Cor pulmonale

To determine whether or not the left ventricle is pathologically involved in patients with chronic cor pulmonale, right and left ventricular weights, wall thickness, myocyte diameters, and percentage of fibrosis in 18 autopsied hearts were examined in patients with chronic pulmonary disease (CPD); ten had right ventricular hypertrophy on their electrocardiograms, and eight were without right ventricular hypertrophy. Five with extracardiopulmonary disease were used as controls. The weight of the right ventricle was significantly increased in CPD when compared to control subjects. Wars of both ventricles were significantly 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.

CPD = chronic pulmonary disease; RVH = right ventricular hypertrophy

The 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 increases,[1] and left ventricular ejection fraction is depressed both at rest and with exercise.[2] Such impairments 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] In addition, some authors have reported pathologic changes of the left ventricle. Studies by Scott and Garvin[4] and by Michelson[5] 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 of patients 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 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 pneumoconiosis. 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 (eight men aged 40 to 77 years; mean age, 64 years), there were 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

None of the 23 patients had had systemic hypertension, diabetes mellitus, collagen disease, angina pectoris, myocardial infarction, left-sided valvular heart disease, or any heart disease other than chronic cor pulmonale. Systemic hypertension was defined as systolic blood pressure higher than 160 mm Hg or diastolic pressure higher than 95 mm Hg. Patients with coronary atheroselerotic stenosis 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.

Pathologic Examination

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 vessels from the hearts and preparing the hearts in three parts according to the method of Fulton et al,[8] we measured the weight of the right ventricle, the interventricular septum, and the free wall of the left ventricle. The left ventricular weight was determined as the sum of the free left ventricular wall weight and the interventricular 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.

Microscopic 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, the free wall of the left ventricle, and the interventricular septum and were fixed in 10 percent Formalin. Routine light-microscopic slides were 3[mu] to 5[mu] thick. The slides were stained with Mallory-azan stain for assessing the extent of myocardial fibrosis and with hematoxylin-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 photographs 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 of the films math a standard copying machine and cut out the traced parts of the copies. We measured the weight of the parts of the copies by an electronic balancer (Shimazu AEL-200) and calculated the distribution of collagen fiber in the myocardium (the weight of the paper of the traced parts divided by the weight of the paper covering the myocardium).

An optical microscope (Nikon Biophoto) and a micrometer were used for the measurement of myocyte diameters. Histologic sections were observed directly by mounting the micrometer math 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; and (5) the outer half of the left ventricle. The myocyte diameter of the left ventricle was defined as a mean of that of the inner half and the outer half of the left ventricle in this study. Because the myocardial fiber is cylindrically shaped, the smallest diameter was taken as the myocyte diameter at each myocyte. in each hematoxylin-eosin-stained histologic section, 200 randomly selected fibers were measured according to the method of Ishikawa et al.[9]

Statistical Analysis

The difference in the variables used in this study among the three groups was assessed by both analysis of variance 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 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 analysis. A value of p < 0.05 in these tests was considered indicative for significant difference. All data are represented as the mean [+ or -] SD.

The reproducibility of measuring the percentage of fibrosis by the method in this study was assessed by the same observer, as well as by two independent observers selecting 20 samples at random. Intraobserver differences were 2.24 percent and 1.91 percent. Interobserver difference was 10.06 percent.

RESULTS

All data on pathologic findings are shown in Tables 2 and 3. Comparisons between the CPD group and control group are shown in Table 4. Comparisons among the RVH group, non-RVH group, and control group are shown in Table 5.

[TABULAR DATA OMITTED]

Ventricular Weight. The weight of the right ventricle in the CPD group was significantly more increased than that in the control group. The weight of the interventricular septum was not different among the three groups. The weight of the left venticle was substantially increased in patients with CPD, although there were no statistically significant differences among the groups.

Ventricular Wall Thickness. The walls of both the right and the left ventricle in the CPD group were significantly thicker than those in the control group.

Extent of Myocardial Fibrosis. The values for the percentage of fibrosis of the right ventricle and the interventricular septum in the CPD group were significantly increased compared to those in the control group. The values for the percentage of fibrosis of the right ventricle and the interventricular septum in the RVH group were significantly increased compared to those in the non-RVH group. The values for the percentage of fibrosis of the right ventricle and the interventricular septum in the non-RVH group were not different from those in the control group.

The percentage of fibrosis of the left ventricle in the CPD group was not different from that in the control group. The percentage of fibrosis of the left ventricle in the RVH group was significantly increased compared to both those in the non-RVH group and the CPD group. The percentage of fibrosis of the left ventricle in the non-RVH group was not different from that in the control group.

Myocyte Diameter The myocyte diameters of all five sites of the ventricles in the RVH group were significantly larger than those in the other two groups. The myocyte diameters were also significantly larger in the non-RVH group than those in the control group in four sites of the heart, except for the inner half of the left ventricle.

Significant correlations were found between the percentage of fibrosis and the myocyte diameter in both ventricles (r = 0.50 and p < 0.05 in the right ventricle; r = 0. 51 and p < 0.05 in the left ventricle). Significant correlations were found in the myocyte diameter and the percentage of fibrosis between the right ventricle and the left ventricle (r = 0.91 and p < 0.01 for the myocyte diameter; r = 0.54 and p < 0.01 for the percent fibrosis).

DISCUSSION

Our findings demonstrated that myocardial fibrosis and hypertrophy develop in the left ventricle in patients with chronic cor pulmonale. Myocardial fibrosis and cellular hypertrophy of the left ventricle increased with the increase in right ventricular fibrosis and hypertrophy, indicating that these pathologic changes of the left ventricle may be brought about by systemic factors but not by left ventricular overload. These changes of the left ventricle may cause left ventricular dysfunction in patients with chronic cor pulmonale.

In patients with chronic cor pulmonale, the impairment of left ventricular function has been documented by systolic time intervals[10] and left ventricular ejection fraction on radionuclide angiography[11] and two-dimensional echocardiography.[12] The causes of the impaired left ventricular function have been attributed to mechanical and chemical factors. Krayenbuehl et al[3] reported that septal bulging and hypertrophy may increase in left ventricular end-systolic pressure in patients with chronic cor pulmonale. Slutsky et al[2] demonstrated that exercise produced a severe exacerbation of pulmonary hypertension in COPD, resulting in right ventricular dilatation and right ventricular failure. Chemical factors, such as the decrease in arterial oxygen tension,[13,14] the increase in carbon dioxide,[15] and the increase in levels of hydrogen ion concentration,[13,14,16,17] have been considered to impair left ventricular systolic function.

In addition, our results suggested the pathologic changes of the left ventricle such as myocardial fibrosis and hypertrophy in patients with severe chronic cor pulmonale who died of respiratory failure or congestive heart failure (or both) may contribute to the left ventricular dysfunction. Samad and Noehren[6] reported focal myocardial ischemic lesions in the left ventricle in patients with cor pulmonale of emphysema. Selye[18] also described focal myocardial fibrosis occurring frequently in patients with CPD. These findings agree with our results. Regarding left ventricular hypertrophy, Scott and Garvin[4] reported that left ventricular hypertrophy in patients with chronic cor pulmonale was frequently observed at autopsy. Michelson[5] also reported bilateral ventricular hypertrophy due to CPD. Jardin et al[12] observed left ventricular hypertrophy in ten patients with COPD by echocardiography. These results are comparable to our results. Ishikawa et al[9] measured fiber diameter as a function of ventricular size and found that as the right ventricle gained mass, the diameter of the myocardial fibers of the right ventricle increased; however, the diameter of the left ventricular fiber did not increase so much as that of the right ventricle in their study The reason why their results were different from those of our study was probably due to the selection of patients, because myocyte diameter of the right ventricle was also smaller than that in this study Patients with more severe CPD may be included in this study

In our study, no cause of hypertrophy or myocardial fibrosis of the left ventricle was detected. No history of systemic hypertension was pointed out in our patients. Myocardial fibrosis of the left ventricle was frequently observed in patients with myocardial cellular hypertrophy of the left ventricle. These findings suggest that myocardial fibrosis and cellular hypertrophy in the left ventricle may be induced by the same systemic or chemical factors other than mechanical overload against the left ventricle.

Increased plasma epinephrine levels, which have been reported in chronic cor pulmonale,[19-21] hypoxia,[22] and arterial acidosis[23-26] may be probable causes of these pathologic changes of the left ventricle in chronic cor pulmonale. It has been postulated by Barach and Bickerman[23] that adrenal stimulation may be induced from hypoxia in patients with CPD, resulting in a consequent reduction of serum potassium levels. Hypokalemia has been emphasized as a cause of degenerative changes of the myocardial fibers. Molnar et al[24] demonstrated that potassium depletion produces myocardial necrosis and subsequent fibrosis in rats. The low tissue pH prevailing during severe hypoxia may bring about intracellular proteolysis.[25]

We conclude that chronic cor pulmonale is not restricted to right ventricular myocardial disease but is a bilateral ventricular myocardial disease in the end stage of the disease.

Limitation of the Study

It is important to precisely measure the percentage of fibrosis and the myocyte diameter in the ventricles in this study

There is no established method for measuring the percentage of fibrosis in autopsied hearts. There is a well-used method measuring the percent fibrosis in specimens obtained by endomyocardial biopsy,[27,28] in which the percentage of fibrosis is the area of fibrosis calculated from developed photographs of the small specimens. Our method was substantially the same as measuring the area of fibrosis. This method to measure the percentage of fibrosis had a good reproducibility. Our data for control subjects were comparable to previous data.[29]

We used a method of measuring myocyte diameter of ventricles which was invented by Ishikawa et al.[9] Our data from control subjects were comparable to the previous data.[9,30]

A limitation of this study is that we examined only autopsied heart of patients with chronic cor pulmonale who died of respiratory failure or congestive heart failure (or both); however, these pathologic changes of the left ventricle should contribute to left ventricular dysfunction to some extent.

REFERENCES

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