Right Atrial Ultrastructurein Congenital Heart Disease II.Atrial Septal Defect: Effects of Volume Overload
JOHN J. FENOGLIO, Jr., MD, FACC” TUAN DUC PHAM, PhD ALLAN HORDOF, MD RICHARD N. EDIE, MD ANDREW L. WIT, PhDt New York, New York
From the Departments of Pathology, Pediatrics, Pharmacolqy and Surgery, College of Physicians and Surgeons, Columbia University, New York, New York. This study was supported by U.S. Public Health Service Grant HL-12738 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received October 18, 1978; revised manuscript received November 29, 1978 accepted November 29, 1978. t Dr. Wit was a Career Scientist of the Irma T. Hirschel Trust, New York, New York, at the time of this study. Recipient of Career Development Award 5K044HL00185 from the National Heart, Lung and Blood Institute, Bethesda, Maryland. Address for reprints: John J. Fenoglio, Jr., MD, Department of Pathology, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. l
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Portions of operatively resected right atrium from 15 patients with atrial septal defect were studied ultrastructurally to determine whether the cell hypertrophy in the right atrium of patients with increased right atrial blood flow and increased right atrial pressure is caused by the increased blood flow. In 12 patients with normal right atrial mean pressure but increased right atria1blood flow the atrium was dilated but no atrial arrhythmias were noted clinically. Ultrastructurally, the atrial myocardial cells in these patients were normal, measuring 6 to 10 p in diameter, and there was no evidence of cell hypertrophy or degeneration. The remaining three patients had elevated right atrial mean pressure and Increased right atrlal blood flow. Ultrastructurally, the atrial myocardial cells in all three patients were hypertrophied, and two patients had evidence of focal cell degeneration; the atrium was markedly dilated, but atrial arrhythmias were not noted. The lack of cell hypertrophy in the right atrium of the 12 patients with increased blood flow but normal mean pressure suggests that in congenital heart dlsease volume overload alone does not lead to cell hypertrophy of the right atrial myocardium.
In a previous report’ we described changes in the ultrastructure of the dilated right atrium of six patients with endocardial cushion defect. These patients had elevated right atria1 mean pressure and increased right atria1 blood flow. The ultrastructural changes consisted of cell hypertrophy in all patients and cell degeneration in two patients with markedly elevated right atria1 mean pressure. The data suggested that the changes of cell hypertrophy might be secondary to increased blood flow or increased pressure, or both, whereas the degenerative changes appeared to be directly related to increased right atria1 pressure. However, we were unable to separate these two hemodynamic values in this group of patients and were thus unable to determine whether increased blood flow or elevated atria1 pressure was related to the changes of cell hypertrophy seen in the dilated atrium of these patients with congenital heart disease. The purpose of this study was to determine whether increased right atria1 blood flow in the absence of increased right atria1 pressure resulted in hypertrophy of the right atria1 myocardium. We studied the ultrastructure of right atria1 tissue obtained from patients with atria1 septal defect who had a well defined left to right shunt and no evidence of increased right atria1 pressure. Although the atrium in these patients was dilated, there was no evidence of cell hypertrophy. Structurally, the atrium was identical to the right atrium of patients with ventricular septal defect1 and was therefore presumably normal. In addition, portions of the right atrium from three patients with atria1 septal defect and increased right atria1 mean pressure and blood flow were also studied to determine if the structural changes were the same as those previously reported in patients with endocardial cushion defect.’ In the patients
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ULTRASTRUCTURE
with increased mean pressure and blood flow the right. atria1 myocardial cells were hypertrophied and there were focal degenerative changes. Our findings suggest that in congenital heart disease increased right atria1 blood flow in the absence of increased right atria1 mean pressure is not associated with structural changes of the right atrium. Methods Patients studied (Table I): Tissue was obtained from 16 patients at the time of open heart surgery for closure of an atria1 septal defect. Twelve patients (Group I) had normal right atria1 mean pressure (less than 5 mm Hg) and evidence of a left to right shunt across the atria1 septum. These patients ranged in age from 8 to 47 years, although 8 of the 12 patients were less than 10 years of age. The atrium was moderat,ely dilated, although the pulmonary arterial pressure was normal (less than 20 mm Hg), and none of these 12 patients had atria1 arrhythmias. Three patients (Group II) had elevated right atria1 mean pressure (more than 5 mm Hg) as we11 as a Ieft to right shunt, across the atria1 septum. These patients ranged in age from 7 to 58 years. The atrium was markedly dilated and the pulmonary arterial pressure was elevated (more than 40 mm Hg) in all three patients; however, they had no at.rial arrhythmias. Tissue preparation: The atria1 biopsy specimen was obtained adjacent to the site of the atriotomy on the anterior wall of the right atrium. The tissue was fixed in phosphate buffered (pH 7.3) 2.6 percent glutaraldehyde as previously described.’ All tissue was fixed overnight in glutaraldehyde, and postfixed fur I hour in chilled 1 percent osmium tetroxide in 0.1 molar phosphate buffer (pH 7.3). The tissue was rinsed in phosphate buffer, dehydrated in graded acetones and embedded in Swiss araldite. Flat silicone embedding molds were used to facilitate the orientation of muscle fibers to the endocardium.? Thick sections (0.5 to 1 cl) were cut from all tissue blocks in each patient and st.ained with 1 percent toluidine
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blue:Ultrathin sections (600 to 800 A) were cut with a Sorvall MT 2 ultramicrotome, stained with uranyl acetate and lead citrate and examined with a Philips 300 electron microscope at 80 kv. The incidence of ultrastructural changes in atria1 cells of all 15 patients was evaluated. Low power electron micrographs (X:3,000) were taken from each grid, and the cells in the thin section counted. At least eight grids and approximately 400 cells were studied in each patient. The cells with ultrastructural changes were counted, and an approximate incidence rate of each ultrastructural change was calculated. The extent of the changes in each patient was then graded on a scale of 1 to 4 (Table II).
Results Patients With Normal Right Atrial Mean Pressure
(Group I, Table II) Cell size and interstitium: The atria1 cells were regularly arranged and relatively uniform in size in each patient. The cells ranged from 6 to 10 p in diameter at the nuclear level and averaged 8 p. In well defined pectinate muscles, the atria1 cells were aligned parallel to the long axis of the muscle bundles. In the areas where the pectinate muscles merged, the atria1 cells were arranged in small bundles, often coursing at right angles to one another. The endocardium measured from 40 to 200 p in thickness and consisted of collagen fibers, elastic fibers, fibroblasts and smooth muscle cells arranged in a well defined layer beneath the covering endocardial cells. The atria1 muscle bundles were surrounded by delicate connective tissue. Scattered normal blood vessels and nerves were present in the interstitium between muscle bundles. Sarcolemma and specialized junctions: The atria1 cells were invested by a basement lamina except at the intercalated discs. The basement lamina was 300 A thick and consisted of fine filamentous material. This lamina followed the contour
TABLE II Structural Changes in 15 Patients With Atrial Septal Defect
TABLE I
Case
Clinical Data in 15 Patients With Atrial Septal Defect Case no.
Age (yr) & Sex
Right Atrial Pressure (mm’fig) V Wave A Wave Mean
:
6.3
3’ 4 6”
5.5 8.0 7.7 7.8 7.5
8 + 0 :
0 T
8
:+
08
: 1:
6.0 7.9 8.0 7.5
T+ ;
: 0
: 0
::
7.0 7.5
:+
+ r:
0 8
-I++ ++++ ++++
0
2 3
2.2/l 2.911
3+
6 :
65”
44”
2.011 2.011 1.971
3+ it*
6
6F
6
;
s
1.911
3+
: 1:
8F 6M 11M 11F
4 66
3 2
3 2
2.871 1.811 1.911 1.711
3”: 3+
::
47F 11F
5
5.Of 1 3.011
4-l4+ :: 15
:;
2:; 58M
19” 10
287 9
1:7
3.911
4+
5.011
4+
As assessed at the time of surgery: l+ = near normal size; 2+ = mild dilatation; 3+ = moderate dilatation: 4-l- = marked dilatation. Qp/Qs ratio = ratio of pulmonary blood flow to systemic blood flow. l
0
Group II
Group II (increased right atrial mean pressure) 13
I
1
5M E
2
Degenerative Changest
Atrial Size*
3 5”
-!
Intercalated Discs’
Z bands’ Group
Qp/Qs Ratio
Group I (normal right atrial mean pressure) :
Average Cell Size (fi)
no.
9.5 11.0 16.0
: ++
++ +
2 band changes include both thickening of Z bands and abnormal accumulations of Z band-like material. + Intercalated disc changes include increased fibrillar material and irregularity and widening of discs. t Degenerative changes include loss of myofilaments, aggregation of mitochondria and condensation of sarcoplasmic reticulum. 0 = not present; + = present in less than 1 percent of cells; ++ = present in 1 to 5 percent of cells; +++ = present in 5 to 10 percent of cells: ++-H = present in more than 10 percent of cells. l
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FIGURE 1. Case 10. Section of a normal atrial cell. The nucleus (N) is centrally located and a has regular contour. The myofibrils extend from one end of the cell to the other. The sarcomeres are arranged regularly with distinct A bands (A) and Z bands (Z). Mitochondria (M) are interspersed between myofibrils and are uniform in size. The Golgi apparatus (G) is present in the perinuclear region as are scattered atrial specific granules (arrow). The sarcolemma is intact, and T tubular invaginations of the sarcolemma are not seen. (X10,800, reduced by 8 percent.)
FIGURE 2. Case 10. End to end intercalated disc (closed arrows) between two normal atrial cells. The components of this junction are well defined and represent a typical end to end intercalated disc. Nexuses (thin arrow) as well as macular adherens, fascia adherens and undifferentiated portions are easily identified, and the disc has a step-like appearance. Segments of the sarcoplasmic reticulum are prominent (open arrows) and frequently associated with Z bands. (X 8,100, reduced by 6 percent.)
of the atria1 cells but was separated from the sarcolemma by a space 200 to 300 A in width. The sarcolemma was intact and slightly indented at the level of the Z bands (Fig. l), except at the intercalated discs. Clusters of pinocytic vesicles were often found beneath the sarcolemma. Deep invaginations of the sarcolemma to form T tubules were not seen in the atria1 cells examined. On the interior aspect of the sarcolemma, there were scattered irregular deposits of Z band material (less than 1 percent of cells examined). Occasionally these deposits were continuous with the Z bands of adjacent sarcomeres. The atria1 cells were interconnected at their ends by well developed intercalated discs (Fig. 2). At side to side junctions, the intercalated discs were often short and consisted of macula adherens, fascia adherens and unspecialized areas (Fig. 3). Occasionally, extensive side to side intercalated discs were complete with fascia adherens, macula adherens, macula occludens and unspecialized areas. Less than 1 percent of the intercalated discs in 6 of the 12 patients were either irregular in appearance or had extensive accumulations of fibrillar material (Fig. 4). Contractile elements: The sarcomeres were regularly arranged and extended uninterrupted across the cell. The sarcomeres were limited by Z bands and had distinct A bands, I bands and M lines. The thickening of the Z bands was found
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in all 8 of the 12 patients but was present in less than 1 percent of the cells examined in all but 2 patients. Occasionally single Z bands were thickened. More often, multiple Z bands (in consecutive sarcomeres) were thickened within a single cell (Fig. 5). These abnormal Z bands consisted of several irregular nodules that were either connected to one another by a normal segment of the Z band or completely separated from one another by glycogen particles. The involved sarcomeres were disorganized with focal loss of myofilaments, but A bands and M lines remained recognizable (Fig. 5). Cell organelles: The nucleus was centrally placed and elliptical. Only small invaginations of the nuclear membrane were noted (Fig. 1 and 3). Nucleoli were prominent and occasionally multiple. The mitochondria were abundant and most numerous in the perinuclear regions as well as between the myofibrils (Fig. 1 and 3). The mitochondria were round or ovoid, ranging from 0.1 to 0.8 p in diameter. The cristae were well defined, and the matrix was highly electron-opaque and often contained small dense bodies and glycogen particles. Glycogen was abundant and consisted primarily of beta particles with a diameter of approximately 280 A. Atrial-specific granules were numerous (Fig. 3). These granules were completely enveloped by a membrane; they measured 0.1 to 0.4 P in diameter and were most numerous in the perinuclear zones. Lysosomal granules were occasionally found in the perinuclear zones. The Golgi apparatus was well developed
ULTRASTRUCTURE
IN CONGENITAL
HEART DlSEASE~--FENOGLlO
ET AL.
FIGURE 3. Case 10. Two adjacent normal atrial cells joined by a side to side intercalated disc. The disc (closed arrows) is arranged regularly and consists of macular adherens, fascia adherens and tindifferentiated portions. Macular occludens (nexuses) are present (open arrows). Thin arrows indicate atrial specific granules. M = mitochondria; N = nucleus. (X 14,200, reduced by 6 percent.)
and consisted
of stacks of cisternae 150 to 200 A apart and groups of microvesicles ranging from 400 to 800 A in diameter. The Golgi apparatus was invariably present in the perinuclear zone in apposition to the nucleus (Fig. 1). The sarcoplasmic reticulum was extensive and was most conspicuous at the periphery of the cell or in cytoplasmic areas devoid of myofilaments. It was usually seen in profile as ves-
icles with a diameter of 300 to 800 A: however, t.uhules of the sarcoplasmic reticulum were also seen overlying sarcomeres at the level of the Z band (Fig. 2). Tuhules of rough sarcoplasmic reticulum were occasionally found near the nuclear membrane or at the periphery of the cell. Small lipid droplets were present adjacent to mitochondria, and lipochrome pigment was occasionally present in the perinuclear region.
FIGURE 4. Case 6. An irregular, abnormal end to end intercalated disc (closed arrows) associated with extensive deposition of fibrillar material (F) between two otherwise normal atrial cells. This disc abnormality was more extensive in patients in Group II. Note the disanay of sarcomeres bordering the fibrillar masses (open arrows). (X10.500, reduced by 7 percent.)
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Patients With Increased Right Atrial Mean Pressure (Group II, Table II) There were extensive structural changes in the right atrium of these three patients. The cells were generally hypertrophied, although there were focal degenerating cells in Patients 14 and 15. The interstitial connective tissue was increased in amount, and the endocardium was thickened, measuring 300 to 500 /.L.Blood vessels and nerves were numerous and appeared normal. Cell size: The atria1 cells varied in size, shape and arrangement. The diameter of the cells at the nuclear level ranged from 7 to 18 p. There were three distinct populations of myocardial cells: normal cells, hypertrophied nondegenerated cells and degenerating cells. The ultrastructural criteria for hypertrophy and degeneration in human atria1 myocardium have previously been published.’ The normal cells measured 7 to 12 p in diameter. In Patients 13 and 14 approximately 50 percent of the cells examined were greater than 12 k in diameter. The most extensive cell hypertrophy was seen in Patient 15. The average cell diameter in this patient was 16 ~1,and more than 75 percent of cells examined were greater than 12 k. The hypertrophied cells bulged slightly at the nuclear level and tapered sharply at both ends. These cells were arranged in bundles of three to five cells, all aligned parallel to one another; however, the muscle bundles were separated from one another by abundant interstitial connective tissue. FIGURE 5. Case 8. A small portion of an atrial cell with multiple 2 band thickenings (arrows). The thickenings are small and nodular and extend along the entire 2 band in beaded fashion. The myofilaments in affected sarcomeres are slightly disarrayed, but there is no apparent loss of myofilaments. G = glycogen; M = mitochondira. (X8,100, reduced by 8 percent.)
Less than 5 percent of the cells examined demonstrated degenerative changes. Cells with early degenerative changes
(Fig. 6) were generally hypertrophied and measured 14 to 18 in diameter. Cells with severe degenerative changes (Fig. 7, left) were generally smaller and averaged 10 k in diameter. These cells were isolated from the surrounding atria1 myocardium by abundant connective tissue.
F
FiGURE 6. Case 15. A portion of an intercalated disc (closed arrows) between a hypertrophied cell (left) and a cell with early degenerative changes (right). The disc is irregular, widened and associated with fibrillar material (F). In the degenerating cell, profiles of sarcopiasmic reticulum (SR) and clumps of mitochondria (M) are evident in areas devoid of myofibrils. The remaining sarcomeres (S) are intact but disarrayed. In the hypertrophied cell the nucleus (N) is markedly convoluted and there are focal thickened 2 bands (Z). The sarand well orcomeres (S) are intact dered. Atriai-specific granules (open arrows) are numerous. The sarcoiemma and basement membrane of both ceils are normal. (X8,100. reduced by 8 percent.)
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ULTRASTRUCTURE
Sarcolemma and specialized junctions: The sarcolemma and basement membrane were normal in both hypertrophied and degenerative cells (Fig. 6 and 7, left). Many of the intercalated discs in hypertrophied cells and cells with early degenerative changes were markedly irregular and had increased amounts of fibrillar material. These disc changes were identical to those described in patients with normal right atria1 mean pressure; however, they were present with increased frequency in patients with elevated pressure (10 percent or more of the cells examined). Intercalated discs were not found in severely degenerative cells (Fig. 7, left); however, less than
IN CONGENITAL
HEART DISEASE--FENOGLIO
ET AL.
1 percent of cells examined demonstrated these severe degenerative changes. Contractile elements: The hypertrophied cells had increased numbers of well formed, well ordered myofilament bundles with distinct sarcomeres. As previously reported,’ loss of myofilaments was one hallmark of degenerating cells. In severely degenerating cells (Fig. 7, left) only remnants of myofibrils were present at the periphery of the cell. Z band changes similar to those described in patients in Group I were present in all three patients in Group Il. Thickened Z bands and accumulations of abnormal Z band material were present in all cells with degenerative changes. In addition, accumulations of Z band material against the sarcolemma were prominent in degenerating cells. Z band changes were also present in hypertrophied cells but were found in less than 5 percent of the cells examined. Cells organelles: The cell organelles appeared to be increased in number but were normal in hypertrophied cells. In degenerating cells there were aggregates of sarcoplasmic reticulum tubules, glycogen and mitochondria in areas of myofilament loss (Fig. 6 and 7). The mitochondria were small and irregular with dense matrixes and occasionally vacuolated. Atrial-specific granules were present in both hypertrophied and degenerating cells. Approximately 10 percent of the degenerating cells in Pa-
FIGURE 7. Case 14. Left, severely degenerating cell isolated by abundant collagen (C) from the surrounding cells. The cytoplasm is devoid of myofilaments and filled with collapsed sarcoplasmic reticulum tubules, glycogen (G) and mitochondria (M). The mitochondria are aggregated at the periphery and elongated. The sarcolemma and basement membrane are normal. Against the sarcolemma are focal accumulations of abnormal Z band material (arrows) associated with disordered myofilaments. No well formed sarcomeres are identified. Below, a small portion of a cell with “lysosomal degeneration.” The central portion of the cell is filled with dense bodies that occasionally appear to be enclosed by membranes (arrows). The dense bodies are associated with irregular mitochondria and aggregates of glycogen. The remaining sarcomeres (S) are disarrayed with loss of thick filaments and thickened Z bands (Z). (X8.100, reduced by 8 percent.)
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IJLTRASTRUCTURE
IN CONGENITAL
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tients 14and 15contained large numbers of myelin figures and dense bodies (Fig. 7, bottom). The dense bodies were variably sized masses of electron-dense material without distinct substructure. Clusters of this material were frequently enclosed by membranes. These clusters of presumably lysosomal digested organelles were frequently located in the central area of the cells and were bordered by normal myofibrils. Similar accumulations of myelin figures and dense bodies have been reported in the left atrium of patients with mitral valve disease.”
Discussion Role of increased right atria1 flow in presence of normal pressure: This study did not demonstrate any relation between increased right atria1 blood flow and the development of structural changes in the right atrium. In the 12 patients with increased right atria1 blood flow and normal mean pressure (Group I) there were no significant structural changes in the tissue available for study. Accumulations of abnormal Z band material were present, but in less than 5 percent of the cells examined, in 8 of these 12 patients. Z band changes have been reported in both diseaseda-6 and normal atria1 cells.‘T7 Although Z band changes are frequent in hypertrophied atria1 cells1 they appear to be nonspecific changes and are apparently not indicative of either cell hypertrophy or degeneration. Irregular intercalated discs with increased amounts of associated fibrillar material were also found in 6 of these 12 patients but in less than 1 percent of the cells examined. Although we have previously interpreted this type of change as an indicator of cell hypertrophy,’ there was no other structural evidence of cell hypertrophyQ and cell size was within normal range in all six patients. These same disc changes were found with increased frequency in the hypertrophied cells of patients in Group II with elevated right atria1 pressure (more than 20 percent of the cells examined). Such intercalated disc changes, although not specific for cell hypertrophy, are clearly more prominent in hypertrophied right atria1 myocardial cells. We previously determined that the right atrium of patients with ventricular septal defect is structurally normal.’ Except for the rare intercalated disc and Z band changes, the right atrium in the 12 patients with normal right atria1 mean pressure but increased blood flow was ultrastructurally identical to the atrium in patients with ventricular septal defect and, therefore, presumably normal. These findings are in contrast to the struct,ural changes previously reported in the right atrium of patients with both increased right atria1 blood flow and mean pressure, who had changes of both cell hypertrophy and degeneration.’ Similar structural changes were found in the three patients in Group II with increased right atria1 blood flow and mean pressure. The presence of an atria1 septal defect, therefore, does not, in some way prevent the development of structural changes in the right atrium. Rather, the development of structural changes appears to depend on whether or not right atria1 pressure is increased. We were unable to determine if increased right atria1 pressure alone is related to the development of structural changes or whether these changes are related to
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increased right atria1 pressure in the presence of creased right atria1 blood flow. However, this study shown that increased right atria1 blood flow alone is related to the development of structural changes in right atria.
inhas not the
Role of increased right atria1 pressure with increased blood flow in hypertrophy and degeneration: Nine patients with increased right atria1 mean pressure and blood flow (three patients in Group II of this study plus six patients with endocardial cushion defectl) constitute too small a sample to evaluate whether the magnitude of increased pressure in the right atrium is related to the development of structural changes. Although only four of these nine patients had degenerative changes, the marked degenerative changes were found in the patients with the highest right atria1 mean pressure (Patients 14 and 15 of this study and the two patients with the most pronounced elevations of pressure in our previous study.i) The suggestion is that pressure elevation is directly related to the development of degenerative changes. In contrast, changes of hypertrophy were present in all three patients in Group II of this study, as well as in all six patients with endocardial cushion defect.l We have demonstrated that increased blood flow alone is not related to structural changes in the right atrium; therefore, hypertrophy of the right atrium may be secondary to slight increases in right atria1 pressure or the result of slightly increased pressure in the presence of increased blood flow. Role of pulmonary hypertension: Seven of the patients in Group I and the three patients in Group II had a large atria1 septal defect, as indicated by a pulmonary to systemic blood flow ratio of greater than 2.0.g In spite of the greatly increased atria1 blood flow and large size of the atria1 defect, the seven atria of the patients in Group I were structurally normal, whereas there were structural changes in the atria of the three patients in Group II. Similarly, the duration of the increased blood flow did not correlate with the development of structural changes. Patient 12 was 47 years old and had a normal right atrium; Patient 13 had structural changes at age 7 years. In both instances the presence of increased right atria1 pressure determined whether structural changes were found in the right atria1 myocardium. This increase in right atria1 pressure was not directly related to either the magnitude of the shunt or the duration of the shunt; rather, increased atria1 pressure appeared to be related to increases in pulmonary atria1 pressure. The three patients with increased atria1 pressure had elevated pulmonary arterial pressures, whereas the pulmonary arterial pressures in the 12 patients in Group I were normal. The development of increased right atria1 pressure in patients with an atria1 septal defect is probably secondary to changes in the pulmonary circulation. The increased pulmonary pressure causes an increase in right ventricular pressure with a corresponding decrease in right ventricular compliance. The decreased right ventricular compliance leads to elevation of right atria1 pressure. Atria1 arrhythmias: The right atrium was moderately to markedly dilated in all 15 patients in this study, yet none of the patients had atria1 arrhythmias. Previ-
ULTRASTRUCTURE
ous studieslOJ1 have suggested that left atrial dilatation is directly related to the occurrence of atria1 arrhythmias. Our results suggest that right atria1 dilatation even of marked degree need not be associated with atria1 arrhythmias. Implications: These studies indicate that volume overload of the right atrium in the absence of changes
IN CONGENITAL
HEART DISEASE-FENOGLIO
ET AL.
in other hemodynamic factors, such as pressure, does not result in cell hypertrophy or degeneration. Further studies are needed to determine whether the structural changes in the right atrium of patients with congenital heart disease are the result of the increased right atria1 pressure or of the combination of increased pressure and volume overload.
References 1. Pham TD, Wit AL, Hordof AJ, Maim, JR, Fenoglio JJ Jr: Right atrial
2.
3. 4. 5. 6. 7.
ultrastructure in congenital heart disease. I. Comparison of ventricular septal defect and endocardial cushion defect. Am J Cardiol 421973-982, 1978 Friedman PL, Fenoglio JJ Jr, Wit AL: Time course of electrophysiological and ultrastructural abnormalities in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res 36:127-144, 1975 Thiedeman KU, Ferrans VJ, Roberts WC: Myocardial ultrastructure in mitral valvular disease. Am J Pathol 89575-604, 1977 Cote G, Mohluddin SM, Roy PE: Occurrence of Z band widening in human atrial cells. Exp Mol Pathol 13:307-318, 1970 Roy PE, Morin PJ: Variations of the Z band in human auricular appendage. Lab Invest 25422-426, 197 1 Legato NM, Bull MB, Ferrer, MI: Atrial ultrastructure in patients with fixed intra-atrial block. Chest 65252-261, 1974 Legato MJr Ultrastructure of the atrial, ventricular and Purkinje cell
a.
9.
10.
11.
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with special reference to the genesis of arrhythmias. Circulation 47:i78-189, 1973 Jones M, Ferrans VJ, Morrow AG, Roberts WC: Ultrastructure of cristae supraventricularis muscle in patients with congenital heart disease associated with ventricular outflow tract obstruction. Circulation 51:39-67, 1975 Andersen M, Lyngborg K, M#ler I, Wenneuold A: The natural history of small atrial septal defects: long-term follow-up with serial heart catheterizations. Am Heart J 92:302-307, 1976 Henry WL, Morganroth J, Pearfman AS, Clark CE, Redwood DR, ltscoftz SB, Epstein SE: Relation between echocardiographically determined left atrial size and atrial fibrillation. Circulation 52: 273-279, 1973 Watson DC, Henry WL, Epstein SE, Morrow AG: Effects of operation on left atrial size and the occurrence of atrial fibrillation in patients with hypertrophic subaortic stenosis. Circulation 55: 178-181, 1977
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JOHN J. FENOGLIO, Jr., MD, FACC” TUAN DUC PHAM, PhD ALLAN HORDOF, MD RICHARD N. EDIE, MD ANDREW L. WIT, PhDt New York, New York
From the Departments of Pathology, Pediatrics, Pharmacolqy and Surgery, College of Physicians and Surgeons, Columbia University, New York, New York. This study was supported by U.S. Public Health Service Grant HL-12738 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received October 18, 1978; revised manuscript received November 29, 1978 accepted November 29, 1978. t Dr. Wit was a Career Scientist of the Irma T. Hirschel Trust, New York, New York, at the time of this study. Recipient of Career Development Award 5K044HL00185 from the National Heart, Lung and Blood Institute, Bethesda, Maryland. Address for reprints: John J. Fenoglio, Jr., MD, Department of Pathology, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. l
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Portions of operatively resected right atrium from 15 patients with atrial septal defect were studied ultrastructurally to determine whether the cell hypertrophy in the right atrium of patients with increased right atrial blood flow and increased right atrial pressure is caused by the increased blood flow. In 12 patients with normal right atrial mean pressure but increased right atria1blood flow the atrium was dilated but no atrial arrhythmias were noted clinically. Ultrastructurally, the atrial myocardial cells in these patients were normal, measuring 6 to 10 p in diameter, and there was no evidence of cell hypertrophy or degeneration. The remaining three patients had elevated right atrial mean pressure and Increased right atrlal blood flow. Ultrastructurally, the atrial myocardial cells in all three patients were hypertrophied, and two patients had evidence of focal cell degeneration; the atrium was markedly dilated, but atrial arrhythmias were not noted. The lack of cell hypertrophy in the right atrium of the 12 patients with increased blood flow but normal mean pressure suggests that in congenital heart dlsease volume overload alone does not lead to cell hypertrophy of the right atrial myocardium.
In a previous report’ we described changes in the ultrastructure of the dilated right atrium of six patients with endocardial cushion defect. These patients had elevated right atria1 mean pressure and increased right atria1 blood flow. The ultrastructural changes consisted of cell hypertrophy in all patients and cell degeneration in two patients with markedly elevated right atria1 mean pressure. The data suggested that the changes of cell hypertrophy might be secondary to increased blood flow or increased pressure, or both, whereas the degenerative changes appeared to be directly related to increased right atria1 pressure. However, we were unable to separate these two hemodynamic values in this group of patients and were thus unable to determine whether increased blood flow or elevated atria1 pressure was related to the changes of cell hypertrophy seen in the dilated atrium of these patients with congenital heart disease. The purpose of this study was to determine whether increased right atria1 blood flow in the absence of increased right atria1 pressure resulted in hypertrophy of the right atria1 myocardium. We studied the ultrastructure of right atria1 tissue obtained from patients with atria1 septal defect who had a well defined left to right shunt and no evidence of increased right atria1 pressure. Although the atrium in these patients was dilated, there was no evidence of cell hypertrophy. Structurally, the atrium was identical to the right atrium of patients with ventricular septal defect1 and was therefore presumably normal. In addition, portions of the right atrium from three patients with atria1 septal defect and increased right atria1 mean pressure and blood flow were also studied to determine if the structural changes were the same as those previously reported in patients with endocardial cushion defect.’ In the patients
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ULTRASTRUCTURE
with increased mean pressure and blood flow the right. atria1 myocardial cells were hypertrophied and there were focal degenerative changes. Our findings suggest that in congenital heart disease increased right atria1 blood flow in the absence of increased right atria1 mean pressure is not associated with structural changes of the right atrium. Methods Patients studied (Table I): Tissue was obtained from 16 patients at the time of open heart surgery for closure of an atria1 septal defect. Twelve patients (Group I) had normal right atria1 mean pressure (less than 5 mm Hg) and evidence of a left to right shunt across the atria1 septum. These patients ranged in age from 8 to 47 years, although 8 of the 12 patients were less than 10 years of age. The atrium was moderat,ely dilated, although the pulmonary arterial pressure was normal (less than 20 mm Hg), and none of these 12 patients had atria1 arrhythmias. Three patients (Group II) had elevated right atria1 mean pressure (more than 5 mm Hg) as we11 as a Ieft to right shunt, across the atria1 septum. These patients ranged in age from 7 to 58 years. The atrium was markedly dilated and the pulmonary arterial pressure was elevated (more than 40 mm Hg) in all three patients; however, they had no at.rial arrhythmias. Tissue preparation: The atria1 biopsy specimen was obtained adjacent to the site of the atriotomy on the anterior wall of the right atrium. The tissue was fixed in phosphate buffered (pH 7.3) 2.6 percent glutaraldehyde as previously described.’ All tissue was fixed overnight in glutaraldehyde, and postfixed fur I hour in chilled 1 percent osmium tetroxide in 0.1 molar phosphate buffer (pH 7.3). The tissue was rinsed in phosphate buffer, dehydrated in graded acetones and embedded in Swiss araldite. Flat silicone embedding molds were used to facilitate the orientation of muscle fibers to the endocardium.? Thick sections (0.5 to 1 cl) were cut from all tissue blocks in each patient and st.ained with 1 percent toluidine
IN CONGENITAL
HEART DISEASE-FENOGLIO
ET AL.
blue:Ultrathin sections (600 to 800 A) were cut with a Sorvall MT 2 ultramicrotome, stained with uranyl acetate and lead citrate and examined with a Philips 300 electron microscope at 80 kv. The incidence of ultrastructural changes in atria1 cells of all 15 patients was evaluated. Low power electron micrographs (X:3,000) were taken from each grid, and the cells in the thin section counted. At least eight grids and approximately 400 cells were studied in each patient. The cells with ultrastructural changes were counted, and an approximate incidence rate of each ultrastructural change was calculated. The extent of the changes in each patient was then graded on a scale of 1 to 4 (Table II).
Results Patients With Normal Right Atrial Mean Pressure
(Group I, Table II) Cell size and interstitium: The atria1 cells were regularly arranged and relatively uniform in size in each patient. The cells ranged from 6 to 10 p in diameter at the nuclear level and averaged 8 p. In well defined pectinate muscles, the atria1 cells were aligned parallel to the long axis of the muscle bundles. In the areas where the pectinate muscles merged, the atria1 cells were arranged in small bundles, often coursing at right angles to one another. The endocardium measured from 40 to 200 p in thickness and consisted of collagen fibers, elastic fibers, fibroblasts and smooth muscle cells arranged in a well defined layer beneath the covering endocardial cells. The atria1 muscle bundles were surrounded by delicate connective tissue. Scattered normal blood vessels and nerves were present in the interstitium between muscle bundles. Sarcolemma and specialized junctions: The atria1 cells were invested by a basement lamina except at the intercalated discs. The basement lamina was 300 A thick and consisted of fine filamentous material. This lamina followed the contour
TABLE II Structural Changes in 15 Patients With Atrial Septal Defect
TABLE I
Case
Clinical Data in 15 Patients With Atrial Septal Defect Case no.
Age (yr) & Sex
Right Atrial Pressure (mm’fig) V Wave A Wave Mean
:
6.3
3’ 4 6”
5.5 8.0 7.7 7.8 7.5
8 + 0 :
0 T
8
:+
08
: 1:
6.0 7.9 8.0 7.5
T+ ;
: 0
: 0
::
7.0 7.5
:+
+ r:
0 8
-I++ ++++ ++++
0
2 3
2.2/l 2.911
3+
6 :
65”
44”
2.011 2.011 1.971
3+ it*
6
6F
6
;
s
1.911
3+
: 1:
8F 6M 11M 11F
4 66
3 2
3 2
2.871 1.811 1.911 1.711
3”: 3+
::
47F 11F
5
5.Of 1 3.011
4-l4+ :: 15
:;
2:; 58M
19” 10
287 9
1:7
3.911
4+
5.011
4+
As assessed at the time of surgery: l+ = near normal size; 2+ = mild dilatation; 3+ = moderate dilatation: 4-l- = marked dilatation. Qp/Qs ratio = ratio of pulmonary blood flow to systemic blood flow. l
0
Group II
Group II (increased right atrial mean pressure) 13
I
1
5M E
2
Degenerative Changest
Atrial Size*
3 5”
-!
Intercalated Discs’
Z bands’ Group
Qp/Qs Ratio
Group I (normal right atrial mean pressure) :
Average Cell Size (fi)
no.
9.5 11.0 16.0
: ++
++ +
2 band changes include both thickening of Z bands and abnormal accumulations of Z band-like material. + Intercalated disc changes include increased fibrillar material and irregularity and widening of discs. t Degenerative changes include loss of myofilaments, aggregation of mitochondria and condensation of sarcoplasmic reticulum. 0 = not present; + = present in less than 1 percent of cells; ++ = present in 1 to 5 percent of cells; +++ = present in 5 to 10 percent of cells: ++-H = present in more than 10 percent of cells. l
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ULTRASTRUCTURE IN CONGENITAL HEART DISEASE-FENOGLIO
ET AL
FIGURE 1. Case 10. Section of a normal atrial cell. The nucleus (N) is centrally located and a has regular contour. The myofibrils extend from one end of the cell to the other. The sarcomeres are arranged regularly with distinct A bands (A) and Z bands (Z). Mitochondria (M) are interspersed between myofibrils and are uniform in size. The Golgi apparatus (G) is present in the perinuclear region as are scattered atrial specific granules (arrow). The sarcolemma is intact, and T tubular invaginations of the sarcolemma are not seen. (X10,800, reduced by 8 percent.)
FIGURE 2. Case 10. End to end intercalated disc (closed arrows) between two normal atrial cells. The components of this junction are well defined and represent a typical end to end intercalated disc. Nexuses (thin arrow) as well as macular adherens, fascia adherens and undifferentiated portions are easily identified, and the disc has a step-like appearance. Segments of the sarcoplasmic reticulum are prominent (open arrows) and frequently associated with Z bands. (X 8,100, reduced by 6 percent.)
of the atria1 cells but was separated from the sarcolemma by a space 200 to 300 A in width. The sarcolemma was intact and slightly indented at the level of the Z bands (Fig. l), except at the intercalated discs. Clusters of pinocytic vesicles were often found beneath the sarcolemma. Deep invaginations of the sarcolemma to form T tubules were not seen in the atria1 cells examined. On the interior aspect of the sarcolemma, there were scattered irregular deposits of Z band material (less than 1 percent of cells examined). Occasionally these deposits were continuous with the Z bands of adjacent sarcomeres. The atria1 cells were interconnected at their ends by well developed intercalated discs (Fig. 2). At side to side junctions, the intercalated discs were often short and consisted of macula adherens, fascia adherens and unspecialized areas (Fig. 3). Occasionally, extensive side to side intercalated discs were complete with fascia adherens, macula adherens, macula occludens and unspecialized areas. Less than 1 percent of the intercalated discs in 6 of the 12 patients were either irregular in appearance or had extensive accumulations of fibrillar material (Fig. 4). Contractile elements: The sarcomeres were regularly arranged and extended uninterrupted across the cell. The sarcomeres were limited by Z bands and had distinct A bands, I bands and M lines. The thickening of the Z bands was found
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in all 8 of the 12 patients but was present in less than 1 percent of the cells examined in all but 2 patients. Occasionally single Z bands were thickened. More often, multiple Z bands (in consecutive sarcomeres) were thickened within a single cell (Fig. 5). These abnormal Z bands consisted of several irregular nodules that were either connected to one another by a normal segment of the Z band or completely separated from one another by glycogen particles. The involved sarcomeres were disorganized with focal loss of myofilaments, but A bands and M lines remained recognizable (Fig. 5). Cell organelles: The nucleus was centrally placed and elliptical. Only small invaginations of the nuclear membrane were noted (Fig. 1 and 3). Nucleoli were prominent and occasionally multiple. The mitochondria were abundant and most numerous in the perinuclear regions as well as between the myofibrils (Fig. 1 and 3). The mitochondria were round or ovoid, ranging from 0.1 to 0.8 p in diameter. The cristae were well defined, and the matrix was highly electron-opaque and often contained small dense bodies and glycogen particles. Glycogen was abundant and consisted primarily of beta particles with a diameter of approximately 280 A. Atrial-specific granules were numerous (Fig. 3). These granules were completely enveloped by a membrane; they measured 0.1 to 0.4 P in diameter and were most numerous in the perinuclear zones. Lysosomal granules were occasionally found in the perinuclear zones. The Golgi apparatus was well developed
ULTRASTRUCTURE
IN CONGENITAL
HEART DlSEASE~--FENOGLlO
ET AL.
FIGURE 3. Case 10. Two adjacent normal atrial cells joined by a side to side intercalated disc. The disc (closed arrows) is arranged regularly and consists of macular adherens, fascia adherens and tindifferentiated portions. Macular occludens (nexuses) are present (open arrows). Thin arrows indicate atrial specific granules. M = mitochondria; N = nucleus. (X 14,200, reduced by 6 percent.)
and consisted
of stacks of cisternae 150 to 200 A apart and groups of microvesicles ranging from 400 to 800 A in diameter. The Golgi apparatus was invariably present in the perinuclear zone in apposition to the nucleus (Fig. 1). The sarcoplasmic reticulum was extensive and was most conspicuous at the periphery of the cell or in cytoplasmic areas devoid of myofilaments. It was usually seen in profile as ves-
icles with a diameter of 300 to 800 A: however, t.uhules of the sarcoplasmic reticulum were also seen overlying sarcomeres at the level of the Z band (Fig. 2). Tuhules of rough sarcoplasmic reticulum were occasionally found near the nuclear membrane or at the periphery of the cell. Small lipid droplets were present adjacent to mitochondria, and lipochrome pigment was occasionally present in the perinuclear region.
FIGURE 4. Case 6. An irregular, abnormal end to end intercalated disc (closed arrows) associated with extensive deposition of fibrillar material (F) between two otherwise normal atrial cells. This disc abnormality was more extensive in patients in Group II. Note the disanay of sarcomeres bordering the fibrillar masses (open arrows). (X10.500, reduced by 7 percent.)
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ULTRASTRUCTURE
IN CONGENITAL HEART DISEASE-FENOGLIO
ET AL
Patients With Increased Right Atrial Mean Pressure (Group II, Table II) There were extensive structural changes in the right atrium of these three patients. The cells were generally hypertrophied, although there were focal degenerating cells in Patients 14 and 15. The interstitial connective tissue was increased in amount, and the endocardium was thickened, measuring 300 to 500 /.L.Blood vessels and nerves were numerous and appeared normal. Cell size: The atria1 cells varied in size, shape and arrangement. The diameter of the cells at the nuclear level ranged from 7 to 18 p. There were three distinct populations of myocardial cells: normal cells, hypertrophied nondegenerated cells and degenerating cells. The ultrastructural criteria for hypertrophy and degeneration in human atria1 myocardium have previously been published.’ The normal cells measured 7 to 12 p in diameter. In Patients 13 and 14 approximately 50 percent of the cells examined were greater than 12 k in diameter. The most extensive cell hypertrophy was seen in Patient 15. The average cell diameter in this patient was 16 ~1,and more than 75 percent of cells examined were greater than 12 k. The hypertrophied cells bulged slightly at the nuclear level and tapered sharply at both ends. These cells were arranged in bundles of three to five cells, all aligned parallel to one another; however, the muscle bundles were separated from one another by abundant interstitial connective tissue. FIGURE 5. Case 8. A small portion of an atrial cell with multiple 2 band thickenings (arrows). The thickenings are small and nodular and extend along the entire 2 band in beaded fashion. The myofilaments in affected sarcomeres are slightly disarrayed, but there is no apparent loss of myofilaments. G = glycogen; M = mitochondira. (X8,100, reduced by 8 percent.)
Less than 5 percent of the cells examined demonstrated degenerative changes. Cells with early degenerative changes
(Fig. 6) were generally hypertrophied and measured 14 to 18 in diameter. Cells with severe degenerative changes (Fig. 7, left) were generally smaller and averaged 10 k in diameter. These cells were isolated from the surrounding atria1 myocardium by abundant connective tissue.
F
FiGURE 6. Case 15. A portion of an intercalated disc (closed arrows) between a hypertrophied cell (left) and a cell with early degenerative changes (right). The disc is irregular, widened and associated with fibrillar material (F). In the degenerating cell, profiles of sarcopiasmic reticulum (SR) and clumps of mitochondria (M) are evident in areas devoid of myofibrils. The remaining sarcomeres (S) are intact but disarrayed. In the hypertrophied cell the nucleus (N) is markedly convoluted and there are focal thickened 2 bands (Z). The sarand well orcomeres (S) are intact dered. Atriai-specific granules (open arrows) are numerous. The sarcoiemma and basement membrane of both ceils are normal. (X8,100. reduced by 8 percent.)
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ULTRASTRUCTURE
Sarcolemma and specialized junctions: The sarcolemma and basement membrane were normal in both hypertrophied and degenerative cells (Fig. 6 and 7, left). Many of the intercalated discs in hypertrophied cells and cells with early degenerative changes were markedly irregular and had increased amounts of fibrillar material. These disc changes were identical to those described in patients with normal right atria1 mean pressure; however, they were present with increased frequency in patients with elevated pressure (10 percent or more of the cells examined). Intercalated discs were not found in severely degenerative cells (Fig. 7, left); however, less than
IN CONGENITAL
HEART DISEASE--FENOGLIO
ET AL.
1 percent of cells examined demonstrated these severe degenerative changes. Contractile elements: The hypertrophied cells had increased numbers of well formed, well ordered myofilament bundles with distinct sarcomeres. As previously reported,’ loss of myofilaments was one hallmark of degenerating cells. In severely degenerating cells (Fig. 7, left) only remnants of myofibrils were present at the periphery of the cell. Z band changes similar to those described in patients in Group I were present in all three patients in Group Il. Thickened Z bands and accumulations of abnormal Z band material were present in all cells with degenerative changes. In addition, accumulations of Z band material against the sarcolemma were prominent in degenerating cells. Z band changes were also present in hypertrophied cells but were found in less than 5 percent of the cells examined. Cells organelles: The cell organelles appeared to be increased in number but were normal in hypertrophied cells. In degenerating cells there were aggregates of sarcoplasmic reticulum tubules, glycogen and mitochondria in areas of myofilament loss (Fig. 6 and 7). The mitochondria were small and irregular with dense matrixes and occasionally vacuolated. Atrial-specific granules were present in both hypertrophied and degenerating cells. Approximately 10 percent of the degenerating cells in Pa-
FIGURE 7. Case 14. Left, severely degenerating cell isolated by abundant collagen (C) from the surrounding cells. The cytoplasm is devoid of myofilaments and filled with collapsed sarcoplasmic reticulum tubules, glycogen (G) and mitochondria (M). The mitochondria are aggregated at the periphery and elongated. The sarcolemma and basement membrane are normal. Against the sarcolemma are focal accumulations of abnormal Z band material (arrows) associated with disordered myofilaments. No well formed sarcomeres are identified. Below, a small portion of a cell with “lysosomal degeneration.” The central portion of the cell is filled with dense bodies that occasionally appear to be enclosed by membranes (arrows). The dense bodies are associated with irregular mitochondria and aggregates of glycogen. The remaining sarcomeres (S) are disarrayed with loss of thick filaments and thickened Z bands (Z). (X8.100, reduced by 8 percent.)
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IJLTRASTRUCTURE
IN CONGENITAL
HEART DISEASE-FENOGLIO
ET AL.
tients 14and 15contained large numbers of myelin figures and dense bodies (Fig. 7, bottom). The dense bodies were variably sized masses of electron-dense material without distinct substructure. Clusters of this material were frequently enclosed by membranes. These clusters of presumably lysosomal digested organelles were frequently located in the central area of the cells and were bordered by normal myofibrils. Similar accumulations of myelin figures and dense bodies have been reported in the left atrium of patients with mitral valve disease.”
Discussion Role of increased right atria1 flow in presence of normal pressure: This study did not demonstrate any relation between increased right atria1 blood flow and the development of structural changes in the right atrium. In the 12 patients with increased right atria1 blood flow and normal mean pressure (Group I) there were no significant structural changes in the tissue available for study. Accumulations of abnormal Z band material were present, but in less than 5 percent of the cells examined, in 8 of these 12 patients. Z band changes have been reported in both diseaseda-6 and normal atria1 cells.‘T7 Although Z band changes are frequent in hypertrophied atria1 cells1 they appear to be nonspecific changes and are apparently not indicative of either cell hypertrophy or degeneration. Irregular intercalated discs with increased amounts of associated fibrillar material were also found in 6 of these 12 patients but in less than 1 percent of the cells examined. Although we have previously interpreted this type of change as an indicator of cell hypertrophy,’ there was no other structural evidence of cell hypertrophyQ and cell size was within normal range in all six patients. These same disc changes were found with increased frequency in the hypertrophied cells of patients in Group II with elevated right atria1 pressure (more than 20 percent of the cells examined). Such intercalated disc changes, although not specific for cell hypertrophy, are clearly more prominent in hypertrophied right atria1 myocardial cells. We previously determined that the right atrium of patients with ventricular septal defect is structurally normal.’ Except for the rare intercalated disc and Z band changes, the right atrium in the 12 patients with normal right atria1 mean pressure but increased blood flow was ultrastructurally identical to the atrium in patients with ventricular septal defect and, therefore, presumably normal. These findings are in contrast to the struct,ural changes previously reported in the right atrium of patients with both increased right atria1 blood flow and mean pressure, who had changes of both cell hypertrophy and degeneration.’ Similar structural changes were found in the three patients in Group II with increased right atria1 blood flow and mean pressure. The presence of an atria1 septal defect, therefore, does not, in some way prevent the development of structural changes in the right atrium. Rather, the development of structural changes appears to depend on whether or not right atria1 pressure is increased. We were unable to determine if increased right atria1 pressure alone is related to the development of structural changes or whether these changes are related to
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increased right atria1 pressure in the presence of creased right atria1 blood flow. However, this study shown that increased right atria1 blood flow alone is related to the development of structural changes in right atria.
inhas not the
Role of increased right atria1 pressure with increased blood flow in hypertrophy and degeneration: Nine patients with increased right atria1 mean pressure and blood flow (three patients in Group II of this study plus six patients with endocardial cushion defectl) constitute too small a sample to evaluate whether the magnitude of increased pressure in the right atrium is related to the development of structural changes. Although only four of these nine patients had degenerative changes, the marked degenerative changes were found in the patients with the highest right atria1 mean pressure (Patients 14 and 15 of this study and the two patients with the most pronounced elevations of pressure in our previous study.i) The suggestion is that pressure elevation is directly related to the development of degenerative changes. In contrast, changes of hypertrophy were present in all three patients in Group II of this study, as well as in all six patients with endocardial cushion defect.l We have demonstrated that increased blood flow alone is not related to structural changes in the right atrium; therefore, hypertrophy of the right atrium may be secondary to slight increases in right atria1 pressure or the result of slightly increased pressure in the presence of increased blood flow. Role of pulmonary hypertension: Seven of the patients in Group I and the three patients in Group II had a large atria1 septal defect, as indicated by a pulmonary to systemic blood flow ratio of greater than 2.0.g In spite of the greatly increased atria1 blood flow and large size of the atria1 defect, the seven atria of the patients in Group I were structurally normal, whereas there were structural changes in the atria of the three patients in Group II. Similarly, the duration of the increased blood flow did not correlate with the development of structural changes. Patient 12 was 47 years old and had a normal right atrium; Patient 13 had structural changes at age 7 years. In both instances the presence of increased right atria1 pressure determined whether structural changes were found in the right atria1 myocardium. This increase in right atria1 pressure was not directly related to either the magnitude of the shunt or the duration of the shunt; rather, increased atria1 pressure appeared to be related to increases in pulmonary atria1 pressure. The three patients with increased atria1 pressure had elevated pulmonary arterial pressures, whereas the pulmonary arterial pressures in the 12 patients in Group I were normal. The development of increased right atria1 pressure in patients with an atria1 septal defect is probably secondary to changes in the pulmonary circulation. The increased pulmonary pressure causes an increase in right ventricular pressure with a corresponding decrease in right ventricular compliance. The decreased right ventricular compliance leads to elevation of right atria1 pressure. Atria1 arrhythmias: The right atrium was moderately to markedly dilated in all 15 patients in this study, yet none of the patients had atria1 arrhythmias. Previ-
ULTRASTRUCTURE
ous studieslOJ1 have suggested that left atrial dilatation is directly related to the occurrence of atria1 arrhythmias. Our results suggest that right atria1 dilatation even of marked degree need not be associated with atria1 arrhythmias. Implications: These studies indicate that volume overload of the right atrium in the absence of changes
IN CONGENITAL
HEART DISEASE-FENOGLIO
ET AL.
in other hemodynamic factors, such as pressure, does not result in cell hypertrophy or degeneration. Further studies are needed to determine whether the structural changes in the right atrium of patients with congenital heart disease are the result of the increased right atria1 pressure or of the combination of increased pressure and volume overload.
References 1. Pham TD, Wit AL, Hordof AJ, Maim, JR, Fenoglio JJ Jr: Right atrial
2.
3. 4. 5. 6. 7.
ultrastructure in congenital heart disease. I. Comparison of ventricular septal defect and endocardial cushion defect. Am J Cardiol 421973-982, 1978 Friedman PL, Fenoglio JJ Jr, Wit AL: Time course of electrophysiological and ultrastructural abnormalities in subendocardial Purkinje fibers surviving extensive myocardial infarction in dogs. Circ Res 36:127-144, 1975 Thiedeman KU, Ferrans VJ, Roberts WC: Myocardial ultrastructure in mitral valvular disease. Am J Pathol 89575-604, 1977 Cote G, Mohluddin SM, Roy PE: Occurrence of Z band widening in human atrial cells. Exp Mol Pathol 13:307-318, 1970 Roy PE, Morin PJ: Variations of the Z band in human auricular appendage. Lab Invest 25422-426, 197 1 Legato NM, Bull MB, Ferrer, MI: Atrial ultrastructure in patients with fixed intra-atrial block. Chest 65252-261, 1974 Legato MJr Ultrastructure of the atrial, ventricular and Purkinje cell
a.
9.
10.
11.
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with special reference to the genesis of arrhythmias. Circulation 47:i78-189, 1973 Jones M, Ferrans VJ, Morrow AG, Roberts WC: Ultrastructure of cristae supraventricularis muscle in patients with congenital heart disease associated with ventricular outflow tract obstruction. Circulation 51:39-67, 1975 Andersen M, Lyngborg K, M#ler I, Wenneuold A: The natural history of small atrial septal defects: long-term follow-up with serial heart catheterizations. Am Heart J 92:302-307, 1976 Henry WL, Morganroth J, Pearfman AS, Clark CE, Redwood DR, ltscoftz SB, Epstein SE: Relation between echocardiographically determined left atrial size and atrial fibrillation. Circulation 52: 273-279, 1973 Watson DC, Henry WL, Epstein SE, Morrow AG: Effects of operation on left atrial size and the occurrence of atrial fibrillation in patients with hypertrophic subaortic stenosis. Circulation 55: 178-181, 1977
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