Main research fields:
- Modelling and simulation of the physiology mechanisms of
excitation-contraction coupling and disease-related processes in
cardiomyocytes
- Effects of uremia on cardiac activity
- Artificial kidney and hemodialysis therapy
- Virtual Physiological Human initiative, aiming at
patient-specific computer models for personalised and predictive
healthcare
Research projects:
- Theoretical investigation of action potential
duration dependence on extracellular Ca2+ in human ventricular
myocytes.
- Mechanisms of ß-adrenergic modulation of IKs in
the guinea-pig ventricle
- Analysis of the effects of uremia on cardiac
activity in rabbits
- Cardiovascular effects of dialysate calcium
profiling during hemodialysis:
- Role of extracellular calcium in cardiac
electrophysiology analysed in vitro and in
silico.
- Influence of plasma potassium changes on the
myocardial cell repolarization during hemodialysis
- Computational and experimental analysis of the
role of hemodialysis in atrial fibrillation onset
- Role of acquired long QT syndrome in sudden
cardiac death in nephrology.
- Analysis of the polycystic disease progress in
APDK patients by RM image processing
Theoretical investigation
of action potential duration dependence on extracellular
Ca2+ in human ventricular myocytes.
Background: Reduction in
[Ca2+]o prolongs the AP in ventricular
cardiomyocytes and the QTc interval in patients.
Although this phenomenon is relevant to arrhythmogenesis in the
clinical setting, its mechanisms are counterintuitive and
incompletely understood. Aim: To evaluate in silico the mechanisms
of APD modulation by
[Ca2+]o in human cardiomyocytes.
Mechanisms of ß-adrenergic modulation of
IKs in the guinea-pig ventricle
Detailed
understanding of IKs gating complexity may provide clues
on the mechanisms of repolarization instability and the resulting
arrhythmias. We developed and tested a kinetic
model to interpret physiologically relevant IKs
properties, including pause-dependency and modulation by
β-adrenergic receptors (β-AR).
Analysis of the effects of uremia on
cardiac activity in rabbits
Cardiovascular
diseases are frequently observed in patients with chronic renal
failure. Several studies evidenced that cardiovascular diseases are
the principal cause
of
death, responsible for more than 40% of total mortality. Patients
affected by uremic cardiomyopathy develop left ventricular
hypertrophy, systolic and diastolic
dysfunction,
arrhythmias and repolarization dispersion. Although a number of
known factors have been implicated in the pathogenesis of uremic
cardiomyopathy, our
understanding
of these processes is still incomplete. In addition, despite of
technological developments improved patient tolerance to
hemodialysis treatment,
cardiovascular
complications still remain the most dangerous intradialytic side
effects. For these reasons increasing efforts are devoted to study
cardiac cellular
mechanisms
underlying electrocardiographic and hemodynamic dialysis-induced
alterations and to novel hemodialysis techniques to improve the
cardiac impact of
dialysis
therapy. The aim of the research project is to characterize an
experimental model (rabbit) of the uremic heart and ventricular
cardiomyocyte and to develop a theoretical computational model of a
uremic ventricular cardiomyocyte in order to improve knowledge
about uremic cardiomyopathy and of its associated
proarrhythmic
tendency.
Cardiovascular effects of dialysate
calcium profiling during hemodialysis:
Low
dialysate calcium concentration is used to prevent or treat
hemodialysis (HD)-induced hypercalcemia, but its use has been
complicated by intradialytic hypotension and QT interval
prolongation in some patients. Our goal is to explore the
possibility that dialysis calcium profiling can ameliorate
intradialytic hypotension and cardiac repolarization in HD patients
who need to have dialysis performed with low dialysate
calcium.
Role
of extracellular calcium in cardiac electrophysiology analysed in vitro and in
silico.
The problem of setting the appropriate Ca2+
concentration ([Ca2+]) in computational cardiac models in order to correctly
reproduce the physiological extracellular environment is
addressed. In spite
of its potential impact on simulation results this aspect seems to
be usually not appropriately considered in the model formulation.
In fact, cardiac computational models usually derive extracellular
[Ca2+] values from the electrophysiology conditions in
which the experimental data they are based on were obtained.
Unfortunately, the Tyrode's Ca2+ content (1.8 or 2 mM)
is significantly far from the physiological [Ca2+] in
blood serum (1.0÷1.3 mM).
Influence of plasma potassium changes
on the myocardial cell repolarization during
hemodialysis
Dialysis therapy has a strong impact on cardiac
excitability and the frequency of ectopic beats increases in the
course of the session. Dispersion of ventricular repolarization
could be a cause of the dialysis arrhythmogenic effect. In fact, QT
dispersion increases during dialysis and this increase seems to be
related to electrolyte, particularly potassium and calcium,
concentration changes. However, some concerns have been raised
about uncertainty of the QT dispersion measurement. Principal
component analysis of the T wave applied to 12-lead ECG recording
has been proposed as a novel approach to study the complexity of
repolarization without having to determine the end of T-wave. The
aim of this study is to assess and quantify the 24-hour changes in
the complexity of ventricular repolarization in patients undergoing
hemodialysis by means of principal components analysis. The effects
of two dialysis protocols leading to different plasma potassium
levels are also analyzed.
Computational and experimental
analysis of the role of hemodialysis in atrial fibrillation
onset
Atrial fibrillation (AF) is the most common and
troublesome arrhythmia in clinical practice and is a significant
contributor to cardiovascular morbidity and mortality. It has been
demonstrated that in end stage renal disease (ESRD) patients AF
prevalence is extremely high. Moreover, the hemodialysis (HD)
session can trigger paroxysmal AF episodes. AF onset is determined
by two important phenomena: a) extrasystolic firing from atrial
ectopic foci, b) structural and electrical atrial remodeling.
Supraventricular ectopic beat occurrence increases in the last
stage of the HD session and structural remodeling is often present
in ESRD patients. There are two electrophysiological aspects of
electrical atrial remodeling: a) action potential (AP) shortening
and consequent reduction of the atrial cell refractory period, b)
slowing of intra-atrial electrical conduction. The ECG P wave
duration reflects the atrial conduction velocity, whereas through
computational analysis the effects of electrolytes variations on AP
morphology and duration can be quantified. This combined
experimental and computational study aims to highlight the role of
hemodialysis-induced acute electrical remodeling on the AF
onset.
Role of acquired long QT syndrome in
sudden cardiac death in nephrology.
Among dialysis patients cardiovascular disease
(CVD) mortality
is 30 times higher than in general population and accounts for 58%
of all-cause mortality, and the risk for arrhythmogenic death is
one of the highest among any other populations. The
situation is greatly exacerbated by the fact that
there is a clinically proven lack of benefits from: (a) implantable
cardioverter-defibrillators in patients with severe renal disease
and heart failure, and (b) the statins on the risk of
cardiovascular events in the advanced cronic kidney disease. This
presents the questions: why are renal patients so vulnerable to
fatal arrhythmias and what else can be done to prevent sudden
cardiac death (SCD) in this population? The main goal of this
project is to computationally analyse the ionic and pharmacological
aspects of acquired long QT syndrome (LQTS) in uremic
patients.
Analysis of the polycystic disease
progress in APDK patients by RM image
processing
Studi recenti condotti su pazienti
con malattia policistica dei reni hanno evidenziato come il
progressivo ingrandimento dei reni sia conseguente principalmente
all'ingrandimento delle cisti renali. Inoltre, è altrettanto
dimostrato come l'aumento del volume delle cisti sia uno dei
fattori responsabili
della comparsa e della progressione dell'insufficienza renale
risultando una correlazione inversa tra l'ingrandimento delle cisti
e la funzionalità renale valutata con la clearance della
creatininemia. Allo scopo quindi di stabilire se l'ingrandimento
delle cisti possa essere un marker predittivo sullo sviluppo
dell'insufficienza renale, sono stati condotti studi con CT su reni
di pazienti con ADPKD che tuttavia hanno dato risultati
discordanti. Inoltre la TCscan ha lo svantaggio di dover impiegare
il mezzo di contrasto che può risultare nefrotossico nei pazienti
con insufficienza renale cronica. Più di recente, studi basati
sull'impiego in pazienti con ADPKD della RM con la tecnica della
diffusione (DWI) hanno consentito di differenziare le aree
funzionanti (costituite dai nefroni) da quelle non funzionanti
(costituite dalle cisti) . Al momento tuttavia, non esiste un
protocollo standard di diffusione per acquisizioni renali e la
valutazione del fenomeno della diffusione per altri distretti
anatomici avviene semplicemente attraverso la valutazione
qualitativa di mappe ADC (Coefficiente di Diffusione
Apparente) derivate dalle sequenze di diffusione.
Obiettivo dello studio è l'utilizzo
delle sequenze di diffusione per una valutazione quantitativa
volumetrica delle cisti e del parenchima funzionante e delle sue
variazioni nel tempo al fine di correlare i vari stadi di CKD
secondo la classificazione KDOQI e le variazioni delle
cisti.
