clinical investigations PathologicInvolvementof the Left Ventriclein ChronicCor Pulmonale* Akio Kohama, M.D.; Jun Tanouchi, M.D.; Masatsugu Hori, M.D.; Akira Kitabatake, Takenobts Kamada, M.D.
To determine whether or not the left ventricle is patholog ically involved in patients with chronic our pulmonale, right and left ventricular weights, wall thickness, myocyte di ameters, and percentage of fibrosis in 18 autopsied hearts were
examined
in patients
with chronic
pulmonary
(CPD); ten had right ventricular
hypertrophy
electrocardiograms,
without
and eight
were
right
disease
on their ventric
ular hypertrophy. Five with extracardiopulmonary disease were
used
as controls.
The
weight
of the
right
T
he impairment of left ventricular function has been documented in some patients with chronic cor pulmonale. In patients with severe chronic cor pulmonale, left ventricular end-diastolic pressure in creases,' and left ventricular ejection fraction is de pressed both at rest and with exercise.2 Such impair ments of left ventricular function have been considered to be brought about by sustained hypoxia or interventricular septal bulging towards the left ventricle due to right ventricular pressure overload.3 some
authors
have reported
pathologic
changes of the left ventricle. Studies by Scott and Garvin4 and by Miche1son@demonstrated frequently observed left ventricular wall thickening in patients with chronic cor pulmonale. Samad and Noehren6 found focal degenerative changes in left ventricular myocardium in some autopsies ofpatients with chronic cor pulmonale. These reports suggest that pathologic involvement in the left ventricle is also one of the causes of the impairment of left ventricular function in chronic cor pulmonale; however, the pathologic involvement has not been extensively studied in *From the First Department of Internal Medicine, Osaka Univer sity School of Medicine, Osaka, Japan. Presented in part at the 38th Annual Scientific Session, American College ofCardiology, Anaheim, Calif, March, 1989. Manuscript received January 2; revision accepted March 26. Reprint requests: Dr Kohama, 28 Yokomakura-Higashi, Higashi Osaka, Osaka, Japan 578
794
thicker in CPD. Myocyte diameters of both ventricles were significantly
greater
in CPD.
The percentage
of fibrosis
in
the right venticle was significantly greater in CPD. The percentage of fibrosis in the left ventricle was significantly greater only in patients with right ventricular hypertrophy. We concluded that the left ventricle was also involved
pathologically in patients with chronic cor pulmonale in the end stage of the disease.
(Chest 1990; 98:794-806)
ventricle
was significantly increased in CPD when compared to control subjects. Walls of both ventricles were significantly
In addition,
M.D.; and
CPD = chronic hypertrophy
pulmonary
disease;
RVH
right ventricular
patients with chronic cor pulmonale. In this study, to clarify whether
the left ventricle
is
pathologically involved or not, we studied autopsies of patients with chronic cor pulmonale who died of respiratory failure or heart failure (or both), especially in relation to myocardial fibrosis and myocardial cellular hypertrophy. MATERIALS
AND
METHODS
Materials We examined 18 autopsied hearts from patients with CPD (CPD group)
who died of respiratory
failure
or congestive
heart
failure
(or
both). None had complications of malignant neoplasm or pneumo coniosis. The 18 cases were subdivided into two groups according
to electrocardiographic criteria of RVH:7 (1) ten cases of CPD with RVH (RVH group); and (2) eight cases of CPD without RVH (non RVH group). In ten patients of the RVH group (eight men and two women, aged 36 to 80 years; mean age, 62 years), there were four with interstitial pneumonia, three with old pulmonary tuberculosis, and three with COPD. In eight patients of the non-RVH group
(eightmenaged40to 77years;meanage,64years),therewere three with interstitial pneumonia, three with COPD, one with old pulmonary tuberculosis, and one with multiple cystic pulmonary disease
(Table 1).
Five autopsied hearts of patients with extracardiopulmonary disease (control group) were used as controls (three men and two women, aged 45 to 68 years; mean age, 58 years). There were two with colon cancer and one each with gastric cancer, pancreatic cancer, and cholangiocarcinoma (Table 1). Patients with malignant neoplasm who received doxorubicin treatment or radiation therapy against pulmonary lesions were excluded from this study, The Left Ventriclein ChronicCor Puimonale(Kohama et a!)
None of the 23 patients had had systemic mellittis, collagen disease, angina pectoris,
Table 1—¿Diagnosesin Control Subjects and
Patientswith CPD
left-sided valvular heart disease, or any heart disease other than chronic cor ptilmonale. Systemic hypertension was defined as
Group and Case,
hypertension, diabetes myotardial infarction,
systolic higher
Sex,
(yr)DiagnosisControl Age
stenosis @O)Ll@)1,
blood pressure higher than 160 mm Hg or diastolic pressure than 95 mm Hg. Patients with coronary atherosclerotic of more than 50 percent
narrowing
of the cross-sectional
area were excluded from this study. There was no significant difference in age among the three groups.
cancer2, F,67Colon 58Cholangiocarcinoma3, F, cancer4, M, 68Pancreatic
Pathologic Examination
cancer5, M, 45Colon
At autopsy, we first examined atherosclerosis of the coronary arteries and then measured whole heart weights after stripping the coronary arteries and fat tissue. After removing the atria and great
cancerRVH M, 52Gastric
group6, 36COPD7, F,
tuberculosis8,M,62COPD9, NI, 73Old 59COPD10, F, tul)erdulosis11, M, 73Old tuberculosis12, M, 65Old
vessels from the hearts according to the method
pulmonary
and preparing the hearts in three parts of Fulton et al,' we measured the weight
of the right ventricle, the interventricular septum, and the free wall ofthe left ventricle. The left ventricular weight was determined as the sum of the free left ventricular wall weight and the
pulmonary pulmonary
interventricular
pneumonia13, NI, 62Interstitial pneumonia14, NI, 53Interstitial
septal
weight.
The wall thickness of the right ventricle was measured 1 cm below the pulmonary valve, that of the interventricular septum 3 cm below the aortic valve, and that of left ventricle was measured at the same level in the interventricular septum.
pneumonia15, M, 56Interstitial pneumoniaNon-RVH NI, 80Interstitial group16, tul)erculosis17, NI, 59Old
Microscopic
pulmonary
73COPD18, M, pneumonia19, NI, 70Interstitial disease20, M, 77Multiple
sections
were
obtained
from the part where
wall
thickness was measured . Transmural blocks of tissue were obtained from the free wall of the right ventricle, ventricle,
cystic pulmonary
percent
68COPD21, NI,
and
the
Formalin.
interventricular
Routine light-microscopic
thick. The slides were stained
pneumonia22, NI, 54Interstitial pneumonia23,M,69COPD M, 40Interstitial
septum
the free wall of the left and
were
fixed
in 10
slides were 3p. to 5@i
with Mallory-azan
stain for assessing
the extent of myocardial fibrosis and with he@natoxylin-eosin stain for measuring
myocyte
diameter.
For the assessment of the extent of myocardial fibrosis, the percentage of fibrosis was determined. After taking photographs of each histologic section stained with Mallory-azan stain, the photo
.f@-..@L@V7J
FIGURE 1. Example
of the left ventricle.
ofmeasuring
percentage
of fibrosis
A (top): Photograph of Mallory
azan-stained histologic section. Collagen fibers stained blue. B (bottom): Copy of transparent which was set above photograph and blue-stained
were film parts
traced. Fibrosis was 2.80 percent in this case. CHEST
I 98 I 4 I OCTOBER,
1990
795
Table 2—ThthologicFindings in Control Croup@ Weight, g
Case
Whole Heart
RV
IVS
F-LV
LV
Wall Thickness, mm
Myocardial Fibrosis, percent
RV
IVS
LV
RV
IVS
Myocyte Diameter,
LV
RV
@i
IVS-R
IVS-L
LV-IN
LV-OT
Mean LV 12.1
1
125
30
30
38
68
3
9
11
1.85
1.49
2.59
12.3
9.8
11.3
11.3
12.8
2
175
35
45
50
95
2.5
9
10
1.35
0.75
0.69
11.1
10.1
11.2
11.6
11.5
11.5
3 4 5
260 185 173
32 37 24
90 58 55
65 56 55
155 114 110
3.5 3.5 3
13 10 11
12 11 12
0.71 1.53 0.87
1.40 2.56 1.24
1.84 1.71 1.03
10.1 10.3 10.9
10.3 11.6 12.0
11.8 11.0 9.3
10.6 14.5 12.1
12.3 13.3 12.3
11.5 13.9 12.2
*RV, Right ventricle; IVS, interventricular septum; LV, left ventricle; F-LV, free wall of LV; IVS-R, right half of IVS; IVS-L, left half of IVS; LV-IN, inner halfofLV; LV-OT, outer halfofLV; and mean LV, mean ofLV-IN and LV-OT graphs were enlarged up to ten times the original size. We set the transparent films on the photograph and traced the blue-stained parts because the collagen fibers were stained blue by Mallory-azan stain. We made copies ofthe films with a standard copying maclane and cut out the traced parts ofthe copies (Fig 1). We measured the weight ofthe parts ofthe copies by an electronic balancer (Shimazu AEL-200) and calculated the distribution of collagen fiber in the myocardium (the weight ofthe paper ofthe traced parts divided by
fiber is cylindrically myocyte diameter stained histologic measured according
Statistical Analysis The difference in the variables used in this study among the three groups was assessed by both analysis ofvariance and Student's t-test. To determine the relation of the wall thickness, the myocyte diameter, and the percentage of fibrosis between both ventricles, simple regression analysis was performed. The relationship between
the weight ofthe paper covering the myocardium). An optical microscope (Nikon Biophoto) and a micrometer were used for the measurement ofmyocyte diameters. Histologic sections were observed directly by mounting the micrometer with a scale of 0.1 mm between the eye lens (10 x) and the object lens (40 x) at 400 x magnification. For the evaluation of cellular hypertrophy, myocyte diameters were measured separately at the following five sites in each heart: (1) the free wall of the right ventricle; (2) the right half of the interventricular septum; (3) the left half of the interventricular
septum;
(4) the inner
half of the left ventricle;
the myocyte diameter and the percentage of fibrosis in both ventricles and the relation of the percentage of fibrosis between both ventricles were also studied by simple regression analysi& A value of p
To determine whether or not the left ventricle is patholog ically involved in patients with chronic our pulmonale, right and left ventricular weights, wall thickness, myocyte di ameters, and percentage of fibrosis in 18 autopsied hearts were
examined
in patients
with chronic
pulmonary
(CPD); ten had right ventricular
hypertrophy
electrocardiograms,
without
and eight
were
right
disease
on their ventric
ular hypertrophy. Five with extracardiopulmonary disease were
used
as controls.
The
weight
of the
right
T
he impairment of left ventricular function has been documented in some patients with chronic cor pulmonale. In patients with severe chronic cor pulmonale, left ventricular end-diastolic pressure in creases,' and left ventricular ejection fraction is de pressed both at rest and with exercise.2 Such impair ments of left ventricular function have been considered to be brought about by sustained hypoxia or interventricular septal bulging towards the left ventricle due to right ventricular pressure overload.3 some
authors
have reported
pathologic
changes of the left ventricle. Studies by Scott and Garvin4 and by Miche1son@demonstrated frequently observed left ventricular wall thickening in patients with chronic cor pulmonale. Samad and Noehren6 found focal degenerative changes in left ventricular myocardium in some autopsies ofpatients with chronic cor pulmonale. These reports suggest that pathologic involvement in the left ventricle is also one of the causes of the impairment of left ventricular function in chronic cor pulmonale; however, the pathologic involvement has not been extensively studied in *From the First Department of Internal Medicine, Osaka Univer sity School of Medicine, Osaka, Japan. Presented in part at the 38th Annual Scientific Session, American College ofCardiology, Anaheim, Calif, March, 1989. Manuscript received January 2; revision accepted March 26. Reprint requests: Dr Kohama, 28 Yokomakura-Higashi, Higashi Osaka, Osaka, Japan 578
794
thicker in CPD. Myocyte diameters of both ventricles were significantly
greater
in CPD.
The percentage
of fibrosis
in
the right venticle was significantly greater in CPD. The percentage of fibrosis in the left ventricle was significantly greater only in patients with right ventricular hypertrophy. We concluded that the left ventricle was also involved
pathologically in patients with chronic cor pulmonale in the end stage of the disease.
(Chest 1990; 98:794-806)
ventricle
was significantly increased in CPD when compared to control subjects. Walls of both ventricles were significantly
In addition,
M.D.; and
CPD = chronic hypertrophy
pulmonary
disease;
RVH
right ventricular
patients with chronic cor pulmonale. In this study, to clarify whether
the left ventricle
is
pathologically involved or not, we studied autopsies of patients with chronic cor pulmonale who died of respiratory failure or heart failure (or both), especially in relation to myocardial fibrosis and myocardial cellular hypertrophy. MATERIALS
AND
METHODS
Materials We examined 18 autopsied hearts from patients with CPD (CPD group)
who died of respiratory
failure
or congestive
heart
failure
(or
both). None had complications of malignant neoplasm or pneumo coniosis. The 18 cases were subdivided into two groups according
to electrocardiographic criteria of RVH:7 (1) ten cases of CPD with RVH (RVH group); and (2) eight cases of CPD without RVH (non RVH group). In ten patients of the RVH group (eight men and two women, aged 36 to 80 years; mean age, 62 years), there were four with interstitial pneumonia, three with old pulmonary tuberculosis, and three with COPD. In eight patients of the non-RVH group
(eightmenaged40to 77years;meanage,64years),therewere three with interstitial pneumonia, three with COPD, one with old pulmonary tuberculosis, and one with multiple cystic pulmonary disease
(Table 1).
Five autopsied hearts of patients with extracardiopulmonary disease (control group) were used as controls (three men and two women, aged 45 to 68 years; mean age, 58 years). There were two with colon cancer and one each with gastric cancer, pancreatic cancer, and cholangiocarcinoma (Table 1). Patients with malignant neoplasm who received doxorubicin treatment or radiation therapy against pulmonary lesions were excluded from this study, The Left Ventriclein ChronicCor Puimonale(Kohama et a!)
None of the 23 patients had had systemic mellittis, collagen disease, angina pectoris,
Table 1—¿Diagnosesin Control Subjects and
Patientswith CPD
left-sided valvular heart disease, or any heart disease other than chronic cor ptilmonale. Systemic hypertension was defined as
Group and Case,
hypertension, diabetes myotardial infarction,
systolic higher
Sex,
(yr)DiagnosisControl Age
stenosis @O)Ll@)1,
blood pressure higher than 160 mm Hg or diastolic pressure than 95 mm Hg. Patients with coronary atherosclerotic of more than 50 percent
narrowing
of the cross-sectional
area were excluded from this study. There was no significant difference in age among the three groups.
cancer2, F,67Colon 58Cholangiocarcinoma3, F, cancer4, M, 68Pancreatic
Pathologic Examination
cancer5, M, 45Colon
At autopsy, we first examined atherosclerosis of the coronary arteries and then measured whole heart weights after stripping the coronary arteries and fat tissue. After removing the atria and great
cancerRVH M, 52Gastric
group6, 36COPD7, F,
tuberculosis8,M,62COPD9, NI, 73Old 59COPD10, F, tul)erdulosis11, M, 73Old tuberculosis12, M, 65Old
vessels from the hearts according to the method
pulmonary
and preparing the hearts in three parts of Fulton et al,' we measured the weight
of the right ventricle, the interventricular septum, and the free wall ofthe left ventricle. The left ventricular weight was determined as the sum of the free left ventricular wall weight and the
pulmonary pulmonary
interventricular
pneumonia13, NI, 62Interstitial pneumonia14, NI, 53Interstitial
septal
weight.
The wall thickness of the right ventricle was measured 1 cm below the pulmonary valve, that of the interventricular septum 3 cm below the aortic valve, and that of left ventricle was measured at the same level in the interventricular septum.
pneumonia15, M, 56Interstitial pneumoniaNon-RVH NI, 80Interstitial group16, tul)erculosis17, NI, 59Old
Microscopic
pulmonary
73COPD18, M, pneumonia19, NI, 70Interstitial disease20, M, 77Multiple
sections
were
obtained
from the part where
wall
thickness was measured . Transmural blocks of tissue were obtained from the free wall of the right ventricle, ventricle,
cystic pulmonary
percent
68COPD21, NI,
and
the
Formalin.
interventricular
Routine light-microscopic
thick. The slides were stained
pneumonia22, NI, 54Interstitial pneumonia23,M,69COPD M, 40Interstitial
septum
the free wall of the left and
were
fixed
in 10
slides were 3p. to 5@i
with Mallory-azan
stain for assessing
the extent of myocardial fibrosis and with he@natoxylin-eosin stain for measuring
myocyte
diameter.
For the assessment of the extent of myocardial fibrosis, the percentage of fibrosis was determined. After taking photographs of each histologic section stained with Mallory-azan stain, the photo
.f@-..@L@V7J
FIGURE 1. Example
of the left ventricle.
ofmeasuring
percentage
of fibrosis
A (top): Photograph of Mallory
azan-stained histologic section. Collagen fibers stained blue. B (bottom): Copy of transparent which was set above photograph and blue-stained
were film parts
traced. Fibrosis was 2.80 percent in this case. CHEST
I 98 I 4 I OCTOBER,
1990
795
Table 2—ThthologicFindings in Control Croup@ Weight, g
Case
Whole Heart
RV
IVS
F-LV
LV
Wall Thickness, mm
Myocardial Fibrosis, percent
RV
IVS
LV
RV
IVS
Myocyte Diameter,
LV
RV
@i
IVS-R
IVS-L
LV-IN
LV-OT
Mean LV 12.1
1
125
30
30
38
68
3
9
11
1.85
1.49
2.59
12.3
9.8
11.3
11.3
12.8
2
175
35
45
50
95
2.5
9
10
1.35
0.75
0.69
11.1
10.1
11.2
11.6
11.5
11.5
3 4 5
260 185 173
32 37 24
90 58 55
65 56 55
155 114 110
3.5 3.5 3
13 10 11
12 11 12
0.71 1.53 0.87
1.40 2.56 1.24
1.84 1.71 1.03
10.1 10.3 10.9
10.3 11.6 12.0
11.8 11.0 9.3
10.6 14.5 12.1
12.3 13.3 12.3
11.5 13.9 12.2
*RV, Right ventricle; IVS, interventricular septum; LV, left ventricle; F-LV, free wall of LV; IVS-R, right half of IVS; IVS-L, left half of IVS; LV-IN, inner halfofLV; LV-OT, outer halfofLV; and mean LV, mean ofLV-IN and LV-OT graphs were enlarged up to ten times the original size. We set the transparent films on the photograph and traced the blue-stained parts because the collagen fibers were stained blue by Mallory-azan stain. We made copies ofthe films with a standard copying maclane and cut out the traced parts ofthe copies (Fig 1). We measured the weight ofthe parts ofthe copies by an electronic balancer (Shimazu AEL-200) and calculated the distribution of collagen fiber in the myocardium (the weight ofthe paper ofthe traced parts divided by
fiber is cylindrically myocyte diameter stained histologic measured according
Statistical Analysis The difference in the variables used in this study among the three groups was assessed by both analysis ofvariance and Student's t-test. To determine the relation of the wall thickness, the myocyte diameter, and the percentage of fibrosis between both ventricles, simple regression analysis was performed. The relationship between
the weight ofthe paper covering the myocardium). An optical microscope (Nikon Biophoto) and a micrometer were used for the measurement ofmyocyte diameters. Histologic sections were observed directly by mounting the micrometer with a scale of 0.1 mm between the eye lens (10 x) and the object lens (40 x) at 400 x magnification. For the evaluation of cellular hypertrophy, myocyte diameters were measured separately at the following five sites in each heart: (1) the free wall of the right ventricle; (2) the right half of the interventricular septum; (3) the left half of the interventricular
septum;
(4) the inner
half of the left ventricle;
the myocyte diameter and the percentage of fibrosis in both ventricles and the relation of the percentage of fibrosis between both ventricles were also studied by simple regression analysi& A value of p
