INTERNAL MEDICINE INTERNAL MEDICINE
Volume 46 No. 1, 2008
R. TĂNĂSESCU, ADRIANA NICOLAU, MARINA ŢICMEANU, DIMELA LUCA, SIMONA CARAIOLA, INIMIOARA
MIHAELA COJOCARU, A. FRĂSINEANU, R. IONESCU, ADRIANA HRISTEA, AMALIA ENE, RUXANDRA
TĂNĂSESCU, C. BĂICUŞ, An Immunological Approach to Cerebral Ischemia. Immune Cells and Adhesion Molecules
ANA MARIA VLĂDĂREANU, CRISTINA CIUFU, H. BUMBEA, MINODORA ONISÂI, S. ARAMĂ, An Update on the
Platelet Dysfunction in Chronic Myeloproliferative Syndromes ......................................................................................
D. ZDRENGHEA, LAURA POANTĂ, DANA POP, V. ZDRENGHEA, M. ZDRENGHEA, Physical Training – Beyond
Increasing Exercise Capacity ...........................................................................................................................................
MARIA DOROBANŢU, ELISABETA BĂDILĂ, S. GHIORGHE, ROXANA DARABONT, M. OLTEANU, P. FLONDOR,
Total Cardiovascular Risk Estimation in Romania. Data from the Sephar Study .............................................................
D.M. DUDA-SEIMAN, SILVIA MANCAŞ, D. GAIŢĂ, SIMONA DRĂGAN, DANA VELIMIROVICI, STELA IURCIUC,
C.A. SARĂU, M. IURCIUC, MARIA RADA, BILEANA PETCOV, Lifestyle, Cardio-metabolic Risk and Arterial
O.S. PLEASCAR, D. COZMA, L. PETRESCU, DANIELA POPA, M. SLOVENSKI, S.I. DRĂGULESCU, Left Atrial
Surface Cut Point to Detect Trapezoidal Shape for Characterisation of Atrial Anatomical Remodeling .........................
LUCICA AGOŞTON-COLDEA, L.D. RUSU, RALUCA PAIS, ADRIANA ALBU, M.L. RUSU, TEODORA MOCAN,
S. PERNA, The Impact of the Metabolic Syndrome on the Patients with Acute Coronary Syndrome ............................
MARIA ILEA, D. ZDRENGHEA, G. BODISZ, ADINA MĂLAI, LILIANA GHEORGHIU, D. PREDESCU, MARIA
BEUDEAN, VICTORIA OSSIAN, ELENA GLIGOR, CRISTINA VLAD, DANA POP, E. BOGDAN, R. ROŞU,
Cardiac Peptides During Exercise Test in Ischemic and Non-ischemic Heart Failure Patients ........................................
SILVIA MANCAŞ, GEORGETA MIHALAŞ, D. GAIŢĂ, SIMONA DRĂGAN, D.M. DUDA-SEIMAN, C.A. SARĂU,
LAVINIA NOVEANU, BILEANA PETCOV, GEORGIANA MANCAŞ, V. IONESCU, MONICA PĂCURAR,
Environmental Factors and Cardiovascular Risk in Young Individuals ...........................................................................
INIMIOARA MIHAELA COJOCARU, M. COJOCARU, R. TĂNĂSESCU, CECILIA BURCIN, ADINA NICOLETA
ATANASIU, ANA MARIA PETRESCU, ANDREEA CRISTINA MITU, IULIA ILIESCU, LAURA DUMITRESCU,
Changes in Plasma Levels of Complement in Patients with Acute Ischemic Stroke ........................................................
T. MOGOŞ, CARMEN DONDOI, Which Dose of Omega-3 Fatty Acids Must be Taken in Different Cases of
I. COPACI, MIHAELA ENACHE, C. JURCUŢ, M. ŞOTCAN, C. CONSTANTINESCU, Polycystic Hepatic Disease ..........
A. MIRONIUC, LAVINIA COMES, IOANA CONSTANTINESCU, CLARA MIRONIUC, DANA BONTEA, Cryoglobulinemic
Vasculitis with Multiple Digital Necrosis in Viral Hepatitis ............................................................................................
ROM. J. INTERN. MED., 2008, 46, 1, 1–96
An Immunological Approach to Cerebral Ischemia (I).
Immune Cells and Adhesion Molecules
R. TĂNĂSESCU1*, ADRIANA NICOLAU2, MARINA ŢICMEANU1, DIMELA LUCA1, SIMONA CARAIOLA2*,
INIMIOARA MIHAELA COJOCARU1, A. FRĂSINEANU1, R. IONESCU2*, ADRIANA HRISTEA3, AMALIA ENE4,
RUXANDRA TĂNĂSESCU3, C. BAICUŞ2*
1Department of Neurology, Colentina Hospital, Bucharest, Romania
2Department of Internal Medicine, Colentina Hospital, Bucharest, Romania
3“Prof. Matei Balş” Institute of Infectious Diseases, Bucharest, Romania
4Department of Neurology, University Hospital, Bucharest
*Réseau d’Epidémiologie Clinique International Francophone (RECIF)
Ischemic stoke is a major cause of death and an important source of disability in industrialized
countries. Since there is no ideal treatment for cerebral ischemia, any approach aiming to limit the
devastating consequences of the ischemic process is justified. Concerning immune responses, it has
become clear in the latest years that actors of the immune system are involved in multiple and various
neurobiological processes such as cerebral ischemia, neurodegeneration, neuroprotection and
neuroregeneration. An immunological approach to cerebral ischemia can distinguish, besides the
implication of inflammation in the developing of atherothrombosis thus leading to stroke, the clear
involvement of immune cells and mediators in processes continuing the initial stage of ischemia,
having consequences on recovery or lesion extent. Cerebral infarctions develop within minutes to
hours of cessation of the cerebral blood flow, but may expand over subsequent days. There is
increasing evidence that leukocytes, cytokines, cell adhesion molecules, and other immune mediators
contribute to secondary infarction growth, but inflammatory cytokines are also involved in signaling
pathways leading to neuroprotection related to ischemic pre-conditioning. The aim of this review is to
show some aspects concerning the complex and diverse functions of immune modifications occurring
in cerebral ischemia. This first part will focus on the involvement of immune cells, adhesion
molecules and immunological transcription factors in the development of ischemic lesion.
Since ischemic stoke is, in industrialized
countries, the third leading cause of death and an
important source of disability, any approach aiming
to limit the devastating consequences of cerebral
ischemia is justified. Even if immune responses in
the nervous system have been mainly studied in the
context of autoimmunity and infections, it has
become clear in recent years that actors of the
immune system are involved in multiple and
various neurobiological processes such as cerebral
ischemia, neurodegeneration, neuroprotection. An
immunological approach to cerebral ischemia can
distinguish, on the one hand, the implication of
inflammation in the developing of atherothrombosis.
Inflammation of the vessel wall is an essential part
of atherosclerosis, in general, but immune interactions
play a decisive role in the destabilization of
atherosclerotic plaque. This leads to local formation
of thromboemboli that may transiently or
permanently occlude intracranial arteries and
induce focal ischemia. On the other hand, cerebral
infarctions develop within minutes to hours after
cessation of cerebral blood flow and may expand
over days. There is increasing evidence that cells
and mediators are involved in immunological
cascades continuing the initial stage of ischemia
with processes apparently silent, but with
consequences on recovery or lesion extent.
Leukocytes, cytokines, cell adhesion molecules, and
other immune mediators contribute to secondary
infarction growth. At the same time, inflammatory
cytokines are involved in neuroprotection related to
ischemic pre-conditioning. This review is aiming to
present some aspects concerning the immune
modifications occurring in central nervous system
(CNS) ischemia. The present section will focus
on the involvement of immune cells (neutrophils,
macrophages, microglia, T cells), adhesion molecules
and immunological transcription factors in the
development of ischemic lesion. Cytokine participation
ROM. J. INTERN. MED., 2008, 46, 1, 3–8
4 R. Tănăsescu et al. 2
in brain ischemia will be treated separately in a future
MECHANISMS OF NEURAL DEATH. THE EXTENT
OF INFARCTION IS DEPENDENT ON THE
DURATION OF BLOOD FLOW CESSATION
Ischemic impairment or cessation of cerebral
focal blood flow restricts the delivery of oxygen
and glucose, leading to an impaired energy-
dependent maintenance of ionic gradients. This
conducts to neuron and glia depolarization leading
to extracellular accumulation of Ca2+ and release of
glutamate, an excitatory aminoacid . Ca2+
accumulation activates proteolytic enzymes and
generates the production of free-radical species,
and release of glutamate. These processes induce
rapid necrotic cell death of the cells most affected
by ischemia, located in the core of the ischemic
territory, where the flow reduction is the most severe.
On the other hand, a significant proportion of neurons
die by an internal program of self-destruction
(apoptosis or programmed cell death), ongoing for
several days after the initial insult. It must be
emphasized that this must be differentiated by the
physiological apoptosis processes, occurring in the
natural evolution of the cell. Apoptosis involves
activation of caspases and requires partially preserved
protein synthesis. Other key injury mechanisms
include the production of oxygen- and nitrogen-based
free radicals, inflammatory mediators such as tumor
necrosis factor (TNF), interleukin (IL)-1, inducible
nitric oxide synthase (iNOS), cyclo-oxygenase-2,
protease activation (calpains, caspases, extracellular
proteases), mitochondrial and endoplasmic reticulum
Initially during cerebral ischemia, developing
infarctions are surrounded by an ischemic penumbra
that can be salvaged by reperfusion. This ischemic
penumbra means cortical areas where the blood
flow is reduced, but still exceeds a flow and
duration threshold that produces an irreversible
state of ischemic neuronal injury. In order to study
progression and mechanisms of focal ischemic
brain injury, several animal models have been used,
in which surgical occlusion of major arteries was a
widely performed method . In the model of
permanent occlusion of the middle cerebral artery
(MCA) at proximal sites, leading to complete
infarctions of the basal ganglia and the neocortex,
the infarction volume has been observed to change
significantly during the first 3 days. Early reperfusion
reconstitutes perfusion and significantly modifies
stroke development: ischemia lasting less than
30 minutes leads to a restricted infarction with
pannecrosis of neurons and glial cells in the
caudatoputamen, but only partly affects the neocortex.
Further delay in reperfusion produces an increasing
neocortical infarction. Depending on the timing of
reperfusion, neocortical infarctions can be surrounded
by areas of selective neuronal death characterized
by loss of large pyramidal neurons but preservation of
endothelial and glial structures .
IMMUNE CELLS IN FOCAL ISCHEMIA
Focal cerebral ischemia leads to local activation
of microglia and astroglia and to an important influx
of blood leukocytes . Granulocytes are the first
blood cells that appear in the brain in response to
focal ischemia . They are attracted by chemokines
released from ischemic tissue and accumulate in the
cerebral vessels within hours before they invade the
infarction and its boundary zone, with a peak at
24 hours after infarction onset, thereafter rapidly
decreasing in number. Within the second week after
infarction, granulocytes have mostly disappeared. It
was suggested that in transient ischemia models
accumulation of intravascular granulocyte probably
reduces the blood flow in the reperfusion phase thus
contributing to infarction extent .
The main population of leukocytes that enter
the brain after focal cerebral ischemia are monocytes/
macrophages, attracted into areas of pannecrosis
and the border zones by chemokines . The
infiltrates demarcate the necrotic brain tissue, and
rapidly remove debris leaving a glial scar, helped
additionally by resident microglia which contribute
to the phagocytic response. These microglia
become indistinguishable from macrophages upon
Trying to distinguish between hematogenous
macrophage infiltration and local microglial responses,
super-paramagnetic iron particles were injected
into the circulation. They are rapidly taken up by
circulating macrophages. When these iron-laden
macrophages infiltrate lesions they become detectable
as areas of signal loss on T2-weighted magnetic
resonance (MR) images. With this imaging technique
3 An immunological approach to cerebral ischemia
it was demonstrated that hematogenous macrophages
were recruited in the rat model with a delay of several
days to ischemic brain lesions, and that macrophage
invasion was temporally unrelated to the breakdown
of the blood-brain barrier (BBB) . In a pilot study
of human stroke, this late recruitment was recently
confirmed . These data suggest that macrophages
could play a role in tissue remodeling and
repair, rather than in aggravating the neuronal injury
because they appear at a stage in which delayed
neuronal cell death has already ceased. On the
other hand, microglial activation appears to play a
detrimental role as it occurs early. It is maybe in this
respect that minocyclin (a tetracyclin derivative) was
shown to attenuate microglial responses and reduce
infarction volume .
Important to note is that macrophage/microglial
responses to cerebral ischemia are diverse. In the
murine model two different populations are
described . On the one hand, CD4+ macrophages/
microglia that are also present in other models of
CNS lesion are gradually increasing from day 2 with
a peak at day 14 when they covered the entire area of
infarction. Secondly, macrophages/microglia expressing
the T- and NK-cell surface molecule, CD8,
constitute a separate and unusual population .
This population of CD8+ macrophages/ microglia
was exclusively located in the border zone and the
core of necrotic brain tissue transiently between days
3 and 6 and had almost disappeared at day 14. Their
functional role in brain ischemia is not completely
clarified at present. These CD8+ cells could
contribute to exacerbation of ischemic brain damage
as well as to tissue remodeling and healing
processes. It was shown on alveolar macrophages
studied in vitro that signaling via the CD8 molecule
led to expression of TNF, IL-1β, and iNOS. It is
important to emphasize that CD8+ macrophages/
microglia appear to be relatively specific to areas
of ischemic pannecrosis (necrotic lesion of all brain
structures) and are not seen in areas of selective
neuronal death or degeneration .
T cells preferentially infiltrate in a large
amount the border zones of infarctions within the
first 7 days after stroke . This was demonstrated
in both experimental and human stroke studies.
One important point is that T-cell CNS recruitment
is usually observed in autoimmune and infectious
conditions, but not in degenerative disorders. In
experimental autoimmune encephalomyelitis (EAE),
systemic immunization with myelin basic protein
generates CD4+ helper/inducer T cells that are
antigen specific and accumulate within the CNS
after 10 to 12 days to induce myelin destruction by
macrophages . In cerebral ischemia, the T-cell
response is likely to be antigen non-specific
because the period between lesion induction and
T-cell infiltration is too short for generation of
systemic, antigen-specific immune responses .
The signals that attract T cells and keep them in the
CNS parenchyma for many days are unknown, but
studies suggest that infiltration of tolerized T cells
into ischemic brain lesions can be beneficial. Naive
rats fed with myelin basic protein, a procedure
known to induce immunological tolerance to EAE
induction, had reduced infarction volumes at 24
and 96 hours after MCA occlusion (10). This effect
was attributed to the infiltration with T cells that
produced transforming growth factor (TGF)-β1 of
evolving ischemic brain lesions. TGF-β1 is known
as having neuroprotective effects and being a
strong immunosuppressant. It was shown that the
neuroprotective effect of myelin basic protein
tolerance in cerebral ischemia can be transferred to
naive animals by infusion of tolerized lymphocytes
(adoptive transfer) .
CELL ADHESION MOLECULES AND THEIR
FUNCTIONAL ROLE IN CEREBRAL ISCHEMIA
Cell adhesion comprises multiple steps
during the inflammatory response in focal
ischemia, providing the traffic signals for entry of
leukocytes into the brain . Selectins (E-selectin,
P-selectin, L-selectin) are supporting leukocyte
rolling on luminal endothelium, thus reducing the
velocity of leukocytes in the blood flow. Integrins
are mediating firm adhesion of leukocytes to the
endothelium. There are different molecules of the
integrin family directed to the adhesion of leukocyte
subsets. In this respect, lymphocytes have on their
surface the CD11a/CD18 (leukocyte function
associated antigen-1; LFA-1) and the very late
antigen-4 (VLA-4) complex, monocytes LFA-I,
VLA-4, and the CD11b/CD18 complex, and
granulocytes LFA-1 and the CD11b/CD18 complex
. The corresponding endothelial counter-receptors
are intercellular adhesion molecule-1 (ICAM-1) for
LFA-1 and C11lb/CD18, and the vascular cellular
6 R. Tănăsescu et al. 4
adhesion molecule-1 (VCAM-1) for VLA-4. ICAM-1
is induced on brain endothelial cells 3 hours after
focal ischemia, have a peak of expression at 6 till
12 hours, and persists for several days. Similar to
ICAM-1 are E-selectin (endothelial leukocyte adhesion
molecule-1; ELAM-1) and VCAM-1 .
The importance from a functional point of view
of cell adhesion processes in stroke development was
proved in transient focal ischemia [12–14].
Treatments with antibodies or with a
recombinant neutrophil inhibiting factor directed
against the CD11b/CD18 complex present on
granulocytes and monocytes/macrophages were
used. Antibodies against the CD11b/CD18 complex
in a murine model subjected to 2 hours of transient
occlusion of MCA led to a significant reduction in
infarction volume and to a decrease in the number
of apoptotic cells. At the same time, infiltration by
granulocytes was reduced. Similar results were
obtained with a recombinant neutrophil inhibiting
factor directed against the CD11b/CD18 complex.
Blocking of the corresponding ligand on endothelial
cells, ICAM-1, reduced stroke volumes on day 2 by
80% . Accordingly, in the ICAM-1 knockout
mice it was shown a five-fold decrease in infarction
size . Blocking of lymphocyte and monocyte
entry by antibodies to the α4 integrin in the rat
model decreased infarction volume and improved
neurological outcome even when instituted after
onset of focal ischemia .
The effects seen in transient focal ischemia by
inhibiting leukocyte adhesion are not reproducible in
permanent ischemia models: the use of antileukocyte
antibodies in models of permanent MCA occlusion
was ineffective . This discrepancy can be explained
by the fact that granulocytes adhere to the microvascular
endothelium via the ICAM-1/ CD11b/CD18 adhesion
pathway thereby realizing a mechanic disconnection
of the dependent parenchyma from reperfusion (“no
reflow phenomenon”). This prolonged hypoxia period
leads thereafter to the extension into the penumbra
zone of the infarction area. A relatively recent study
in human stroke using a rat monoclonal antibody
against ICAM-1 conjugated with polyethylene
glycol in order to reduce immunogenicity,
Enlimolab, failed and led to unacceptable side-
effects by activating human neutrophils .
Adverse effects of Enlimomab may have been
caused by immunological factors, maybe by
activation of the complement, neutrophils, and
endothelial cells, as seen in murine model in which
monoclonal anti-ICAM-1 was administered .
TRANSCRIPTION FACTORS AND NITRIC OXIDE:
IMPLICATIONS IN PRO-INFLAMMATORY AND
NEUROTOXIC PATHWAYS IN CEREBRAL
It has been proved that immune cascades
contribute to significant infarction growth beyond
24 hours after focal cerebral ischemia .
The cellular responses in focal cerebral ischemia
are accompanied by the expression of immunological
transcription factors, iNOS, and cytokines.
Interferon regulatory factor 1 (IRF) is a
transcription factor that can be activated by TNF
and IL-1β. IRF gene expression is markedly up-
regulated at 12 hours after focal ischemia, with a
peak on day 4. It was shown that transgenic mice
lacking the IRF gene were protected from ischemic
brain damage and developed smaller infarctions
. The molecular mechanisms underlying
ischemic neuroprotection in IRF knockout mice
have not been completely understood, but they can
imply lack of nitric oxide induction . It is
known that IRF can induce gene transcription of
interleukin-1 converting enzyme (ICE or caspase 1)
and inducible NO synthase (iNOS). Lack of nitric
oxide (NO) induction is a likely mechanism since
macrophages from IRF knockout mice produced
virtually no NO and synthesized only low levels of
iNOS mRNA in vitro. NO is a small molecule but
that exerts pleiotropic actions. NO is synthesized
by oxidation of L-arginine by the enzyme NO
synthase (NOS) which exists in three isoforms,
neuronal NOS (nNOS), endothelial NOS (eNOS),
and inducible NOS (iNOS) . The three ways of
NO production are different in some aspects: the
NO secretion via eNOS and nNOS is calcium-
dependent and small amounts of NO are produced
(nano), while iNOS that is expressed by astrocytes
and microglia is implied in a NO production that
typically occurs only in an inflammatory setting.
NO production via iNOS is calcium-independent
and in higher concentrations (micro). NO
production is enhanced at all stages of cerebral
ischemia, but the effects on brain parenchyma can
vary in function of the concentration . Early
during ischemia NO produced through eNOS
activation in endothelial cells is beneficial and
induces an increase of the cerebral blood flow by
vasodilatation as well as anti-adhering effects on
leukocytes . In contrast, iNOS appears to be
detrimental, inducing synthesis of large amounts of
NO continuously for long periods, then reacts with
superoxide to form peroxynitrite, which has cytotoxic
5 An immunological approach to cerebral ischemia
actions. In the murine model with MCA occlusion,
iNOS mRNA expression in the postischemic brain
started between 6 and 12 hours, with a peak at
96 hours, and subsided after 7 days . Conversely,
disruption of the iNOS gene in mice led to smaller
infarctions and reduced motor deficits after focal
ischemia. It is very important to note that this
reduction in ischemic damage was not observed in
the first 24 hours from stroke onset, but it was
found at day four. This supports the idea that iNOS
expression is one of the critical factors participating
in the delayed expansion of brain damage .
Accidentul vascular ischemic reprezintă o cauză importantă de dizabilitate şi
deces în ţările industrializate. Cunoaşterea aspectelor neuroimunologice care
privesc ischemia cerebrală este importantă, câtă vreme implicarea sistemului imun
în geneza şi evoluţia leziunilor ischemice este astăzi o certitudine. Infarctul
cerebral se instalează în intervale de la minute la ore după oprirea fluxului
sanguin cerebral, dar la nivelul zonelor afectate există procese care durează zile
sau săptămâni. Actorii sistemului imun (leucocite, citokine, molecule de adeziune,
alţi neuromediatori) vor contribui la majorarea sau limitarea zonelor infarctizate.
Citokinele inflamatorii sunt implicate, pe lângă posibile acţiuni deletare asupra
parenchimului cerebral, în procese de neuroprotecţie asociate fenomenului de
precondiţionare ischemică. Articolul de faţă face o trecere în revistă a principalelor
aspecte legate de implicarea sistemului imun asociată ischemiei cerebrale.
Abordarea subiectului a fost împărţită în două secţiuni. Cea de faţă se referă la
implicarea versantului celular (macrofage, microglii, limfocite T) în modelarea
leziunii ischemice, urmând ca participarea citokinelor la procesele legate de
leziunea ischemică cerebrală să fie abordată într-o secţiune separată.
Correspondence author: R. Tănăsescu, MD, PhD, AFS
“Carol Davila” University of Medicine and Pharmacy, Bucharest
Department of Neurology, Colentina Hospital
19–21 Şos. Ştefan cel Mare, 020125, Bucharest, Romania
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Received January 16, 2008
An Update on the Platelet Dysfunction in Chronic Myeloproliferative Syndromes
ANA MARIA VLĂDĂREANU1, CRISTINA CIUFU1, H. BUMBEA1, MINODORA ONISÂI1, S. ARAMĂ2
1Department of Hematology, Emergency Universitary Hospital, “Carol Davila” University of Medicine and Pharmacy
2Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
The thrombotic and hemorrhagic diathesis represents a frequent complication in myelo-
proliferative disorders (CMPD). They are correlated with the number of platelets, but also with their
qualitative disorders, such as membrane glycoprotein changes. The latter are revealed by many
platelet essays including flow-cytometry and include modified activation, secretion and aggregation
patterns. The thrombopoietin platelet receptor (cMPL), affected by the JAK2 V617 mutation
encountered in CMPD, may be associated with a prothrombotic status. Its implication reveals the
importance of the molecular genetics profile in defining molecular diagnostic hallmarks and makes it
a candidate in the early diagnosis of myeloproliferative disorder and a predictor of thrombotic
complications in this group of diseases.
Key words: myeloproliferative syndromes, thrombosis, hemorrhage, JAK2 V617 mutation.
The clonal stem cell disorders, including
chronic myeloproliferative disorders (CMPD), are
associated with qualitative and quantitative disorders
of the erythroid, granulocyte, and thrombocyte
These dysfunctions are thought to cause
bleeding and thrombotic complications. This is
the reason why thrombotic and hemorrhagic events
occur quite frequently in patients suffering from
myeloproliferative syndromes and are also considered
important causes of morbidity and mortality .
The qualitative defects of the platelets together
with their quantitative alterations such as thrombocytosis
(which occurs mainly in myeloproliferative syndromes)
produce important disorders of hemostasis.
Chronic myeloproliferative disorders are stem-
cell disorders, in this group being included essential
thrombocythemia, polycythemia vera, myeloid
metaplasia with myelofibrosis and chronic myeloid
leukemia. In all of these diseases there are
described hemorrhagic diathesis, thrombo-embolic
complications and qualitative defects of the
platelets. Although these diseases have many common
features, the spectrum of platelets’ disorders and
their clinical picture is different in CMPD. The
thrombotic complications are more frequent in
essential thrombocythemia and polycythemia vera,
and the hemorrhagic complications are more
frequent in MMM, especially when there is an
32% of the patients with CMPD may develop
arterial or microvascular thrombotic complications;
venous thrombosis is reported as well .
The thrombotic risk is increasing with age, a
previous thrombosis history and the occurrence of
general associated risk factors such as hyper-
cholesterolemia, smoking, diabetes mellitus, arterial
THE PLATELET ROLE IN THE
ETHIOPATHOGENESIS OF THROMBOSIS IN
CHRONIC MYELOPROLIFERATIVE DISORDERS
The importance of the platelet’s role in the
etiopathogenesis of thrombotic events in CMPD is
multifactor through: their number, their qualitative
defects, the pattern of platelet activation, the
formation of platelet leukocyte aggregates, the
appearance of platelet micro-particles, and the
impact of JAK mutation .
1. In CMPD, especially in polycythemia vera,
erythrocytosis leads to increased blood viscosity
which may rheologically contribute to the
thrombosis tendency. But, this rheologic effect of
erythrocytosis is not the only mechanism explaining
the thrombotic tendency in MPD .
2. Thrombocytosis is a contributing factor in
the ethiopathogenesis of thrombosis in PV and ET
. There is a relative correlation between the
ROM. J. INTERN. MED., 2008, 46, 1, 9–15
Ana Maria Vlădăreanu et al. 2
degree of thrombocytosis and the thrombotic
complications in chronic myeloproliferative disorders
 and there is evidence that platelet count control
reduces the incidence of thrombosis.
Even if the control of thrombocytosis is
decreasing the frequency of thrombotic complications,
especially in patients with previous thrombosis, the
degree of the thrombocytosis is not correlated with
the thrombotic risk all the time .
In the ECLAP analysis, antiplatelet therapy,
but not cytoreductive treatment, was significantly
associated with a lower risk of cardiovascular
3. Qualitative disorders of the platelets in
chronic myeloproliferative disorders
Optic microscopy reveals heterogeneity in
size and morphology of platelets, which is
expressed by the large mean platelet volume 
and by anisocytosis and anisochromia on blood
smears as shown in Fig. 1.
Electronic microscopy revealed the decrease
of alpha granules and mitochondria and also
changes of the dense tubular and canalicular system
. A decrease of the ADP, ATP and serotonin
content of dense granules was also proved .
Some patients suffering from chronic myelo-
proliferative disorder have a prolonged bleeding
time, this change being more frequent in MMM
than in the other chronic myeloproliferative diseases.
The prolonged bleeding time is not correlated with
high bleeding risk .
Waddell et al.  were the first to describe
the membrane glycoprotein platelet changes in
chronic myeloproliferative disorders, such as: the
decrease of the alfaIIb betaIII and Ib receptors and
a low fibrinogen surface binding, indicating a
decrease of alfaIIb betaIII receptor. Besides the
quantitative decrease, the surface receptors alfaIIb
betaIII were also proved to have an altered
activation pattern .
Other qualitative platelet defects in CMPD
include: impaired dense granule release, defective
Ca mobilization, lipoxygenase accumulation .
4. The pattern of platelet activation
The pattern of platelet activation and the
changes in the surface receptors are presented in Fig. 2.
The platelet secretion and aggregation as a response
to epinephrine, ADP, collagen is decreased in chronic
myeloproliferative disorders and in myelodysplastic
syndromes. This aggregation defect is expressed by
the absence of the first aggregation wave .
The pathogenesis of platelet activation pattern
in chronic myeloproliferative syndromes is not quite
defined. It is multifactorial and includes: the lipo-
oxygenase deficiency, the disturbances in bone
marrow microenvironment, the hematocrit range, the
implication of activated leucocytes, the impaired
platelet NO synthetase, elevated thrombopoietin
level, the effect of JAK2 mutation .
In CMPD, especially in polycythemia vera,
the rise of haematocrit increases blood viscosity.
The axial migration of the erythrocytes in the
bloodstream “pushes” the platelets to the wall of
the vessel, increasing the platelet-vessel interaction,
especially in high shear conditions – in small
arteries and capillaries – contributing to platelet’s
As reported by Schafer, a large number of
patients have a lipooxygenase deficiency, which
could increase the capacity of endoperoxidasis to
produce thromboxan A2 .
Cooper et al. were the first to prove the
decrease of adenylate-cyclase activation GPD2
induced, correlated with a decrease of 50% of PGD2
receptors on the platelets, and normal responses to
PGE2 and PGI2 . This is suggestive for an
inhibitor mechanism defect in MPD.
It was recently established that platelets of the
PV and MMM patients, but not of ET and CML
patients, have a low expression of the thrombopoietin
receptor and the tyrosin-phosphorylation thrombopoietin
induced is also decreased; tyrosin-phosphorylation
thrombin induced is preserved .
In normal platelets, PGD2 increases AMP
because of adenylate-cyclase stimulation, leading
to platelet response inhibition .
Fujimoto et al.  proved the decrease of
Ca mobilization agonist-induced, the signaling by
thromboxan-receptor and the proteic phosphorylation
because of GMPc protein-kinase deficiency .
According to their observations platelet calcium
influx was lower than in control patients. Their
conclusion was that GP IIb/IIIa anomalies are
involved in the decrease of platelet calcium influx
in chronic myeloproliferative diseases patients .
The increase of P selectin expression,
thrombospondin and GP IIb/IIIa was correlated
with thorombosis. In chronic myeloproliferative
syndrome patients it has been shown an expression
and functional decrease of GP IIb/IIIa (CD41/
CD61) receptor, also of fibrinogen receptor, fibronectin
receptor, vitronectine receptor, thrombospondin
receptor, von Willebrand factor receptor. Also it
3 An update on the platelet dysfunction
has been found a low von Willebrand factor
binding on the platelet .
Some studies  showed an increase of
VEGF level that demonstrates increased endothelial
activation. The leukocyte activation (especially
monocytes and neutrophils) allows the release of
the granules content which activate the coagulation
pathways, induce platelet aggregation, release
inflammatory cytokines and oxygen superoxide, all
of the above contributing to the endothelial
The interaction between neutrophils and
platelets becomes apparent after the adhesion
cascade, when CD62P binds to P-selectin on the
neutrophil. The adhesion is stabilised by two other
complexes: CD11b of the beta-integrin complexed
with CD18 with GP Ib of the platelet and the
binding of fibrinogen with the platelet GP IIb/IIIa.
Some studies noticed an increase of the CD62P,
CD11b, CD42b expression in patients with
polycythemia vera and essential thrombocythemia
; the level of CD11b/CD42b and CD62P/
CD11b complexes was also increased.
Falanga et al.  underline that the
expression of JAK2 mutation in ET patients
confers to neutrophils a different haemostatic
property in terms of increased interaction with
platelets and increased expression of surface TF
and fibrinogen, suggesting a new link of the
mutation with the prothrombotic state.
It was also described a deficiency of GP Ia-IIa
and an abnormal response to collagen stimulation;
GP IV (CD 36) – a membrane glycoprotein
implicated in platelet-collagen interaction and
platelet-thrombospondin interaction – is known to
be decreased in essential thrombocythemia .
In chronic myeloproliferative disorders, there
are also other alterations of the platelet membrane
receptors – GP IV (CD36), thrombospondin receptor
which is released by platelet secretion. Its effect is
on the strength of the platelet aggregates, making
this process irreversible. The expression of this
receptor is increased in chronic myeloproliferative
disorders – all the patients with essential thrombo-
cythemia presented a proteolysed form of thrombo-
spondin (TSP) and this form was not detected in
reactive thrombocytosis . A study showed that
he level of normal GP IV and the associated
proteins may become normal during the treatment
with Interferon, but the altered form of TSP
receptor still persists .
It was proved over twenty years ago that the
Fc-IgG platelet receptors are increased in
chronic myeloproliferative diseases .
The variability of the platelet receptors is
thought to be genetically determined and there are
few studies establishing that platelet’s glycoproteins
polymorphism could contribute to thrombosis.
PLA2 allele of GPIIIa was correlated to the
increased incidence of arterial thrombosis, but this
conclusion must be confirmed by more studies .
5. The acquired von Willebrand disease
The acquired von Willebrand disease seems
to be an important factor contributing to the
bleeding diathesis in patients with thrombocytosis
in MPD. The von Willebrand factor multimers
analysis on agarosis gel electrophoresis has shown
the decrease of ultra-large multimers, similar to
von Willebrand disease type 2. It is correlated to
the degree of thrombocytosis and could be
corrected by cytoreduction therapy .
Possible mechanisms of production: high
clearance of ultra-large multimers by selective
platelet binding, or increased proteolysis of von
Willebrand factor, perhaps by the exposure of von
Willebrand factor cleavage loci to ADAMT13.
Because this acquired defect was also reported in
secondary thrombocytosis, it represents more a
favoring factor and not the cause of bleeding
complications in chronic myeloproliferative diseases,
especially in severe thrombocytosis .
6. The formation of platelet leucocyte
aggregates and the appearance of platelet
The formation of platelet leucocyte aggregates
(Fig. 3) is increased in MPD patients . They
form after platelet and neutrophil activation and
contribute to thrombus formation by the release of
granule contents, by inducing tissue factor expression
on monocytes, by the release of superoxide and
cytokines, by enhancing platelet activation and
endothelial activation and damage .
Harrison, C.N. (ASH-2005)  reported that
the increased level of highly thrombogenic platelet
microparticles in ET and PV was correlated with
the thrombotic tendency.
7. The impact of JAK mutation
An alternative explanation of modified platelet
activation includes the effect of JAK2 mutation
(Fig. 4). Recent data suggest that JAK2 mutation
affects cMPL platelet receptor of thrombopoietin .
Ana Maria Vlădăreanu et al. 4
The JAK2V617F represents a G to T somatic
mutation of Jak2 at nucleotide 1849, in exon 14,
resulting in the substitution of valine to phenyl-
alanine at codon 617.
In chronic myeloproliferative syndromes, the
mutation occurs in multipotent stem-cell . The
homozygous progenitors are more frequent in PV
patients and very rare in ET patients .
The JAK2V617F mutations occur in 90–95%
of PV patients, 50–70% of ET patients and 40–
50% of MMM patients . This mutation has
also been demonstrated in other myeloproliferative
disorders, including atypical MPD and also in
myelodysplastic syndromes .
The presence of JAK2 mutation has also been
revealed in elderly AML patients and it underlines
the possibility that these patients have had
previously undiagnosed chronic myeloproliferative
syndromes. Recent data revealed that JAK2
mutation occurs in a significant number of AML
secondary to chronic myeloproliferative syndromes
patients. In de novo AML patients the incidence of
this mutation is low .
The intracytoplasmic domain of this receptor
is correlated to JAK2, member of kinase family
Janus. The correlation between the JAK mutation
and the thrombopoietin receptor is shown in Figure 5.
The thrombopoietin stimulates the phosphorylation
of some proteins, including Janus kinase JAK2 and
TYK2. The thrombopoietin and its receptor
represent the control-key to regulate the platelet
number; the most of PV and MMM patients have a
decrease of thrombopoietin receptors and an
incomplete glycosylation of these receptors. This
defect cannot be found in other platelet membrane
glycoproteins (GPIIb), but it is related to the disease
duration and extramedullar hematopoiesis .
According to Campbell  the presence of
the JAK2V617 mutation divides essential thrombo-
cythemia into two distinct subtypes. Patients with
the mutation present higher hemoglobin levels,
higher white cell counts and bone marrow
hypercellularity . The risk of thrombosis in
mutated ET patient has not been reported by all
A group of investigators from Italy –
Bergamo  have reported that JAK2 mutation in
ET brings up a distinct clinical entity with a
biological phenotype intermediate between JAK2
wild-type ET and PV. For the first time they
present a comparison between the thrombotic risk
of ET and PV patients defined on the basis of their
JAK2 mutational status .
They have reported for JAK2 mutation ET
and PV that hemoglobin and hematocrit levels as
well as white cells number and activation parameters
(PRV1 and LAP)  increase whereas platelet
number decreases as compared with those with
JAK2 wild-type ET.
The association between increased granulocyte
PRV-1 and LAP expression and thrombosis is
noteworthy. Their recent data showing that
leukocytes of JAK2 mutated ET patients present a
prothrombotic state indicated by a significantly
increased expression of surface tissue factor and
fibrinogen and a tendency to form higher numbers
of leukocyte-platelet aggregates . These results
explain why hydroxyurea is more effective in
reducing the thrombotic events particularly in
JAK2 mutated ET patients and anagrelide (a
megakaryocyte restricted inhibitory agent) is not
, and also hydroxyurea possibly reduces
the leukocytes-platelet aggregates by endothelin
1gene and ICAM-1 overexpression and by
increasing the NO level .
J. Smalberg et al. reported the association
between thrombosis of the hepatic veins – the
Budd-Chiari syndrome – BCS and the JAK2V617
mutation status. The mutation occurred in 59% of
BCS patients  and may be used to characterize
occult MPD – as a molecular diagnostic hallmark –
and could be included in the early diagnosis for
MPD in BCS.
Tefferi  underlines that it is reasonable to
consider the screening of JAK2V617 mutation in
the initial evaluation of unexplained thrombocytosis,
unusual thrombotic complication including abdominal
or cerebral vein thrombosis, arterial events at
young age and other MPD characteristic clinical
manifestations including erythromelalgia .
Despite the rare occurrence of thrombocytopenia,
some patients with MPD may sometimes develop life
threatening thrombotic complications like PTE
(pulmonary thromboembolism), DVT (Deep vein
thrombosis)  highlighting the importance of the
functional study of the platelet mainly through the
flow-cytometric study of their activation.
Since the platelet number is not the only
factor that controls the thrombotic or hemorrhagic
5 An update on the platelet dysfunction
diathesis in MPD, the importance of studying
platelet function is increasing. Outlining the genetic
profile (hence the molecular changes) may provide
early predictors for potentially vital complications
in patients diagnosed or susceptible of MPD.
Acknowledgements. The current article was written
based on the data collected during a National Research Grant
in the Program “Excellence in Research” – MULTRO (A
complex, multidiscipline study of platelet in myelodysplastic
and myeloproliferative syndromes with 5 partners) sponsored
by the Romanian Ministry of Research and Development.
Diateza trombotică şi cea hemoragică reprezintă complicaţii frecvente în
sindroamele mieloproliferative cronice (SPMC) şi în sindroamele mielodisplazice
(SMD). Aceste modificări sunt corelate atât cu numărul absolut de trombocite, cât
şi cu prezenţa anumitor defecte calitative, precum alterări ale glicoproteinelor
membranare, care pot fi evidenţiate prin diferite teste plachetare, inclusiv examenul
flowcytometric. Modificările glicoproteinelor membranare induc alterarea activării,
secreţiei şi agregării plachetare. Receptorul pentru trombopoietina (cMPL) afectat
de mutaţia JAK2 V617, întâlnită în sindroamele mieloproliferative, poate fi asociat
cu apariţia unui status protrombotic. Implicaţia sa relevă importanţa profilului
genetic molecular în definirea unor markeri moleculari de diagnostic, făcându-l
astfel candidat pentru diagnosticul precoce al sindroamelor mieloproliferative şi
predictor pentru complicaţiile trombotice apărute în acest grup de boli.
Author correspondence: Ana-Maria Vlădăreanu, Assistant Professor
Department of Hematology, Emergency Universitary Hospital
169, Splaiul Independenţei, 050098, Bucharest, Romania
Phone no: +4021 318 05 22, Fax: +4021 318 05 70
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Received February 7, 2008
Ana Maria Vlădăreanu et al. 8
Physical Training – Beyond Increasing Exercise Capacity
D. ZDRENGHEA1, LAURA POANTĂ2, DANA POP2, V. ZDRENGHEA2,
1Cardiology Department, Rehabilitation Clinical Hospital, Cluj-Napoca
2“Iuliu Haţieganu” University of Medicine and Pharmacy, Department of Internal Medicine, Cluj-Napoca, Romania
Physical training has traditionally represented the main method used in cardiovascular
rehabilitation of ischemic patients in the past years. Nowadays, cardiovascular rehabilitation has been
extended to other cardiovascular diseases, such as heart failure. Also, cardiovascular rehabilitation
included psychological, social and professional measures along with secondary prevention methods
such as lifestyle changes.
It has also been found that physical training has other additional effects which increased
exercise tolerance. Effects on the risk factors regard beneficial effect on body weight, on the serum
lipids levels, on psychosocial stress, on high blood pressure and on insulin resistance and diabetes
mellitus. Physical exercise has also beneficial effects on the balance between sympathetic – vagal
tone, inducing a vagal predominance, has anti-atherogenic and anti-ischemic effects, influencing the
endothelial function, the inflammation (anti-inflammatory effect), both arteriogenesis and
angiogenesis and thrombosis. Physical training could improve the symptoms of coronary patients by
preconditioning, which has a protective effect for the myocardium.
We may state that physical exercise has beneficial effects in cardiovascular patients because it
increases exercise tolerance with positive consequences on the quality of life and professional
reintegration, but also because it has positive effects beyond this. Thus, physical exercise should be
practiced through cardiac rehabilitation programs, by all cardiovascular patients.
Physical training has traditionally represented
the main, if not the only, method used in
cardiovascular rehabilitation of ischemic patients in
the past decades. Nowadays, cardiovascular
rehabilitation has been extended to other types of
cardiovascular diseases. The benefits of physical
exercise and physical training were clearly
evidenced in the patients with heart failure and
rhythm disturbances and, like secondary prevention,
it practically turned from a therapeutic means into a
lifestyle . Gradually, cardiovascular rehabilitation
included psychological and socio-professional
assistance and later secondary prevention measures,
concerning diet and other measures against risk
factors . In parallel with this evolution, it has
also been found that physical training has other
additional effects that increased exercise tolerance,
as it will be shown below.
In the body’s adaptation response to exercise
of both the healthy individuals and the cardiovascular
patients, there are peripheral and central mechanisms
Peripheral mechanisms consist of arteriolar
vasodilatation in the active areas, arteriolar vaso-
constriction in the inactive areas, with redistribution
of the cardiac output and increase of tissue oxygen
extraction from 20% to 80% in all the muscles,
except for the cardiac one (already maximal
extraction at rest) .
The central mechanisms are represented by
the increase of the ventricular stroke volume
secondary to the increase of venous return and
increase of the ejection fraction following
sympathetic activation, and the increase of heart
rate, which in the healthy individual represents the
most important central mechanism of adaptation to
exercise. The difference between trained and
untrained healthy individuals consists in an earlier
involvement of the central mechanisms in unfit
A similar decrease of exercise tolerance is
found in patients with coronary disease, heart
failure or other cardiovascular disease; with coronary
disease, exercise is limited by pain (ischemic
threshold), while in heart failure, by dyspnea
(Figs 1 and 2). Physical training increases the
efficiency and the contribution of the peripheral
mechanisms of adaptation to exercise [4–6].
ROM. J. INTERN. MED., 2008, 46, 1, 17–27
18 D. Zdrenghea et al. 2
Fig. 1. – The imbalance between oxygen supply (coronary blood
flow and arterial oxygen content) and oxygen demand (heart rate,
myocardial contractility and wall stress) in ischemic heart disease.
MVO2 = myocardial oxygen consumption.
Fig. 2. – Mechanism of exercise capacity limitation in subjects
with congestive heart failure.
MVO2 = myocardial oxygen consumption;
VO2 max = maximal oxygen consumption.
It was already shown several decades ago that
inpatients with myocardial infarction undergoing
rehabilitation programs had a significantly lower
mortality rate than those not enrolled in such
programs, at the same time return to work being
double . The benefits of physical training
beyond the increase of the exercise capacity have
been clearly demonstrated by a series of meta-
analyses of numerous clinical trials . These
meta-analyses showed that cardiac rehabilitation
and physical training reduced overall and cardiac
mortality and also that the benefits of rehabilitation
decrease with time, the difference in mortality
between trained and untrained patients disappearing
after 10 years .
The favorable effects are registered because
in fact physical training represents more than a
useful tool to increase exercise capacity. We will
discuss briefly these pleiotropic effects of physical
activity and training.
I. EFFECTS ON THE RISK FACTORS
Two aspects should be considered in the
relationship between physical training and cardiovascular
The first concerns the increase of compliance
to preventive measures in patients undergoing
physical rehabilitation. The second is the direct
benefic effect of physical exercise on some risk
factors. The two aspects are difficult to differentiate
because they are inseparable components of
It has been proved that patients enrolled in
exercise-based cardiac rehabilitation programs are
more compliant to other risk factors-modification
measures. In one of the most important studies
(PIN) the percentage of smokers, patients with high
blood pressure and increased cholesterol levels,
decreased from 36%, 24% and 57% respectively to
5% and 21% respectively after phase II of
rehabilitation. The importance of the rehabilitation
program was proved by the fact that after
12 months the above-mentioned risk factors increased
again to 10, 25 and 51%, respectively .
Adherence to low-salt, calories and lipids diet
is also much better in patients included in
rehabilitation programs .
It also increased adherence to preventive
medication, which came to compete with non-
pharmacological measures in the last decade, as
patients prefer to take drugs than give up what they
call “the joy of life” . The EUROASPIRE II
and III studies  showed that during almost ten
years the proportion of smoking, obesity and
sedentarism remained the same, while intake of aspirin,
angiotensin-converting enzyme inhibitors, beta-
blockers and statins increased significantly (Fig. 3).
The inclusion of patients in rehabilitation
programs was associated with increased intake of
preventive drugs, the maximal percentage being
evidenced for inpatient rehabilitation. Recent
studies  showed that 77% of inpatients
undergoing physical rehabilitation used beta-
blockers, 50% angiotensin conversion enzyme
inhibitors, 70% lipid-lowering drugs, the percentages
being less for outpatient rehabilitation: 44%, 32%
and 35% respectively.
3 Physical training and exercise capacity
Fig. 3. – Drug use in coronary secondary prevention in EUROASPIRE I, II and III trials
ACEI = angiotensin-converting enzyme inhibitors.
The direct effects are of relatively little
importance as compared to the indirect ones,
resulting from the observance of other preventive
measures. However, they cannot be overlooked as
they may considerably reduce the risk factors and
therefore influence the prognosis and mortality of
cardiovascular disease .
Effect on body weight showed that patients
included in exercise-based rehabilitation programs
may lose on the average 8.5 kilos body weight. If the
role of other body weight loss measures, especially
of low calories intake, is not taken into account, the
weight loss ascribed solely to physical exercise is 2–
3 kg, but this is important when other risk factors are
also influenced. It is also important that long-term
physical training of 3.5 hours per week contributes
to maintaining body weight, knowing that obese
patients who lose weight by diet and exercise tend to
regain weight if measures are discontinued .
There are studies, requiring further confirmation,
that reported that physical activity improved body
composition and fat distribution, which contributes
to the decrease of abdominal obesity, an important
component of the metabolic syndrome . From
this viewpoint, the importance of physical training
could increase, as metabolic syndrome is characterized
with an abdominal circumference over 80 cm in
women and over 92 cm in men, after the last
European definition .
Effect on the serum lipids levels is not
important quantitatively, but similar to that
reported for low-fat and low-calorie diet. There is a
general consensus regarding the beneficial effect of
serum triglycerides reduction, increase of HDL
concentration and mild decrease of total and LDL
cholesterol levels, the percent being around 5% in
all cases .
Physical exercise may reduce the percent of
small LDL levels and increase the percent of large
HDL, thus delaying the atherogenesis process, even
without any quantitative changes or with little
changes in LDL and HDL fractions .
In primary prevention, physical exercise
associated with diet, including dietary supplements,
may be enough to maintain plasma lipids within
normal ranges. However, in cardiovascular patients,
in secondary prevention, lipid-lowering drugs had to
be associated, but in this case physical exercise helps
to reduce drug doses and/or to increase drug effects.
Psychosocial stress proved to be one of the
six major risk factors for ischemic heart disease
and especially for acute myocardial infarction,
together with smoking, obesity, dyslipidemia, high
blood pressure and diabetes mellitus . Physical
exercise does not have a direct effect on psycho-
social stress, but routine exercising may contribute
to its minimization, especially by acting on
Current research work suggests that the
beneficial effect of physical training upon the impact
of stress on the cardiovascular system, along with the
effect of physical exercise on the vegetative nervous
system, may contribute substantially to the reduction
of arrhythmogenic impact of cardiovascular diseases,
especially of ischemic heart disease .
High blood pressure is favorably influenced
by physical exercise in two ways. First, routine
exercise increases the effects of non-pharmacologic
and pharmacologic measures used in the treatment
of BP. Second, physical exercise itself may lower
BP with 7–8 mmHg for systolic blood pressure and
5–6 mmHg for diastolic blood pressure .
As most patients with hypertension are sedentary, it
may be important that the above-mentioned
reductions may be obtained by moderate exercise
(walking), which may be safely performed by
patients with hypertension .
Insulin resistance and diabetes mellitus (DM).
Clinical trials have shown that in physically fit
individuals DM occurs later in life, while the
20 D. Zdrenghea et al. 4
intensity of vascular complications is lower .
The effect of physical training on insulin resistance
is also important, and positive effects are registered
also with moderate exercising (walking).
In patients with type 2 × DM, physical exercise
decreases fasting and postprandial hyperglycemia,
and reduces glycosylated hemoglobin levels by
0.5–1%. Consequently, cardiovascular complications
of DM are reduced and the evolution of associated
cardiovascular disease is improved.
II. EFFECTS ON THE AUTONOMIC FUNCTION
Physical exercise has beneficial effects on the
balance between sympathetic – vagal tone,
inducing a vagal predominance. On the other hand,
constant activation of the sympathetic nervous
system, decrease of vagal tone or of both increase
the risk of cardiovascular events and mortality in
patients with ischemic heart disease and heart
failure . Tachycardia is now a well-known
cardiovascular risk factor and decreases life
expectancy, while bradycardia increases it. In
patients with ischemic heart disease a lower heart
rate variability is positively correlated with
arrhythmogenic risks, reflecting the sympathetic
nervous system dominance .
In patients with hypertension and left
ventricular hypertrophy (which also represents an
arrhythmogenic risk factor) plasma noradrenaline is
significantly higher than in athletes with the same
degree of left ventricular hypertrophy, but without
high blood pressure . This is correlated with the
finding that in hypertensive patients with left
ventricular hypertrophy, the QT interval is more
prolonged than in athletes with the same degree of
hypertrophy. Continuous physical training has a
beneficial effect in hypertension also by reducing
plasma noradrenalin by 29% and plasma rennin by
III. ANTI-ATHEROGENIC AND ANTI-ISCHEMIC
EFFECTS OF PHYSICAL EXERCISE
A number of mechanisms are involved,
classified into several main categories:
a. EFFECTS ON THE ENDOTHELIAL FUNCTION
Endothelial function plays a major role on the
onset and evolution of atherosclerosis .
Thus, the endothelial function is depressed in
patients with diabetes mellitus, high cholesterol
levels, hypertension, smoking, obesity, as well as
in coronary patients; the decrease of the endothelial
function is directly correlated with the severity of
clinical symptoms . Decreased endothelial
function also contributes, by increasing peripheral
resistance, to the aggravation of symptoms and
evolution in chronic heart failure (CHF) patients,
which is a continuous increasing group because of
the continuous improving treatments for all the
diseases that lead to CHF.
It has been shown that the endothelial
function decreases with age and is clearly better in
physically fit individuals as compared to sedentary
ones . The experimental and clinical study of
endothelial function and dysfunction includes a
number of parameters, the most well-known and
accessible being the vasodilatation response to
acetylcholine or during reactive hyperemia. The
intensity of the vasodilatation response is assessed
by ultrasounds, which is an available, inexpensive
and non-invasive method, but also by coronary
angiography in selected patients. Carotid Doppler
may also assess the flow velocity and thus the
output induced by vasodilating procedures.
There is also an endothelium-independent
vasodilatation which may be induced by the
administration of nitrates or other direct vaso-
dilators like sodium nitroprussiate (29). The
comparison between endothelium dependent and
independent degree of vasodilatation may provide
useful information regarding the impact of certain
drugs or other non-pharmacological methods on the
endothelial function .
Studies of sedentary patients  have
reported that short-term (days) and long-term
(weeks) exercise improved arterial vasodilatation
and flow in the brachial artery during reactive
hyperemia; they were not influenced by physical
exercise in case of administration of nitroglycerin
(endothelium independent vasodilatation). With
short-term exercise, the positive effect disappeared
after 5–6 days, while with the long-term one it
disappeared after two weeks. Both findings support
the necessity of constant and long-term training in
order to improve endothelial function.
In patients with ischemic heart disease,
physical exercise improves endothelial function,
but there are also controversial findings. Heart
failure represents another area in which physical
exercise has been proved beneficial on the
5 Physical training and exercise capacity
endothelial function. During six months of aerobic
physical low / moderate training peripheral and
pulmonary vascular resistance decreased, while in
untrained patients they increased in the same period
of time . Peripheral vascular resistance decrease
is reflected in the increase of ventricular stroke
volume during maximal exercise, resulting in the
improvement of cardiac function and increase of
Physical exercise may also improve the
endothelial function in patients with hypertension
or metabolic syndrome , in which a significant
increase of the brachial diameter post reactive
hyperemia was reported after 12 weeks, 3 times a
week exercise .
b. ANTI-INFLAMMATORY EFFECT
The role of inflammation in the progression
of atherosclerosis is well established. There are
numerous studies on this subject; it should only be
mentioned that in ischemic heart disease inflammatory
factors cause endothelial dysfunction, associated
with low levels of nitric oxide and increased
oxidative stress, which is responsible for the initiation
and the progression of atherosclerosis and substantially
contribute to the instability of the atherosclerotic
plaque, which entails major complications like acute
coronary syndrome or sudden death .
Besides the reduction of inflammation by
statins, angiotensin-converting enzyme inhibitors,
angiotensin receptor blockers or calcium channel
antagonists, physical exercise also proved able
to lower inflammatory response through non-
pharmacological methods, with benefic clinical
Short-term physical exercise has a pro-
inflammatory effect , less marked in trained
individuals, but in time, with sustained physical
training, the pro-inflammatory response is diminished
and the rest inflammatory status is markedly decreased
in patients with heart ischemia and failure [40–42].
The CRP, as an acute phase reactant and
overall indicator of the inflammatory reaction,
decreases in ischemic patients during physical
training . In a recent study, , after 12 weeks
of exercise in patients with ischemic heart disease,
the authors described not only a considerable
decrease of the C reactive protein, but also a
decrease of pro-inflammatory cytokines IL1 and
IL6. In older adults, over 180 minutes exercise per
week significantly lowers C reactive protein after a
few weeks (Fig. 4) .
Fig. 4. – Concentration of serum C reactive protein (CRP) by amount of weekly exercise in elderly adults
(after Colbert LH et al., 2004).
c. EFFECTS ON ARTERIOGENESIS AND
Artreriogenesis and angiogenesis represent two
mechanisms by which the circulation in the ischemic
muscular and myocardial tissues may be improved. If
arteriogenesis refers to the enlargement of pre-existing
collateral arterioles (development of collateral
circulation), angiogenesis refers to the proliferation of
capillaries within a tissue, in fact neo-angiogenesis.
22 D. Zdrenghea et al. 6
Angiogenesis may be of two types . The
first is the intussusceptive type, consisting of a
growth process of the capillaries by longitudinal
intra-luminal division. The second type, true
angiogenesis or sprouting angiogenesis, consists of
the appearance of new capillaries following
extensive proliferation of endothelial cells and
degradation of the cell matrix, which allows the
endothelial cells to migrate and form new luminal
structures . This type of angiogenesis is
initiated by ischemia of a certain territory, mainly
of the muscular one. A primary role in the
appearance and development of angiogenesis has
been attributed in the last decade to endothelial
progenitor cells (EPC) originating in the bone
marrow, which migrate with the blood flow to a
certain tissue where they initiate and develop
angiogenesis, resulting in new capillary structures
and improvement of distal circulation [47–49].
It has been demonstrated that EPC are
reduced in the blood of patients with manifest
coronary heart disease or at risk of ischemic heart
disease. Physical exercise has a positive effect on
angiogenesis, acting on the EPC count, which
increased both in experimental animals and in
studied patients .
Besides increasing EPC by bone marrow
mobilization, physical exercise also enhances their
availability for angiogenesis by decreasing EPC
apoptosis in circulating blood .
The effect of exercise-based cardiac rehabilitation
programs on myocardial angiogenesis is possible and
probable because silent ischemia is often found in
coronary patients during their daily activities and
physical exercise and it contributes to angiogenesis
via EPC .
d. ANTITHROMBOTIC EFFECTS OF PHYSICAL
Thrombosis plays a major role in the clinical
complications of atherosclerosis, being often responsible
for the sudden death occurring with ischemic heart
disease and CHF .
The effects of physical exercise and physical
training on the prothrombotic factors in atherosclerotic
patients are so far uncertain and contradictory. It seems
that exercise does not influence platelet aggregation
and function in healthy individuals, but it increases
those parameters in ischemic patients, during and
immediately after physical training .
Studies suggest that, in turn, long-term
exercise may have beneficial effects in this respect
. The effects of physical exercise on the
coagulation factors are less known. After six weeks
of intense physical exercise in patients with angina
pectoris, serum fibrinogen significantly decreased,
while the effect on fibrin was absent .
Most studies report that physical exercise,
acute or chronic, may activate fibrinolysis, which
represents the main mechanism of its antithrombotic
e. ISCHEMIC PRECONDITIONING
Ischemic preconditioning refers to the
finding, experimental at first and then clinical, that
short episodes of myocardial ischemia protect the
myocardium from unwanted effects of subsequent
ischemic events . The protective effect occurs a
few minutes after the initial preconditioning
episode and lasts 1–2 hours, representing the so-
called early window of ischemic preconditioning or
early ischemic preconditioning . After 24 hours
the protective effect reappears even in the absence
of other ischemic episodes, the protective effect
being weaker but longer, up to 72 hours, achieving
the second window of preconditioning or late
Both early and late ischemic preconditioning
has clinical, electric, arrhythmic, hemodynamic and
metabolic consequences. Preconditioning correlates
with mitochondrial protection, thus preserving
mitochondrial activity and energy production,
which increases cell survival .
Regarding the relationship between pre-
conditioning and physical exercise, experimental
studies in dogs have evidenced that exercising
before inducing coronary obstruction led to early
and late ischemic preconditioning, reducing the
size of myocardial infarction .
In human pathology the early preconditioning
has been incriminated in the so-called “warm-up”
phenomenon, consisting in the appearance of an
anginous episode at the beginning of exercising; then
angina occurs with much heavier exercise or is even
absent during exercise (walking, daily activities, etc.).
Several studies have mimicked the phenomenon by
performing successive exercise tests at 30 to 60 min
intervals; with exercise testing performed in the first
window of preconditioning, the depression of the ST
segment was delayed, the ischemic threshold was
7 Physical training and exercise capacity
increased (double product) and maximal ST segment
depression was reduced .
It has been demonstrated that in elderly
patients there is a loss of ischemic preconditioning,
but exercise and diet can restore the preconditioning
capacity; this has been evidenced experimentally,
attributed the restoration of noradrenaline release
after the preconditioning episode (noradrenaline
proved to be one of the triggers of preconditioning)
. In a clinical setting, pre-infarction angina was
found to be beneficial in elderly patients only if
patients performed physical exercise weeks and
months before the infarction .
Direct evidence of the importance of
rehabilitation in the initiation and maintenance of
late preconditioning was provided by Zdrenghea et
al. , who showed that after moderate to intense
physical training for weeks, ST depression was
delayed, maximal ST depression was lowered and
the ischemic threshold was raised, demonstrated by
the results of exercise testing at the end of the
rehabilitation program, compared with those at the
beginning of the program. The same authors
evidenced that by successive exercise tests at 24
hours interval, during the 2nd test, serum nitrites
levels were significantly higher post effort, which
is in accordance with the mechanism of late
preconditioning, which is increased NO production.
All these data suggest that physical training
could improve the symptoms of coronary patients
by preconditioning, provided that the interval
between exercise sessions should not exceed
48–72 hours, ideally they should be 24–48 hours.
From the presented data it is clear that
physical exercise has a number of beneficial effects
in cardiovascular patients, beyond the increase of
In order to translate the effects obtained from
the experimental and clinical studies to practice,
several questions must be answered. One of the
most important is the following: how important is
the role of exercise as compared to other anti-
atherogenic and anti-ischemic measures like drug
therapy or revascularization? In order to validate its
uses physical training should establish its place as a
substitution or associated measure to obtain the
end-points for each of the above-mentioned measures,
namely the reduction in cardiovascular morbidity
If we refer to the treatment of risk factors,
the question is whether regular exercising allows
for a less restrictive lifestyle which includes
smoking, a salty, fatty or high-calorie diet, or does
it only lead to a better acceptance of a healthy life
style. It seems that the main benefit of exercise is a
better adherence to other preventive measures,
along with direct effects for most of the
cardiovascular risk factors, except for smoking .
A much more difficult question refers to
drug prevention: the association of physical
exercise may reduce the number of necessary
drugs, their dosage, or may have no influence at
all? None of the essential preventive drugs, such as
antiplatelet drugs, ACE inhibitors, beta-blockers or
statins, should be given up, but it seems that long-
term exercise may enhance the effects of these
The third question which refers to the
comparison between the effects of physical training
and myocardial revascularization has a clear
answer , especially concerning PTCA, but the
effect may be extended to the coronary bypass. The
costs were much lower in the case of training, but
cardiovascular events were reduced and exercise
tolerance increased in the conservative and exercise
therapy group, as compared with the PTCA
revascularization group (without subsequent training).
This finding is extremely important for the communities
or countries in which costs should be kept low, but
also for developed countries in which an alternative
to the “risky” myocardial revascularization may be
preferred by the patient.
Another category of questions refers to the
intensity and duration of physical exercise. Not
all the benefic effects of physical exercise require
high level training. In patients with heart failure, an
intensity of 40–60% of the maximal exercise
capacity, established by exercise testing, may be
beneficial for the increasing of effort capacity and
for influencing risk factors, inflammation or the
endothelial function itself . However, other
effects, such as angiogenesis, cannot be obtained
without high level physical training, about 80–85%
of the maximal VO2.
Regarding the duration of exercise, if initially
it was considered that improved exercise capacity
could be achieved by 30 to 60 minutes sessions three
times per week, at present duration is increased,
exceeding 3.5 hours per week, or 30 minutes per
24 D. Zdrenghea et al. 8
day. Though daily exercising provides optimal
results, 3.5 hours per week in weekly sessions
yields similar results .
Another question is raised: should the
patients which cannot, or do not have the means to
perform 3.5 hours of physical training per week
abandon this idea entirely? The answer is no. The
patients will beneficiate both after more preventive
measures at a lower intensity or after one intense
measure for a certain risk factor.
The last question is for how long physical
training should be undertaken in order to influence
cardiovascular morbidity and mortality. Physical
exercise is indicated to be taken for the whole
lifetime. This is the reason why, after the initial
rehabilitation (phase II), physical training is
recommended in an organized form for periods of
6–12 months (phase III). The fourth phase depends
În mod tradiţional, antrenamentul fizic a reprezentat mulţi ani principala metodă
folosită în recuperarea pacienţilor coronarieni. În zilele noastre, recuperarea
cardiovasculară a fost extinsă şi la alte categorii de pacienţi cu boli cardiovasculare,
cum este cazul celor cu insuficienţă cardiacă. De asemenea, recuperarea
cardiovasculară s-a extins şi la măsuri de ordin psihologic, social, profesional, alături
de cele specifice de prevenţie secundară, cum ar fi schimbarea stilului de viaţă.
S-a dovedit şi faptul că antrenamentul fizic are şi efecte adiţionale benefice,
care cresc toleranţa individului la efort. Efectele antrenamentului fizic asupra
factorilor de risc se reflectă asupra greutăţii corporale, asupra nivelului seric al
lipdelor, stresului psihosocial, valorilor tensiunii arteriale şi insulinorezistenţei.
Antrenamenul fizic are efecte benefice şi asupra balanţei simpato-vagale, în sensul
creşterii tonusului vagal, are efecte antiischemice, influenţând favorabil funcţia
endotelială, inflamaţia (efect anti-inflamator dovedit), angiogeneza şi arteriogeneza în
egală măsură, precum şi trombogenza. Efortul fizic se pare că ameliorează
simptomele pacienţilor coronarieni prin mecanismul precondiţionării, cu efect
protector asupra miocardului.
Putem afirma că antrenamentul fizic are efecte benefice la pacienţii
cardiovasculari prin creşterea toleranţei la efort – cu efecte pozitive asupra calităţii vieţii
şi reintegrării profesionale, dar şi prin efecte adiţionale care trec dincolo de aceasta.
Astfel, antrenamentul fizic, prin programele complexe de recuperare cardiovasculară,
ar trebui practicat, individualizat, de toţi pacienţii cu boli cardiovasculare.
almost exclusively on the patient as it should be
performed for the whole duration of life.
In conclusion we may state that physical
exercise has beneficial effects in cardiovascular
patients, because it prevents the effects of
sedentarism or prolonged bed rest, it increases
exercise tolerance with positive consequences on
the quality of life and social and professional
reintegration, but also because it has effects beyond
the increase of exercise capacity. Thus, due to its
multiple quality features, physical exercise should
be practiced by all cardiovascular patients. This is
not possible exclusively in institutions such as
hospitals or ambulatory; therefore, it should be
performed as a lifestyle feature of cardiovascular
patients, but within the limits imposed by the
functional parameters related to the particular
Corresponding author: D. Zdrenghea, Professor of Cardiology
Cardiology Department, Rehabilitation Clinical Hospital
46–50 Viilor St., Cluj-Napoca, Romania
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Received January 8, 2008
28 D. Zdrenghea et al. 12
Total Cardiovascular Risk Estimation in Romania.
Data from the SEPHAR Study
MARIA DOROBANŢU1, ELISABETA BĂDILĂ1, S. GHIORGHE1,
ROXANA O. DARABONT2, M. OLTEANU3, P. FLONDOR3
1Department of Cardiology and Internal Medicine, Floreasca Emergency Hospital, Bucharest
2Department of Cardiology, University Hospital, Bucharest
3Polytechnical University, Bucharest
Objective of this sub-study was to assess the impact of major CV risk factors on mortality due
to CV diseases among Romanian adult subjects using the SCORE System.
Study Design and Setting. In 2005, a survey for CV risk factors (SEPHAR) was performed in
Romania involving 2017 subjects aged over 18 yrs, a representative sample for the Romanian adult
population. Romania’s area was divided into ten regions recommended by The National Commission
of Statistics. We evaluated the relationship between gender, age, smoking status, systolic blood
pressure and total cholesterol and cardiovascular risk. Ten year risk of fatal cardiovascular disease
was estimated according to the SCORE (Systematic COronary Risk Evaluation) System.
Results. Average total risk in Romanian adult population was 3.5%. Male population had a
significantly higher risk than females (5.4% vs. 1.7%, p<0.01). About one fifth of subjects (20.7%)
had a high risk ≥5%. Four percent of subjects (all males) had a very high risk ≥15%. The CV risk was
relatively homogeneously distributed between Romania’s geographic regions. The prevalence of
hypercholesterolemia as CV risk factor was high (40%), and also was the prevalence of high systolic
blood pressure (36.6%). The prevalence of smoking was similar to other European countries (27%).
Conclusion. Our study showed Romania as a country with a high cardiovascular risk, being
also one of the regions in Europe with the highest CV risk.
Key words: cross-sectional survey; global CV risk; SCORE system.
Cardiovascular disease (CVD) is a major
cause of disability and mortality. Identification of
people who are at high risk of developing CVD but
currently having no symptoms has become an
accepted method for the primary prevention in many
countries. Interventions targeted at modifiable risk
factors, such as hyper-cholesterolemia, hypertension,
and smoking, can delay or even prevent the
occurrence of CVD. Furthermore, multiple risk
factor interventions in high risk groups are more
beneficial than single risk factor interventions .
Recognition that major cardiovascular risk
factors, such as high blood pressure (BP),
dyslipidemia, and diabetes mellitus, often cluster
together, has focused attention on the concept of
total cardiovascular risk.
The need to estimate total CV risk in apparently
healthy individuals has been strongly advocated
since 1994 by the joint recommendations from the
European Society of Cardiology, European Society
of Hypertension, European Atherosclerosis Society
and other societies. The goal was to find a tool
which clinicians could use to better identify
patients at high total risk of developing CV disease.
The challenge is now to use this tool to reduce the
risk of CV disease and death.
Probably the simplest type of quantitative
risk assessment should be based on cardiovascular
death as the endpoint. This is gaining favour as the
preferred endpoint among European epidemiologists.
Another logical endpoint is all cardiovascular
events, which include coronary heart disease
(CHD) events and stroke. Some authors prefer to
include heart failure among the CHD events, but
others restrict it to fatal and nonfatal myocardial
infarction (MI). This endpoint is particularly favoured
by many groups interested in hypertension treatment,
because BP lowering reduces stroke more than CHD
(in terms of relative risk about 36% vs. 18–21%) in
nearly all clinical trials. Several comparisons of
ROM. J. INTERN. MED., 2008, 46, 1, 29–37
Maria Dorobanţu et al. 2
various risk estimators suggest that a cut-off of CVD
risk ≥ 20% over ten years is roughly equivalent to a
CHD risk ≥ 15% over ten years [2, 3].
The algorithms that have been used in risk
assessment vary in complexity from simply
counting the existing risk factors  to complex
equations (derived from a Weibull accelerated
failure regression model) . These scores have
been calculated by different research groups and
scientific organizations with the aim of better
defining the real risk of a given population over
time. Many of these risk scores have been conceived
by American and European scientific groups on the
basis of the epidemiology of different risk variables
in the respective populations; in general, North
American hypertensives are exposed to a higher
cardiovascular risk compared to Europeans and some
European countries have a higher risk than others.
The European Society of Cardiology initiated
the development of a risk score system – SCORE
(Systematic COronary Risk Evaluation) using data
from 12 European cohort studies (N=205 178)
covering a wide geographic spread of countries at
different level of CV risks . The SCORE data
contains some 3 million person-years of observation
and 7 934 fatal CV events. The SCORE system
estimates risk of cardiovascular death based on age,
sex, smoking habits, blood pressure values and blood
cholesterol (or cholesterol/HDL ratio).
The absence of data that are representative for the
entire adult population of Romania regarding the
prevalence of hypertension and of other cardiovascular
risk factors determined the performance in 2005 of a
national study intended to obtain such parameters.
Thus, between February–November 2005, the
SEPHAR – Study for Evaluation of Prevalence of
Hypertension and cardiovascular risk in Adult
population in Romania – was performed. This is the
first epidemiologic study in Romania based on a
representative sample for the whole population of the
country. At the same time it is the first study that
assessed, together with hypertension, other cardiovascular
risk factors: smoking, dyslipidaemia, insulin
resistance, diabetes, obesity, family history of CV
disease and the plasma level of C-reactive protein.
The purpose of this sub study was to assess the
impact of major CV risk factors on mortality due to
cardiovascular disease among Romanian adult
subjects using the SCORE System.
The sample selection of the subjects was meant
to maintain the principle that every person among the
adult population of Romania should have
approximately the same chance of being included in
the study, irrespective of the place of residence, by
applying the method of stratified proportional
sampling. The programme of selecting the sample was
elaborated and applied by a specialized company. In
order to have a statistical significance in relation to the
whole population of the country, the size of the sample
was designed for a minimum of 2000 finalized cases.
Romania’s area was divided into ten regions –
recommended by The National Commission of
Statistics, on the basis of some criteria which are
also made up of health indices. The regions are:
South, South–East, East, Nord–East, North, Central,
North–West, West, South–West and Centre–South.
The number of locations of a certain size was
selected in direct proportion with the population of
the respective region. The structure of the
population aged ≥ 18, according to gender, from
every layer, was obtained from the Central Bureau
of Statistics, having as a source – document the
Census made in 2002, while the number of male
and women to be interviewed in a certain layer had
to maintain the rule of proportion once again. On
the whole, 4457 addresses were selected. In
relation to these, the subjects were found, they
agreed to participate in the study and signed the
informed consent and they filled in the
questionnaires in 2143 cases, 2017 cases being
finalized (response rate 45%). We have to point out
the fact that a case was considered to be finalized
when the subject accepted to participate in the
study, answered the questionnaire and had his/her
blood tested according to the agreement.
By using the SCORE chart for the countries
with a high risk of cardiovascular disease, we
analyzed the risk of fatal cardiovascular events for
the next 10 years globally for the whole country
and separately for the 10 regions. The factors used
to calculate the risk were those recommended in
SCORE: age, sex, smoking, values of systolic
blood pressure (SBP) and total cholesterol .
The “smoking” variable comprised current smokers.
Total cholesterol (TC) levels were determined by the
enzymatic method. The cut-point for TC was based
on the NCEP–ATP III  and was considered high at
values ≥ 200 mg/dL (5.18 mmols/L).
3 Total cardiovascular risk estimation in Romania
Descriptive analyses (means, medians, standard
deviation, standard kurtosis, standard skewness,
frequency tabulation, confidence intervals, frequency
histograms and density traces) were calculated for the
risk factors of interest: high blood pressure, total
cholesterol, gender, smoking and age.
By using the SCORE chart for high-risk
regions we computed the score for each subject.
Descriptive analysis of the SCORE was performed
for each of the ten regions, separately for male and
female populations. The total SCORE risk (for
males and females) was calculated by using the
weighted method according to the last census (due to
the above-mentioned proportions in the sampling).
In order to compare the SCORE risk (and the
risk factors prevalence) between different categories
of population (regions, country, males, females) we
used two-samples and multiple-samples comparison
analysis: multifactorial ANOVA, Kruskal-Wallis test
(due to the fact that for the SCORE, the standard
kurtosis and standard skewness are not within the
range expected for data with a normal distribution)
and some other tests.
All computations were run with SPSS 12.0
(Statistical Package for the Social Science) and
MatLab 6.5 on a PC.
The demographic characteristics and the
distribution of risk factors for the analyzed population
are shown in Table I.
Demographic characteristics and prevalence of the analyzed risk factors
48.2 ± 16.5
137.5 ± 23.7
48.9 ± 17.0
47.7 ± 16.2
p M vs F
Mean age (yrs)
Mean SBP (mmHg)
Mean SBP for age
Smokers 27% (545) 37.3% (316) 19.4% (227) <0.01
High cholesterol 40% (808) 39.1% (332) 40.6% (476) Ns
M – males, F – females
The gender distribution indicates that the
female population prevails over the male one with
58% versus 42%. The youngest participant was
18 years old, while the oldest was 85 years old.
The average age in the global group was 48.20±
16.55 years (CI±0.72).
Maria Dorobanţu et al. 4
The average values of systolic blood pressure
in the global sample per gender and age groups are
shown in Table I. The average value of SBP for the
entire sample was of 137.5±23.7 mmHg (CI±1.0;
136.5–138.5). As expected, the average SBP values
increased with age in males, as well as in females;
it is indeed well-known that the systolic blood
pressure is dominant in elderly people. A statistically
significant difference was noted between the average
SBP in males, 141.4±22.0 mmHg, as compared to
females, 134.9±24.0 mmHg (p<0.01). The gender
difference of average SBP was significant until the age
of 55 years, after which it became non-significant.
The percentage of subjects with optimal,
normal or high blood pressure (grade 1, 2 or 3) is
shown in Table I for the global sample, as well as
for gender distribution. The lowest systolic blood
pressure value was 82 mmHg, while the highest
was 234 mmHg. In our sample, the prevalence of
systolic hypertension was 36.6%, with a dominance
of males with grade 1 hypertension. It is to be
noted that the optimal blood pressure is more
frequent in females, while the mild hypertension
prevails in males. No significant differences were
noted in the prevalence of the moderate or severe
grade of the systolic hypertension between sexes.
The dominance of smoking as factor of
cardiovascular risk in the general population was as
high as 27% (545 subjects). The percentage of
smoking males is considerably higher than the
female subgroup, as well as than the general sample
(p<0.01). Regarding the distribution of smokers in
younger and middle age groups, this percentage was
stable in people aged between 25 and 55 (22.9%
smokers in the 25–34 age group, 22.2% in people
aged 35–44, 24.9% in people aged 45–54, p ns).
The prevalence of hypercholesterolemia (the
levels of total cholesterol ≥ 200 mg/dl) in the
global sample was 40% (808 subjects). The
average of cholesterol level in all subjects was
193.9±2.9 mg/dl (CI±1.8; 192.0–195.8); the lowest
level was 85 mg/dl and the maximum level 385
mg/dl. Unlike the other previous 2 risk factors,
there were no significant differences between
males and females (p=ns).
Taking into account the risk factors we
analyzed above: sex, age, smoking, values of systolic
blood pressure and values of total cholesterol, we
calculated the global risk of fatal cardiovascular
events using the SCORE chart. According to this
method, the average risk of fatal cardiovascular
events for the next 10 years in the analyzed sample (a
representative group for the adult population of
Romania) was of 3.5 [95.0% confidence interval for
mean: 3.5±0.2 (3.3–3.7); SD 4.9]; the minimum score
calculated was 0 and the maximum one was 35.
Figure 1 shows the scores as histograms for the entire
sample we analyzed.
0123456789 1011121314 15 161719 202122 242526 29 3035
Fig. 1. – Distribution of risk for fatal cardiovascular events according to SCORE chart.
5 Total cardiovascular risk estimation in Romania
The separate analysis of risk of fatal
cardiovascular events in males versus females was
statistically significant (p<0.01); the risk is
considerably higher in males (Table II, Fig. 2).
Comparison of global CV risk between males and females
± 0.4 (5–5.8)
± 0.1 (1.6–1.8)
Number of subjects
Average CV risk
Confidence interval (95%)
Median value (50%)
Fig. 2. – Comparison of global CV risk between males and females (comparison of
risk distribution density according to SCORE).
Regarding the regional distribution, the risk
of fatal cardiovascular events calculated according
to the SCORE chart was quite homogeneous
(Table III), except for the South-Eastern region,
where the average risk was significantly lower than
the average risk at the level of the whole sample
(2.5 vs. 3.5, p <0.05). In Northern and Western
regions, although the average risk value seemed
higher (4.2 and 4.2) as compared to the global risk
(3.5), the difference was not statistically significant
(p=ns), but the difference became significant as
compared to the region with the lowest risk
(Northern or Western region as compared to the
South-Eastern region, p<0.05). The difference in
the mean risk score between N, W and S-E regions
could reflect the old pre-First World Map of
Romania. The ethnical and cultural factors (not
measured in our study) could possibly explain the
Among the 847 males included in the study
sample, 36.8% (312) had a risk of ≥ 5% to develop
a fatal cardiovascular event in the next 10 years.
Moreover, 9.5% of the male population in Romania
had a very high risk level of ≥ 15%. Among the
female population, the risk of ≥ 5% was
significantly lower, of 9.1% (107); no female had
the calculated risk > 15%. As compared to the
whole lot, we could say that approximately 1/5 of
the adult population in Romania (20.7%) had a
high risk (≥ 5%) to develop fatal CV events in the
next 10 years. Four percent of the subjects (all
males) had an increased risk of ≥ 15%.
Maria Dorobanţu et al. 6
CV risk at regional level
± ± CI SD
CI – confidence interval; SD – standard deviation; M – males; F – females.
* p<0.05 for average risk of region vs. average risk of country
Fig. 3. – Comparison of the distribution of CV risk (as densities) between the regions with the highest,
lowest and average country risk level.
The SEPHAR study is the first epidemiologic
study performed in Romania, which provides data
about the prevalence of major CV risk factors. Taking
into consideration the study methodology, we can
consider that the data we obtained are representative
at national level for the population of Romania.
The increased prevalence of hypercholesterolemia
and of systolic hypertension proves that these are
major factors of cardiovascular risk in the assessment
of the global risk. It is obvious that an inappropriate
diet, an increased intake of salt and the lack of
physical activity substantially contribute to the
increased prevalence of hypertension and obesity.
These factors may also explain the differences
between some regions of the country and the
increase of the high blood pressure levels as people
get older. The guidelines for hypertension
treatment – ESH/ESC  and JNC 7  suggest
an intake of sodium chloride of 6 g/day at most and
promote a diet rich in fruits, vegetables and fish,
the decrease of the intake of saturated fats and
cholesterol. The intake of vegetables and fruits is
7 Total cardiovascular risk estimation in Romania
remarkably higher in southern European countries
(Mediterranean diet) as compared to countries of
Central and Eastern Europe, including Romania.
Smoking, high blood pressure and high
cholesterol have been identified as major CV risk
factors, and account for a great proportion of total
and cardiovascular mortality worldwide. According
to the latest estimation of the World Health
Organization, more than five million deaths are
attributable to the smoking habit and no less than
seven million to high BP .
The prevalence of smoking habit is estimated
to be around 30% of the adult population all over
the world (47% in men and 12% in women) .
In Romania, the prevalence of smoking was similar
with other countries, with a smaller percentage of
females, but a larger percentage of males.
Regarding the high blood pressure, it is found
no less than 30% of the adult population in most
countries, either developed or developing . In
our sample, the prevalence of systolic hypertension
was higher, with a dominance of males with grade 1
hypertension. This is important, because most
cardiovascular events occur in patients with only
mildly elevated blood pressure . In addition,
BP lowering in high CV risk patients decreases the
incidence of CV events, even in the absence of
All of the analyzed risk factors (smoking,
high BP, hypercholesterolemia) increase the final
cardiovascular risk when acting independently, but
their interaction in the same individual contributes
to a rise in risk by approximately 16-fold . The
underlying mechanism is mainly the acceleration of
atherosclerosis jointly with vascular and endothelial
Estimates of absolute risk in the next 10 years
are potentially useful for the identification of
patients who need aggressive risk reduction in the
clinical setting. Patients at a high risk may need
pharmacological agents to control risk factors and
this level of risk justifies aggressive risk reduction
SCORE chart takes into account gradations in
risk factors when estimating absolute risk. The
scoring does not adequately account for severe
abnormalities of risk factors, e.g., severe hypertension,
severe hypercholesterolemia, or heavy cigarette
smoking. In such cases, SCORE chart can
underestimate absolute risk. This underestimation is
particularly evident when only one severe risk factor
is present. Thus, heavy smoking or severe hyper-
cholesterolemia can lead to premature CHD even
when the summed score for absolute risk is not
high. In the SCORE chart, HDL-cholesterol levels
were not included. HDL-C is a powerful independent
risk factor, and its absence as risk factors in
SCORE must be considered a limitation. Another
difference of SCORE chart from other risk charts is
that diabetes is not included in the variables,
because diabetic patients are always considered as
high-risk patients, irrespective of the presence of
other risk factors or target organ damage.
Total cardiovascular risk models do not
consider the duration of exposure to a risk factor or
disease and their quantification is usually based on
some risk factors only, while paying limited
attention to other variables linked to cardiovascular
outcomes (e.g. physical activity and stress).
On the other hand, the risk for fatal CV
events within the next 10 years estimated according
to the SCORE chart represents an aid for the
practitioner to make clinical decisions about the
intensity needed when intervening in lifestyle
changes and whether to use drug therapy in the
management of risk factors. The prevention of
CVD should begin decades before middle age
because even the presence of a single major risk
factor at young age is associated with substantial
increased lifetime risk for CVD and a markedly
shorter survival. Younger and middle-aged individuals
with a modest risk level may have low short-term
risk, but a substantial life-time risk. Therefore, not
only those subjects who are at highest risk should
be identified and managed, but also those at high
risk should receive advice regarding lifestyle
changes and, in some situations, drug therapy will
be needed to control their risk factors. In those
individuals at medium risk we should do all that we
can to prevent a further development of their total
risk and promote efforts of primary prevention. In
subjects who are at low risk, we should keep their
risk as low as possible.
The management of patients with CV risk
factors has changed over the past decade. The focus
on single risk factor such as high BP or serum
cholesterol has given way to an approach that
accounts for the multifactorial origin of CV disease
and the requirement for a comprehensive management
of patients at high risk.
From the last guidelines of hypertension, we
must be aware about the strong effect of age on
total cardiovascular risk models. The younger
adults (particularly women) are unlikely to reach
Maria Dorobanţu et al. 8
high risk levels even when they have more than one
major risk factor and a clear increase in relative risk
(i.e. the existing risk compared to their peers). By
contrast, most elderly men (e.g. > 70 years) will
often reach a high total risk level whilst being at
very little increased risk relative to their peers. The
consequences are that
concentrated on older subjects, whose potential
lifespan is relatively short despite intervention, and
little attention is given to young subjects at high
relative risk despite the fact that, in the absence of
intervention, their long term exposure to an increase
risk may lead to a high and partly irreversible risk
situation in middle age, with potential shortening of
their otherwise longer life expectancy .
This study has some limitations. Measurement
of risk factors was performed once only at baseline,
which would likely lead to underestimation of the
impact of risk status. The use of death certificates for
ascertaining cause of death may result in overestimation
of CVD mortality .
Another limit of our study consists in the
absence of long term follow-up, as we have just
begun the follow-up procedure.
There were 58% female and 42% male
respondents in the sample. The 2002 Census for
Romania reported 52% female and 48% male in the
Obiectiv. Aprecierea impactului factorilor majori de risc asupra mortalităţii
cardiovasculare (CV) în populaţia adultă a României pe baza sistemului SCORE.
most resources are
population of adults aged 18 and over. This means
that females are over-represented in the sample as
compared to the Census.
Despite the limitations of our study, we
believe that our results present an important practical
issue. A significant percentage of Romanian adult
population had a high or very high risk for fatal CV
events. Our study proves that Romania is a country
with a high cardiovascular risk, being also one of
the highest risk regions in Europe. These results
might have a major public health impact. Indeed,
under-estimation of CV risk may lead to
insufficient, delayed or inadequate treatment and
further increase in morbidity and mortality.
Acknowledgements. The conduction of this study was
possible with the support of the Romanian Ministry of Health,
the Romanian Society of Cardiology and with the logistic
support provided by the company Servier Pharma Romania.
Data centralization and statistical analysis were performed by
the Mercury Research Company.
We are also grateful to all doctors and nurses who brought
their contribution to the good performance of this study.
Material şi metodă. În 2005, în România s-a desfăşurat studiul epidemiologic
SEPHAR, de depistare a factorilor majori de risc CV, incluzând 2017 subiecţi adulţi
>18 ani, un eşantion reprezentativ pentru populaţia adultă a României. Suprafaţa
ţării a fost împărţită în 10 regiuni, recomandate de Comisia Naţională de
Statistică. Am evaluat relaţia între sex, vârstă, statusul de fumător, tensiunea
arterială sistolică, colesterolul total şi riscul CV global. Riscul la 10 ani de
evenimente CV fatale a fost estimat conform sistemului SCORE (Systematic
COronary Risk Evaluation).
Rezultate. Valoarea medie a riscului în populaţia adultă a României este de
3.5%. Populaţia masculină are un risc semnificativ mai mare comparativ cu cea
feminină (5.4% vs. 1.7%, p<0.01). Aproximativ unul din cinci subiecţi (20.7%) are
un risc înalt ≥5%. Risc foarte înalt ≥15% au 4% subiecţi (toţi bărbaţi). Scorul de
risc CV a fost relativ omogen distribuit pe regiunile geografice ale României.
Prevalenţa hiper-colesterolemiei ca factor de risc CV a fost mare (40%), de
asemenea prevalenţa hipertensiunii arteriale sistolice (36.6%). Prevalenţa
fumatului a fost similară cu cea a altor ţări europene (27%).
Concluzii. Studiul nostru confirmă că România este o ţară cu risc cardiovascular
înalt, ea fiind dealtfel plasată între regiunile cu risc înalt din Europa.
9 Total cardiovascular risk estimation in Romania
Corresponding author: Professor MARIA DOROBANŢU
Department of Internal Medicine and Cardiology,
Floreasca Emergency Hospital Bucharest,
8 Calea Floreasca, Bucharest, Romania
Tel: +40 722 454 329 Fax: +40 21 317 01 08
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Received February 4, 2008
Maria Dorobanţu et al. 10
Lifestyle, Cardio-Metabolic Risk and Arterial Stiffness
D.M. DUDA-SEIMAN1, SILVIA MANCAŞ1, D. GAIŢĂ1, SIMONA DRĂGAN1, DANA VELIMIROVICI1,
STELA IURCIUC1, C.A. SARĂU1, M. IURCIUC1, MARIA RADA1, BILEANA PETCOV2
1“Victor Babeş” University of Medicine and Pharmacy, Dept. of Medical Ambulatory,
Cardiovascular Rehabilitation, Timişoara
2ASCAR Hospital Timişoara, Romania
HDL-cholesterol plays a key role defining the functional state of the arteries and the relation to
Aim. To assess the degree of arterial stiffness in asymptomatic subjects with and without
cardiovascular risk, depending on lipidic parameters behavior and on the insulin resistance state.
Methods. Arterial stiffness was assessed using the carotid-radial pulse wave velocity
(PWV-CR) measured with Complior; cardiovascular risk was calculated using the SCORE chart;
metabolic risk was quantified by assessing fasting lipidic (TC, TG, HDL, LDL) and glycemic
parameters (HOMA-IR>1 defines the insulin resistance state).
Results. 58 asymptomatic subjects, 57.62±14.40 years: 46.55% with (SCORE≥5%) and
53.45% without (SCORE<5%) cardiovascular risk. In subjects with SCORE<5% and low HDL
(<40mg/dL), PWV-CR is influenced by the TG/HDL ratio (R2=0.27, p=0.04); LDL<115mg/dL has a
powerful influence on PWV-CR (R2=0.58, p=0.02); the association of lipidic alterations is predictive
for increased PWV-CR (≥9.5m/s) (R2=0.85, p=0.008). In subjects with SCORE≥5%, protective HDL
level (≥40mg/dL) and HOMA-IR>1, PWV-CR is strongly related to the insulin resistance state
(R2=0.74, p=0.02), also to the association with LDL levels (R2=0.92, p=0.01).
Conclusions. The association between low HDL levels and other lipidic alterations in
asymptomatic subjects with low cardiovascular risk influences the degree of arterial stiffness.
Increased HDL levels and the presence of insulin resistance syndrome in high risk asymptomatic
subjects are predictive for arterial stiffness. This prediction is amplified by LDL association to the
metabolic state of the insulin resistance syndrome. It is necessary to establish target levels for HDL
and TG in the cardiovascular disease prevention guidelines.
There is general agreement and it is established
and emphasized in current guidelines that, beyond
specific pharmacologic therapy, a healthy lifestyle is
an important part of cardiovascular and cardio-
metabolic risk management for coronary artery
disease risk reduction . The atherosclerosis
process is initiated already during early childhood and
progresses with aging  as the result of the action
and interaction of many factors: genetic constellation
and a number of environmental factors  which
determine a certain lifestyle. The first impact of
different cardiovascular risk factors is on the vascular
wall and on the endothelium which are undergoing a
constant process of injury and repair .
Normal endothelium modulates the vascular
tone, the coagulation balance and the inflammatory
response. Endothelial dysfunction is an early
functional alteration stage of the arterial wall which
precedes structural atherosclerotic lesions . This
is also the case in the insulin resistance syndrome.
In 2003, the American Association of Clinical
Endocrinologists (AACE) modified ATP III criteria
to refocus on insulin resistance as the primary
cause of metabolic risk factors . Studies suggest
that the smallest particles in LDL fraction carry the
greatest atherogenicity and low levels of HDL are
independently atherogenic .
Low levels of HDL increase the coronary
artery disease risk, independent of the LDL level.
Studies suggest that an improvement with 1 mg/dL
in the HDL level reduces with 3% the risk of
coronary artery disease . HDL-cholesterol plays a
key role defining the functional state of the arteries
and the relation to cardiovascular risk. High-density
lipoproteins inhibit LDL oxidation, suppress the
expression and activity of adhesion molecules and
ROM. J. INTERN. MED., 2008, 46, 1, 39–45
D.M. Duda-Seiman et al. 2
are essential in the cholesterol inverse transport from
the arterial wall to the liver .
The aim of this work was to assess the degree
of arterial stiffness in asymptomatic subjects with
and without cardiovascular risk, depending on
lipidic parameters behavior and on the insulin
In the study 58 asymptomatic subjects
(without documented atherothrombotic cardiovascular
disease) were enrolled.
An anthropometrical physical exam was
performed. The following aspects were considered
a. Overweight and obesity: body mass index
(BMI ≥ 25 kg/m2 and ≥ 30 kg/m2, respectively)
 and/or waist circumference ≥ 94 cm in
men and ≥ 80 cm in women ;
b. Systolic blood pressure SBP ≥ 120 mmHg
(including individuals with high-normal blood
Pulse pressure was calculated as the difference
between systolic and diastolic blood pressure .
Fasting plasma lipidic parameters were
assessed on the Reflotron device (total cholesterol
[mg/dL], triglycerides [mg/dL], high-density lipoproteins
[mg/dL]); low-density lipoproteins LDL were
calculated using Friedewald’s formula (triglyceride
levels ≥ 400 mg/dL were excluded) :
LDL [mg/dL] = TC [mg/dL] – HDL [mg/dL] –
Fasting plasma glucose was expressed mg/dL
and mmol/L; the level ≥ 100 mg/dL was considered
abnormal. Insulin resistance was assessed from
fasting insulin and glucose levels and the
previously validated homeostasis model assessment
(HOMA-IR) , thus: HOMA-IR = fasting
glucose (mmol/L) x fasting insulin (µU/mL)/22.5.
 HOMA-IR > 1 was considered pathological.
In each subject the cardiovascular SCORE
risk was assessed online ; subjects with
SCORE ≥ 5% were at absolute cardiovascular risk
. Study population was divided into two
groups: with significant cardiovascular risk
(SCORE ≥ 5%) and with low cardiovascular risk
(SCORE < 5%), respectively.
Arterial elasticity was assessed with Complior
(Artech Medical), by measuring the carotid-radial
pulse wave velocity (PWV-CR). Subjects rested in
the supine position for 15 minutes; measurements were
taken immediately after measurement of brachial blood
pressure. The mean of 2 PWV-CR measurements was
taken for each subject. PWV-CR ≥ 9.5 m/s was
considered as an index of arterial stiffness.
Standard echocardiography with Doppler
studies was performed (Vingmed-General Electric).
Left ventricular diastolic dysfunction was classified
as abnormal relaxation pattern (defined as E/A ratio
< 1 or E/A ratio = 1 to 2 and deceleration time
[DT] > 240 ms) [16, 17].
Continuous variables were expressed as mean
value ± standard deviation; % lot were calculated.
validated with unpaired t Student test. Stepwise
regression was used to assess arterial stiffness
determinants in asymptomatic subjects with or
without cardiovascular risk. P-values < 0.05 were
considered significant. All statistical analysis was
performed using the Epi Info 6 statistical software
(version 6.04d, CDC – USA, WHO Geneva –
Switzerland) and Statistica (version 5.0).
the subgroups were
58 asymptomatic subjects (with no documented
atherothrombotic cardiovascular disease) were
enrolled in the study (mean age = 57.62±14.40 years).
27 subjects (46.55%) were at significant absolute
cardiovascular risk (SCORE ≥ 5%). Baseline
characteristics depending on the SCORE risk value
are shown in Table I.
Comparing the two subgroups (asymptomatic
subjects with SCORE ≥ 5% vs. those with SCORE
< 5%), we found that age was significantly higher
in the subjects at increased cardiovascular risk
(p=0.00009), as well as the pulse pressure level
(p=0.001). Obesity (defined by the body mass
index) was a significant feature in the subgroup of
low SCORE risk (p=0.006) (Fig. 1).
A. SCORE < 5% (31 subjects)
The TG/HDL ratio influences the functional state
of the endothelium measured by PWV-CR (R=0.52,
3 Lifestyle, cardio-metabolic risk
Baseline characteristics depending on the SCORE level
Age, years 65.11 ± 8.45 51.09 ± 15.41
BMI, kg/m2 27.64 ± 3.38 31.41 ± 6.17
HOMA-IR 2.21 ± 1.73 3.55 ± 4.86
TC, mg/dL 194.03 ± 44.88 195.77 ± 43.23
TG, mg/dL 179.33 ± 63.84 168.80 ± 36.66
HDL, mg/dL 41.22 ± 11.44 40.35 ± 9.43
TG/HDL 4.86 ± 3.32 4.47 ± 1.60
LDL, mg/dL 116.74 ± 35.24 122.16 ± 41.46
SBP, mmHg 143.14 ± 22.40 127.35 ± 18.77
PP, mmHg 57.96 ± 11.86 48.16 ± 10.60
PWV-CR, m/s 10.61 ± 2.00 10.37 ± 2.63
Diastolic dysf., E/A 0.77 ± 0.19 0.88 ± 0.30
List of abbreviations:
HOMA-IR = homeostasis model assessment for estimating insulin resistance
HDL = high-density lipoproteins
LDL = low-density lipoproteins
PP = pulse pressure
PWV-CR = carotid-radial pulse wave velocity
SBP = systolic blood pressure
TC = total cholesterol
TG = triglycerides
R2=0.27, p=0.04) when the HDL level is below
40 mg/dL. In this case, PWV-CR is not significantly
dependent on the entire metabolic constellation
(insulin resistance state, LDL level, TG/HDL
body mass index
ratio): R=0.64, R2=0.41, p=0.1. Left ventricular
diastolic dysfunction shows no significant influence
on the arterial stiffness when HDL < 40 mg/dL:
R=0.30, R2=0.09, p=0.2.
D.M. Duda-Seiman et al. 4
Fig. 1. – Comparisons between asymptomatic subjects with high SCORE levels vs. low SCORE levels
A. Age comparison
B. BMI comparison
C. PP comparison.
Decreased LDL levels (<115 mg/dL) have
powerful influence on PWV-CR when the HDL is
below the protective level (<40 mg/dL): R=0.76,
R2=0.58, p=0.02. The association of lipidic
alterations is predictive for increased PWV-CR ≥
9.5 m/s: R=0.92, R2=0.85, p=0.008 (Table II).
PWV-CR ≥ 9.5 m/s in asymptomatic subjects with low SCORE levels and HDL < 40 mg/dL
Dependent variable: PWV-CR ≥ 9.5 m/s
TG/HDL p=0.07 n=8
LDL, mg/dL p=0.005
B. SCORE ≥ 5% (27 subjects)
Subjects with protective HDL level (≥ 40 mg/dL)
and insulin resistance state (HOMA-IR > 1) show a
powerful influence of insulin resistance on the
functional arterial state: R=0.86, R2=0.74, p=0.02.
The association with atherogenic lipoproteins
increases the determination power on PWV-CR:
5 Lifestyle, cardio-metabolic risk
R=0.96, R2=0.92, p=0.01 (Table III). In this
case, PWV-CR does not correlate with the left
ventricular diastolic dysfunction (R=0.004, R2=0.00002,
PWV-CR in asymptomatic subjects with high SCORE levels,
HDL ≥ 40 mg/dL and HOMA-IR > 1
Dependent variable: PWV-CR
HOMA-IR > 1
LDL, mg/dL p=0.07
Our study focuses on metabolic alterations
(lipidic and insulin resistance) and their impact on
the endothelial function in asymptomatic individuals
(without documented atherothrombotic cardiovascular
disease) with and without absolute cardiovascular
risk (SCORE ≥ 5% or < 5%). The SCORE
cardiovascular risk estimation points out the
measures to be taken in order to prevent disability
and early death . The actual global trend is
oriented towards improving endothelial function in
order to delay as long as possible the clinical stage
of atherothrombotic cardiovascular disease. In this
light, the aim of our study was to point out those
factors which act on the arterial wall by inducing
and promoting endothelial dysfunction and which
can be corrected with non-pharmacological and,
where the case is, with pharmacological measures.
Others’ findings have shown the deleterious
effects of impaired metabolic parameters (components
of the metabolic syndrome) on arterial stiffness and
its age-related increase in young adults underscore the
importance of the presence of the cardio-metabolic
syndrome in cardiovascular risk assessment even in a
younger population .
A low level of HDL cholesterol is an independent
risk factor for future cardiovascular events . It has
been established that nearly in all subjects with low
HDL levels, the LDL particles are small and with
increased atherogenic potentiality . Oxidized
LDL-cholesterol molecules (LDL-ox) are highly
immunogenic, attack the arterial intima and
provoke endothelial dysfunction, platelet aggregation,
metalloproteinase expression and favor thrombo-
This work concludes: (1) The association
between low HDL levels and other lipidic alterations
in asymptomatic subjects with low cardiovascular
risk influences the degree of arterial stiffness.
(2) Increased HDL levels and the presence of
insulin resistance syndrome in high risk asymptomatic
subjects are predictive for arterial stiffness. (3) This
prediction is amplified by LDL association to the
metabolic state of the insulin resistance syndrome.
(4) It is necessary to establish target levels for HDL
and TG in the cardiovascular disease prevention
HDL-colesterolul joacă un rol esenţial în definirea statusului funcţional
arterial şi în relaţia cu riscul cardiovascular.
Scop. Stabilirea gradului de rigiditate arterială în cazul subiecţilor asimptomatici
cu sau fără risc cardiovascular, în funcţie de profilul lipidic şi de starea de
Metode. Gradul de rigiditate arterială a fost evaluat prin măsurarea vitezei
undei pulsatile carotidă-radială (PWV-CR) prin metoda Complior; riscul cardiovascular
a fost calculat utilizând carta SCORE, varianta online; riscul metabolic a cuprins
evaluarea à jeun a profilului lipidic (CT, TG, HDL, LDL) şi a parametrilor
glicemici (HOMA-IR> 1 a definit starea de insulinorezistenţă).
Rezultate. Au fost înrolaţi 58 de subiecţi asimptomatici cu vârsta medie
57,62±14,40 ani: 46,55% cu (SCORE≥5%) şi respectiv 53,45% fără (SCORE<5%)
D.M. Duda-Seiman et al. 6
risc cardiovascular semnificativ. La cei cu SCORE<5% şi HDL scăzut (<40 mg/dL),
PWV-CR este influenţat de raportul TG/HDL (R2=0.27, p=0.04); nivelul redus
<115mg/dL al LDL are o influenţă puternică asupra PWV-CR (R2=0.58, p=0.02);
asocierea tulburărilor metabolismului lipoproteinelor este predictivă pentru
creşterea PWV-CR≥9,5m/s (R2=0.85, p=0.008). În cazul subiecţilor cu SCORE≥5%,
fracţiune lipidică protectivă la nivel normal (HDL≥40mg/dL) şi HOMA-IR>1,
PWV-CR este puternic corelată cu insulinorezistenţa (R2=0.74, p=0.02), dar şi cu
nivel scăzut de LDL (R2=0.92, p=0.01).
Concluzii. Asocierea nivelului scăzut de HDL-colesterol cu alte modificări
ale profilului lipidic la asimptomaticii cu risc cardiovascular scăzut influenţează
gradul rigidităţii arteriale. HDL crescut, dar cu insulinorezistenţă la asimptomaticii
cu risc cardiovascular înalt, determină rigidizare arterială. Predicţia este amplificată
de asocierea nivelului redus de LDL la starea de insulinorezistenţă. Este necesară
stabilirea ţintelor pentru HDL şi trigliceride în prevenţia bolilor cardiovasculare
aterosclerotice / aterotrombotice.
Corresponding authors: Prof. D. Gaiţă, MD, PhD; D. Duda-Seiman, MD
Dept. of Medical Ambulatory, Cardiovascular Rehabilitation,
49, Bd. C.D. Loga, 300020 Timişoara, Romania
e-mail: email@example.com; firstname.lastname@example.org
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Received January 5, 2008
D.M. Duda-Seiman et al. 8
Left Atrial Surface Cut Point to Detect Trapezoidal Shape for Characterisation
of Atrial Anatomical Remodeling
O.S. PLEASCAR, D. COZMA, L. PETRESCU, DANIELA POPA, M. SLOVENSKI, ST.I. DRĂGULESCU
Institute of Cardiovascular Medicine, Timişoara, Romania
Background. Complete geometrical and shape characterization of left atrium has not been
performed. Ellipse formula has been proved to underestimate the real LA volume. The aim of the
study is to analyze the relation between LA area and shape in order to predict their value in the
assessment of the severity of anatomical remodeling.
Methods. 216 consecutive patients (pts) aged 53±27 years were included. The following
parameters were assessed: LA dimensions (LAd=M-mode, parasternal long axis, LAt and LAl are the
measurements of short- and long-axis in apical four chamber view), LA surface in apical four
chamber view (LAs). A new measurement was introduced, the basal dimension of the LA (LAb) as
the maximal transverse distance at the base of LA apical four chamber view. LA measurements were
calculated at end-systole (maximal). Trapezoidal LA shape was defined if transverse dimension <
Results. LAs ranged 10.5–54.5cm2. Trapezoidal LA was found in 149 pts. ROC curve for
prediction trapezoidal LA showed a 0.89 area under the curve. The analysis demonstrates a cutoff
value of 22.3 cm2 for LAs to detect trapezoidal shape with a sensitivity of 85% and specificity of
82.5%. The simple regression analysis demonstrated a statistically significant linear correlation
between LAd and LAs (r2=0.63, p<0.0001) but LAl was better correlated with LAs (r2=0.7,
p<0.0001). Trapezoid LA with atrialization of the pulmonary veins and predominant dilatation of
bazal atrium than annular side may explain underestimation of LA volume using ellipse formula.
Conclusion. LAs is a reliable parameter and may be the best choice to estimate LA dilatation;
LAs is related to shape remodeling; LAl is a better parameter than LAd for estimating LA dilatation
and complete characterization of LA remodeling should include shape definition and LAb.
Key words: left atrium, anatomical remodeling.
In most research and clinical applications, the
single dimension is used to represent the size of the
left atrium (LA) despite the potential limitation [1–3].
Although not often used, LA area / surface (LAs) is
recommended in current guidelines for echo
assessment of cavity size .
Atrial dilatation plays an important role in the
pathophysiology of atrial fibrillation. Numerous
clinical investigations as well as recent experimental
studies demonstrated that atrial fibrillation (AF) is
a progressive arrhythmia in direct relation with LA
size which represents a robust predictor of
cardiovascular outcome . Complete geometrical
and shape characterization to define LA dilatation
has not been performed. Several methods of
evaluation of left atrial volume have been studied
and validated among which recently ellipse model
which assumes that LA dilatation may be
approximated by prolate ellipse . There are no
other true geometrical models to analyze and compare
the pattern of LA dilatation and meanwhile ellipse
formula has been proved to underestimate the real
LA volume in patients with atrial fibrillation. The
main hypothesis of this study is that atrial shape
changes while progressive dilatation occurs and
dilated LA tend to become trapezoidal . The aim
of the study is to analyze the relation between LA
area and shape in order to predict their value in the
assessment of the severity of anatomical remodeling.
MATERIAL AND METHODS
Consecutive patients > 16 years old which
underwent standard echocardiography were included
into the study. The exlusion criteria were: congenital
heart disease and important modifications in
cardiac structures (e.g. tumors) which may alter LA
shape by other reason than volume or pressure
overload. Patients with changes in overall heart
ROM. J. INTERN. MED., 2008, 46, 1, 47–53
O.S. Pleascar et al. 2
normal anatomical position due to external
compression, retractions, intrathoracic tumors or
surgical intervention, were also excluded.
Images were taken with patients in the left
lateral decubitus position, using a SONOS 5500 echo
machine (Hewlett Packard, Andover, Massachusetts,
USA) or a VIVID 7 System. The echocardiographic
examination was done using standard views and
Standard echocardiographic measurements,
including interventricular septum thickness (IVS),
left ventricular end-diastolic diameter (LVEDD),
and ejection fraction (EF) (Simpson’s method),
LEFT ATRIUM 2D AND M-MODE PARAMETERS
Left atrial diameter (LAd) was measured by
M-mode in the parasternal long-axis view. Left
atrial transversal (LAt) and longitudinal (LAl)
diameters were measured in the apical 4-chamber
view, at ventricular end-systole.
Left atrial area / surface (LAs) was measured
by two-dimensional planimetry in the apical
4-chamber view, by tracing the endocardial border
cavity. The standard 4 chamber view accepted to
measure LA parameters was considered when
visualization of the maximal number of pulmonary
veins was possible. The LAs excluded the
pulmonary veins (PV) but not the antrum. The
boundary between LA and PV was defined by the
pulmonary vein ostia. Left atrial appendage was
excluded from the assessment and did not
contribute to the definitions of LA shape.
Additional 2D LA parameters were introduced
in order to define LA shape:
1. LA anular dimension measured as the
maximal distance between septal and lateral mitral
ridges (LAa); the measurement was not done as
internal dimension of mitral annulus; LAa was
calculated immediately under the mitral annulus
inside LA, at the junction between mitral annulus
and LA lateral wall or interatrial septum.
2. LA basal dimension, as the maximal
transverse distance between septal and lateral basal
wall of LA (Fig. 1).
Fig. 1. – Main LA linear parameters and example of trapezoid left atrium.
All LA measurements were calculated at end-
systole (maximal) at the time of mitral valve
opening (maximal volume). The first measurement
to be performed was LAs, after defining PV ostia.
The 2D distance measurements were done inside
the LA area.
Left atrial volume was calculated using the
ellipse formula (7): LAvol e = π/6 (LAdxLAlxLAt).
LEFT ATRIAL SHAPE DEFINITIONS
Trapezoidal LA shape was considered if
LAb> LAt while ellipsoid LA shape was defined
for the opposite condition. In cases with borderline
shape, visual assessment was performed by 2
independent observers and finally a decision was
3 Left atrium trapezoid shape remodeling
reached by consensus. No interpretable images
were excluded from the study (Fig. 1).
All results are expressed as mean ± SD. Subgroup
data were compared using independent samples t-test
for continuous variables. Correlations of the results of
various measurements recorded were tested using
simple regression analysis. Receiver-operating
characteristic (ROC) curves were constructed to
determine the best cut-off values for LAs in
predicting vulnerability to AF and susceptibility to
vulnerability. A p<0.05 (two-tailed test) was considered
significant. Statistical analysis was performed using
Stat View 5.0 version (SAS Institute, USA) and SPSS
11.5 for Windows (SPSS Inc., Chicago, Illinois).
216 consecutive patients (141 males), aged
53±27 years, were included. Measurements of described
parameters were possible in all patients.
Of the 216 participants, 68 had no history of
cardiovascular, renal, or pulmonary disease and
were taking no cardiovascular medication; this
subgroup had normal EF (50%), no wall motion
abnormalities, normal diastolic function, no valve
disease, and normal sinus rhythm. These 68 subjects
form the normal subgroup.
Main demographic data are presented in Table I.
Main LA linear parameters in all patients are
presented in Table II.
LAs ranged 10.5–54.5cm2. Trapezoidal LA
was found in 149 pts (%) (Fig. 2).
Clinical characteristics of the total population
Control (structural normal heart)
Heart Failure NYHA II
Heart Failure NYHA III
LA linear parameters characteristics of the total population
Linear LA parameter
Fig. 2. – Example of trapezoid (left) and ellipsoid (right) left atrium.
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O.S. Pleascar et al. 4
The simple regression analysis demonstrated a
statistically significant linear correlation between
LAd and LAs (r2=0.64, p<0.0001) but LAl was
better correlated with LAS (r2=0.7, p<0.0001) Fig. 3.
Fig. 3. – Statistically significant linear correlation between LAd and LAs; LAl is better correlated with LAs.
One hundred and nine (109) pts presented
LAd >3.5cm but <4.5 cm; in this subgroup average
LAs was 18.5±5.3 cm2, range 11.4–35.4 cm2.
There was no significant correlation either
between LAs and LAd (r2=0.12, p=0.21), or
between LAs and LAV (r2=0.15, p=0.32) Fig. 4.
ROC curve for prediction trapezoidal LA
showed a 0.89 area under the curve, Fig. 5. The
analysis demonstrates a cutoff value of 22.3 cm2
for LAs to detect trapezoidal shape with a
sensitivity of 85% and a specificity of 82.5%.
This study provides new information regarding
the relation between anatomical remodeling and
LA shape/size. Firstly, left atrial area which is a
parameter independent of geometrical assumptions
may be a reliable parameter to describe left atrial
Secondly, LA dilatation is accompanied by changes
in shape: with increasing LA size, the proportion of pts
1015 202530 35 40 4550 55
Y = 2.508 + .071 * X; R^2 = .647
1015 2025 303540 4550 55
Y = 3.127 + .096 * X; R^2 = .7