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(Circulation. 1996;93:1424-1438.)
© 1996 American Heart Association, Inc.

Articles

Apoptosis as a Possible Cause of Gradual Development of Complete Heart Block and Fatal Arrhythmias Associated With Absence of the AV Node, Sinus Node, and Internodal Pathways

Thomas N. James, MD; Edward St. Martin, MD; Park W. Willis, III, MD; Thomas O. Lohr, MD

From the Department of Medicine, Department of Pathology, and the World Health Organization Cardiovascular Center, University of Texas Medical Branch, Galveston (T.N.J.); Southern Baptist Hospital, New Orleans, La (E.St.M.); the Division of Cardiology, Michigan State University College of Human Medicine, East Lansing (P.W.W.); and the Saginaw Bay (Mich) Internal Medicine Group (T.O.L.).

Correspondence to Thomas N. James, MD, Office of the President, University of Texas Medical Branch, Galveston, TX 77555-0129.

	Abstract

Top Abstract Introduction Clinical Descriptions Anatomic Methods and Findings Discussion References

 
Background Gradually progressive development of complete heart block in young people often is associated with cardiac arrhythmia and sudden death, but the pathogenesis remains unexplained.

Methods and Results A young woman with complete heart block died suddenly. Her mother had serological but no clinical evidence of antiphospholipid syndrome. Five brothers of another family had arrhythmia and heart block. Three died suddenly; the other two have automatic defibrillators and are alive. The hearts from the young woman and two of the three brothers who died were available for our histological examination of their cardiac conduction systems. In two of the three hearts, the AV node was absent; in the third heart, only fragments of the AV node remained. In all three hearts, the sinus node was nearly destroyed by a noninflammatory degeneration with no abnormal fibrosis or infiltrate. In each heart, the interatrial and internodal pathways were similarly involved, and in the young woman, there were no myocardial cells in which these pathways normally exist.

Conclusions In these three subjects with progressive development of complete heart block and various arrhythmias, all of whom died suddenly, the histological abnormalities of their cardiac conduction systems are best interpreted as resulting from apoptosis. Programmed cell death is a logical explanation for the pathogenesis of this puzzling clinical picture.

Key Words: atrioventricular node • death, sudden • morphogenesis

	Introduction

Top Abstract Introduction Clinical Descriptions Anatomic Methods and Findings Discussion References

 
A familiar but frustrating challenge in clinical cardiology is presented by those patients in adolescence or early adult life who first develop some degree of heart block, which then proceeds gradually to complete heart block without any ready explanation.^{1 2 3} The clinical course typically includes bouts of either brief or prolonged syncopal attacks. Various forms of atrial and/or ventricular arrhythmia are frequently recorded. There is always the dilemma of deciding whether and when to put in an electronic pacemaker. Some guides, such as a normal heart rate or narrow QRS complexes, can be helpful, as can the frequency and severity of syncope, but regrettably sudden death still occurs too often. A better understanding of the pathogenesis of these clinical features would be helpful.

Postmortem examination of the cardiac conduction system in such cases sometimes reveals a surprising anatomic explanation for which there was no clinical clue during life. Examples include focal fibromuscular dysplastic narrowing of the AV node artery,^{4 5 6} benign congenital polycystic tumor of the AV node,⁷ and various forms of congenital heart block,^{8 9 10 11} especially those associated with lupus erythematosus.^{12 13 14 15 16} In all these examples, it remains unexplained why the heart block progressed, usually gradually, and why associated electrical instability of the heart came or went when it did. It has been demonstrated recently that apoptosis can involve the human cardiac conduction system.^{17 18} We present here several such cases of sudden death for which apoptosis is the best explanation.

	Clinical Descriptions

Top Abstract Introduction Clinical Descriptions Anatomic Methods and Findings Discussion References

 
Case 1
A 17-year-old cheerleader was robustly healthy although known to have heart block on her ECG (Fig 1). She died suddenly early one evening without any premonitory symptoms. An autopsy was performed and was essentially normal except for the heart, which we describe later. Toxicological studies were negative.

View larger version (78K): [in this window] [in a new window]   Figure 1. ECG demonstrating complete heart block in case 1 during the last year of her life. Black dots indicate atrial complexes; circles, ventricular complexes; and squares, superimposed complexes. The ventricular rate (VR) is 66% of the atrial rate (AR; see text for discussion).

Since early infancy, this subject had a slow heart rate associated with AV block. With exercise, however, the heart rate increased appropriately, and narrow QRS complexes always appeared on the ECG. There were occasional examples of AV conduction of sinus beats, but only for a few minutes. When she was 8 years old, a cardiac catheterization was performed during which the basal heart rate was 55 beats per minute (bpm) with complete heart block; however, after isoproterenol infusion, her heart rate increased to 83 bpm, and there was 2:1 AV conduction for a brief time, after which complete heart block returned but QRS complexes stayed the same. In the absence of clinical symptoms and the presence of a satisfactory heart rate and narrow QRS complexes, it was the consensus of several physicians that she should be followed conservatively.

After the young woman's death, her mother agreed to have serological examinations for antiphospholipid antibodies. The subject was found to have a homogeneous ANA HEp-2 cell pattern at 1:40 dilution. She was positive for antibody to SS-A/Ro and RANA but was negative for antibody to SSA (Wilz). The mother had no clinical evidence of lupus erythematosus or other collagen disease and had a normal ECG. There were no significant clinical abnormalities in the family history, and all close relatives (including two brothers) had normal ECGs.

Case 2
Next we studied the tragic medical history of five brothers in a different family unrelated to case 1. The first (oldest) brother who was otherwise healthy had a single syncopal episode at 10 years of age from which he was resuscitated successfully. When he was 12 years old, he died suddenly while running after he ate lunch. Although an excellent athlete, he had mentioned brief sensations of dizziness when running. The autopsy was said to be normal but did not include examination of the cardiac conduction system. That heart was not available for our study.

Case 3
The second brother was healthy and asymptomatic until the age of 13 years, when he fainted while playing soccer. During that episode, he was apneic and had no pulse for >1 minute. He then responded to chest thumps and mouth-to-mouth ventilation. After being admitted to a hospital, he was found to have multiple atrial, AV junctional, and occasional ventricular premature beats and sinus bradycardia. While sleeping, he had AV junctional rhythm at 40 bpm, but when awake, his sinus rhythm ranged from 70 to 80 bpm. No additional cardiac abnormalities were found.

An electrophysiological study demonstrated Wenckebach phenomenon at atrial pacing rates of 180 bpm but otherwise normal AH and HV intervals. Sinus node recovery time was normal. Because of persisting sinus bradycardia, a permanent cardiac pacemaker was implanted by thoracotomy for the additional advantage of safer use of ß-receptor blocking therapy.

The next year, this subject had another syncopal episode while playing touch football during which he had a clonic seizure. Local resuscitative efforts were successful, and his ECG was unremarkable and unchanged from previous examinations. One month later, he felt faint during a school fire drill. He collapsed the following week while standing in the cold waiting for a school bus and was pulseless and apneic. Resuscitative efforts this time were more difficult, and during them he aspirated vomitus. After a prolonged hospitalization, his cardiac situation stabilized and his pulmonary complications from aspiration cleared.

For the next 6 years, this young man did surprisingly well. But at 22 years of age, after discontinuing his medications and making a long automobile drive home from a neighboring state, he lost consciousness while sitting in his car. Resuscitation was again successful, although ventricular fibrillation was documented when he was brought to a local hospital. Once more he remained asymptomatic for the next year until one cold day when he collapsed in his yard and died. An autopsy provided no explanation for his sudden death except for the cardiac abnormalities that we describe later. Toxicological examinations were negative.

Case 4
The third brother has never had recognized syncope, but because of the family history and electrical instability during an electrophysiological study in which he was found to have repeated bouts of torsade de pointes and sinus node dysfunction, an automatic cardioverter-defibrillator was implanted. He is doing well and is 29 years old.

Case 5
The fourth brother also had no recognized clinical symptoms but did have frequent ventricular premature beats on long-term monitoring and exercise testing. He also has been successfully treated with an implanted automatic cardioverter-defibrillator and is still alive at the age of 25 years.

Case 6
The fifth brother had no syncope or recognizable cardiac symptoms but did have multiple premature beats on long-term monitoring and during exercise tests. At 14 years of age, he was found dead in his bed one morning. Autopsy findings were unremarkable except for the heart as described below. Toxicological examinations were negative.

The mother of the five brothers had no clinical evidence of lupus erythematosus or other collagen disease, and neither she nor the father (there were no other siblings) has any known cardiac disease, but we have no additional information on the family.

	Anatomic Methods and Findings

Top Abstract Introduction Clinical Descriptions Anatomic Methods and Findings Discussion References

 
The heart from the first brother (case 2) was no longer available, but the hearts from the young woman (case 1) and two of the brothers (cases 3 and 6) were available for special examinations. They form the basis of our anatomic descriptions of their conduction systems and related cardiac findings.

Our methods for histological examination of the sinus node,¹⁹ internodal and interatrial pathways,^{20 21} and AV junctional tissues (AV node, His bundle, and its branches)²² were described previously. In summary, the sinus node block includes 2 cm extending up into the superior vena cava from its junction with right atrium and at least 2 cm of adjacent right atrium; this block also includes the crista terminalis plus most of the proximal course of all three internodal pathways. The AV junctional block extends from the root of the aorta along the entire atrial and ventricular septal junction and through the coronary sinus, including at least 3 cm of each septum; this block contains the entire AV node, His bundle, and proximal several centimeters of both bundle branches. The AV junctional block also contains all the distal half (at least) of the three internodal pathways and virtually all the interatrial pathway (Bachmann's bundle).

Each block was cut in the frontal plane into serial slices 5 mm thick, which were processed for embedding in paraffin. An initial screening sample of 10 serial sections (8 µm thick) was cut from each slice, with additional sections, including complete serial sectioning, added as necessary. Slides were routinely stained with the Goldner trichrome method. Selected adjacent sections were chosen for staining with the Verhoeff–van Gieson elastic method or the periodic acid–Schiff method.

For immunohistochemical recognition of apoptotic cells, we used the TUNEL method (TdT-mediated dUTP-biotin nick end labeling),²³ which identifies early DNA fragmentation in the nucleus based on the specific binding of terminal deoxynucleotidyl transferase (TdT) to the 3'-OH ends of DNA. Commercially available staining kits (Apoptag Plus, ONCOR) were used for this purpose. Interpretation is assisted by the contrasting presence of counterstained (blue) nonapoptotic neighboring nuclei and the absence of inflammatory cellular infiltration in the vicinity of the apoptotic cells (brown nuclei).

Case 1
Extensive abnormalities of the cardiac conduction system of the young woman are described in detail here, but she also had several surprising other cardiac abnormalities. There were a thin-walled aneurysmal left atrial appendage and a small thick right atrial appendage (Fig 2). The fossa ovalis was sealed normally, but the entire interatrial septum was very thin. Although the heart was enlarged, most of this enlargement was due to dilatation; total heart weight was only 410 g. Cardiac valves were normal. Both the right and left coronary arteries were entirely normal in their epicardial courses.

View larger version (172K): [in this window] [in a new window]   Figure 2. Photograph of the aneurysmal left atrial appendage (LA App.) and small thick right atrial appendage (RA) of case 1. RV indicates right ventricle; PA, pulmonary artery; Ao, aorta; and LV, left ventricle (see also Fig 3).

On histological examination, the ventricular myocardium was normal. Fig 3 shows the microscopic appearance of the thick right atrial appendage and the very thin left atrial appendage. The AV node and the entire internodal and interatrial pathway system were absent (Figs 4 and 5). Within the central fibrous body, there was a relatively normal His bundle (Fig 6) from which both right and left bundle branches proceeded in their usual course. Fig 7 shows higher magnification of scattered cells undergoing noninflammatory "resorptive degeneration" in remaining fragments of the AV node. Much of the sinus node was destroyed, and no true node remained (Fig 8), although small shreds of nodal tissue could be recognized.

View larger version (173K): [in this window] [in a new window]   Figure 3. Histological sections compare the left atrial appendage (LA App.) and right atrial appendage (RA App.) of case 1. The thin left atrial myocardium with focal fat contrasts with the massive hypertrophy of the right atrial appendage. Goldner trichrome stain was used here and in other tissue sections except as noted. Magnifications as indicated by reference bars.

View larger version (188K): [in this window] [in a new window]   Figure 4. These two frontal plane sections and the two in Fig 5 are approximately evenly spaced through the region of AV node and the His bundle from case 1. A, Near the midpoint of the normal AV node (absent here); B, from the beginning of the His bundle (AVB). LA indicates left atrium; RA, right atrium; IAS, interatrial septum; CFB, central fibrous body; IVS, interventricular septum; TV, tricuspid valve; MV, mitral valve; and LV, left ventricle. All the myocytes are absent from the interatrial septum shown here and in Fig 5. Magnifications as indicated by reference bars.

View larger version (171K): [in this window] [in a new window]   Figure 5. Proceeding anteriorly from the two sections in Fig 4, A here passes through the midportions of Bachmann's bundle (BB) and the undivided His bundle (AVB). B is from the anterior margin of Bachmann's bundle and through the membranous interventricular septum (MIVS). LBB marks the origin of the left bundle branch. Contrast the absence of myocardium in Bachmann's bundle and the interatrial septum with the completely normal myocardium of the interventricular septum. See also Figs 10 and 11. Abbreviations as in Fig 4. Magnifications as indicated by reference bars.

View larger version (152K): [in this window] [in a new window]   Figure 6. Higher magnifications of the His bundle in case 1. Two adjacent foci of persistent fetal dispersion of the His bundle in the central fibrous body are marked with open arrows in A. Origin of the left bundle branch is seen in B. No myocytes are seen in the adjacent interatrial septum. Abbreviations as in Fig 4.

View larger version (140K): [in this window] [in a new window]   Figure 7. More details of the cells in sites of persistent fetal dispersion of the His bundle from case 1. The oval cross section of a patent AV node artery in A is also seen in Fig 6A. Area boxed in A is shown at higher magnification in B (see also Fig 9). Magnifications as indicated by reference bars.

View larger version (149K): [in this window] [in a new window]   Figure 8. Four open arrows in A indicate the area where sinus node artery (SNA) should normally be present in case 1. In B, an adjacent area of sinus node 100 µm from the section in A is shown at slightly higher magnification. Only a few scattered nodal cells remain.

Immunohistochemical studies revealed numerous TUNEL-positive cells among the few residual fragments of the AV node (Fig 9) and sinus node. Apoptosis thus defined involved not only the myocytes of the sinus node and AV node but also small nerves, ganglia, and small arteries. Numerous macrophages were present in these regions, some containing apoptotic bodies within their cytoplasm. The few surviving fragments of her internodal pathways also included many TUNEL-positive cells.

View larger version (138K): [in this window] [in a new window]   Figure 9. Photomicrographs illustrating results with the TUNEL stain23 of sections cut directly adjacent to the ones shown in Fig 6A (case 1). Fragments of AV node dispersed in the central fibrous body are undergoing apoptotic degeneration. A can be compared directly with the Goldner trichrome stain section in Fig 6A, whereas B shows the boxed area in A at a higher magnification. Nuclei in apoptotic cells stain dark brown (black arrows in B); nuclei in nonapoptotic cells are blue (open arrows in B). Myofilaments stain various shades of purple (see also bottom of Fig 14). Curved arrow in B indicates an apoptotic smooth muscle cell in a small vessel. Representative apoptotic and nonapoptotic cells are indicated, but there are numerous other unmarked examples.

Case 3
The heart of the second son was grossly normal in appearance and size. The cardiac septa were intact, and the pericardium was normal, as were the four cardiac valves and all the epicardial coronary arteries. The ventricular myocardium was normal. As in the young woman, this young man's AV node was absent (Fig 10). Many portions of his internodal pathways also were absent, especially Bachmann's bundle (Fig 11), but in some places these pathways contained preserved myocardium. Below the usual location of the AV node (absent in this case), there were portions of the His bundle dispersed within the central fibrous body and a small remaining His bundle giving rise to the right and left bundle branches.

View larger version (151K): [in this window] [in a new window]   Figure 10. Absence of the AV node in case 3 is demonstrated in A and compared with a normal AV node in B from a young man the same age. Note the pocket in the central fibrous body in A in which the AV node was most likely located earlier in his life. Also note the normally patent AV node artery in A. Abbreviations as in Fig 4.

View larger version (116K): [in this window] [in a new window]   Figure 11. The area of the anterior interatrial myocardial band (Bachmann's bundle [BB]) is illustrated here from cases 1, 3, and 6. In case 1, where the myocardium is completely gone, numerous small vessels and nerves are preserved. In cases 3 and 6, most of Bachmann's bundle also exhibits no myocardial cells. The section from case 3 cuts through the anterior margin of the membranous interventricular septum and contains some myocardium from the posterior margin of the crista supraventricularis (CrS), where it normally joins the interventricular septum. The section from subject 6 is located slightly posterior to that from case 3. Abbreviations as in Fig 4.

The remnants of his shredded sinus node were similar to those of the young woman, exhibiting focal noninflammatory degeneration and extensive loss of normal cells (Fig 12). Immunohistochemical staining demonstrated many TUNEL-positive cells among surviving fragments of both the sinus node and AV node and in his internodal pathways.

View larger version (143K): [in this window] [in a new window]   Figure 12. The remains of the sinus node (SN) of case 3 are shown in B and compared with a normal sinus node of a young man his age seen in A. A few more recognizable shreds of sinus node are visible in B than in Fig 8 from case 1, but the node generally has been destroyed. Note the normally patent sinus node artery (SNA). RA indicates right atrium.

Case 6
As in his sibling, the heart of the fifth brother was grossly normal. The ventricular myocardium also was histologically normal, but the conduction system was not. Portions of the posterior area of the AV node were present only as fragments, but there was no connection with the His bundle, which itself was small. Many portions of the internodal pathways were replaced with fatty tissue as in the other two cases, but in all three pathways and Bachmann's bundle, there was a surprising preservation of normal-appearing small vessels and nerves in these same regions where the myocardial cells were gone (Fig 11). Both the AV node and sinus node arteries were normally patent in all three hearts studied. Shredded fragmentation of the sinus node in the fifth brother was similar in appearance to the AV node in his heart and resembled the sinus nodes of the young woman and the second brother.

TUNEL-positive cells were abundant in remnants of both the sinus node and AV node of case 6 (Figs 13 and 14). As in the other two cases, the apoptosis involved not only myocytes but also neural elements and smooth muscle and endothelial cells in small arteries of the conduction system components, including the internodal pathways.

View larger version (133K): [in this window] [in a new window]   Figure 13. Apoptotic cells from both the sinus node (SN) and AV node (AVN) from case 6. Round or ovoid nuclei are typical of P cells normally present in both the sinus node and AV node of human hearts,19 22 and elongated slender nuclei are present in transitional cells (Tr). Examples of both apoptotic (black arrows) and nonapoptotic (open arrows) cells are indicated in both the sinus node and AV node. In the sinus node, there are also two apoptotic endothelial (E) cells. P cells normally occur in small clusters, as seen in the middle of the left margin of the sinus node, in which one nonapoptotic nucleus is bracketed by two apoptotic ones.

View larger version (111K): [in this window] [in a new window]   Figure 14. Other examples of TUNEL-positive apoptotic cells of the sinus node (SN) and AV node (AVN) from case 6 are identical to findings in cases 1 and 3. Cells and fibers of both nodes form interweaving meshworks within which P cells typically cluster and transitional cells (Tr) often course parallel to one another. The surrounding cell membrane delimits the typically "clear" cytoplasm of a nonapoptotic P cell seen in the middle of the bottom margin of the top photomicrograph. The larger apoptotic mass (bottom) probably is two superimposed nuclei or a nucleus with a cluster of apoptotic bodies faintly visible. Three nuclei of nonapoptotic transitional cells are marked with open arrows (bottom).

	Discussion

Top Abstract Introduction Clinical Descriptions Anatomic Methods and Findings Discussion References

 
In the young woman and the five brothers who together are the basis for this report, there are similarities and differences. The most important clinical similarity is the documented ECG abnormalities, including heart block and both survivable and eventually fatal arrhythmia. All four deaths were sudden (cases 1 through 3 and 6), and the two living brothers have implanted automatic cardioverter-defibrillators, without which it seems likely they also would have died. Each of the three hearts we studied had similar abnormalities in the sinus node, internodal and interatrial pathways, and AV node, including abundant TUNEL-positive cells indicative of apoptosis. Each had some abnormal family history: in the young woman, a mother with positive antiphospholipid antibody; in the five brothers, a familial occurrence of sudden death. All were vigorously active (competitive sports and cheerleading). None had a clinical history of hypertension, diabetes, valvular disease, febrile illness, or cardiomyopathy.

There were also some important differences. The young woman had an aneurysmal left atrial appendage and an abnormally thickened small right atrial appendage, whereas the sizes and configurations of the two atria were normal in the brothers. She had bradycardia and some degree of heart block from birth, whereas the main clinical problem in the two brothers was arrhythmia, although at some time they both also exhibited some degree of heart block. Although the young woman had lifelong bradycardia and varying (gradually increasing) degrees of heart block, her clinical course was rather benign until her sudden death without warning. By contrast, the clinical course in two brothers (cases 3 and 6) could be characterized as stormy, although there were also some long relatively quiet periods.

Children born with complete heart block often die during infancy, and a variety of morphological abnormalities have been demonstrated at autopsy.^{8 9 10} These have included a lack of connection between the atria and the AV node, complete absence of the AV node, lack of connection between a demonstrated AV node and the His bundle, or discontinuity of the His bundle itself.

In South Africa, several families have been identified with progressive heart block inherited as a dominant trait. Sudden death has occurred frequently among them.^{1 2} Recent studies of these families have used linkage analysis in a search for the genetic basis of the disorder.³ Emphasis in the clinical descriptions has been placed on bundle-branch block as an essential and especially early component of the syndrome in the South African families. However, their diagnosis of bundle-branch block (which is correct) is based entirely on ECGs. Whether the morphological lesion responsible is in the bundle branches themselves has not yet been determined and needs to be analyzed from studies of fatal cases. It is possible, for example, that the entire anatomic problem resides in either the AV node or the His bundle and that the early phase of "bundle-branch block" represents more proximally located small lesions. Such an interpretation would be based on the principle of longitudinal dissociation of electrical propagation thought to be normally present in the His bundle.^{24 25}

Lupus erythematosus may damage the human cardiac conduction system in different ways,²⁶ including inflammatory lesions such as arteritis and pericarditis. None of these features was present in our cases, including case 1 in whom the mother had serological but no other clinical evidence of the antiphospholipid syndrome. However, in view of the numerous immunological responses known to trigger apoptosis,^{27 28 29} a noninflammatory immunological basis for lupus-associated apoptosis could account for our findings in that heart.

In reported reviews of the association between congenital heart block and either maternal lupus or an asymptomatic state of the antiphospholipid syndrome,^{12 13 14 15} several paradoxes exist. Many mothers of babies born with heart block are asymptomatic with lupus not only at the time of their children's birth but also for many years later. Virtually none of these babies has documented clinical features of lupus. Not all babies born to mothers with serological evidence of lupus will develop heart block. Congenital heart block occurs without clinical or serological evidence of lupus in the mother either at the time of birth or for many years later. Furthermore, although an absent AV node may have a special association with maternal lupus, it is not known how many examples of congenitally absent AV node had no such association. Finally, the true incidence of heart block that developed at any stage of gestation will probably continue to be underestimated because an unknown but possibly large number may be lost as spontaneous abortions and never be recognized as fundamentally cardiac deaths.

Almost total absence of the internodal and interatrial pathways in case 1 and a similar but less complete absence (except for Bachmann's bundle) in cases 3 and 6 warrant comment. This abnormality in association with the absence of the AV node would suggest some process of selective destruction, especially in these tissues, which are essential components of the conduction system. We were surprised to find no previous comment on or description of such selective destruction of internodal or interatrial pathway cells with conspicuous sparing of working myocardium of the atria (except for the left atrial appendage of case 1). However, we did find that one of the earliest reports of heart block and absent AV node³⁰ specifically emphasized that the entire interatrial septum was very thin. With occasional exceptions,³⁰ previous reports of absent AV nodes have not commented on the sinus node in those hearts.

In case 3, there was a well-formed pocket in the central fibrous body where the AV node should have been (Fig 10A). We believe that this is evidence that the AV node was present initially but later was gradually destroyed. Furthermore, there were foci of fetal dispersion of AV nodal cells within the central fibrous body (Figs 6A and 7), most of them undergoing quiet, noninflammatory degeneration. Our positive immunohistochemical stains (Figs 9, 13, and 14) suggest that this noninflammatory degeneration is due to apoptosis.

Some studies of other special immunological characteristics of myocytes in the heart have examined particularly the cells of the internodal pathways.^{31 32 33} Such cell surface features could explain why apoptosis (or any other immunologically mediated type of destruction) could selectively target the internodal pathways and spare the ordinary working myocardium of the atria or ventricles.

Disuse atrophy could be an explanation for the aneurysmal left atrial appendage of case 1 because any normal sinus impulse in the heart (as long as the remnants of sinus node present were capable of producing such an impulse) was precluded from reaching the left atrial appendage because Bachmann's bundle had been destroyed (Figs 5 and 11). Thus, there would be no need for additional explanation in the form of selective deletion by apoptosis in the left atrial appendage, which might have atrophied simply because it was not being stimulated. As a corollary, however, intermittent electrical activation may serve as an essential apoptosis-inhibiting influence, with an intracellular control mechanism triggering apoptosis when electrical activation no longer occurs.

The combination of right atrial hypertrophy and left atrial hypoplasia (aneurysmal) in case 1 was not present in the other two hearts. Several reports of heart block associated with absent AV node have commented on the presence of right atrial hypertrophy,^{8 13 30} although there has been no explanation as to why the right atria were hypertrophied. Numerous descriptions of aneurysmal left atrial appendages also are available, especially in the surgical literature,^{34 35 36} but no studies of the cardiac conduction systems of the same hearts are available. Except for one report describing a giant right atrial appendage (the reverse of our case 1) and diminutive left atrial appendage associated with heart block and absent AV node,³⁰ we are unaware of any reports associating heart block or absent AV node with an abnormal left atrial appendage.

When the AV node is absent, and even earlier when it is in the process of being destroyed, survival depends on either an effective escape rhythm or electronic pacing. Most of the efficient AV junctional escape rhythms probably originate near the anatomic junction of the AV node and His bundle, as experimental evidence suggests.³⁷

Both experimentally^{38 39} and in human subjects,⁷ the rate of this stable AV junctional escape rhythm bears a remarkable mathematical relationship to the rate of the sinus rhythm (Fig 1), although it may be anticipated that concomitant damage in the sinus node, as was present in our cases, would eventually distort that mathematical relationship.

The normal postnatal morphogenesis of the infant's AV node and His bundle⁴⁰ exhibits a remarkable selectivity in molding and shaping the relatively enormous His bundle of the human fetus⁴¹ into the more sharply outlined and smoothly cylindrical His bundle of the human adult heart.²² The adult anatomic configuration is probably electrically safer. But the limited and selective destruction of cells that are crucially important for cardiac conduction sometimes seems to resume in later adult life and then completely destroy both the AV node and His bundle, ending in sudden death.¹¹

It has previously been emphasized that there is almost always a powerful element of chance in the determination of exactly when sudden death happens,⁴² and the same reasoning applies to paroxysmal arrhythmia. In the present cases, for example, an apoptotic explanation would still fail to tell us why any of the deaths occurred when they did rather than during some previous clinical episode that also may have involved apoptosis. The chance concurrence of a mild fever, bowel disturbance, fright, or exercise, or any number of familiar aspects of life not ordinarily thought of in relation to sudden death, could be the added factor that makes one bout of apoptosis fatal and others not.

Both the clinical and postmortem anatomic features of our cases suggest a selectively targeted destructive process, one that is intermittently quiescent but overall is relentlessly progressive for many years. We submit that all this is best explained by apoptosis. The paradox lies in the fact that unchecked apoptosis, which is normally a process with exquisitely controlled activity that is ordinarily and purposefully beneficial, can become so destructive as to be fatal. A primary goal for future research must be to determine what these normal control mechanisms for apoptosis may be and how they could be therapeutically manipulated to ensure safety and prevent otherwise lethal outcomes.

	Acknowledgments

 
This work was supported by the Pegasus Fund of the University of Texas Medical Branch, Galveston.

Received September 12, 1995; revision received October 25, 1995; accepted November 3, 1995.

	References

Top Abstract Introduction Clinical Descriptions Anatomic Methods and Findings Discussion References

 
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11. James TN, Spencer MS, Kloepfer JC. De Subitaneis Mortibus, XXI: adult onset syncope, with comments on the nature of congenital heart block and the morphogenesis of the human atrioventricular septal junction. Circulation. 1976;54:1001-1009. [Free Full Text]

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13. Ho SY, Esscher E, Anderson RH, Michaelsson M. Anatomy of congenital complete heart block and relation to maternal anti-Ro antibodies. Am J Cardiol. 1986;58:291-294. [Medline] [Order article via Infotrieve]

14. Waltuck J, Buyon JP. Autoantibody-associated congenital heart block: outcome in mothers and children. Ann Intern Med. 1994;120:544-551. [Abstract/Free Full Text]

15. Goble MM, Dick M II, McCune WJ, Ellsworth J, Sullivan DB, Stern AM. Atrioventricular conduction in children of women with systemic lupus erythematosus. Am J Cardiol. 1993;71:94-98. [Medline] [Order article via Infotrieve]

16. Frohn-Mulder IM, Meilof JF, Szatmari A, Stewart PA, Swaak TJ, Hess J. Clinical significance of maternal anti-Ro/SS-A antibodies in children with isolated heart block. J Am Coll Cardiol. 1994;23:1677-1681. [Abstract]

17. James TN, Terasaki F, Pavlovich ER, Vikhert AM. Apoptosis and pleomorphic micromitochondriosis in the sinus nodes surgically excised from five patients with the long QT syndrome. J Lab Clin Med. 1993;122:309-323. [Medline] [Order article via Infotrieve]

18. James TN. Normal and abnormal consequences of apoptosis in the human heart: from postnatal morphogenesis to paroxysmal arrhythmias. Circulation. 1994;90:556-573. [Abstract/Free Full Text]

19. James TN. The sinus node. Am J Cardiol. 1977;40:965-986. [Medline] [Order article via Infotrieve]

20. James TN. The connecting pathways between the sinus node and A-V node and between the right and left atrium in the human heart. Am Heart J. 1963;66:498-508. [Medline] [Order article via Infotrieve]

21. Sherf L, James TN. Fine structure of cells and their histologic organization within internodal pathways of the heart: clinical and electrocardiographic implications. Am J Cardiol. 1979;44:345-369. [Medline] [Order article via Infotrieve]

22. James TN. Structure and function of the AV junction: the Mikamo Lecture for 1982. Jpn Circ J. 1983;47:1-47.

23. Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992;119:493-501. [Abstract/Free Full Text]

24. James TN, Sherf L. Fine structure of the His bundle. Circulation. 1971;44:9-28. [Abstract/Free Full Text]

25. Sherf L, James TN. QRS abnormalities in AV block: variations and their significance. In: Schlant RC, Hurst JW, eds. Advances in Electrocardiography. New York, NY: Grune and Stratton; 1972:81-103.

26. James TN, Rupe CE, Monto RW. Pathology of the cardiac conduction system in systemic lupus erythematosus. Ann Intern Med. 1965;63:402-410.

27. Duvall E, Wyllie AH. Death and the cell. Immunol Today. 1986;7:115-119.

28. Golstein P, Ojcius DM, Young JD-E. Cell death mechanisms and the immune system. Immunol Rev. 1991;121:29-65. [Medline] [Order article via Infotrieve]

29. Cohen JJ. Programmed cell death in the immune system. Adv Immunol. 1991;50:55-85. [Medline] [Order article via Infotrieve]

30. Lev M, Benjamin JE, White PD. A histopathologic study of the conduction system in a case of complete heart block of 42 years' duration. Am Heart J. 1958;55:198-214. [Medline] [Order article via Infotrieve]

31. Mandarim-de-Lacerda CA, Le Floch-Prigent P, Hureau J. Etude du tissu de conduction atrial chez l'embryon humain de 17 mm V-C: contribution morphologique a la pathogenic du dysfonctionnement du noeud sinu-auriculaire. Arch Mal Coeur Vaiss. 1985;10:1504-1509.

32. Deschesne C, Leger J, Bouvagnet P, Claviez M, Leger JJ. Fractionation and characterization of two molecular variants of myosin from adult human atrium. J Mol Cell Cardiol. 1985;17:753-767. [Medline] [Order article via Infotrieve]

33. Gorza L, Sartore S, Schiaffino S. Myosin types and fiber types in cardiac muscle, II: atrial myocardium. J Cell Biol. 1982;95:838-845. [Abstract/Free Full Text]

34. Hebert WM, Arismendi L, Ruhstaller FD, Petersen HC. Aneurysm of the left atrium associated with syncope and cyanosis. J Thorac Cardiovasc Surg. 1965;49:535-539.

35. Grinfeld R, Trainini JC, Roncoroni A, Fabrykant F, Cacheda H, Tripodi G. Congenital aneurysm of the left atrium. Ann Thorac Surg. 1984;39:469-471. [Abstract]

36. Amato JJ, Sewell DH, Rheinlander HF, Cleveland RJ. Congenital aneurysm of the left atrium with associated defects in the fibrous skeleton of the heart. J Thorac Cardiovasc Surg. 1975;69:639-643. [Medline] [Order article via Infotrieve]

37. James TN, Isobe JH, Urthaler F. Correlative electrophysiological and anatomical studies concerning the site of origin of escape rhythm during complete atrioventricular block in the dog. Circ Res. 1979;45:108-119. [Abstract/Free Full Text]

38. Urthaler F, Katholi CR, Macy J Jr, James TN. Mathematical relationship between automaticity of the sinus node and the AV junction. Am Heart J. 1973;86:189-195. [Medline] [Order article via Infotrieve]

39. Urthaler F, Katholi CR, Macy J Jr, James TN. Electrophysiological and mathematical characteristics of the escape rhythm during complete AV block. Cardiovasc Res. 1974;8:173-186. [Medline] [Order article via Infotrieve]

40. James TN. Sudden death in babies: new observations in the heart. Am J Cardiol. 1968;22:479-506. [Medline] [Order article via Infotrieve]

41. Keith A, Flack MW. The auriculo-ventricular bundle of the human heart. Lancet. 1906;2:359-364.

42. James TN. Chance and sudden death. J Am Coll Cardiol. 1983;1:164-183.[Abstract]

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