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Abstract

To evaluate the role of cigarette smoke exposure (CSE) on ventricular remodeling following acute myocardial infarction (AMI). Rats were submitted to myocardial infarction and divided into two groups: C (control, n = 31) and F (CSE: 40 cigarettes/day, n = 22). After 6 months, the survivors were submitted to echocardiogram, functional study with isolated heart, and morphometric analysis. For comparison purposes, we used the t test (mean +/- standard deviation) or the Mann-Whitney test (with median and 25th and 75th percentiles). The CSE animals tended to have larger diastolic (C = 1.5 +/- 0.4 mm2, F = 1.9 +/- 0.4 mm2; p = 0.08) and systolic (C = 1.05 +/- 0.3 mm2, F = 1.32 +/- 0.4 mm2; p = 0.08) left ventricular(LV) areas. The systolic function of the LV, assessed according to the fractional area change, tended to be impaired in CSE animals (C = 31.9 +/- 9.3%, F = 25.5 +/- 7.6%; p = 0.08). The dp/dt values for CSE animals were statistically lower (C = 1474 +/- 397 mmHg, F = 916 +/- 261 mmHg; p = 0.02) than for control animals. The CSE animals presented higher right ventricle (RV) weight adjusted for body weight (C = 0.8 +/- 0.3 mg/g, F = 1.3 +/- 0.4 mg/g; p = 0.01), higher content of water in lungs (C = 4.8 (4.3-4.8)%, F = 5.4 (5.1-5.5); p = 0.03), and larger LV myocyte cross-sectional areas (C = 239.8 +/- 5.8 microm2, F = 253.9 +/- 7.9 microm2; p = 0.01). Cigarette smoke exposure intensifies ventricular remodeling following acute myocardial infarction.
Arquivos Brasileiros de Cardiologia - Volume 86, Nº 4, Abril 2006
Original Article
Artigo Original
276
A Exposição à Fumaça de Cigarro Intensifica a
Remodelação Ventricular após o Infarto Agudo do
Miocárdio
Cigarette Smoke Exposure Intensifies Ventricular Remodeling Process
following Myocardial Infarction
Leonardo A. M. Zornoff, Beatriz B. Matsubara, Luiz S. Matsubara, Marcos F. Minicucci,
Paula S. Azevedo, Álvaro O. Camapanha, Sergio A. R. Paiva
Faculdade de Medicina de Botucatu – Unesp - Botucatu, SP
Correspondência: Leonardo A. M. Zornoff • Departamento de Clínica Médica – Rubião Jr. - 18618-000 – Botucatu, SP
E-mail: lzornoff@cardiol.br / lzornoff@fmb.unesp.br Recebido em 16/12/04 • Aceito em 25/07/05
OBJETIVO
Analisar os efeitos da exposição à fumaça de cigarro
(EFC) na remodelação ventricular após o infarto agudo
do miocárdio (IAM).
MÉTODOS
Ratos foram infartados e distribuídos em dois grupos: C
(controle, n = 31) e F (EFC: 40 cigarros/dia, n = 22). Após
seis meses, foi realizado ecocardiograma, estudo funcional
com coração isolado e morfometria. Para comparação, foi
utilizado o teste t (com média ± desvio padrão) ou teste
de Mann-Whitney (com mediana e percentis 25 e 75).
RESULTADOS
Os animais EFC apresentaram tendência a maiores
áreas ventriculares diastólicas (C = 1,5 ± 0,4 mm
2
, F =
1,9 ± 0,4 mm
2
; p = 0,08) e sistólicas (C = 1,05 ± 0,3
mm
2
, F = 1,32 ± 0,4 mm
2
; p = 0,08) do VE. A função
sistólica do VE, avaliada pela fração de variação de área,
tendeu a ser menor nos animais EFC (C = 31,9 ± 9,3
%, F = 25,5 ± 7,6 %; p = 0,08). Os valores da - dp/dt
dos animais EFC foram estatisticamente inferiores (C =
1474 ± 397 mmHg, F = 916 ± 261 mmHg; p = 0,02)
aos animais-controle. Os animais EFC apresentaram maior
peso do VD, ajustado ao peso corporal (C = 0,8 ± 0,3
mg/g, F = 1,3 ± 0,4 mg/g; p = 0,01), maior teor de água
nos pulmões (C = 4,8 (4,3-4,8)%, F = 5,4 (5,1-5,5);
p = 0,03) e maior área seccional do miócito do VE (C =
239,8 ± 5,8 µm
2
, F = 253,9 ± 7,9 µm
2
; p = 0,01).
CONCLUSÃO
A exposição à fumaça de cigarro intensifica a
remodelação ventricular após IAM.
PALAVRAS-CHAVE
Função ventricular, dilatação ventricular, hipertrofi a
ventricular.
OBJECTIVE
To evaluate the role of cigarette smoke exposure (CSE)
on ventricular remodeling following acute myocardial
infarction (AMI).
METHODS
Rats were submitted to myocardial infarction and
divided into two groups: C (control, n = 31) and F
(CSE: 40 cigarettes/day, n = 22). After 6 months, the
survivors were submitted to echocardiogram, functional
study with isolated heart, and morphometric analysis.
For comparison purposes, we used the t test (mean ±
standard deviation) or the Mann-Whitney test (with
median and 25
th
and 75
th
percentiles).
RESULTS
The CSE animals tended to have larger diastolic (C
= 1.5 ± 0.4 mm
2
, F = 1.9 ± 0.4 mm
2
; p = 0.08) and
systolic (C = 1.05 ± 0.3 mm
2
, F = 1.32 ± 0.4 mm
2
; p
= 0.08) left ventricular(LV) areas. The systolic function of
the LV, assessed according to the fractional area change,
tended to be impaired in CSE animals (C = 31.9 ± 9.3%,
F = 25.5 ± 7.6%; p = 0.08). The - dp/dt values for
CSE animals were statistically lower (C = 1474 ± 397
mmHg, F = 916 ± 261 mmHg; p = 0.02) than for control
animals. The CSE animals presented higher right ventricle
(RV) weight adjusted for body weight (C = 0.8 ± 0.3 mg/g,
F = 1.3 ± 0.4 mg/g; p = 0.01), higher content of water
in lungs (C = 4.8 (4.3-4.8)%, F = 5.4 (5.1-5.5); p =
0.03), and larger LV myocyte cross-sectional areas (C =
239.8 ± 5.8 µm
2
, F = 253.9 ± 7.9 µm
2
; p = 0.01).
CONCLUSION
Cigarette smoke exposure intensifi es ventricular
remodeling following acute myocardial infarction.
KEY WORDS
Ventricular function, ventricular dilatation, ventricular
hypertrophy.
Arquivos Brasileiros de Cardiologia - Volume 86, Nº 4, Abril 2006
277
A EXPOSIÇÃO À FUMAÇA DE CIGARRO INTENSIFICA A REMODELAÇÃO VENTRICULAR APÓS O INFARTO AGUDO DO MIOCÁRDIO
Após o infarto agudo do miocárdio (IAM), podem
ocorrer complexas alterações da arquitetura ventricular
envolvendo tanto a região infartada como a não-infartada.
Após a oclusão coronariana, pode ocorrer dilatação
ventricular aguda, caracterizada por adelgaçamento
e distensão da região infartada. Essa alteração é
denominada expansão do infarto e resulta do deslizamento
de grupos musculares necróticos em conseqüência da
desintegração do colágeno interfi brilar
1
. Na fase tardia,
observaram-se diferentes graus de dilatação cavitária.
Esse fenômeno é resultado do processo de hipertrofi a
que envolve ambos os ventrículos e parece manifestar-
se como resposta ao aumento do estresse parietal.
Paralelamente, foi observado que há acúmulo anormal
de colágeno (fi brose) nas áreas viáveis do miocárdio,
tanto no ventrículo infartado como no outro ventrículo.
Esse conjunto de adaptações, em que ocorrem alterações
na composição, massa, volume e geometria cardíaca, é
chamado de remodelação miocárdica
2-4
.
A intensidade do processo de remodelação ventricular
está diretamente associado a pior prognóstico, em razão
de maior incidência na formação de aneurismas, ruptura
ventricular e arritmias, bem como está associada a
progressão da disfunção ventricular. Assim, inúmeras
estratégias vêm sendo utilizadas para prevenir ou atenuar
o processo de remodelação ventricular após o IAM
5-7
.
Doença aterosclerótica coronariana e IAM estão
intimamente relacionados ao tabagismo. Esse fator de
risco é importante causa independente de morbidade e
mortalidade
8,9
. Entretanto, enquanto os efeitos vasculares
da exposição à fumaça de cigarro são bem conhecidos,
os efeitos do tabagismo no coração têm recebido
menos atenção. Algumas evidências experimentais e
clínicas sugerem que o tabagismo pode estar associado
a alterações funcionais e morfológicas cardíacas
10-19
.
Entretanto, os efeitos do tabagismo em variáveis cardíacas
após o IAM ainda não foram estudados. Assim, o objetivo
deste estudo foi analisar os efeitos da exposição da
fumaça do cigarro no processo de remodelação ventricular
em ratos.
MÉTODOS
Grupos experimentais
O protocolo experimental do presente trabalho foi
aprovado pela Comissão de Ética em Experimentação
Animal de nossa instituição, estando em conformidade com
os Princípios Éticos na Experimentação Animal adotado
pelo Colégio Brasileiro de Experimentação Animal.
Foram utilizados ratos wistar machos, pesando
entre 200 e 250 gramas. O primeiro passo do estudo
foi a indução do infarto experimental (fi g. 1). O infarto
agudo foi produzido de acordo com método já descrito
previamente
20
. Em resumo, os ratos foram anestesiados
com éter e submetidos a toracotomia lateral esquerda.
Após exteriorização do coração, o átrio esquerdo foi
afastado e a artéria coronária esquerda ligada com fi o
mono-nailon 5.00 entre a saída da artéria pulmonar e o
átrio esquerdo. A seguir, o coração retornou ao tórax, os
pulmões foram infl ados com pressão positiva e o tórax
fechado por suturas com algodão 10.
Os animais foram mantidos em gaiolas para recupe ração,
alimentados com ração comercial padrão e livre acesso a
água, com controle de luz – ciclos de 12 horas, temperatura
de aproximadamente 25°C e umidade controlada.
A segunda etapa do protocolo foi a constituição dos
grupos experimentais. Após 48 horas do infarto, os
animais sobreviventes foram aleatoriamente divididos em
dois grupos: Grupo C (n = 31): formado pelos animais
Controle
Dias
-2 -1
0 1 2 3 4 183
IAM Eco
Estudo funcional/
morfológico in vitro
EFC
Randomização
180
Ratos
Fig. 1 – Protocolo experimental. Controle: animais infartados; EFC: animais infartados e expostos à fumaça de cigarro; Eco: estudo funcional e
morfológico por meio do ecocardiograma
Arquivos Brasileiros de Cardiologia - Volume 86, Nº 4, Abril 2006
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A EXPOSIÇÃO À FUMAÇA DE CIGARRO INTENSIFICA A REMODELAÇÃO VENTRICULAR APÓS O INFARTO AGUDO DO MIOCÁRDIO
infartados que não receberam nenhuma intervenção
terapêutica; Grupo F (n = 22): formado pelos animais
infartados que foram expostos à fumaça de cigarro.
A exposição ao fumo
A terceira etapa do estudo compreendeu o período
de observação de seis meses. Para os animais do Grupo
F, utilizamos o método proposto por Wang e cols.
21
e
já padronizado em nosso laboratório
22
, para expor os
animais à fumaça de cigarro em incubadora modifi cada.
Os ratos foram colocados na câmara transparente,
com um volume de aproximadamente 95x80x65 cm,
conectado ao aparelho de fumar. Puffs de fumaça foram
tirados do cigarro por vácuo por meio do aparelho de
fumar e depois jogados na câmara durante período de
30 minutos. Após esse período, a fumaça era exaurida
e o procedimento, repetido. Durante a primeira semana,
a fumaça foi liberada a uma taxa de cinco cigarros,
duas vezes por dia, no período da tarde, com intervalos
de descanso de 10 minutos. O número de cigarros foi
aumentado para uma taxa de 10 cigarros/30 minutos,
duas vezes no período da manhã e duas no período da
tarde, até o fi nal do período de estudo. Assim, ao fi nal, os
animais foram expostos à fumaça de 40 cigarros/dia. O
cigarro utilizado era de marca comercial com a seguinte
composição: 1,1 mg de nicotina, 14 mg de alcatrão e
15 mg de monóxido de carbono.
Avaliação morfológica e funcional pelo
ecocardiograma
A quarta etapa do protoco compreendeu a avaliação
morfológica e funcional pelo ecocardiograma de todos os
animais sobreviventes. Após seis meses de tratamento,
os animais sobreviventes (C, n = 13 e F, n = 11) foram
anestesiados com cloridrato de cetamina (50 mg/kg) e
cloridrato de xilidino (1 mg/kg), por via intramuscular,
para o estudo ecocardiográfico. Após tricotomia da
região anterior do tórax, os animais foram posicionados
em decúbito lateral esquerdo para realização do exame,
utilizando-se equipamento da Hewlett-Packard (modelo
Sonos 2000) dotado de transdutor eletrônico de 7,5 MHz.
A avaliação dos fl uxos transvalvar mitral e aórtico foi
realizada com o mesmo transdutor operando em 5,0 MHz.
As medidas das estruturas cardíacas foram efetuadas
nas imagens monodimensionais, obtidas com o feixe
de ultra-som orientado pela imagem bidimensional, na
posição paraesternal eixo menor. A imagem da cavidade
ventricular esquerda foi obtida posicionando o cursor do
modo-M entre os músculos papilares, logo abaixo do plano
da valva mitral. As imagens da aorta e do átrio esquerdo
foram obtidas na posição paraesternal eixo menor, com o
cursor do modo-M posicionado no nível da valva aórtica.
O registro da imagem monodimensional (velocidade: 100
mm/s) foi realizado por meio da impressora modelo UP-
890MD da Sony Co.
Posteriormente, as estruturas cardíacas foram
medidas manualmente com o auxílio de um paquímetro
de precisão, de acordo com as recomendações da
American Society of Echocardiography
23
e já validadas
no modelo de ratos infartados
24
. As estruturas cardíacas
foram medidas em, pelo menos, cinco ciclos cardíacos
consecutivos. O diâmetro diastólico do ventrículo esquerdo
(DDVE) e a espessura da parede posterior do VE (EDVE)
foram medidos no momento correspondente ao diâmetro
máximo da cavidade. O diâmetro sistólico do VE (DSVE)
foi medido no momento da excursão sistólica máxima da
parede posterior da cavidade. As áreas diastólicas (AD)
e sistólicas (AS) foram medidas no modo bidimensional,
por meio de planimetria. A função sistólica do VE foi
avaliada calculando-se a fração de variação de área
(FVA=AD-AS/AD x 100)
24
. O fl uxo diastólico transmitral
(ondas E e A) foi obtido com o transdutor na posição apical
quatro câmaras. As medidas referentes aos fl uxos foram
realizadas diretamente no monitor do ecocardiógrafo.
Avaliação funcional in vitro
A quinta etapa do protoco compreendeu a avaliação
funcional in vitro. Entre um e três dias após o estudo
ecocardiográfi co, os mesmos animais (C, n = 13 e F,
n = 11) receberam pentobarbital sódico (50 mg/kg)
e heparina (1.000 UI) por via intraperitoneal e foram
ventilados com pressão positiva e oxigênio a 100%. A
seguir, o tórax foi aberto e a aorta cateterizada com cânula
de metal número 15, iniciando-se a perfusão miocárdica
retrógrada, com solução nutriente de Krebs-Henseleit,
com a seguinte composição, em mmol/l: 115 NaCl;
5,4 KCl; 1,2 MgSO4; 1,25 CaCl2; 1,15 NaH2PO4; 25
NaHCO3; 11 glicose. A solução acima foi acrescida de
insulina 10UI/l e manitol, na concentração de 8 mmol/l,
para assegurar maior preservação miocárdica
25
. Os
corações foram removidos da caixa torácica e colocados
em aparelho de estudo de coração isolado, tamanho 3
tipo 830 (Hugo Sacks Eletronic-Germany), com pressão
de perfusão constante de 75 mmHg. A solução nutriente
foi continuamente oxigenada com mistura gasosa de 95%
de oxigênio e 5% de CO
2
, mantendo-se a pressão parcial
de oxigênio entre 500-600 mmHg, temperatura de 37
o
C
e pH entre 7,3 e 7,4. O átrio esquerdo foi aberto e o
ápice do ventrículo esquerdo puncionado com agulha,
para drenar a cavidade ventricular, evitando-se acúmulo
de líquido no seu interior.
Um balão de látex, atado a tubo de polietileno
PE 90, foi colocado na cavidade ventricular. A outra
extremidade do tubo de polietileno foi conectada a uma
torneira de três vias, sendo uma das vias acoplada a
um transdutor de pressão (Stathan P23 XL) e a outra, a
uma seringa de 1 ml, que permitiu a variação do volume
do balão intracavitário. A musculatura atrial direita,
compreendendo o nódulo sinoatrial, foi extirpada e um
eletrodo de marcapasso artifi cial colocado no miocárdio
do ventrículo direito para se manter, artifi cialmente, a
freqüência cardíaca entre 200-250 bpm. Por meio da
preparação descrita, curvas de Starling foram obtidas com
infusão de líquido no balão, que permitiu variar a pressão
Arquivos Brasileiros de Cardiologia - Volume 86, Nº 4, Abril 2006
279
diastólica no ventrículo esquerdo de 0 a 25 mmHg,
mediante incrementos graduais de 5 mmHg, registrando-
se a pressão sistólica correspondente a cada variação de
volume. Nessa preparação, em que o coração opera em
condições isovolumétricas, foram obtidos os registros da
pressão sistólica (PS), da derivada positiva (dp/dt) e da
derivada negativa (-dp/dt) máximas
26
.
Estudo morfométrico
A sexta etapa do protoco compreendeu a avaliação
morfométrica in vitro dos corações. Após o estudo
funcional in vitro, os corações dos mesmos animais
(C, n = 13 e F, n = 11) foram retirados, dissecados
e os ventrículos direito e o esquerdo, incluindo o septo
interventricular foram separados e pesados. O peso
úmido do VE e do VD, normalizado para peso corpóreo
nal do rato (PC), foi utilizado como índice de hipertrofi a
ventricular. O conteúdo de água do pulmão foi avaliado
pela relação entre peso úmido e seco dos tecidos.
Amostras de tecido cardíaco foram fi xadas em solução
de formol a 10% por um período de 48 horas, segundo
método já descrito
27
. Após fi xação, o tecido foi incluso em
blocos de parafi na, obtendo-se a seguir cortes histológicos
coronais de 4 micras. Os cortes histológicos foram corados
em lâmina com solução Hematoxilina - Eosina (HE) ou
Masson para aferição de áreas da secção transversa
dos miócitos, empregando-se microscópio LEICA DM
LS acoplado a câmera de vídeo, que envia imagens
digitais a computador dotado de programa de análise
de imagens Image Pro-plus (Media Cybernetics, Silver
Spring, Maryland, USA ). Foram mensuradas cinqüenta
a setenta células por ventrículo analisado. Os miócitos
selecionados estavam seccionados transversalmente e
apresentavam forma redonda, núcleo visível no centro da
célula e localizavam-se na camada subendocárdica da
parede muscular do VE. Esse cuidado visou uniformizar
ao máximo o conjunto de miócitos dos diferentes grupos.
As áreas seccionais médias obtidas para cada grupo foram
utilizadas como indicador do tamanho celular.
Lâminas com cortes histológicos coronais de 6 micras
e corados pela técnica de Picro Sirius red, específi cos
para visualização de colágeno, foram feitas para avaliação
do interstício do miocárdio do VE. A leitura foi feita
utilizando-se microscópio LEICA DM LS acoplado a
câmera de vídeo, que envia imagens digitais a computador
dotado de programa de análise de imagens Image Pró-
plus (Media Cyberetics, Silver Spring, Maryland, USA).
Foram analisados trinta a quarenta campos por ventrículo,
utilizando objetiva de 40X. Os campos escolhidos
estavam localizados longe da área infartada e afastados
da região perivascular.
Análise estatística
As comparações entre os grupos C e F foram feitas
pelo teste t de Student, quando os dados apresentaram
distribuição normal. Quando os dados não apresentaram
distribuição normal, as comparações entre os grupos
foram feitas pelo teste U de Mann-Whitney. Os dados
foram expressos em média ± desvio padrão (para
distribuição normal) ou mediana com os percentis 25 e
75 (para distribuição não normal). Os resultados foram
considerados estatisticamente signifi cantes se p < 0,05.
As análises estatísticas foram feitas com o programa
SigmaStat for Windows v2.03 (SPSS Inc, Chicago, IL).
RESULTADOS
Durante o período de observação, a mortalidade
entre os grupos não atingiu diferença estatisticamente
signifi cante (C = 58%, F = 50%; P = 0,67).
Os resultados do estudo ecocardiográfi co estão na tabela
1. A freqüência cardíaca foi estatisticamente maior nos
animais expostos à fumaça de cigarro (C = 248 ± 31 bpm,
F = 302 ± 39 bpm; p = 0,001). Esse grupo apresentou
tendência a maiores áreas diastólicas (C = 1,5 ± 0,4 mm
2
,
F = 1,9 ± 0,4 mm
2
; p = 0,08) e sistólicas (C = 1,05 ±
0,3 mm
2
, F = 1,32 ± 0,4 mm
2
; p = 0,08) do VE, em
ralação aos animais-controle. A função sistólica do VE,
avaliada pela fração de variação de área, também tendeu
a ser menor nos animais expostos à fumaça de cigarro (C =
31,9 ± 9,3%, F = 25,5 ± 7,6%; p = 0,08). Considerando
as outras variáveis morfométricas e funcionais, não foram
observadas diferenças entre os dois grupos.
Em relação aos resultados do estudo com o coração
isolado, a exposição à fumaça de cigarro não modifi cou
A EXPOSIÇÃO À FUMAÇA DE CIGARRO INTENSIFICA A REMODELAÇÃO VENTRICULAR APÓS O INFARTO AGUDO DO MIOCÁRDIO
Tabela 1 – Estudo ecocardiográfi co
Variáveis Controle (n = 13) EFC (n = 11) p
FC (bpm) 248 ± 31 302 ± 39 0,001
AE (mm) 6,6 ± 1,7 6,8 ± 1,4 0,69
AE/PC (mm/g) 12,2 ± 3,6 14,3 ± 3,2 0,16
DDVE (mm) 11,1 ± 1,1 11,1 ± 1,2 0,94
DDVE/PC (mm/g) 20,5 ± 3,4 23,4 ± 5,3 0,12
HDPP (mm) 1,4 ± 0,2 1,3 ± 0,3 0,55
HD/DDVE 0,13 ± 0,03 0,12 ± 0,03 0,69
E/A 2,7 ± 2,5 4,5 ± 2,7 0,15
AD (mm2) 1,57 ± 0,4 1,90 ± 0,4 0,08
AS (mm2) 1,05 ± 0,3 1, 32 ± 0,3 0,08
FVA (%) 31,9 ± 9,3 25,5 ± 7,5 0,08
Controle: animais infartados; EFC: animais infartados e expostos à
fumaça de cigarro; PC: peso corporal do rato; AE: diâmetro do átrio
esquerdo; DDVE: diâmetro diastólico do ventrículo esquerdo; HDPP:
espessura diastólica da parede posterior; HD/DDVE: relação entre a
espessura diastólica e o diâmetro diastólico do ventrículo esquerdo;
E/A: relação entre as ondas E e A avaliadas do fl uxo transmitral; AD:
área diastólica; AS: área sistólica; FVA: fração de variação de área;
Os dados foram expressos em média ± desvio padrão
os valores da PS (C = 113 ± 19 mmHg, F = 111 ± 30
mmHg; p = 0,89 ) e da dp/dt máximas (C =1887 ± 367
mmHg/s, F = 2177 ± 1017 mmHg/s; p = 0,56), em
relação aos animais-controle. Entretanto, os valores da
- dp/dt dos animais expostos à fumaça de cigarro foram
estatisticamente inferiores (C = 1474 ± 397 mmHg, F
= 916 ± 261 mmHg; p = 0,02) aos valores dos animais
controle (fi g. 2).
Arquivos Brasileiros de Cardiologia - Volume 86, Nº 4, Abril 2006
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A EXPOSIÇÃO À FUMAÇA DE CIGARRO INTENSIFICA A REMODELAÇÃO VENTRICULAR APÓS O INFARTO AGUDO DO MIOCÁRDIO
DISCUSSÃO
O objetivo deste estudo foi avaliar os efeitos da
exposição à fumaça de cigarro no processo de remodelação
ventricular após o IAM, em ratos. Nossos resultados
indicam que a exposição crônica à fumaça resulta em
alterações cardíacas, morfológicas e funcionais. Desse
modo, o hábito de fumar após o infarto poderia resultar na
intensifi cação do processo de remodelação ventricular.
Os efeitos cardíacos do hábito de fumar têm sido
Tabela 2 – Dados morfométricos
Variáveis Controle (n = 13) EFC (n = 11) p
PC (g) 548 ± 68 487 ± 74 0,05
VE/PC (mg/g) 2,9 ± 0,9 2,8 ± 0,5 0,86
VD/PC (mg/g) 0,81 ± 0,3 1,31± 0,4 0,01
Pulmões U/S 4,8 (4,3-4,8) 5,1 (5,1-5,4) 0,03
AS (µm2) 239,8 ± 5,8 253,9 ± 7,9 0,01
IC (%) 4,05 ± 0,4 3,4 ± 0,8 0,29
% IAM 46,3 ± 4,1 47,7 ± 4,9 0,45
Controle: animais infartados; EFC: animais infartados e expostos à
fumaça de cigarro; PC: peso corporal do rato; VE: peso do ventrículo
esquerdo; VD: peso do ventrículo direito; U/S: relação entre o peso
úmido e seco; AS: área seccional do miócito; IC: fração de colágeno
intersticial. % IAM: tamanho do infarto. Os dados foram expressos
em média ± desvio padrão (para distribuição normal) ou mediana
com o percentil 25 e 75 (para distribuição não norma
l
)
0
400
800
1200
1600
2000
Fig. 2 – Resultado funcional por meio do coração isolado. Derivada
negativa máxima, variando-se a pressão diastólica de 0 para 25
mmHg. Controle: animais infartados; EFC: animais infartados e
expostos à fumaça de cigarro. * P < 0,05 versus controle (teste t
de Student)
dp/dt (mmHg)
Controle EFC
*
Os resultados do estudo morfométrico estão na tabela
2. A exposição à fumaça de cigarro foi associada a maior
peso do VD, ajustado ao peso corporal (C = 0,8 ± 0,3
mg/g, F = 1,3 ± 0,4 mg/g; p = 0,01), maior teor de água
nos pulmões (C = 4,8 (4,3-4,8)%, F = 5,4 (5,1-5,5);
p = 0,03) e maior área seccional do miócito do VE (C =
239,8 ± 5,8 µm
2
, F = 253,9 ± 7,9 µm
2
; p = 0,01).
Não foram observadas diferenças em relação às outras
variáveis analisadas (p > 0,05).
estudados nos últimos anos, com alguma inconsistência
nos resultados. Em estudo experimental, foi evidenciado
que a exposição crônica ao monóxido de carbono,
importante componente encontrado na fase de vapor da
fumaça do cigarro, resultou em aumento da expressão
gênica de endotelina-1 e induziu hipertrofi a cardíaca
11
.
Houdi e cols. expuseram ratos à fumaça de cigarro
por quatro dias e verificaram aumento da pressão
arterial e diminuição do débito cardíaco. Esse efeito foi
atenuado por antagonista da vasopressina
12
. Em ratos
espontaneamente hipertensos, a exposição à fumaça
por oito semanas resultou em aumento da pressão
arterial e queda da freqüência cardíaca, em relação aos
controles
14
. Outros autores observaram que a exposição
à fumaça de cigarro por seis meses resultou em aumento
da expressão do RNA mensageiro para a endotelina 1 no
tecido cardíaco de rato
15
.
Em trabalho anterior, mostramos que a exposição à
fumaça de cigarro por 30 dias já resultava em prejuízo da
função do VE
22
. Do mesmo modo, a exposição à fumaça de
cigarro por quatro meses resultou em dilatação ventricular,
com redução da função sistólica. Interessantemente, essas
alterações foram acompanhadas por aumento discreto
da pressão arterial
28
. Assim, apesar de os mecanismos
ainda não serem completamente esclarecidos, o conjunto
das evidências apresentadas sugere que a ativação de
fatores neuro-hormonais poderia participar, pelo menos
em parte, dos mecanismos responsáveis pelas ações do
cigarro. Brooks e cols., contudo, utilizando o modelo de
avaliação de contratilidade por meio de preparações de
músculo papilar isolado, não encontraram diferenças na
função cardíaca entre ratos expostos à fumaça por 180
dias e os animais-controle
13
. No modelo de cães, tanto
a administração de nicotina como a exposição à fumaça
do cigarro, por 22 meses, não modifi caram a fração de
ejeção e a pressão diastólica fi nal do ventrículo esquerdo,
em comparação com os controles
16
.
Alguns estudos clínicos também analisaram os
efeitos cardíacos do tabagismo. Assim, em pacientes
com doença arterial coronariana, a inalação aguda da
fumaça de cigarro foi acompanhada por alterações da
função diastólica
17,18
. No estudo observacional CARDIA,
indivíduos fumantes apresentaram maior massa ventricular
esquerda, em comparação com os não-fumantes,
avaliados por ecocardiograma
19
. Portanto, apesar de
alguma controvérsia, o conjunto dos dados sugere que a
exposição à fumaça de cigarro pode resultar em alterações
cardíacas e funcionais. No entanto, os efeitos da exposição
crônica à fumaça de cigarro no processo de remodelação
após o IAM ainda não são conhecidos.
Um dos achados mais relevantes do presente trabalho
foi que a exposição à fumaça de cigarro resultou em
alterações morfológicas do ventrículo esquerdo. Esse
fenômeno foi caracterizado por aumento da área seccional
dos miócitos, indicando a hipertrofi a cardíaca. Essa
alteração foi associada com aumento dos diâmetros
Arquivos Brasileiros de Cardiologia - Volume 86, Nº 4, Abril 2006
281
ventriculares, tanto sistólico como diastólico, sugerindo
intensifi cação do processo de remodelação ventricular
esquerda com a exposição à fumaça. Em concordância
com os nossos resultados, o tratamento agudo com
nicotina, em ratos com infarto do miocárdio, resultou
em aumento da cavidade ventricular, com afi lamento
da parede infartada, sugerindo que a nicotina também
causou efeitos deletérios no processo de remodelação
após o infarto
10
.
Um conceito bastante aceito é que a remodelação
cardíaca resulta, invariavelmente, em queda progressiva
da função ventricular. Inicialmente, em conseqüência do
crescimento celular, a remodelação pode contribuir para
manter ou restaurar a função cardíaca. Cronicamente,
entretanto, ocorrem alterações bioquímicas, genéticas
e estruturais que vão resultar em disfunção ventricular
progressiva
2-4
. Em consonância com esse conceito,
nos ratos expostos à fumaça de cigarro, o processo de
remodelação foi acompanhado por queda de variáveis
que refl etem tanto a função sistólica, como a fração
de variação de área, como a função diastólica, como a
derivada negativa de pressão. Em conseqüência dessa
disfunção, os animais “fumantes” apresentaram sinais de
congestão pulmonar e hipertrofi a do ventrículo direito.
Em conclusão, o conjunto de nossos dados sugere
que a exposição crônica à fumaça de cigarro intensifi ca
a remodelação ventricular e piora a função cardíaca
após o IAM.
Declaro não haver confl itos de interesses pertinentes.
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Anoitecer em São Sebastião da Grama
Múcio Tavares de Oliveira Jr. - São Paulo - SP
Editor da Seção de fotografias Artísticas: Carlos Vicente Serrano Jr.
Correspondência - InCor • Av. Dr. Enéas de Carvalho Aguiar, 44 - 05403-000 - São Paulo, SP
E-mail: carlos.serrano@incor.usp.br
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Objective Our objective was to test the hypothesis that retinoic acid supplementation could attenuate ventricular remodelling induced by tobacco smoke exposure in rats. Methods and results Wistar rats were allocated into three groups: control (C, n = 8); exposed to tobacco smoke (ETS, n = 9); exposed to tobacco smoke and all-trans-retinoic acid (ETS-RA, n = 9). After two months, cardiac function and geometry were assessed by echocardiography, and geometry changes were confi rmed by morphometric analysis. Data are expressed as mean ± SD or medians (including the lower quartile and upper quartile). ETS showed higher normalized left ventricular diastolic diameters than groups C and ETS-RA (C = 18.4 ± 3.57 mm/kg, ETS = 23.0 ± 1.8, ETS-RA = 19.5 ± 0.99; P < 0.05) and systolic diameters (C = 8.25 ± 2.16 mm/kg, ETS = 11.5 ± 1.31, ETS-RA = 8.25 ± 0.71 mm/kg; P < 0.05). ETS showed reduced ejection fraction (C = 91 ± 2.0, ETS = 87 ± 3.0, ETS-RA = 92 ± 3.0; P < 0.05) and fractional shortening (C = 55.8 ± 4.41 %, ETS = 49.7 ± 4.43 %, ETS-RA = 57.6 ± 5.15 %; P = 0.01) compared to C and ETS-RA. ETS had increased myocyte cross-sectional area (C = 294 ± 21 mm2, ETS = 352 ± 44, ETS-RA = 310 ± 35; P < 0.05) compared to C and ETS-RA. Considering all variables, there were no diff erences between groups C and ETS-RA. Conclusion Retinoic acid prevented ventricular remodelling induced by tobacco smoke exposure.
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Introduction There was no data for cardiac repercussion of exercise training associated with tobacco smoking. This issue is interesting because some smoking people can be enrolled in an exercise-training program. Thus, we evaluated swimming training effects on the function and structural myocardial in rats exposed to tobacco smoking. Methods Male Wistar rats were assigned to one of four groups: C, untrained rats without exposure to tobacco smoking; E, exercised rats without exposure to tobacco smoking; CS, untrained rats exposed to tobacco smoking; ECS, exercised rats exposed to tobacco smoking. Rats swam five times a week twice daily (60 min per session) for eight weeks. Before each bout exercise, rats breathed smoke from 20 cigarettes for 60 min. Twenty-four hours after the last day of the protocol, papillary muscles were isolated for in vitro analysis of myocardial mechanics. The myocardial mass and nuclear cardiomyocyte volume were used as hypertrophy markers, and collagen content was determined by picro-sirius red staining. Results There was a well-pronounced myocardial hypertrophic effect for two interventions. The exercise blunted myocardial collagen increases induced by tobacco smoking. However, exercise and tobacco-smoking association was deleterious to myocardial performance. Thereby, in vitro experiments with papillary muscles contracting in isometric showed impairment myocardial inotropism in exercised rats exposed to tobacco smoking. Conclusions This work presents novel findings on the role of exercise training on cardiac remodeling induced by tobacco smoking. Although exercise has mitigated tissue fibrosis, their association with tobacco smoking exacerbated hypertrophy and in vitro myocardial dysfunction. IMPLICATIONS This is first study to show that the association of an aerobic exercise training with tobacco smoking intensifies the phenotype of pathological cardiac hypertrophy. Therefore, the combination of interventions resulted in exacerbated myocardial hypertrophy and contractility dysfunction. These findings have significant clinical implication because some smoking people can be enrolled in an exercise-training program.
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Background Different patients with ST-elevation myocardial infarction (STEMI) have different symptoms. A third of them may have medical emergencies caused by symptoms such as vomiting and syncope. These concomitant symptoms may influence subsequent therapy and final outcomes. The aim of this study was to determine whether cardiogenic vomiting is a predictor of clinical outcomes in patients with STEMI. Material/Methods We classified 152 STEMI patients from different areas into 2 groups on the basis of vomiting: group A and group B. Their demographics and conditions of hospitalization were recorded. After follow-up, major adverse cardiac events (MACE) were regarded as study endpoints for the effect of cardiogenic vomiting in STEMI patients. Results We found no significant difference in demographic and clinical characteristics of the 2 groups (P>0.05). The hospitalized conditions of group A were more serious than in group B. During a follow-up of 6 months, MACE rate was higher in vomiting patients (42; 67.7%) compared with group B (25; 27.8%). Multivariate Cox regression analysis revealed that cardiogenic vomiting was an independent predictor of clinical outcomes. Conclusions Cardiogenic vomiting is a useful predictor of major adverse cardiac events in STEMI patients for the hospitalization and after discharge.
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Cigarette smoking is considered a risk factor for many diseases especially for cardiovascular disease. Cigarette smoking it has been related with atherosclerosis from the endothelial dysfunction until the appearance of an acute coronary event. Both the active smoker as the passive are exposed to cardiovascular risk, and it is thought there are a direct relationship and dependent dose with the exhibition to the smoke of the cigarette. This fact however is since debatable because recent experimental clinical studies they have demonstrated that a non lineal relationship exists among the exhibition to the smoke of the cigarette and the cardiovascular illness. The toxic components of cigarette smoke and the mechanisms that relate it with the cardiovascular disease are largely unknown, but it is known that the smoke of the cigarette increases the inflammatory process, the thrombosis and the oxidation of low density lipoprotein cholesterol. Recent studies support the hypothesis that the exhibition to the smoke of the cigarette increases the oxidative stress as a potential mechanism for the initiating cardiovascular dysfunction. Epidemiological studies have been established that the cigarette consumption has been related to an increment of up to 2,5 times more risk for cardiovascular disease than the non smokers. Furthermore, was demonstrated as for long term this risk factor predicts that is increased in a significant way the risk of heart attack in those patients that continue with this habit after this event, compared with smokers that stopped to smoke after the first acute coronary event. This way, the evidence that relates the exhibition to the smoke of the cigarette with the cardiovascular illness this clearly supported, but still the specific components of the smoke of the cigarette and the responsible mechanisms for their association have not been elucidated.
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OBJETIVO: Determinar as alterações cardíacas estruturais e funcionais causadas pela exposição à fumaça do cigarro em ratos. MÉTODOS: Os animais foram aleatoriamente distribuídos em dois grupos: fumante (F), composto por 10 animais, expostos à fumaça do cigarro, na taxa de 40 cigarros/dia e controle (C), constituído por 10 animais não submetidos à exposição. Após 4 meses, os animais foram submetidos a estudo morfológico e funcional por meio do ecocardiograma. As variáveis estudadas foram analisadas pelo teste t ou pelo teste de Mann-Whitney. RESULTADOS: Os ratos fumantes apresentaram maior átrio esquerdo (F=4,2± 0,7mm; C=3,5±0,6mm; p<0,05), maiores diâmetros diastólicos (F=7,9±0,7mm; C=7,2±0,5mm; p<0,05) e sistólicos (F=4,1 ±0,5; C=3,4±0,5; p<0,05) do ventrículo esquerdo (VE). O índice de massa do VE foi maior nos animais fumantes (F=1,5 mg/kg± 0,2; C=1,3 mg/kg±0,2; p<0,05), e a fração de ejeção (F=0,85±0,03; C=0,89±0,03; p<0,05) e a fração de encurtamento (F=47,8 %±3,7; C=52,7%±4,6; p<0,05) maiores no grupo controle. Não foram identificadas diferenças nas variáveis de fluxo diastólico (onda E, na onda A e na relação E/A) transmitral. CONCLUSÃO: A exposição crônica à fumaça do cigarro resulta em remodelação cardíaca, com diminuição da capacidade funcional ventricular.
Article
Although smoking has been suggested to be involved in the development of cardiovascular diseases, details of the mechanism still need to be revealed. We investigated the effects of cigarette smoking on the tissue mRNA expression of endothelin-1 (ET-1). Male Wistar rats of 4 weeks of age were exposed to smoke from six cigarettes for 30 min (acute exposure) and six cigarettes for 30 min/day, 5 days a week for 6 months (chronic exposure). Half of the rats exposed to 6 months smoking were kept in clean-air conditions for a further 3 months to clear the effects. Tissue expression of ET-1 mRNA in the kidney, aorta, heart and lung was determined by reverse transcriptase polymerase chain reaction (RT-PCR) followed by Southern blot analysis. There was no significant difference in body and organ weight of the heart and kidney between the control and smoking group in either the acute or chronic experiment. In the acute-exposure experiment, expression of ET-1 mRNA was increased in the heart and lung, while that in the kidney and aorta was unchanged. In the chronic-exposure experiment, however, there was no significant difference in the expression of ET-1 mRNA in all the tissues between the smoking and control groups. These results suggest that cigarette smoking could cause cardiovascular and pulmonary diseases by modulating ET-1 mRNA expression in the tissues. (C) 2000 Lippincott Williams & Wilkins, Inc.
In summary, beta-blockade is currently the most promising "new" treatment undergoing Phase III testing in chronic heart failure. Multiple studies on the effects of these agents on LV function and chamber characteristics as well as limited survival data strongly suggest that these agents produce a beneficial effect on the natural history of heart failure. If this promise is borne out in the currently active or planned large-scale clinical trials, this form of therapy will emerge as the most valuable treatment available for chronic heart failure.
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The nature of the cardiovascular risk in cigarette smokers has not been characterized. To compare the relative effects of long-term smoking and nicotine administration on the cardiovascular system, 18 month old beagle littermates were prepared with a permanent tracheostomy. They were classified into three groups: I, seven control dogs; II, nine dogs that smoked seven cigarettes/day; and III, eight dogs that received an equivalent amount of nicotine. After a period of up to 22 months, the animals were catheterized under anesthesia for assessment of left ventricular function and volumes by indicator-dilution technique. Heart rate, stroke volume, left ventricular end-diastolic pressure and volume and intraventricular conduction times did not differ significantly in the three groups. Left ventricular ejection fraction was 44 ± 3 percent (mean ± standard error of the mean) in the control group, 35 ± 3 percent in the dogs that smoked cigarettes (P < 0.05) and 27 ± 3 percent in those given nicotine (P < 0.01) despite similar values for end-diastolic variables in the three groups. The first derivative of left ventricular pressure ( dP dt) normalized for pre- and afterload was 2.4 ± 0.2 cm/sec-1 in the control group, 1.41 ± 0.12 in the cigarette-smoking group (P < 0.005) and 1.34 ± 0.08 in the nicotine group (P < 0.01). Although mean aortic pressure was significantly elevated in both the smoking (127 ± 5 mm Hg) and nicotine (27 ± 10 mm Hg) groups, there was no significant correlation with the contractility indexes. Reduction of afterload to normal levels did not affect the abnormal ventricular performance. Hypertrophy, inflammation and abnormalities of cell ultrastructures were not present, and myocardial lipid and cation composition were normal. Since interstitial fibrosis was evident in both experimental groups, an alteration of elastic elements may be operative. These cardiovascular abnormalities appear to be predominantly dependent on the nicotine of cigarettes.
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Left ventricular dilatation and dysfunction after myocardial infarction are major predictors of death. In experimental and clinical studies, longterm therapy with the angiotensin-converting--enzyme inhibitor captopril attenuated ventricular dilatation and remodeling. We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infarction. Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive doubleblind treatment with either placebo (1116 patients) or captopril (1115 patients) and were followed for an average of 42 months. Mortality from all causes was significantly reduced in the captopril group (228 deaths, or 20 percent) as compared with the placebo group (275 deaths, or 25 percent); the reduction in risk was 19 percent (95 percent confidence interval, 3 to 32 percent; P = 0.019). In addition, the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group. The reduction in risk was 21 percent (95 percent confidence interval, 5 to 35 percent; P = 0.014) for death from cardiovascular causes, 37 percent (95 percent confidence interval, 20 to 50 percent; P less than 0.001) for the development of severe heart failure, 22 percent (95 percent confidence interval, 4 to 37 percent; P = 0.019) for congestive heart failure requiring hospitalization, and 25 percent (95 percent confidence interval, 5 to 40 percent; P = 0.015) for recurrent myocardial infarction. In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. These benefits were observed in patients who received thrombolytic therapy, aspirin, or beta-blockers, as well as those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infarction.
Article
Cigarette smoking increases coronary resistance in patients with coronary artery disease, causing profound disturbances in myocardial perfusion. The acute effects of smoking a single cigarette on left ventricular diastolic function were studied in 20 smokers with typical angina pectoris and angiographically documented coronary artery disease. Twenty healthy smokers served as a control group. We used simultaneous M-mode echocardiography of the mitral and aortic valves to measure isovolumic relaxation time, and pulsed Doppler echocardiography of transmitral blood flow was recorded to evaluate left ventricular filling before and immediately after smoking. In the patients with coronary artery disease, systemic blood pressure and heart rate significantly increased after smoking. The isovolumic relaxation time, the deceleration time as well as peak A velocity remained unchanged. The peak E velocity decreased by 006 m.s⁻¹ (P=0.02) and the peak E/A velocity ratio by 0.17 m.s⁻¹ (P=0.01). There were no significant changes in left ventricular diastolic function indexes in the controls. These results indicate that in patients with coronary artery disease, each cigarette provokes disturbances of left ventricular diastolic function.
Article
In 28 chronic smokers (11 women, 17 men, 53 +/- 10 years old) with coronary artery disease (greater than 75% stenosis), left ventricular (LV) relaxation and filling behavior was assessed before and after inhalation of 0.9 mg nicotine (1 cigarette) by echocardiography. The following acute nicotine-mediated changes were noted (one-sided Wilcoxon test): heart rate increased from 67 to 81 beats/min (p greater than .001); the early diastolic flow (E wave) integral decreased from 49 to 39 mm (p less than .001); the late diastolic flow integral (A wave) increased from 36 to 41 mm (p less than .01). Consecutively, the ratio between E and A wave flow integrals decreased from 1.4 to 0.9 (p less than .001); the atrial contribution to LV filling rose from 42 to 53% (p less than .001); and the isovolumetric relaxation period increased from 89 to 122 ms (p less than .001). In cigarette smokers with coronary artery disease acute administration of nicotine hence causes a shift of mitral blood flow from early (E wave) to late (A wave) diastole and a prolongation of the isovolumetric relaxation time. Thus, cigarette smoking significantly affects LV diastolic function independently of its role as a risk factor for coronary atherosclerosis.
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An acute myocardial infarction, particularly one that is large and transmural, can produce alterations in the topography of both the infarcted and noninfarcted regions of the ventricle. This remodeling can importantly affect the function of the ventricle and the prognosis for survival. In the early period, infarct expansion has been recognized by echocardiography as a lengthening of the noncontractile region. The noninfarcted region also undergoes an important lengthening that is consistent with a secondary volume-overload hypertrophy and that can be progressive. The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival. The process of ventricular enlargement can be influenced by three interdependent factors, that is, infarct size, infarct healing, and ventricular wall stresses. A most effective way to prevent or minimize the increase in ventricular size after infarction and the consequent adverse effect on prognosis is to limit the initial insult. Acute reperfusion therapy has been consistently shown to result in a reduction in ventricular volume. The reestablishment of blood flow to the infarcted region, even beyond the time frame for myocyte salvage, has beneficial effects in attenuating ventricular enlargement. The process of scarification can be interfered with during the acute infarct period by the administration of glucocorticosteroids and nonsteroidal antiinflammatory agents, which result in thinner infarcts and greater degrees of infarct expansion. Modification of distending or deforming forces can importantly influence ventricular enlargement. Even short-term augmentations in afterload have deleterious long-term effects on ventricular topography. Conversely, judicious use of nitroglycerin seems to be associated with an attenuation of infarct expansion and long-term improvement in clinical outcome. Long-term therapy with an angiotensin converting enzyme inhibitor can favorably alter the loading conditions on the left ventricle and reduce progressive ventricular enlargement as demonstrated in both experimental and clinical studies. With the former therapy, this attenuation of ventricular enlargement was associated with a prolongation in survival. The long-term clinical consequences of long-term angiotensin converting enzyme inhibitor therapy after myocardial infarction is currently being evaluated. Although studies directed at attenuating left ventricular remodeling after infarction are in the early stages, it does seem that this will be an important area in which future research might improve long-term outcome after infarction.