzosi, R. Marchioli,
- 5.8. Technology Transfer and International Health
Following a pilot project on the quality of care of AMI in several countries of Latino-America, the Department is at present participating in a major international case-control surveillance of ACS patients (coordinated by the Canadian CardioVascular Collaboration, under the name of Inter-Heart) and activated in ~ 30 countries from both the North and the South of the world. The field of activity includes also training programs for the participating groups and a rather intensive advisory role on the activation and monitoring of epidemiological projects (Latino-America is the area where most of this activity is being developed).
Reference persons: G. Tognoni, R. Marchioli, A.P. Maggioni
- 5.9. Nursing Research
The activity includes at present: the analysis of the databases generated by the companion studies linked to the respective clinical protocols (GISSI, MAST, i.c.a.i.); the elaboration of methodology oriented manuals for training programs; the formulation of research protocols to monitor epidemiologically the organizational transformations occurring in the Italian health system.
In collaboration with the ad hoc working group of ANMCO.
Reference person: P. Di Giulio
- 5.10. Medical Informatics and Statistics
Training on the Information Technology and the Internet in medicine
The Department is actively involved in the training on the use of the Information Technology and the Internet in the medical field. The courses are addressed to General Practitioners, health professionals (including cardiologists), drug companies and health institutions personnel.
Reference persons: E. Santoro, E. Nicolis
Medical web sites
CARDIO.CARE is an index of resources available on the Internet in cardiology. This web site has been developed by the Department in order to collect, classify, evaluate, and describe the most useful information in cardiology, providing the Internet users with an easy mean to surf the net. Similar projects have been developed in oncology and neurology fields in collaboration with Department of Oncology and the Laboratory of Neurological Disorders.
Reference persons: E. Santoro