Revista Médica do Instituto de
Ano 3 / Volume 1 - www.cardiologia.org.br
______________________________________________ INDICE 2003
DYNAMICS OF THE PULMONARY VENOUS FLOW IN THE FETUS AND ITS ASSOCIATION
Paulo ZIELINSKY, Antônio L. PICCOLI Jr, Eduardo I. GUS, João Luiz MANICA, Fabíola SATLER,
Luiz Henrique NICOLOSO, Stelamaris LUCHESE, Silvana MARCANTONIO, Marlui SCHEID, Do-
mingos M. HATEM. Circulation 2003;108:2377-2380
COMPARISON OF LEFT VENTRICULAR ELECTROMECHANICAL MAPPING AND LEFT VENTRICULAR
ANGIOGRAPHY: DEFINING PRACTICAL STANDARTS FOR ANALYSIS OF NOGATM MAPS.
Rogério SARMENTO-LEITE, Guilherme V. SILVA, Hans F.R. DOHMAN, Ricardo M. ROCHA, Hans
J.F. DOHMAN, Nelson Durval S.G. MATTOS, Luis Antonio CARVALHO, Carlos A.M.
GOTTSCHALL. Texas Heart Institute Journal 2003;30:19-26
Impact of renal denervation on renal content of GLUT1, albuminuria, and urinary TGF-B1 in
streptozotocina-induced diabetic rats.
Beatriz D. SCHAAN, Sílvia LACCHINI, Marcello C. BERTOLUCI, Maria C. IRIGOYEN, Ubiratan F.
MACHADO, Helena SCHMID. Neuroscience: Basic and Clinical 2003;104:88-94
RIGHT VENTRICLE BRONCHOGENIC CYST.
Paulo R. PRATES, , Abud HOMSI-NETO, Marinez BARRA, João Ricardo M. SANT’ANNA, Renato
A.K. KALIL, Ivo A. NESRALLA. Texas Heart Institute Journal 2003;30(1):71-73.
NEW LEAD FOR IN UTERO PACING FOR FETAL CONGENITAL HEART BLOCK.
Renato S. ASSAD, Paulo ZIELINSKY, Renato A.K. KALIL, Gustavo G. LIMA, Anna M.
ARAMAYO. Journal Thoracic and Cardiovascular Surgery 2003;126(1):300-302
O PAPEL DA PROTEÍNA QUINASE C NO DESENVOLVIMENTO DAS COMPLICAÇÕES VASCULARES
DO DIABETES MELLITUS.
Beatriz D. SCHAAN. Arquivos Brasileiros de Endocrinologia e Metabologia 2003;47(6):654-662
PULSATILIDADE VENOSA PULMONAR EM FETOS DE MÃES DIABÉTICAS: UM ESTUDO
Paulo ZIELINSKY, Antonio L. PICCOLI Jr, Lucas TEIXEIRA, Eduardo I. GUS, João L. MANICA,
Fabíola SATLER, Humberto VAZ, Luiz Henrique NICOLOSO, Stelamaris LUCHESE, Marlui
SCHEID, Silvana MARCANTONIO, Domingos M. HATEM. Arquivos Brasileiros de Cardiologia
2003; 81(6): 600-603
FATORES PREDITIVOS DE COMPLICAÇÕES APÓS O IMPLANTE DE “STENTS” CORONARIANOS.
Alexandre S. QUADROS, Carlos A.M. GOTTSCHALL, Rogério SARMENTO-LEITE, Miguel GUS,
Rodrigo WAINSTEIN, André BUSSMANN. Arquivos Brasileiros de Cardiologia 2003;80(5): 531-537
ASSOCIAÇÃO ENTRE A DOENÇA ATEROSCLERÓTICA CORONARIANA E A ESPESSURA MÉDIO-
INTIMAL DA CARÓTIDA COMUM ATRAVÉS DA ULTRA-SONOGRAFIA.
Eduardo M. ROSA, Caroline KRAMER, Iran CASTRO. Arquivos Brasileiros de Cardiologia
BEHAVIOUR OF THE “SEPTUM PRIMUM” MOBILITY IN THIRD TRIMESTER FETUSES WITH
Cora FIRPO, Paulo ZIELINSKY. Ultrasound in Obstetrics & Gynecology 2003;21:445-50
A Teoria do Autocuidado no Manejo dos Fatores de Risco (Obesidade, Hipertensão e
Tabagismo) em Pacientes Pós-Infarto Agudo do Miocárdio.
Autor: Silvia GOLDMEIER - Orientador: Prof. Dr. Iran CASTRO
Variações da Função Diastólica do Ventrículo Esquerdo de Acordo com a Idade Através da
Ecocardiografia com Doppler Tissular.
Márcia D. PEDONE - [Orientador: Prof. Dr. Iran CASTRO]
Correlação e concordância entre medidas ecocardiográficas obtidas durante o exame no
ecocardiógrafo, com medidas de imagens digitalizadas em estação de trabalho dedicada.
Maria Amélia B. HATEM - [Orientador: Prof. Dr. Iran CASTRO]
Aferição da Taxa de Eritroblastos e dos Parâmetros do Equilíbrio Acidobásico no Sangue da
Veia Umbilical no Nascimento Capacitação da Enfermagem na Aplicação da Metodologia.
Maria Antonieta MORAES [Orientador: Prof. Dr. Ivo BEHLE]
O Uso do Balão Intra-Aórtico no Pré-Operatório de Cirurgia de Revascularização Miocárdica
Associada à Disfunção Ventricular Grave.
Marcelo KERN [Orientador: Prof. Dr. João Ricardo Sant’Anna]
Triiodotironina Oral na Prevenção da Redução do Hormônio da Tireóide em Cirurgia Cardíaca
Valvar em Adultos.
Ana Paula Arbo MAGALHÃES [Orientador: Profª. Drª. Beatriz D. SCHAAN]
Associação do perfil lipídico, da proteína C reativa ultra sensível, do fibrinogênio e da
glicemia com a evolução intra e pós-hospitalar de pacientes com síndrome isquêmica
Elizabeth DUARTE [Orientador: Profª. Drª. Vera L. PORTAL]
Prevalência de Hipertensão Arterial Sistêmica em uma População acima de 40 anos em
Caxias do Sul.
José Antonio V. MASCIA [Orientador: Prof. Dr. Mauro R.S. MOURA]
Banca avaliadora: Prof. Dr. Celso Blacher / UFRGS; Prof. Dr. Iran Castro / FUC; Profª. Drª.
Vera L. PORTAL / FUC.
Alternativa Prática do Uso de Amiodarona Oral na Prevenção de Fibrilação e Flutter Atrial no
Pós-Operatório de Cirurgia de Revascularização Miocárdica.
Rafael ALCALDE [Orientador: Prof. Dr. Iran CASTRO]
Distribuição do Fluxo em Artérias Pulmonares na Anastomose de Blalock-Taussig Modificada
Conforme Modelo Computadorizado.
Francisco MICHIELIN FILHO [Orientação: Prof. Dr. João Ricardo M. SANT’ANNA]
Ablação da condução atrioventricular por cateter de radiofreqüência em pacientes com
fibrilação atrial: efeitos na qualidade de vida.
Carlos Antônio KALIL [Orientador: Prof. Dr. Renato A.K. Kalil]
A REVISTA MÉDICA DO INSTITUTO DE CARDIOLOGIA DO RIO GRANDE DO SUL/
FUNDAÇÃO UNIVERSITÁRIA DE CARDIOLOGIA foi criada por Rubem Rodrigues como o Órgão de
divulgação cultural e científico desta Instituição, tendo retratado artigos de grande utilidade cultural
nas áreas de Cardiopatia Isquêmica (Vol 1 Nº 1e 2) Prevenção em Cardiologia (Vol 1 Nº 3) e
Cardiologia Pediátrica e Fetal (Revista Vol 2 Nº 2 - Cardiologia Pediátrica e Fetal II) tendo contribuído
para a divulgação da ciência cardiovascular e da melhoria da prática cardiológica em nosso meio.
Recentemente, a revista sofreu as conseqüências das dificuldades econômicas de nosso país e
teve sua divulgação interrompida por falta de patrocinadores.
Inconformados com a impossibilidade de levar adiante o projeto iniciado pelo Prof. Rubem e tão
bem conduzido posteriormente pelo Editor Nelson C. Nonohay com auxílio de um excelente Conselho
Editorial tendo como Presidente Ivo A. Nesralla, Cardiologia Clínica Oscar Dutra, Cardiologia Setorial
Nestor S. Daudt e Epidemiologia Iseu Gus , os professores do curso de pós-graduação reunidos
decidiram manter a revista em um formato eletrônico, sem custos e com a intenção de divulgar a
produção intelectual da Instituição.
Esta mudança de foco deve ficar bem definida para os nossos leitores e associados,
particularmente os que não atuam no âmbito acadêmico. As modificações em nosso perfil editorial
foram motivadas pela impossibilidade econômica de manter a revista em papel e os artigos menos
voltados às questões utilitárias e sim à investigação cardiovascular inovadora, provenientes de teses
da nossa pós-graduações e das publicações realizadas por nossa massa crítica acadêmica em
revistas nacionais e internacionais.
Assim pretendemos dar continuidade a revista atualizando nossos leitores do que tem-se
produzido em publicações na casa, de forma concentrada e acessível.
Por motivos alheios a nossa vontade não podemos em um primeiro número dispor toda a
demanda reprimida de publicações realizadas por membros desta casa, assim pedimos colaborações
no sentido de nos balizar as publicações que lhes forem mais prementes de serem divulgadas neste
meio de comunicação.
Aproveitamos para lembrar a todos que a pesquisa no IC/FUC depende de verbas e que o novo
FAPICC esta aceitando qualquer tipo de doação, assim como a possibilidade de comerciais nesta
página são bem-vindas, bastando entrar em contato conosco, firstname.lastname@example.org
Dr. Iran Castro
Prof. do Programa de Pós-Graduação IC/FUC, Editor
Dr. Renato A. K. Kalil
Diretor Científico do IC/FUC
Pulmonary venous flow was assessed in the upper right vein at 2
different sites: adjacent to the opening to the left atrium (“distal”
position) and in the middle of the vein (“proximal” position), below
the level of the middle lobe vein.12 The vessel diameter was
measured at the 2 sites by 2D echocardiography enhanced with
power Doppler (Figure 1). PVPI was obtained by the pulsed Doppler
ratio, as follows: (maximal velocity [systolic or diastolic
peak]Ϫminimal velocity [presystolic peak])/mean velocity, electron-
ically calculated by the equipment after manual tracing of the
pulmonary waveforms during the entire cardiac cycle (Figure 2). The
mean of 5 measurements was considered, in the absence of fetal
Informed consent was obtained in every case.
Statistical analysis used t test and exponential correlation studies,
with a confidence limit of 99%.
Mean distal internal diameter was 0.33Ϯ0.10 cm (0.11 to
0.57 cm), with a median of 0.32 cm, and mean proximal
diameter was 0.16Ϯ0.08 cm (0.11 to 0.25 cm), with a median
of 0.16 cm (PϽ0.0001) (Figure 3).
There was no statistical difference between mean systolic
(S wave) and diastolic (D wave) peak velocities at the 2 sites
(distal Sϭ0.20Ϯ0.09 m/s [0.17 to 0.58 m/s], proximal
Sϭ0.22Ϯ0.08 m/s [0.14 to 0.52 m/s]; distal Dϭ0.21Ϯ0.09
m/s [0.14 to 0.53 m/s], proximal Dϭ0.19Ϯ0.14 m/s [0.10 to
Mean peak presystolic velocity (A wave) was significantly
higher in the distal position (Aϭ0.12Ϯ0.04 m/s [0.06 to 0.16
m/s]) than at the proximal site (AϭϪ0.12Ϯ0.07 m/s [Ϫ0.13
to 0.09 m/s]) (Pϭ0.002).
Figure 1. Right upper pulmonary (PULM)
vein imaging in a 33-week fetus by 2D
echocardiography enhanced by power
Doppler. Notice progressive increase of
vessel diameter toward left atrium (LA).
Figure 2. Doppler tracing of a typical distal pulmonary vein ﬂow.
Velocities were electronically calculated after manual tracing of
waveforms. Presystolic velocity is 0.09 m/s, and calculated pul-
satility index is 1.21.
Figure 3. Diagram showing median distal and proximal pulmo-
nary vein (PV) diameters. Horizontal bars above and below
median boxes represent maximal and minimal values of PV
2378 Circulation November 11, 2003
Mean distal PVPI was 0.84Ϯ0.21 (0.59 to 1.38), with a
median of 0.77, and mean proximal PVPI was 2.09Ϯ0.59
(1.23 to 3.11), with a median of 2.22 (PϽ0.0001) (Figure 4).
Exponential inverse correlation between pulmonary vein
diameter and pulsatility index was highly significant
(PϽ0.0001), with a determination coefficient of 0.439 (Fig-
Studies on human embryonic and fetal lungs demonstrate that
the pulmonary arteries form by vasculogenesis,13 but there is
less information on the early development of the pulmonary
veins. Studies on maturation of pulmonary venous smooth
muscle suggest that a developmentally regulated remodeling
of the vein walls may reduce resistance to blood flow in fetal
life.14 It has also been shown that the development of the
airways and pulmonary veins occurs at different times and
that the branching patterns of these structures are not inter-
dependent.15–17 The common pulmonary vein develops within
the sinus venosus segment18 and is later incorporated into the
morphological left atrium.19 Morphometric studies in ani-
mals4 and in humans5 demonstrate that the branching patterns
of the pulmonary veins show many orders of tapering, from
the left atrium, where the diameter of the vessel (and its
cross-sectional area) is maximal, toward the pulmonary bed,
where it is minimum.
An experimental hemodynamic study showed that the
pulmonary vein pressure varied depending on the recording
site, resembling pulmonary artery pressure closer to the
pulmonary capillary bed and left atrial pressure closer to the
venoatrial junction.20 The same rationale applies when
the flow velocities from the lung to the heart are considered,
with the pulmonary vein diameter at the different sites
probably being the main determinant, as is demonstrated in
the present study. Other factors involved have been evalu-
ated, such as left atrium relaxation and compliance and left
ventricular function.21–27 Pulmonary vein relaxation, medi-
ated by C-type natriuretic peptide, is uniform and thus does
not allow segmental variations.28
The effects of vessel tapering in the pulmonary circulation
have been studied by nonlinear models,6,10 and the role of the
vessel cross-sectional area in the flow wave dynamics has
also been assessed.7 A theoretical model designed to evaluate
the wave transmission in a stenotic tube suggests that nonse-
vere stenoses may cause significant wave reflections,8 which
is consistent with the idea that the flow impedance is related
to the diameter of the tube.
Because Doppler analysis of the pulmonary venous wave-
forms is widely used in clinical practice,1–3,29–35 it is imper-
ative to have the sample volume correctly positioned in the
distal portion of the pulmonary vein, near the venoatrial
junction, to achieve reliable results, because this fetal study
showed that the presystolic velocity decreases and the pulsa-
tility index increases when a more proximal site is sampled.
It has been demonstrated that, in the normal fetus, the
pulsatility of the pulmonary vein decreases along the way
from the lung to the heart and that this parameter is inversely
correlated to the cross-sectional diameter of the pulmonary
vein, which increases from the proximal to the distal portion
of the vessel.
1. Hong YM, Choi JY. Pulmonary venous flow from fetal to neonatal
period. Early Hum Dev. 2000;57:95–103.
2. Crowe DA, Allan LD. Patterns of pulmonary venous flow in the fetus
with disease of the left heart. Cardiol Young. 2001;11:369–374.
3. Lenz F, Chaoui R. Reference ranges for Doppler-assessed pulmonary
venous blood flow velocities and pulsatility indices in normal human
fetuses. Prenat Diagn. 2002;22:786–791.
4. Gan RZ, Tian Y, Yen RT, et al. Morphometry of the dog pulmonary
venous tree. J Appl Physiol. 1993;75:432–440.
5. Huang W, Yen RT, McLaurine M, et al. Morphometry of the human
pulmonary vasculature. J Appl Physiol. 1996;81:2123–2133.
6. Lucas CL. Fluid mechanics of the pulmonary circulation. Crit Rev
Biomed Eng. 1984;10:317–393.
7. Demiray H. Waves in initially stressed fluid-filled thick tubes. J Biomech.
8. Stergiopulos N, Spiridon M, Pythoud F, et al. On the wave transmission
and reflection properties of stenoses. J Biomech. 1996;29:31–38.
9. Huang W, Tian Y, Gao J, et al. Comparison of theory and experiment in
pulsatile flow in cat lung. Ann Biomed Eng. 1998;26:812–820.
10. Segers P, Verdonck P. Role of tapering in aortic wave reflection:
hydraulic and mathematical model study. J Biomech. 2000;33:299–306.
Figure 4. Diagram showing median distal and proximal PVPIs.
Horizontal bars above and below median boxes represent maxi-
mal and minimal values of PVPI.
Figure 5. Diagram depicting inverse correlation between PVPI
and vessel diameter.
Zielinsky et al Fetal Pulmonary Vein Diameter and Flow Dynamics 2379
11. Hole T, Urheim S, Skjaerpe T. Intra- and inter-observer reproducibility of
transthoracic pulmonary venous Doppler flow indices after acute myo-
cardial infarction. Eur J Echocardiogr. 2002;3:32–38.
12. Yazar F, Ozdogmus O, Tuccar E, et al. Drainage patterns of middle lobe
vein of right lung: an anatomical study. Eur J Cardiothorac Surg. 2002;
13. Hall SM, Hislop AA, Pierce CM, et al. Prenatal origins of human
intrapulmonary arteries: formation and smooth muscle maturation. Am J
Respir Cell Mol Biol. 2000;23:194–203.
14. Fasouliotis SJ, Achiron R, Kivilevitch Z, et al. The human fetal venous
system: normal embryologic, anatomic, and physiologic characteristics
and developmental abnormalities. J Ultrasound Med. 2002;21:
15. DeMello DE, Reid LM. Embryonic and early fetal development of human
lung vasculature and its functional implications. Pediatr Dev Pathol.
16. Hislop AA. Airway and blood vessel interaction during lung devel-
opment. J Anat. 2002;201:325–334.
17. Hall SM, Hislop AA, Haworth SG. Origin, differentiation, and maturation
of human pulmonary veins. Am J Respir Cell Mol Biol. 2002;26:333–340.
18. Blom NA, Gittenberger-de-Groot AC, Jongeneel TH, et al. Normal devel-
opment of the pulmonary veins in human embryos and formulation of a
morphogenetic concept for sinus venosus defects. Am J Cardiol. 2001;
19. Webb S, Kanani M, Anderson RH, et al. Development of the human
pulmonary vein and its incorporation into the morphologically left atrium.
Cardiol Young. 2001;11:632–642.
20. Appleton CP. Hemodynamic determinants of Doppler pulmonary venous
flow velocity components: new insights from studies in lightly sedated
normal dogs. J Am Coll Cardiol. 1997;30:1562–1574.
21. Barbier P, Solomon S, Schiller NB, et al. Determinants of forward
pulmonary vein flow: an open pericardium pig model. J Am Coll Cardiol.
22. Talbert DG, Johnson P. The pulmonary vein Doppler flow velocity
waveform: feature analysis by comparison of in vivo pressures and flows
with those in a computerized fetal physiological model. Ultrasound
Obstet Gynecol. 2000;16:457–467.
23. Smiseth OA, Thompson CR, Lohavanichbutr K, et al. The pulmonary
venous systolic flow pulse: its origin and relationship to left atrial
pressure. J Am Coll Cardiol. 1999;34:802–809.
24. Rajagopalan B, Friend JA, Stallard T, et al. Blood flow in pulmonary
veins, I: studies in dog and man. Cardiovasc Res. 1979;13:667–676.
25. Rajagopalan B, Friend JA, Stallard T, et al. Blood flow in pulmonary
veins, II: the influence of events transmitted from the right and left sides
of the heart. Cardiovasc Res. 1979;13:677–683.
26. Rajagopalan B, Bertram CD, Stallard T, et al. Blood flow in pulmonary
veins, III: simultaneous measurements of their dimensions, intravascular
pressure and flow. Cardiovasc Res. 1979;13:684–692.
27. Hellevik LR, Segers P, Stergiopulos N, et al. Mechanism of pulmonary
venous pressure and flow waves. Heart Vessels. 1999;14:67–71.
28. Lakshminrusimha S, D’Angelis CAD, Russell JA, et al. C-type natriuretic
peptide system in fetal ovine pulmonary vasculature. Am J Physiol Lung
Cell Mol Physiol. 2001;281:L361–L368.
29. Rossi A, Loredana L, Cicoira M, et al. Additional value of pulmonary
vein parameters in defining pseudonormalization of mitral inflow pattern.
30. Graziano JN, Heidelberger KP, Ensing GJ, et al. The influence of a
restrictive atrial septal defect on pulmonary vascular morphology in
patients with hypoplastic left heart syndrome. Pediatr Cardiol. 2002;23:
31. Lenz F, Machlitt A, Hartung J, et al. Fetal pulmonary venous flow pattern
is determined by left atrial pressure: report of two cases of left heart
hypoplasia, one with patent and the other with closed interatrial commu-
nication. Ultrasound Obstet Gynecol. 2002;19:392–395.
32. Yalcin F, El-Amrousy M, Muderrisoglu H, et al. Pulmonary venous flows
reflect changes in left atrial hemodynamics during mitral balloon val-
votomy. Angiology. 2002;53:323–327.
33. Palazzuoli A, Puccetti L, Pastorelli M, et al. Transmitral and pulmonary
venous flow study in elite male runners and young adults. Int J Cardiol.
34. Yang H, Jones M, Shiota T, et al. Pulmonary venous flow determinants
of left atrial pressure under different loading conditions in a chronic
animal model with mitral regurgitation. J Am Soc Echocardiogr.
2002:15(10 pt 2):1181–1218.
35. Ito T, Harada K, Takada G. Changes in pulmonary venous flow patterns
in patients with ventricular septal defect. Pediatr Cardiol. 2002;23:
2380 Circulation November 11, 2003
parison with LVA findings) that can be used routinely
in the analysis of LV electromechanical maps.
Patients and Methods
Study Design and Inclusion Criteria
We conducted a cohort prospective study of 55 pa-
tients who underwent mapping procedures after elec-
tive left cardiac catheterization at 2 centers (Texas
Heart Institute, Houston, Texas; and Hospital Pro-
Cardíaco, Rio de Janeiro, Brazil). Electromechanical
mapping was performed after LVA. The LVEM proce-
dures were performed only in patients who were clini-
cally stable; excluded were those patients who had
severe peripheral vascular disease, atrial fibrillation,
aortic stenosis, suspected thrombus in the left ventri-
cle, or acute myocardial infarction. The study protocol
was approved by the ethics committees of both hospi-
tals. There was no industry support for this study. The
procedures were explained, and informed written con-
sent was obtained from all patients before they were
enrolled in the study.
NOGA Mapping System andTechnique
A NOGA electromechanical map of the left ventricle
is constructed by the acquisition of a series of points
at multiple locations on the LV endocardial surface
gated to a surface electrocardiogram. NOGA LVEM
uses ultra-low magnetic fields (10-5
tesla) that are
generated by a triangular magnetic pad positioned be-
neath the patient. The intersection of the magnetic
fields with a location sensor just proximal to the de-
flectable tip of a 7F mapping catheter helps to deter-
mine the location and orientation of the catheter tip
inside the left ventricle. An algorithm is used by the
NOGA system to calculate and analyze the movement
of the catheter tip or the location of an endocardial
point throughout systole and diastole. That move-
ment is then compared with the movement of neigh-
boring points in an area of interest. The resulting
value, which is called linear local shortening (LLS) and
is expressed as a percentage, is representative of the
mechanical function of the left ventricle at that point.
Data points are obtained only when the catheter
tip is in stable contact with the endocardium. This
contact is determined automatically by the NOGA
system using the following criteria: 1) point loop sta-
bility (LS), defined as the trajectory of a specific point
during 2 consecutive cardiac cycles (a low value, in-
dicating good-quality data, is preferable); 2) cycle
length (CL) stability, defined as the difference between
the CL of a specific point and the average CL of the
previously recorded 100 beats; 3) local activation time
(LAT) stability, defined as the difference between the
LAT of a point and the LATs of points previously re-
corded (variation should be no more than 3 ms); and
4) location stability (LcS), defined as the variability in
the location of the catheter tip during the cardiac cycle
(between end systole and end diastole). The mapping
catheter also incorporates electrodes that measure en-
docardial electrical signals (unipolar or bipolar volt-
age). Voltage values are assigned to each point acquired
during mapping of the LV, and an electrical map is
constructed. Each data point has an LLS value and a
voltage value. When the map is complete, all the data
points are integrated by the NOGA workstation and
are presented in a 3-D color-coded reconstruction of
the endocardial surface, and in 9- and 12-segment
bull’s-eye views that show average values for LLS and
voltage data in each segment (Fig. 1). These maps can
be spatially manipulated in real time on a Silicon
Graphics workstation (Mountain View, Calif).
The 3-D representations acquired during the cardiac
cycle are used to calculate LV volumes. The NOGA
system uses the largest volume as the end-diastolic vol-
ume (EDV) and the smallest volume as the end-sys-
tolic volume (ESV). The LV ejection fraction (LVEF)
is calculated as (EDV – ESV)/EDV. The NOGA sys-
tem also uses, as predetermined by the operator, a tri-
angle fill threshold (FT) that determines the extent to
which the computer algorithm will interpolate data
into (or “fill in”) the space between adjacent points. In
the present study, a triangle FT of 15 mm was used
(the standard recommended by the manufacturer to
ensure map completeness). After the acquisition of
points, postprocessing analysis is performed with a se-
ries of filters in the moderate setting to eliminate inner
points, points that do not fit the standard stability cri-
teria (LcS <4 mm; LS <6 mm; and CL <10%), points
acquired during ST-segment elevation, and points not
related to the left ventricle (for example, those on the
Volume 30, Number 1, 200320 Comparison of LV Electromechanical Mapping and LV Angiography
Fig. 1 A representative, 3-dimensional, color-coded recon-
struction of the endocardial surface (left) and 9- and 12-
segment bull’s-eye views (right top and bottom, respectively).
LLS = linear local shortening
Left Ventricular Angiography Protocol
Left ventricular angiography was performed through
the femoral approach using a 5F pigtail catheter (Cor-
dis; Miami Lakes, Fla), which was marked at 1-cm
intervals for accurate calculation of the LV volumes
and LVEFs according to the area-length formula.11
LVAs were obtained in 2 planes—a 30° right anterior
oblique (RAO) view and a 60° left anterior oblique
(LAO) view—during a period of stable sinus rhythm.
Ventricular volume was not measured during or after
a premature beat. Wall motion was evaluated in the
RAO view by 2 independent experienced observers.
Segments visible in the angiographic RAO view (that
is, anterobasal, anteromedial, apical, inferomedial, and
posterobasal) were compared with the corresponding
5 segments of the LVEM bull’s-eye view. Wall motion
in each myocardial segment was scored as follows: 0 =
dyskinetic; 1 = akinetic; 2 = hypokinetic; and 3 = nor-
Left Ventricular Electro-
mechanical Mapping Protocol
Left ventricular electromechanical mapping was per-
formed as follows. All patients were heparinized (70
U/kg) after biplane LVA and before LVEM. The map-
ping catheter curve (B, D, or F) was selected on the
basis of LV size. The catheter (7F) was advanced un-
der fluoroscopic guidance to the descending thoracic
aorta, where its tip was fully deflected and then subse-
quently advanced around the aortic arch and across
the aortic valve into the left ventricle. Inside the left
ventricle, the deflection was relaxed and the catheter
tip was oriented toward the LV apex. The initial data
point was acquired at the LV apex, and 2 points were
acquired—one at the base of the septum and one at
the lateral wall—to complete an initial triangle defin-
ing the borders of the LV. Subsequent points were ac-
quired until all endocardial segments were uniformly
sampled (ideally, 3 points in each of 12 segments,
according to the NOGA™ Mapping Excellence Pro-
gram*). Each data point was filtered on-line, immedi-
ately after acquisition, and during postprocessing
analysis with use of the parameters described above.
The LVEMs were analyzed using data on the mechan-
ical function of the myocardium (LLS), which has
been extensively validated in previous studies.1-3
data from the maps were compared with data ob-
tained by angiography. Angiography provides a 2-D
image of the left cardiac chamber that historically has
been compared with images produced by emerging
technologies such as echocardiography, radionuclide
studies, and MRI.7
To compare wall motion as represented by LVEM
versus LVA, the anterobasal, anteromedial, apical, in-
feromedial, and posterobasal segments on the RAO
angiogram (Fig. 2) were matched with those on the
corresponding 5 segments of the 9-segment LVEM
bull’s-eye view. (Again, according to the NOGA™
Mapping Excellence Program, each LVEM segment
should contain at least 3 points after initial filtering
and postprocessing analysis.) The segments were di-
vided into 3 groups according to wall motion score:
Group I (0 or 1, akinetic or dyskinetic); Group II (2,
hypokinetic); and Group III (3, normokinetic).
Texas Heart Institute Journal Comparison of LV Electromechanical Mapping and LV Angiography 21
∗ The NOGA™ Mapping Excellence Program was created by
Biosense-Webster in order to verify and ensure the quality of
NOGA maps. It has been developed and implemented by the
authors in conjunction with Biosense-Webster.
Fig. 2 Schematic illustrations show the 5 myocardial segments
evaluated by left ventricular angiography and left ventricular
electromechanical mapping (top) and corresponding bull’s-eye
view (bottom) for comparison.
AB = anterobasal; AM = anteromedial; Ap = apical; IM = infero-
medial; PB = posterobasal
LVA, compared, and classified into 3 groups. Group I
(akinetic/dyskinetic) comprised 9 segments; Group II
(hypokinetic), 68 segments; and Group III (normo-
kinetic), 198 segments. Table III shows the mean LLS
(± SD) values for each group. Using discriminant
analysis, the cutpoints for differentiation between nor-
mokinetic, hypokinetic, and akinetic/dyskinetic seg-
ments by LLS were set at 12% and 6% (Table IV). As
shown by ROC curves (Figs. 9 and 10), the LLS val-
ues determined by LVEM had an accuracy of 93% in
differentiating between normokinetic and akinetic/
dyskinetic myocardial segments and an accuracy of
73% in differentiating between normokinetic and hy-
pokinetic myocardial segments.
Left ventricular ejection fraction and volume data were
presented as the mean ± standard deviation (SD). The
mean values obtained by LVEM and LVA were com-
pared using the unpaired Student’s t-test. A P value of
<0.5 was considered significant for all comparisons.
Correlation coefficients were reported in terms of the
Pearson correlation index (r), and correction index-
es for each variable were created. The Bland-Altman
technique was used to determine the agreement be-
tween continuous measurements acquired by LVEM
and LVA. For each group of wall motion scores, the
mean LLS (± SD) was determined. Boundaries for
classification of wall motion as normal, hypokinetic,
and akinetic/dyskinetic were derived by discriminant
analysis. This analytic technique finds the 2 bound-
aries that predict classification into a group (in this
case, 1 of the 3 groups determined by LVEM wall mo-
tion score). The Scheffé test was also used for multiple
comparisons of wall motion. Receiver operating char-
acteristic (ROC) curves were used to assess the sensi-
tivity and specificity of LVEM for distinguishing
between normokinetic and hypokinetic and between
normokinetic and akinetic/dyskinetic wall motion.
The study population consisted of 55 consecutive pa-
tients who were scheduled for elective left heart
catheterization, during which LVEM was performed
(Table I). The mean age was 60.4 ± 11.8 years (range,
42–86 years), and there were more men (35 [64%])
than women. The average LVEM procedure time was
37 ± 11 minutes. After application of a moderate
automatic filter, a mean of 62 ± 12 points was ob-
tained in each mapping to render a representative 3-
D reconstruction of the LV. There were no deaths or
major complications associated with LVEM (such as
malignant ventricular arrhythmias or LV perforation
requiring pericardiocentesis). One patient had a left
ventricular perforation that resulted in a small post-
procedural pericardial effusion. This complication was
managed conservatively and was followed with serial
echocardiography until it resolved; pericardiocentesis
was not necessary.
The mean values for EF, EDV, and ESV, obtained
by LVEM and LVA, are shown in Table II. The Pear-
son correlation index and graphs for each variable are
shown in Figs. 3–5. A moderate-to-good correlation
was found between LVEM and LVA findings; how-
ever, as shown by Bland-Altman analysis (Figs. 6–8),
clinical disagreement and lack of interchangeability
was found between all measured parameters for both
In the 55 cases studied, the wall motion scores in a
total of 275 segments were determined by LVEM and
Volume 30, Number 1, 200322 Comparison of LV Electromechanical Mapping and LV Angiography
TABLE I. Characteristics of 55 Patients at Baseline
Patient Characteristic Pts. (%)
Mean age (y) 60.4 ± 11.8*
Male 35 (64)
Female 20 (36)
Diabetes 11 (20)
Hypertension 36 (65)
Smoking 27 (49)
Hyperlipidemia 41 (75)
Myocardial infarction 25 (45)
Cerebral vascular disease 4 (7)
Peripheral vascular disease 5 (9)
Bypass graft 19 (35)
PTCA 27 (49)
Mean LV ejection fraction 55% ± 13%*
Diagnostic catheterization 33 (60)
DMR 2 (4)
PCI 20 (36)
*Mean ± SD
DMR = direct myocardial revascularization; LV = left ventricular;
PCI = percutaneous coronary intervention; PTCA = percutane-
ous transluminal coronary angioplasty
TABLE II. Mean Values for LVA and LVEM Findings
Cardiac Component LVA LVEM
Ejection fraction (%) 55 ± 13 36 ± 9
End-diastolic volume (mL) 174 ± 104 123 ± 65
End-systolic volume (mL) 56 ± 13 36 ± 10
All data are presented as mean ± SD.
LVA = left ventricular angiography; LVEM = left ventricular
Fig. 3 Pearson correlation index for ejection fraction (EF) as
determined by left ventricular angiography (LVA) and left
ventricular electromechanical mapping (LVEM).
Fig. 4 Pearson correlation index for end-diastolic volume (EDV)
as determined by left ventricular angiography (LVA) and left
ventricular electromechanical mapping (LVEM).
Fig. 5 Pearson correlation index for end-systolic volume (ESV)
as determined by left ventricular angiography (LVA) and left
ventricular electromechanical mapping (LVEM).
Fig. 6 Bland-Altman association for ejection fraction (EF)
as determined by left ventricular angiography (LVA) and left
ventricular electromechanical mapping (LVEM).
Fig. 7 Bland-Altman association for end-diastolic volume as
(EDV) determined by left ventricular angiography (LVA) and
left ventricular electromechanical mapping (LVEM).
Fig. 8 Bland-Altman association for end-systolic volume (ESV)
as determined by left ventricular angiography (LVA) and left
ventricular electromechanical mapping (LVEM).
Texas Heart Institute Journal Comparison of LV Electromechanical Mapping and LV Angiography 23
The present study was designed to compare the as-
sessment of global and regional function of the left
ventricle by 2 different techniques: LVEM and LVA.
Both techniques are invasive and yield quantitative
and qualitative information about the performance
of the left ventricle. However, LVEM creates an on-
line, real-time 3-D reconstruction of the endocardial
surface and has proven value for assessing both myo-
and the mechanical function of myo-
Several studies have focused on the ability of LVEM
to distinguish between normal and infarcted myo-
cardium, to enable comparison of hemodynamic
parameters, and to perform wall motion analysis.
Nonetheless, no practical cutpoints for LVEM analy-
sis of wall motion had previously been established.8-10
Therefore, as the primary end point of a study of the
largest LVEM cohort in the literature, we have corre-
lated the findings of LVEM and LVA by analyzing
only those LVEM segments that were also well visual-
ized by LVA and well matched to the same regions of
the LVEM bull’s-eye views.
The values used to define wall motion in the pres-
ent study were similar to those already described in
the literature. However, the mean values (± SD) that
we established for normokinetic, hypokinetic, and
akinetic/dyskinetic wall motion (13.9% ± 5.6%,
8.3% ± 5.2%, and 3.2% ± 3.1%, respectively) over-
lapped and sometimes made it difficult to differen-
TABLE III. Wall Motion Classification and Mean LLS
Wall Motion Segments LLS
Pattern (n = 275) (%)
Group I - Akinetic/dyskinetic 9 3.2 ± 3.1
Group II - Hypokinetic 68 8.3 ± 5.2
Group III - Normokinetic 198 13.9 ± 5.6
Data are presented as mean ± SD. P <0.05 for all comparisons.
LLS = linear local shortening
TABLE IV. Cutpoints for Differentiation of Wall Motion
by LLS According to Discriminant Analysis
Wall Motion Pattern LLS (%)
Group I - Akinetic/dyskinetic <6%
Group II - Hypokinetic ≥6% or <12%
Group III - Normokinetic ≥12%
LS = linear local shortening
Fig. 9 Receiver operating characteristic curve for the differ-
entiation between normokinetic and akinetic/dyskinetic seg-
ments by local linear shortening (LLS).
Area under the curve = 0.93; threshold <6%; sensitivity, 89%;
Fig. 10 Receiver operating characteristic curve for the differ-
entiation between normokinetic and hypokinetic segments by
local linear shortening (LLS).
Area under the curve = 0.73; threshold <12%; sensitivity,
68%; specificity, 62%
tiate between normokinetic and hypokinetic tissue.
This was well exemplified by the ROC curve (Fig. 10),
which showed a weak accuracy of 73%. These find-
ings agree with the data of Lessick and colleagues,13
who compared echocardiography with LVEM data
and reported an accuracy of 69%. On the other hand,
our cutpoints allowed excellent differentiation be-
tween normokinetic and akinetic/dyskinetic myo-
cardial areas, with an accuracy of 93% (Fig. 9).
Volume 30, Number 1, 200324 Comparison of LV Electromechanical Mapping and LV Angiography
demarcation of appropriate “target” zones for treat-
ment is one of the keys to the success of our proce-
dure. Therefore, by defining practical LLS thresholds
for assessing mechanical activity in the present study,
we believe we have made it easier to target viable myo-
cardium (that is, tissues with low LLS and preserved
electrical activity) using the NOGA system and so op-
timize therapy. Moreover, even though the system is
somewhat limited in its ability to differentiate wall
motion, this limitation appears to be restricted to se-
verely dilated or very hypertrophic ventricles. In such
cases, performing a complete LVEM is already tech-
nically challenging. We believe that this limitation can
be overcome by devising mapping procedures that are
more careful and detailed.
In conclusion, our data indicate that there is a mod-
erate correlation between LVA and LVEM findings
and that LVEM can differentiate between normal and
abnormal cardiac wall motion. However, it appears
that LVEM is severely limited in its ability to measure
LV hemodynamics, which will limit its widespread
use for this purpose. Nevertheless, our findings are
important, because they add to the current knowledge
about the interpretation of LVEM findings, and be-
cause they have important implications for the use of
LVEM in conjunction with intramyocardial therapies
in which optimal treatment delivery requires the accu-
rate targeting of viable (normokinetic) versus nonvi-
able (akinetic/dyskinetic) segments.
1. Ben-Haim SA, Osadchy D, Schuster I, Gepstein L, Hayam
G, Josephson ME. Nonfluoroscopic, in vivo navigation and
mapping technology. Nat Med 1996;2:1393-5.
2. Gepstein L, Hayam G, Ben-Haim SA. A novel method for
nonfluoroscopic catheter-based electromechanical mapping
of the heart. In vitro and in vivo accuracy results. Circula-
3. Smeets JL, Ben-Haim SA, Rodriguez LM, Timmermans C,
Wellens HJ. New method for nonfluoroscopic endocardial
mapping in humans: accuracy assessment and first clinical
results. Circulation 1998;97:2426-32.
4. Gepstein L, Hayam G, Shpun S, Ben-Haim SA. Hemody-
namic evaluation of the heart with a nonfluoroscopic elec-
tromechanical mapping technique. Circulation 1997;96:
5. Dodge HT, Sandler H, Baxley WA, Hawley RR. Usefulness
and limitations of radiographic methods for determining
left ventricular volume. Am J Cardiol 1966;18:10-24.
6. Viamonte M Jr. Innovations in angiography. Radiol Clin
North Am 1971;9:361-8.
7. Greenberg SB, Sandhu SK. Ventricular function. Radiol
Clin North Am 1999;37:341-59,vi.
8. Bossi I, Black AJ, Choussat R, Cassagneau B, Farah B, La-
borde JC, et al. Biosense NOGA electro-mechanical mapping
accurately predicts left-ventricular wall motion at cineven-
triculography [abstract]. Am J Cardiol 1999;84(6A):95P.
9. Thambar ST, Sharaf BL, Miele NJ, Williams DO. Assess-
ment of global and regional wall motion by NOGA three-
dimensional electro-mechanical mapping: a correlation
The discrepancy in accuracy of differentating be-
tween normokinetic and hypokinetic tissue and be-
tween normokinetic and akinetic/dyskinetic tissue
may be due to several factors. First, it can be very dif-
ficult in some cases, especially in dilated or very hy-
pertrophic ventricles, to perform a complete LVEM
because the catheter cannot uniformly reach all areas
of the left ventricle. As a result, mapping may be in-
complete, and the average of the mapped values for a
determined region may be misrepresented. Second,
data suggesting low contractility of basal areas of the
LV may in part represent the presence of fibrous tissue
in perivalvular areas. Future development of LVEM in
terms of performance and analysis may improve upon
the completeness of mapping and make the interpre-
tation of the data more accurate.
As shown in a recent study by Van Langenhove and
the hemodynamic data obtained by
LVEM has its limitations. In their study, the correla-
tion between ESV and EF measurements obtained by
LVEM versus LVA was moderate (r = 0.67 and r =
0.78, respectively), and the correlation between EDV
measurements was poor (r = 0.40).14
These results dif-
fer somewhat from ours, which showed better corre-
lations for measurements of ESV (r = 0.81) and EDV
(r = 0.71) and a worse correlation for measurements
of EF (r = 0.56). Except for this difference, the results
of our Bland-Altman analysis and the results from Van
Langenhove’s study were similar, demonstrating that
the dispersion of values is great and that the real clini-
cal application of EDV and EF measurements sup-
plied by LVEM is questionable, even when correction
formulas are applied. Therefore, we do not advocate
the routine use of the NOGA method as an alterna-
tive to other established methods for assessing LVEF.
Similar problems with overlap of wall motion val-
ues obtained by LVEM have been found in other se-
For example (although their comparison was
between the findings of LVEM and nuclear perfusion
studies), Kornowski’s group12
recorded normal and ab-
normal LLS values (normal, 12.5% ± 2.8%; abnor-
mal, 3.4% ± 3.4%), that were very similar to ours in
the present study (normal, 13.9% ± 5.6%; abnormal,
3.2% ± 3.1%).
Despite its limitations, LVEM may assume an im-
portant role in new therapies that directly target isch-
emic heart disease. Such therapies aim to promote
angiogenesis or restore contractility through the trans-
plantation of stem cells16
or by injec-
tion of growth factors.19
The future success of these
and similar therapies depend profoundly on carefully
controlled clinical trials that apply appropriate meth-
ods and end points. In that regard, the NOGA map-
ping system has an advantage over other potential
therapeutic delivery systems (especially those involv-
ing surgery), because it is less invasive. In theory, the
Texas Heart Institute Journal Comparison of LV Electromechanical Mapping and LV Angiography 25
with the “gold standard” contrast left ventriculogram. Cir-
10. Van Langenhove G, Smits PC, Serrano P, Kosuma K, Kay
IP, Albertal M, et al. Assessment of regional LV wall mo-
tion: a comparison between computerized LV angiography
and nonfluoroscopic electromechanical mapping. Circula-
11. Kennedy JW, Trenholme SE, Kasser IS. Left ventricular vol-
ume and mass from single-plane cineangiocardiogram. A
comparison of anteroposterior and right anterior oblique
methods. Am Heart J 1970;80:343-52.
12. Kornowski R, Hong MK, Leon MB. Comparison between
left ventricular electromechanical mapping and radionu-
clide perfusion imaging for detection of myocardial viabili-
ty. Circulation 1998;98:1837-41.
13. Lessick J, Smeets JL, Reisner SA, Ben-Haim SA. Electro-
mechanical mapping of regional left ventricular function in
humans: comparison with echocardiography. Cathet Car-
diovasc Interv 2000;50:10-8.
14. Van Langenhove G, Hamburger JN, Smits PC, Albertal M,
Onderwater E, Kay IP, Serruys PW. Evaluation of left ven-
tricular volumes and ejection fraction with a nonfluoroscop-
ic endoventricular three-dimensional mapping technique.
Am Heart J 2000;140:596-602.
15. Keck A, Schwartz Y, Bahlmann E, Kuchler R, Kitzing R,
Schluter M, Kuck KH. Assessment of regional left ventricu-
lar contractility: comparison between NOGATM
chanical mapping and echocardiography [abstract]. J Am
Coll Cardiol 1999;33(2 Suppl A):442A.
16. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM,
Li B, et al. Bone marrow cells regenerate infarcted myocar-
dium. Natuare 2001;410:701-5.
17. Taylor DA, Atkins BZ, Hungspreugs P, Jones TR, Reedy
MC, Hutcheson KA, et al. Regenerating functional myo-
cardium: improved performance after skeletal myoblast trans-
plantation [erratum appears in Nat Med 1998;4:1200]. Nat
18. Menasche P, Hagege AA, Scorsin M, Pouzet B, Desnos M,
Duboc D, et al. Myoblast transplantation for heart failure.
19. Freedman SB, Isner JM. Therapeutic angiogenesis for coro-
nary artery disease. Ann Intern Med 2002;136:54-71.
Volume 30, Number 1, 200326 Comparison of LV Electromechanical Mapping and LV Angiography
Impact of renal denervation on renal content of GLUT1, albuminuria
and urinary TGF-h1 in streptozotocin-induced diabetic rats
Beatriz D’Agord Schaana,*, Silvia Lacchinib
, Marcello Casaccia Bertolucic
Maria Cla´udia Irigoyend
, Ubiratan Fabres Machadoe
, Helena Schmidf
Instituto de Cardiologia do Rio Grande do Sul/FUC, Unidade de Pesquisa, Av. Princesa Isabel, 395 Santana, 90.620-001 Porto Alegre, RS, Brazil
Laborato´rio de Gene´tica e Cardiologia Molecular, Instituto do Coracßa˜o (InCor), HC-FMUSP, Universidade de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil
Hospital de Clı´nicas de Porto Alegre, Porto Alegre, Brazil
Laborato´rio de Hipertensa˜o Experimental - Unidade de Hipertensa˜o, Instituto do Coracßa˜o (InCor), HC-FMUSP, Universidade de Sa˜o Paulo,
Sa˜o Paulo, SP, Brazil
Departamento de Fisiologia, Instituto de Cieˆncias Biolo´gicas, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
Curso de Po´s-Graduacßa˜o da UFRGS, Hospital de Clı´nicas de Porto Alegre and FFFCMPA, Porto Alegre, Brazil
Received 9 January 2002; received in revised form 30 October 2002; accepted 9 December 2002
In long-term diabetes mellitus, the progression of nephropathy has been related to the occurrence of autonomic neuropathy. This study
was designed to evaluate the effects of bilateral denervation of the kidneys of streptozotocin-diabetic rats, an experimental model that
presents diabetic nephropathy with increased abundance of cortical GLUT1 in the kidney and increased urinary excretion of albumin and
transforming growth factor-h1 (TGF-h1). Twenty-four-hour urinary TGF-h1 (ELISA), urinary albumin (electroimmunoassay) and GLUT1
protein levels (Western blotting) in the renal cortex and medulla were evaluated in diabetic (n = 13) and control (n = 13) rats 45 days after
streptozotocin injection, submitted or not to surgical renal denervation. Evaluations were performed 15 days after the surgery. The effects of
renal denervation were confirmed by intra-renal decrease of norepinephrine levels. Mean arterial pressure did not differ between diabetic and
control rats, whether they underwent renal denervation or not. Renal denervation increased cortical (6905 F 287, 3506 F 193, 4144 F 246
and 5204 F 516 AU in renal-denervated controls, controls, renal-denervated diabetics and diabetics, respectively) and medullar GLUT1
protein in control rats, but reverted the cortical GLUT1 protein rise determined by diabetes. Although kidney denervation in diabetic rats
induced a decrease in cortical GLUT1 abundance toward normal levels, these levels did not reach those of normal animals. However, renal
denervation did not determine any changes in urinary albumin and urinary TGF-h1 in both diabetic (127.3 F 12 Ag/24 h and 111.8 F 24 ng
creatinine, respectively) and control rats (45.9 F 3 Ag/24 h and 13.4 F 4 ng mgÀ 1
creatinine, respectively). In conclusion, early-phase
renal denervation in streptozotocin-diabetic rats produces a normalisation of previously elevated cortical GLUT1 protein content, but is not
enough for reverting the increased urinary TGF-h1 and albuminuria of diabetes.
D 2003 Elsevier Science B.V. All rights reserved.
Keywords: Diabetes mellitus, experimental; Diabetes mellitus, nephropathies; Denervation; Transforming growth factors; Streptozotocin; Glucose transporters
In long-term diabetes mellitus, the progression of nephr-
opathy has been related to the occurrence of autonomic
neuropathy (Sundkvist and Lilja, 1993). The mechanisms
involved are not well understood.
Persistent immunoreactivity for transforming growth
factor-h1 (TGF-h1) protein, a cytokine directly involved
in extracellular matrix production, was previously demon-
strated by us, in the glomeruli of streptozotocin-diabetic
rats. The correlation of these results with the progressive
albuminuria shown by these animals suggests that this
polypeptide is involved in the genesis of rat diabetic
glomerulosclerosis (Bertoluci et al., 1996). More recently,
we showed, in the same animal model, that 45 days of
experimental diabetes significantly increased urinary albu-
min and urinary TGF-h1, as well as GLUT1 protein in the
renal cortex, but not in the renal medulla. These findings
suggest that higher cortical GLUT1 protein levels amplify
the effects of hyperglycemia in determining higher intra-
cellular glucose in mesangial cells, contributing to the
1566-0702/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved.
* Corresponding author. Tel.: +55-513-2232746; fax: +55-513-
E-mail addresses: email@example.com,
firstname.lastname@example.org (B. D’Agord Schaan).
Autonomic Neuroscience: Basic and Clinical 104 (2003) 88–94
kidney damage that complicates diabetes. This premature
appearance of albuminuria and high urinary TGF-h1 in
these experiments probably reflects the metabolic decom-
pensation to which these animals were submitted, since they
did not receive insulin (Schaan et al., 2001).
In human diabetic nephropathy, high blood pressure levels
determine deterioration of renal function. Glomerular hy-
pertension, determining mechanical stretch, enhances extrac-
ellular matrix formation by mesangial cells, which is aggra-
vated in a milieu of high glucose concentration (Cortes et al.,
1997). The cytokine TGF-h1 secreted by mesangial cells is
probably involved in this process (Hirakata et al., 1997).
Decreased renal vascular resistance induced by decreas-
ing sympathetic nerve activity renders diabetes and hyper-
tension-induced mesangial cell stretch unopposed (DiBona
and Kopp, 1997). Since muscle denervation (another model
of decreased sympathetic nerve activity) determines reduc-
tion in GLUT4 mRNA and protein content in myocites, we
hypothesised that renal denervation could induce changes in
kidney glucose transporter content, consequently increasing
glucose content of cortical cells like the mesangial, endo-
thelial and/or epithelial kidney cells (Henriksen et al., 1991;
Block et al., 1991). Even though the streptozotocin-diabetic
rat develops characteristic glomerulosclerotic lesions similar
to those found in human diabetic nephropathy, this animal
model does not develop hypertension, making it a good
model for evaluating the effects of denervation itself. No
studies in the streptozotocin-diabetic rat model have
explored whether autonomic dysfunction could determine
the modifications of renal function that are implicated in the
genesis of diabetic nephropathy.
Since experimental diabetes requires 6–9 months to
determine autonomic denervation of the gastrointestinal
tract (Schmidt and Sharp, 1982), and also of the heart
(Felten et al., 1982), and surgical renal denervation is a
relatively simple and widely used procedure, we propose its
utilisation in rats injected with streptozotocin in order to
evaluate the effects of renal denervation on the diabetic
kidney. The absence of hypertension in this model would
allow us to study only the effects of autonomic innervation
failure on renal function, independently of the effects of
systemic hypertension on renal haemodynamics.
Considering that the progression of nephropathy has been
related to the occurrence of autonomic neuropathy, the aims
of this study were to examine the effects of renal denervation
upon mechanisms involved in the development of nephrop-
athy like cortical GLUT1 and TGF-h1 production, as well as
urinary albumin in the streptozotocin-diabetic rat.
2. Materials and methods
Experiments were performed on male Wistar rats (Ani-
mal Quarter House of the Universidade Federal do Rio
Grande do Sul, Porto Alegre, Brazil) weighing 180–280 g.
They were fasted overnight and rendered diabetic by a
single injection in the tail vein of streptozotocin (60 mg
; Sigma, St. Louis, MO, USA) dissolved in citrate
buffer (pH 4.5) and injected slowly. Controls were injected
with citrate buffer. Animals were subsequently maintained
for 30 days (diabetics: n = 13, controls: n = 13) in individual
cages with free access to tap water and standard rat food.
2.2. Surgical renal denervation
Thirty days after streptozotocin injection, a 24-h urinary
sample was collected and bilateral renal denervation or
sham surgery was performed in the four experimental
groups: renal-denervated diabetic (n = 7), diabetic (n = 6),
renal-denervated control (n = 5) and control (n = 8). Renal
denervation was adapted as previously described and vali-
dated in this laboratory (Oliveira et al., 1992; Lacchini et al.,
1997). As widely described, renal denervation was accom-
plished by using a surgical–pharmacological procedure
(DiBona and Rios, 1980; Kassab et al., 1995; Granger et
al., 1996; Huang et al., 1998; Lohmeier et al., 1998).
Mechanical denervation was performed by carefully
stripping all visible nerves at 16 Â magnification (M90
stereomicroscope, FD Vascocelos) along the renal arteries
and veins from the aorta to the hilum of the kidney.
Chemical denervation was performed by quickly painting
the renal artery with 20% phenol in absolute ethanol. Then
the artery was washed with isotonic saline. For sham
denervation, the surgery was the same, but the renal artery
and vein were not isolated and the nerves were left intact.
Fifteen days later, another 24-h urinary sample was
collected. The effectiveness of the procedure was determined
by measuring renal tissue norepinephrine content, homoge-
nising parts of the tissue in perchloric acid and, subsequently,
assaying it using the alumina extraction procedure. Norepi-
nephrine content of the renal homogenate was determined by
high-performance liquid chromatography coupled with an
electrochemical detector. Previous studies showed that this
procedure markedly deplete the renal tissue norepinephrine
to less than 5% in both kidneys (Granger et al., 1996;
Lacchini et al., 1997). Surgical renal denervation determined
a significant decrease in renal tissue norepinephrine content:
0.0131 pg mgÀ 1
PNC in renal-denervated control animals
compared to 1.658 pg mgÀ 1
PNC in controls ( p < 0.05).
2.3. Arterial pressure measurement
Catheters filled with saline were implanted under ether
anesthesia into the femoral artery (PE-10) for direct meas-
urement of arterial pressure. One day after catheter place-
ment, the arterial cannula was connected to a strain-gauge
transducer (P23Db, Gould-Statham, Oxnard, CA) and blood
pressure signals were recorded during a 40-min period with
a microcomputer equipped with an analog-to-digital con-
verter board (CODAS, 2-kHz sampling frequency, Dataq
B. D’Agord Schaan et al. / Autonomic Neuroscience: Basic and Clinical 104 (2003) 88–94 89
Instruments, Akron, OH). Rats were conscious and moved
freely during the experiments. Recorded data were analysed
on a beat-to-beat basis.
Subsequently, blood was collected for plasma glucose
measurement and the animals were anaesthetised in order to
have the kidneys removed.
2.4. Renal sampling
Anesthesia was performed with sodium pentobarbital (25
mg kgÀ 1
body weight, IV). Immediately after clamping the
aorta up to the renal arteries, the abdominal aorta was
isolated and catheterised below the renal arteries. After that,
the inferior vena cava was cut below the renal veins. The
kidneys were perfused with Hanks buffer and immediately
removed. Renal cortex and medulla were dissected under
ocular control; the tissue fragments of each area were
weighed and frozen at À 70 jC for further procedures.
2.5.1. Glucose, albumin and TGF-
Plasma and urinary glucose were measured using the
colorimetric enzymatic test (commercial kit, Merck, GE,
Centrifichem System 400-Roche/Cobas Mira-Roche).
Urinary albumin was quantified by electroimmunoassay
using antibody anti-rat albumin as previously described
(Schmid et al., 1989).
For the TGF-h1 assay, immediately after collection,
urinary samples were centrifuged at 2000 rpm for 5 min at
room temperature and stored at À 80 jC. On the day of the
assay, in order to activate latent TGF-h1, the samples were
acidified with 1 N HCl to a pH of 2–3 for 30 min at room
temperature, and then re-neutralised to pH 7–8 with the same
amount of 1 N NaOH. The TGF-h1 was measured by using
an enzyme-linked immunosorbent assay kit (TGF-h1 Emax
ImmunoAssay Systems-Promega, Madison, WI, USA) with
a monoclonal antibody to human active TGF-h1 provided by
the manufacturer as previously described (Schaan et al.,
2001). Among the standards, the intra- and inter-assay
coefficients were 6.9% and 12%, respectively. The reprodu-
cibility of the assay was defined by measuring standards for 2
consecutive days: the correlation coefficient was 0.96.
Recovery of samples between expected and apparent TGF-
h1 concentrations after adding known amounts of TGF-h1
was 119%. The detection limit was 32 pg mlÀ 1
. The cross-
reactivity with TGF-h2 was 1.6% and with TGF-h3 0.7%.
Urinary TGF-h1 results were corrected by urinary creatinine
and results expressed as ng mgÀ 1
Renal cortex and medulla were analysed for their GLUT1
protein abundance. The antibody used was raised in New
Zealand, white rabbits from a 15 amino acid peptide of rat
GLUT1, which was synthesised according to the deduced
carboxy-terminal sequence of rat GLUT1. It was coupled to
keyhole limpet hemocyanin and used for immunisation of
male New Zealand white rabbits. This anti-serum has been
successfully used for immunoblotting (Vestri et al., 2001).
The tissue samples were homogenised in 10 w/v buffer
(10 mM Tris–HCl, 1 mM EDTA and 250 mM sucrose, pH
7.4, containing 5 mg/ml aprotinin), using a Polytron set at
24,000 rpm for 30 s, and centrifuged at 3000 Â g for 15 min.
The supernatant was centrifuged at 12,000 Â g for 20 min,
and the pellet was resuspended as a plasma membrane
fraction, in which the alkaline phosphatase activity was
shown to have increased more than three times compared
to the enzyme activity in the supernatant of the first
centrifugation. A Western blotting analysis was then per-
formed as previously described (Vestri et al., 2001). The
results were expressed as arbitrary units (AU) by amount of
electrophoresed total protein.
2.6. Statistical analysis
Data are reported as means F standard error of the mean.
Statistical significance was calculated by the Student’s t-test
for unpaired data when two groups were compared, and
ANOVA (Student–Newman–Keuls as post-test) when four
groups were compared. Urinary albumin and urinary TGF-
h1 data were log10 transformed before analysis. Differences
were considered to be significant for p < 0.05.
At baseline, body weights were similar in all experimen-
tal groups: 250 F 4, 261 F11, 263 F 7 and 241 F11g, for
Characteristics of diabetic (D) and nondiabetic (ND) rats after 15 days of renal denervation (RD) (45 days after STZ injection)
D D-RD ND ND-RD
Body weight (g) 189 F 7* (7) 212 F 18* (6) 295 F 1 (6) 292 F 8 (7)
Plasma glucose (mmol/l) 20.8 F 3* (7) 21.7 F 2* (5) 7.8 F 1 (6) 8.1 F1 (5)
24-h urinary glucose (mg/24 h) 2856 F 484*,#
(12) 6064 F 1242* (8) 3.1 F 0.9 (10) 2.2 F 0.5 (10)
Diuresis (ml/24 h) 59 F 6*,#
(12) 86 F 7* (8) 20 F 1 (10) 24 F 10 (10)
Mean arterial pressure (mmHg) 99 F 7 (5) 103 F 7 (4) 112 F 3 (4) 107 F 2 (4)
Data are mean F S.E.M. Numbers in parenthesis indicate numbers of animals.
*p < 0.05 vs. ND and ND-RD.
p < 0.05 vs. D-RD.
B. D’Agord Schaan et al. / Autonomic Neuroscience: Basic and Clinical 104 (2003) 88–9490
renal-denervated control, control, renal-denervated diabetic
and diabetic animals, respectively ( p = 0.13). The groups
which received streptozotocin presented a slight loss of
weight, whereas controls increased their body weights.
Consequently, control rats were significantly heavier than
diabetic rats at the end of the experiment ( p < 0.05). As
expected, plasma glucose levels after 45 days of streptozo-
tocin injection were elevated (by 2.5-fold) in diabetic rats
when compared to control groups ( p < 0.05). Also, 24-h
urinary glucose and diuresis were significantly higher in
diabetic animals versus their controls, 30 and 45 days after
streptozotocin injection. Therefore, these results confirmed
the severity of the diabetic state obtained by the streptozo-
tocin injection (Table 1).
Renal denervation affected neither weight gain nor
plasma glucose levels in either group, but it increased
urinary glucose by 45% and diuresis by 68% in diabetics
( p < 0.05) (Table 1).
Mean arterial pressure did not differ between diabetic
and control rats (99 F 7 and 112 F 3 mm Hg, respectively),
whether they underwent renal denervation or not (103 F 7
and 107 F 2 mm Hg, respectively). These data are shown in
Thirty days after streptozotocin injection, urinary albu-
min was significantly higher in the diabetic group
(212.3 F 47 vs. 73 F 5 Ag/24 h, p < 0.05). Fifteen days of
renal denervation did not operate changes in albuminuria,
neither between non-diabetic nor between diabetic animals
(46 F 6, 89.1 F18, 127.3 F 19 and 141.3 F 24 Ag/24 h in
renal-denervated control, control, renal-denervated diabetic
and diabetic groups, respectively). These data are shown in
Fig. 2 shows that similar results were observed when
urinary TGF-h1 was measured in the same urinary samples:
30 days of experimental diabetes determined higher levels of
this polypeptide concentration, 71.1 F 9 vs. 10.8 F 2 ng/mg
creatinine in diabetics and controls, respectively ( p < 0.05).
Renal denervation did not determine any change in urinary
TGF-h1, considering all groups (13.4 F 5, 10 F 4,
111.8 F 24 and 89.9 F 27 ng mgÀ 1
creatinine in renal-
denervated control, control, renal-denervated diabetic and
diabetic groups, respectively).
Experimental diabetes and renal denervation in control
animals determined higher levels of cortical GLUT1 protein
independently ( p < 0.05 for each). However, renal denerva-
tion in diabetic animals significantly reduced levels of
cortical GLUT1 protein by 20% ( p < 0.05), in such a way
that these levels were close to those of control animals
Fig. 1. Albuminuria in control (ND) and diabetic (D) rats 30 days after STZ
treatment (left) and 15 days later (right) after sham operation or renal
denervation (RD). Data are mean F S.E.M. Besides the bars, n = indicates
the number of animals. *p < 0.05 vs. ND; #
p < 0.05 vs. ND-RD.
Fig. 2. Urinary TGF-h1 in control (ND) and diabetic (D) rats, 30 days after
STZ treatment (left) and 15 days later (right) after sham operation or renal
denervation (RD). Cre = creatinine. Data are mean F S.E.M. Besides the
bars, n = indicates the number of animals. *p < 0.05 vs. ND; #
p < 0.05 vs.
Fig. 3. Cortical (left) and medullar (right) GLUT1 protein content in
nondiabetic (ND) and diabetic (D) rats submitted to sham operation or renal
denervation (RD). Top, typical autoradiograms; bottom, data are mean F
S.E.M. of four (cortex) or six animals (medulla). **p < 0.05 vs. ND and D-
p < 0.05 vs. D. *p < 0.05 vs. ND, ND-RD and D; #
p < 0.05 vs. ND-RD
B. D’Agord Schaan et al. / Autonomic Neuroscience: Basic and Clinical 104 (2003) 88–94 91
(Fig. 3). Medullar levels of GLUT1 protein decreased by
50% in experimental diabetes ( p < 0.05). The effect of renal
denervation in this group was reverse, but did not com-
pletely restore GLUT1 protein levels to those observed in
non-diabetic animals (Fig. 3).
An association between diabetic neuropathy and nephr-
opathy has been suggested by a possible effect of denerva-
tion in determining an enhancement of kidney vulnerability
to the hemodynamic effects of blood pressure (Sundkvist and
Lilja, 1993). In the streptozotocin-diabetic rat, albuminuria
was related to progressively higher glomerular immunohis-
tochemical TGF-h1 staining and deposition of total and type
I collagen (Bertoluci et al., 1996), even though in this model
there is no hypertension (Schaan et al., 1997), as it is
observed in humans (Parving et al., 1981). In this animal
model, renal diabetic damage is probably highly mediated by
increased glucose utilisation in mesangial cells (Ayo et al.,
1991). This increased glucose utilisation could be mediated
by high levels of facilitative glucose transporters present on
the cell surface of mesangial cells, since it is clear that the
activity of these transporters may be a rate-limiting factor for
increased glucose utilisation and consequently important in
the development of diabetic changes in the kidney (Heilig et
al., 1995). Despite the diuretic, natriuretic and hemodynamic
effects of renal denervation and the kidney GLUT1 abun-
dance currently described in many experimental conditions,
they were not well defined in the streptozotocin-diabetic rat.
The present study intended to observe the effects of renal
denervation upon markers involved in the pathogenesis of
diabetic nephropathy, such as the pattern of cortical GLUT1
expression, urinary albumin and urinary TGF-h1 in the
experimental model of streptozotocin-diabetic rat.
It is largely known that the effectiveness of renal dener-
vation is determined by the reduction in norepinephrine
renal tissue content (Kline and Mercer, 1980; Kassab et al.,
1995; Granger et al., 1996; Lohmeier et al., 1998). Using
these observations, we can consider that renal denervation in
the present study was effective and clearly reduced the renal
norepinephrine content in the animals submitted to the
In control animals, renal denervation determined, as
diabetes also did, an elevation of cortical GLUT1 protein
content. In diabetic animals, however, renal denervation
significantly reduced levels of cortical GLUT1 protein, in
such a way that these levels were almost identical to those of
control animals. These effects could be explained by the
possibility of cell damage or downregulation induced by
glucotoxicity, since other authors, studying cells in culture,
have observed elevation of GLUT1 expression and protein
levels when the glucose medium content was increased
(15–20 mmol lÀ 1
), followed by reduction when glucose
concentration was excessively increased (25–30 mmol lÀ 1
(Wakisaka et al., 1995; Knott et al., 1996). Nevertheless,
even in the presence of downregulation of glucose trans-
porters, other authors have demonstrated that the net glucose
consumption by cultured glomerular cells remains substan-
tially increased and is accompanied by a highly significant
enhancement in types IV and VI collagen production
(Wakisaka et al., 1994). In agreement with these authors,
we observed a tendency to higher urinary TGF-h1 levels in
these rats, indicating that the GLUT1 decrease determined
by 15 days of denervation was not enough to decrease
urinary TGF-h1 levels and, probably, neither the fibrosis
process. In summary, renal denervation normalised previ-
ously elevated cortical GLUT1 protein, but this change was
not accompanied by reduced urinary TGF-h1 levels. More-
over, it is important to emphasize that cortical GLUT1
expression had never been reported to be impaired in
Recently, some clinical studies emphasized the impor-
tance of our findings regarding the potential role of GLUT1
overexpression in the pathogenesis of diabetic nephropathy.
These studies demonstrated, in Chinese and Caucasoid
diabetic patients, the association between polymorphisms
of the glucose transporter GLUT1 gene and diabetic nephr-
opathy (Liu et al., 1999; Hodgkinson et al., 2001; Ng et al.,
2002). Also, the repercussions of GLUT1 gene overexpres-
sion changes were described in cultured mesangial cells: cell
hypertrophy, increased cell glucose mesangial uptake,
extracellular matrix, collagen IV and fibronectin synthesis.
All these alterations were reversed by rhein, which
decreases GLUT1 (Zhu et al., 2001).
Compared to control rats, diabetes determined reduction
of medullar GLUT1 protein content, while denervation
increased it in diabetic animals. Other authors already
observed these changes determined by diabetes: compared
to the cortical GLUT1 protein abundance, medullar GLUT1
levels are modified in a different way; they are reduced by
diabetes (Asada et al., 1997; Dominguez et al., 1994).
However, in diabetic rats, kidney denervation induced an
increase in GLUT1 abundance toward normal levels, but the
levels did not reach those observed in normal animals.
These results suggest that, in order to maintain GLUT1
abundance and glucose metabolism, completely different
mechanisms operate in renal tubular cells when compared to
cortical cells. The different responses of the same glucose
transporter, whether present in cortex or medulla, reflect its
different functions, and these different patterns ratify that, in
the present study, cortex and medulla were adequately
dissected. The modulation of reduced medullar GLUT1
content by insulin administration described by Asada et al.
in renal tubular cells suggests that GLUT1 protein abun-
dance reduction occurs in response to the high glucose
content presented to renal tubular cells (Asada et al., 1997).
Urinary glucose was significantly higher in diabetic rats
1 month after diabetes induction as well as after 45 days of
experimental diabetes, which includes 15 days of renal
denervation. It was also increased in renal-denervated dia-
B. D’Agord Schaan et al. / Autonomic Neuroscience: Basic and Clinical 104 (2003) 88–9492
betic as compared to diabetic animals. Diuresis showed the
same trends, probably because of the osmotic effect of
glucose on tubular fluid. These findings agree with those
described in normal rats (Piryova et al., 1980) and could be
explained by changes in GLUT2, the main glucose trans-
porter found in proximal tubule S1 segment, described to be
increased by diabetes as an adaptive response to maintain
high transtubular glucose flux (Dominguez et al., 1994;
Vestri et al., 2001).
Renal denervation did not operate changes in albuminu-
ria or urinary TGF-h1 in neither group. Since 15 days of
denervation does not decrease urinary albumin or urinary
TGF-h1 in experimental diabetes and does not increase
levels of GLUT1 in renal cortex, acceleration of diabetic
nephropathy cannot be assigned to it. Studying the same
model, Matsuoka did not find any effect of denervation on
albuminuria after 15 days, but he did find higher albumi-
nuria in diabetic denervated rats 30 days after the surgical
procedure (Matsuoka, 1993).
Reinnervation is a definitive phenomenon that begins
14–21 days after surgical denervation (Kline and Mercer,
1980). In this reinnervation process, areas of denervation
and hyperinnervation may develop, as it was recently
described to occur in the heart of diabetic rats (Schmid et
al., 1999). In this case, the result would be an increase in the
sympathetic tonus, which could determine worsening of
diabetic nephropathy. Of course, more extensive studies
concerning the process of denervation and possible reinner-
vation are necessary to fully explain what the effects of
autonomic neuropathy on the kidney of diabetic rats are.
Extending the period of denervation by another 15 days
could not reflect the pattern of changes of denervation.
Since hypertension is considered to have an important
role in the pathogenesis of human diabetic nephropathy
(Parving et al., 1981) and, in rats, diabetes and kidney
denervation do not increase blood pressure levels (Schaan
et al., 1997), we cannot rule out the possibility that this
difference could account for the different end-points
observed. Even though normal levels of blood pressure
could be directly transmitted to the glomerulus in the
denervated kidney, being a cause of injury, the fact that
rats, unlike humans, do not walk in an upright position
could also be protective. Taking all these observations
together, the extent to which this model is really represent-
ing what diabetic autonomic neuropathy determines in
human kidneys is still unknown.
We conclude that early-phase renal denervation in strep-
tozotocin-diabetic rats produces a normalisation of previ-
ously elevated cortical GLUT1 protein content, but urinary
TGF-h1 and albumin are not significantly ameliorated.
Since it has been hypothesised that renal denervation
increases kidney damage, we speculate that this is likely
to happen if animals’ blood pressure is increased (as in
humans with diabetic nephropathy), but it does not occur in
an animal model without increased mechanical stretch in its
Asada, T., Ogawa, T., Iwai, M., Shimomura, K., Kobayashi, M., 1997.
Recombinant insulin-like growth factor I normalizes expression of renal
glucose transporters in diabetic rats. Am. J. Physiol. 42, F27–F37.
Ayo, S.H., Radnik, R.A., Glass, W.F., Garoni, J.A., Rampt, E.R., Appling,
D.R., Kreisberg, J.I., 1991. Increased extracellular matrix synthesis
and mRNA in mesangial cells grown in high-glucose medium. Am. J.
Physiol. 260, F185–F191.
Bertoluci, M.C., Schmid, H., Lachat, J.J., Coimbra, T.M., 1996. Trans-
forming growth factor-beta in the development of rat diabetic nephrop-
athy. Nephron 74, 189–196.
Block, N.E., Menick, D.R., Robinson, K.A., Buse, M.G., 1991. Effect of
denervation on the expression of two glucose transporter isoforms in rat
hindlimb muscle. J. Clin. Invest. 88, 1546–1552.
Cortes, P., Zhao, X., Riser, B., Narins, R.G., 1997. Role of glomerular
mechanical strain in the pathogenesis of diabetic nephropathy. Kidney
Int. 51, 57–68.
DiBona, G.F., Rios, L.L., 1980. Renal nerves in compensatory renal re-
sponse to contralateral renal denervation. Am. J. Physiol. 238, F26–F30.
DiBona, G.F., Kopp, U.C., 1997. Neural control of renal function. Physiol.
Rev. 77, 75–197.
Dominguez, J.H., Camp, K., Maianu, L., Feister, H., Garvey, T., 1994.
Molecular adaptations of GLUT1 and GLUT2 in renal proximal tubules
of diabetic rats. Am. J. Physiol. 266, F282–F290.25.
Felten, S.Y., Peterson, R.G., Shea, P.A., Besch, J.R., Felten, D.L., 1982.
Effects of streptozotocin diabetes on the noradrenergic innervation of
the rat heart: a longitudinal histofluorescence and neurochemical study.
Brain Res. Bull. 8, 593–607.
Granger, J.P., Novak, J., Schnackenberg, C., Williams, S., Reinhart, G.A.,
1996. Role of renal nerves in mediating the hypertensive effects of nitric
oxide synthesis inhibition. Hypertension 27, 613–618.
Heilig, C.W., Concepcion, L.A., Riser, B.L., Freytag, S.O., Zhu, M.,
Cortes, P., 1995. Overexpression of glucose transporters in rat mesan-
gial cells cultured in a normal glucose millieu mimics the diabetic
phenotype. J. Clin. Invest. 96, 1802–1814.
Henriksen, E.J., Rodnik, K.J., Mondon, C.E., James, D., Holloszy, J.O.,
1991. Effect of denervation or unweighting on GLUT-4 protein in rat
soleus muscle. J. Appl. Physiol. 70, 2322–2327.
Hirakata, M., Kaname, S., Chung, U.G., Joki, N., Hori, Y., Noda, M.,
Takuwa, Y., Okazaki, T., Fujita, T., Katoh, T., Kurokawa, K., 1997.
Tyrosine kinase dependent expression of TGF-beta induced by stretch
in mesangial cells. Kidney Int. 51, 1028–1036.
Hodgkinson, A.D., Millward, B.A., Demaine, A.G., 2001. Polymorphisms
of the glucose transporter GLUT1 gene are associated with diabetic
nephropathy. Kidney Int. 59, 985–989.
Huang, W.-C., Fang, T.-C., Cheng, J.-T., 1998. Renal denervation prevents
and reverses hyperinsulinemia-induced hypertension in rats. Hyperten-
sion 32, 249–254.
Kassab, S., Kato, T., Wilkins, C.F., Chen, R., Hall, J.E., Granger, J.P., 1995.
Renal denervation attenuates the sodium retention and hypertension
associated with obesity. Hypertension 25, 893–897.
Kline, R.L., Mercer, P.F., 1980. Functional reinnervation and development
of supersensitivity to NE after renal denervation in rats. Am. J. Physiol.
Knott, R.M., Robertson, M., Muckersie, E., Forrester, J.V., 1996. Regula-
tion of glucose transporters (GLUT-1 and GLUT-3) in human retinal
endothelial cells. Biochem. J. 318, 313–317.
Lacchini, S., Fang, J., Fernandes, T.R.G., Irigoyen, M.C., 1997. Arterial
pressure control in normal rats: role of renal nerves and sodium. J.
Hypertens. 29 (3), 897.
Liu, Z.H., Guan, T.J., Chen, Z.H., Li, L.S., 1999. Glucose transporter
GLUT1 allele (XbaI-) associated with nephropathy in non-insulin de-
pendent diabetes mellitus. Kidney Int. 55, 1843–1848.
Lohmeier, T.E., Reinhart, G.A., Mizelle, H.L., Han, M., Dean, M.M., 1998.
Renal denervation supersensitivity revisited. Am. J. Physiol. 275,
B. D’Agord Schaan et al. / Autonomic Neuroscience: Basic and Clinical 104 (2003) 88–94 93
Matsuoka, H., 1993. Protective role of renal nerves in the development of
diabetic nephropathy. Diabetes Res. 23, 19–29.
Ng, D.P.K., Canani, L.H., Araki, S.I., Smiles, A., Warram, J.H., Krolewski,
A.S., 2002. Polymorphisms in GLUT1 are associated with the develop-
ment of diabetic nephropathy in diabetes mellitus. Diabetes 51 (Suppl. 2),
Oliveira, V.L.L., Irigoyen, M.C., Moreira, E.D., Strunz, C., Krieger, E.M.,
1992. Renal denervation normalizes pressure and baroreceptor reflex in
high renin hypertension in conscious rats. Hypertension 19, II-17–II-21.
Parving, H.-H., Andersen, A.R., Smidt, U.M., Friisberg, B., Svendsen,
P.A., 1981. Reduced albuminuria during early and aggressive antihy-
pertensive treatment of insulin-dependent diabetic patients with diabetic
nephropathy. Diabetes Care 4, 459–463.
Piryova, B., Natcheff, N.B., Kirkova, N.L., 1980. Effect of renal denerva-
tion on glucose transport. Acta Physiol. Pharmacol. Bulg. 6, 3–8.
Schaan, B.D., Bertoluci, M., Lacchini, S., Machado, U., Irigoyen, M.C.,
Schmid, H., 2001. Increased renal GLUT1 abundance, albuminuria and
urinary TGF-h1 in STZ-induced diabetic rats: implications for the de-
velopment of diabetic nephropathy (DN). Horm. Metab. Res. 33, 1–6.
Schaan, B.D., Maeda, C.Y., Timm, H., Medeiros, S., Moraes, R., Ferlin, E.,
Fernandes, T.G., Ribeiro, J.P., Schmid, H., Irigoyen, M.C., 1997. Time
course of changes in heart rate and blood pressure variability in strep-
tozotocin-induced diabetic rats treated with insulin. Br. J. Med. Biol.
Res. 30, 1081–1086.
Schmid, H., Bertoluci, M.C., Coimbra, T.M., 1989. Determinacßa˜o da ex-
crecßa˜o urina´ria de albumina por eletroimunoensaio (EIE). Arq. Bras.
Endocrinol. Metabol. 33, 73–75.
Schmid, H., Forman, L.A., Cao, X., Sherman, P.S., Stevens, M., 1999.
Heterogeneous cardiac sympathetic denervation and decreased myocar-
dial nerve growth factor in streptozotocin-induced diabetic rats: impli-
cations for cardiac sympathetic dysinnervation complicating diabetes.
Diabetes 48, 603–608.
Schmidt, R.E., Sharp, D.W., 1982. Axonal dystrophy in experimental dia-
betic autonomic neuropathy. Diabetes 31, 761–770.
Sundkvist, G., Lilja, B., 1993. Autonomic neuropathy predicts deterioration
in glomerular filtration rate in patients with IDDM. Diabetes Care 16
Vestri, S., Okamoto, M.M., de Freitas, H.S., Aparecida dos Santos, R.,
Nunes, M.T., Morimatsu, M., Heimann, J.C., Machado, U.F., 2001.
Changes in sodium or glucose filtrated rate modulate expression of
glucose transporters in renal proximal tubular cells of rat. J. Membr.
Biol. 182 (2), 105–112.
Wakisaka, M., Spiro, M.J., Spiro, R.G., 1994. Synthesis of type VI colla-
gen by cultured glomerular cells and comparison of its regulation by
glucose and other factors with that of type IV collagen. Diabetes 43,
Wakisaka, M., He, Q., Spiro, M.J., Spiro, R.G., 1995. Glucose entry into rat
mesangial cells is mediated by both Na+
-coupled and facilitative trans-
porters. Diabetologia 38, 291–297.
Zhu, J., Liu, Z., Li, Y., 2001. Inhibition of glucose transporter 1 over-
expression in mesangial cells by rhein. Zhonghua Nei Ke Za Zhi 40,
B. D’Agord Schaan et al. / Autonomic Neuroscience: Basic and Clinical 104 (2003) 88–9494
Referred to surgery with a diagnosis of RV cystic
tumor, the patient underwent median sternotomy,
pericardiotomy, cannulation of the ascending aorta
and of the superior and inferior venae cavae, extracor-
poreal circulation at a flow rate of 4 L/min, infusion
of a hypothermic crystalloid cardioplegic solution,
and hypothermia at 30 °C.
The protrusion caused by the tumor in the RV out-
flow tract was seen. We performed a right ventricu-
lotomy, exposed the cystic mass (Fig. 2), and resected
it completely. We patched the endocardium with a
small piece of preserved bovine pericardium. The
aortic clamping time was 25 minutes, and cardiopul-
monary bypass time was 42 minutes. The surgery
was successful. The patient had an uneventful post-
operative recovery and was completely asymptomatic
at her discharge on the 7th postoperative day. Histo-
logic examination revealed that the mass was a bron-
chogenic cyst (Figs. 3 and 4).
Volume 30, Number 1, 200372 Right Ventricular Bronchogenic Cyst
Fig. 1 A) Sagittal magnetic resonance image shows a high-
intensity lesion (arrow) causing obstruction of the right ven-
tricular outflow tract. B) Axial magnetic resonance image
shows high-intensity lesion (arrow) invading the myocardium
of the anterior wall of the right ventricular outflow tract.
Fig. 2 Operative exposure of the cystic mass.
Fig. 3 Photomicrograph of the cystic wall, low magnification
(H&E, orig. ×200).
Fig. 4 Cystic wall, high magnification (H&E, orig. ×400). Pho-
tomicrograph shows respiratory epithelium and intramural
cartilage, indicated by the arrow.