Savarese / Brambilla

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Alice Savarese, DVM, PhD Student

She graduated in March 2009 in Medical Biotechnologies at the University of Milan (104/110), with a thesis entitled “Study of the levels of methylation of the telomerase gene promoter in steel workers exposed to particulate matter” (Supervisor: Prof. Andrea Baccarelli). After graduating, she obtained a short scholarship at the Epidemiology Laboratory of the Ospedale Maggiore - Policlinico of Milan. But then she decided to change perspective and start a career in Veterinary Medicine. She graduated in March 2015 at the University of Milan (110/110 cum laude) with a thesis entitled “Cardiorenal syndrome – anemia complex in dogs suffering from mitral valve disease: a retrospective study” (Supervisor: Prof. Paola Brambilla). During her career, she spent one year in Spain, at the Veterinary Faculty of Santiago de Compostela, attending the Veterinary Hospital and, especially, the cardiology unit. After graduating and once acquired the professional license, she started a traineeship in a private clinic. At the same time, she continued to attend the Cardiology Unit of the Department of Veterinary Science and Public Health, where she has the opportunity to acquire more skills about cardiology and internal medicine.
Her main research interests are in echocardiography, electrocardiography, small animal internal medicine (cardiology and nephrology), clinical pathology and the analytical validation of innovative diagnostic markers for cardiac diseases and renal injuries.

Paola Brambilla, DVM, PhD

Paola Brambilla is an associate Professor of Veterinary Clinical Epidemiology at the Department of Veterinary Sciences and Public Health, University of Milan and Associate Professor in Small Animal Cardiology at School of Specialization in Clinic and Pathology of Companion Animals, University of Milan.

She graduated with honour at the University of Milan and then obtained a PhD in Large Animal Internal Medicine. She is actually in charge with the Cardiology Unit of Small Animals at the Department of Veterinary Sciences and Public Health, University of Milan.
Paola G. Brambilla is a member of the Commissione Malattie Cardiovascolari – Fondazione Salute Animale [Commission of Cardiovascular Disease - Animal Health Foundation], and of the Italian Society of Veterinary Cardiology (SICARV).
The research interests are focused on the cardiovascular diseases in dog and cat:
• No-invasive echocardiographic and color-Doppler techniques to assess the mitral valve regurgitation (flow mapping of vena contracta)
• No-invasive advanced echocardiographic techniques (speckle-tracking echocardiography) focused on strain and strain rate in the longitudinal, circumferential and radial planes of left and right ventricle
• Survival studies and analysis on prognostic factors in dogs affected by different heart disease, and using different therapeutic approach.
• Cardiac biomarkers (troponine I)
• Diagnosis and therapy of congenital heart disease in dog (Pulmonic Stenosis, Patent Ductus Arteriosus)
• Cardio-Renal Syndrome in dog: study of the survival time and the prognostic indicator
In addition to the expertise in canine and feline cardiology, Prof. Paola G. Brambilla was involved in studies on canine X-linked muscular dystrophy and primary hypertrophic cardiomyopathy in Main Coon.



Cardiorenal syndrome (CRS) can be defined as a pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the other. CRS includes a vast array of interrelated disorders, and stress the bidirectional nature of heart-kidney interactions. In human medicine, CRS is classified in five subtypes that reflect the pathophysiology, the time frame, and the nature of concomitant cardiac and renal dysfunction.
CRS type 2 is the most common in canine patients, and it comprises chronic abnormalities in cardiac function (e.g. chronic congestive heart failure) causing progressive chronic kidney disease. The most common acquired heart disease affecting old dogs and leading to congestive heart failure is chronic mitral valve disease (MVD), also known as myxomatous mitral valve degeneration. The MVD cause systolic regurgitation from left ventricle to left atrium, and decrease in stroke volume. The worsening of the cardiac performance, and the consequent reduction of the renal perfusion contribute to the development of renal insufficiency in the setting of hearth failure (CRS type 2).
In cats, the most common CRS are type 2, as in dogs, and type 4, in which chronic kidney failure leads to chronic heart failure. Unlike that in dogs, in cats the most common cardiac disease is hypertrophic cardiomyopathy (HCM), a primary myocardial disorder characterized by increased cardiac mass and a hypertrophied, not dilated, left ventricle.
Anemia is often associated with heart failure and renal insufficiency, and this unfavorable triad of conditions has been called “CRS-anemia” complex. CRS-anemia complex is well known in human patients: anemia has been recognized as an important comorbidity factor in subjects affected by heart disease, and it appears to be related to bad outcomes in subjects with both heart failure and chronic kidney disease.

In veterinary medicine very few data exists on CRS-anemia complex in small animals, and the investigation of the CRS-anemia complex might be worthy, as the geriatric population of companion animals increases and reaches advanced disease stages.
The aims of the study are:
1) determine the prevalence of CRS - Anemia complex in a clinical population of dogs affected by heart diseases, especially MVD, at different severity stages of heart failure (ACVIM classification - American College of Veterinary Internal Medicine’s Board) and renal failure (IRIS classification – International Renal Interest Society)
2) determine the prevalence of CRS - anemia complex in a clinical population of cats affected by cardiac diseases, especially HCM, at different severity stages, and by CKD, at different severity stages (according to the IRIS classification)
3) describe the patterns of anemia based on red blood cells indices (MCV, MCH, MCHC), reticulocyte production index (IR), and red blood cell distribution width (RDW)
4) monitor the progression of renal and cardiac diseases through the evaluation of biomarkers, useful to identify the stages of organ damage in patients affected by CRS - anemia complex. In human medicine in fact, one of the cornerstones of CRS management is the early identification of patients at risk for worsening kidney and heart function, with the use of imaging technique as well as renal and cardiac biomarkers. Diagnostic and prognostic biomarkers of myocardial and renal injury useful in stadiation of CRS type 2 and type 4 in dog and cat can be:
- Doppler echocardiographic indices
- Blood and urine biomarkers, like for example serum Cystatin C and/or urinary Cystatin C, symmetric dimetylarginine (SDMA), Neutrophil gelatinase-associated lipocalin (NGAL), NT-pro-BNP, selected interleukins and cytokines of generalized inflammation (TNF-α, IL-1, IL2, IL-6, IL-7, IL-8), Troponine I (cTRI), Asymmetric dimethylarginine (ADMA), Pentraxine-3, Galectine-3 and ST2, Paroxonase
- Haematological and blood chemistry parameters, like for example C-reactive protein, Homocysteine, Uric Acid, Serum iron profile, Vitamin B12 and folate.
- Epigenetic biomarkers (methylation of CpG sites, histone methylation, miRNA). Methylation is a process by which methyl groups are added to DNA or histone modifying gene expression, while microRNAs (miRNAs) are single-stranded RNAs of ~22 nt that operate as post-transcriptional gene regulators by base pairing with target mRNAs, and leading to mRNA destruction in the RNA-induced silencing complex through argonaute-catalysed cleavage.

The goal of epigenetic biomarker development is to design experimental assays that produce relevant information for diagnosis, prognosis and therapy optimization in routine clinical treatment of a multifactorial syndrome, such as CRS. Furthermore, epigenetic biomarkers show lower susceptibility to short – term fluctuations.

All the biomarkers listed above have strong bibliographic references in human medicine, but little is known about the use of some of them in small animal medicine: one of our purpose is trying to identify which fits better with veterinary medicine and clinical practice, testing them in our patients and performing statistical analysis. For some of them, validation process could be necessary.

5) Evaluate the effects of selected factors on the survival of these patients to predict the risk of death/worsening renal and cardiac function (e.g. ACVIM/IRIS class vs red blood cells indices, RI, RDW, serum creatinine, uremia, etc.)

The descriptive analysis of the enrolled population of patients will be performed first, and then the biomarkers concentration will be determined in the different ACVIM and IRIS class of patients. The influence on quality of life and survival time of prognostic selected factor using Kaplan Meyer curves and Cox proportional hazards will be executed.
The identification of the stage of the organ damage and the effects of prognostic factors may contribute to a better definition of prognosis, and could also provide new opportunities for novel therapeutic strategies in these patients.