The protean nature of Whipple's disease includes multiorgan arteriopathy.

Knowledge about the arterial abnormalities in Whipple's disease can be useful for our better understanding of both Whipple's disease and the more general question of pathogenesis of atherosclerosis. There are several notable morphological features of Whipple's arteriopathy. First, it appears to involve primarily arteries one millimeter or less in diameter. Second, there is very little evidence of inflammation accompanying invasion of any or all three layers of the walls of affected arteries, and there is almost no evidence of local attraction of platelets to these sites of arterial injury. Third, the nature of arterial injury appears to be one of slow progression. The few sites of actual arteritis are most likely attributable to some other coinciding microbial organism not yet identified. Although the arteriopathy in Whipple's disease is seen mainly in small arteries (the aorta is a notable exception), their significance can be illustrated by consideration of this fact as it applies to the coronary circulation (and probably the arteries of all other organs). In the heart these small arteries comprise almost the entire collateral circulation, the principal blood supply to each component of the conduction system, and most pragmatically, these small arteries represent the terminal distribution of every larger epicardial artery. Small arteries are important. The "cardiomyopathy" so often a feature of Whipple's disease (very much including his original case) is most logically attributable to recurring bouts of focal ischemia and subsequent focal fibrosis ending in myocardial incompetence. However, direct bacillary invasion of cardiac myocytes (22) also occurs. In lamina propria of jejunum, there is also arteriopathy, as there is in brain, lung, kidney, spleen, liver, gall bladder, rectum, stomach, lymph nodes and testis. It is likely that no organ in the body is spared. There is growing evidence that a wide variety of chronic infections (occurring concomitantly or sequentially) may participate in the early pathogenesis of human arterial disease, including atherosclerosis. Given that the coronary plaque represents the cumulative end result of countless earlier injuries and responses, the plaque is not the site to seek evidence of initial pathogenesis although understanding the behavior of coronary plaques is eventually of considerable clinical importance. In the context of original events in pathogenesis, the Whipple bacillus now deserves inclusion in the "total pathogen burden" concept, as it relates not only to coronary disease but to all aspects of atherosclerosis and even other forms of arteriopathy.

On the wide spectrum of abnormalities in the coronary arteries of Whipple's disease.

BACKGROUND: There is growing interest in the role of microbes in the pathogenesis of coronary atherosclerosis but most of the evidence has been seroepidemiologic. It would be useful to know more about the cytology and histology of coronary lesions containing clearly depicted microbes. OBJECTIVE: To define carefully the assorted abnormalities apparent in the coronary arteries of individuals dying with Whipple's disease. METHODS: Myocardial tissue from 12 cases of Whipple's disease was studied by light microscopy. Slides were stained routinely (in sequence) with either the periodic-acid-Schiff (PAS) or Goldner-trichrome method and some with Gomori methenimine silver. Cardiac slides with PAS-positive bacilli were compared to lesions in jejunal lamina propria. RESULTS: There were abundant sites of coronary arterial damage associated with presence of Whipple bacilli, more in the tunica media than in intima and adventitia. Bacilli in the arterial lesions were identical to those in lamina propria. Medial lesions were often associated with a fibroproliferative 'atheroma'. Both intracellular and extracellular bacilli were found. Most lesions were devoid of inflammation, but some sites exhibited either florid arteritis or dense scarring. Arteries that were scarred or inflamed exhibited only a few bacilli. There was an apparent affinity of bacilli for the nuclei in medial smooth muscle cells and in nearby ventricular myocytes. Apoptosis (TUNEL-positive) was present in medial smooth muscle cells, endothelial cells, and ventricular myocytes. CONCLUSIONS: There is a wide spectrum of coronary abnormalities in Whipple's disease. It would be useful to know how often the Whipple bacillus is a part of the total pathogen burden in coronary disease.

Morphological patterns of death by myocytes in arrhythmogenic right ventricular dysplasia.

There are two forms of nuclear loss from eukaryotic cells: biochemical DNA degradation in apoptosis and nuclear extrusion from the cell body as seen in mammalian erythroblasts. In biopsies of right ventricular myocardium from 8 patients with arrhythmogenic right ventricular dysplasia (ARVD), we found not only a terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick-end labeling (TUNEL)-positive nucleus in mononuclear myocytes, but also 1 or 2 TUNEL-positive nuclei in multinuclear myocytes. With electron microscopy, we found a nuclear dislocation to the cell periphery, followed by its extrusion into the extracellular space. Both the migration and extrusion of the nuclei of myocytes resemble the morphogenesis of human erythroblasts. Nuclear extrusion from myocytes may be another form of programmed cell death. In support of this possibility, we also found evidence of cytoplasmic degradation in right ventricular myocytes from our ARVD cases, a process similar to one often seen in developmental programmed cell death and differing from typical nuclear apoptosis. In our ARVD cases, we thus found several different patterns of cell death, all associated with initial preservation of the plasmalemma and avoidance of local inflammation. All these features may be different responses to common signals for selective non-necrotic (apoptotic) death of right ventricular myocytes.

Prevalence of dyslexia among Texas prison inmates.

Approximately 80% of prison inmates are reported to be functionally illiterate. We hypothesized that poor single word decoding (the chief feature of dyslexia) accounts for a significant percentage of that rate. We studied 253 subjects selected randomly from more than 130,000 Texas prison inmates. Among them, we conducted a cross-sectional sample survey of recently admitted Texas inmates, beginning with social and educational background and followed by an educational test battery that included measures of word attack skill and reading comprehension. Deficient performance was defined primarily as single word decoding performance that measured below the 25th percentile on the Woodcock Reading Mastery Test. We found that 47.8% of the inmates were deficient in word attack skills. Word attack skills were detected in each group defined by gender and ethnicity. Nearly two thirds of the subjects scored poorly in reading comprehension.

On the nature of cell death during remodeling of hypertrophied human myocardium.

Cardiocyte loss during myocardial hypertrophy leads to progressive dysfunction in human hearts with chronic hemodynamic overload. The mechanism for such cell elimination is unknown. We examined lysosomal participation in cardiocytic degradation present in human cardiac biopsies, utilizing electron microscopic cytochemistry (acid phosphatase). Lysosomes were significantly increased in number (t-test, P<0.001) in 50 hemodynamically overloaded hearts (375+/-69, mean+/-s.e.m., per 5,000 microm(2) cardiocytic area; eight controls, 38+/-11). Secondary lysosomes were prominent near degenerative intracellular organelles in both hypertrophic and atrophic cardiocytes. Increased lysosomal and phagocytic activity in the cytoplasm without typical nuclear apoptosis resembled cytoplasmic degradation in developmental programmed cell death described in different tissues. We also demonstrated cardiocytic DNA degradation (in situ nick-end labeling) in autopsy hearts, including 299 nuclei normalized per 10(6) observed nuclei from five concentrically hypertrophied hearts, 1961 nuclei from five eccentrically hypertrophied hearts, and no positive nuclei in five controls. We postulate a chronic self-controlled cytoplasmic proteolysis in cardiocytes, not initially associated with either nuclear degradation or intercellular dehiscence but later possibly accompanied by apoptotic nuclear elimination, and leading to apoptotic cell death.

The tendons of Todaro and the "triangle of Koch": lessons from eponymous hagiolatry.

INTRODUCTION: There is growing use of the Todaro tendon and triangle of Koch as anatomic icons for invasive cardiac electrophysiologists. Reasons exist to doubt this validity. METHODS AND RESULTS: Histologic sections were prepared from 96 anatomically normal human hearts. The study area extended from the crista supraventricularis to the eustachian valve and included the AV node and His bundle. This encompasses any tendon of Todaro. Because the purported triangle of Koch includes the tendon of Todaro, all of Koch's available publications were examined. The tendon of Todaro is absent in only one fourth of infant hearts, but in two thirds of adult hearts. Tendons present were less often single than double or more, rarely exceeded 4 mm in length, and were seldom > 1 mm in diameter. Tendons usually originated from the central fibrous body and ended in the eustachian valve. Their origin most often was over the His bundle or its junction with the AV node, rather than the AV node. Tendons were primarily composed of collagen. Koch never described any triangle or acknowledged existence of tendons of Todaro. CONCLUSION: Todaro tendons are too often absent (or multiple) to warrant use as anatomic landmarks. Without this side of the supposed triangle of Koch, the entire tendon and triangle concept collapses and should be abandoned. There are numerous far more constant anatomic landmarks available to orient one to the human AV node and His bundle; these are briefly reviewed.

The variable morphological coexistence of apoptosis and necrosis in human myocardial infarction: significance for understanding its pathogenesis, clinical course, diagnosis and prognosis.

BACKGROUND: Myocardial infarction includes both apoptosis and necrosis, but little is known of the morphological relationship of these two different forms of cell death in the human heart, despite the possibility that this may have clinical importance. METHODS: Hearts from 77 cases of fatal myocardial infarction were examined. Twelve morphologically representative hearts were selected for immunohistochemical staining to define in detail the histology and cytology of apoptotic areas. RESULTS: Both apoptosis and necrosis were present in every heart. Necrotic myocytes quickly disintegrate and evoke acute inflammation. Apoptotic myocytes retain their membrane integrity and do not evoke acute inflammation. Phagocytosis of apoptotic cells and apoptotic bodies occurred with engulfment by either neighboring myocytes or macrophages, but predominantly the latter. In many apoptotic areas, the phagocytic capacity was overwhelmed, resulting in large pools of apoptotic bodies lying free in the extracellular space. CONCLUSIONS: Because apoptotic cells retain their membrane integrity, enzymatic diagnosis of myocardial infarction that is due to necrosis. Measurement of any intracellular enzyme consequently always underestimates the extent of myocardial infarction, often by a large margin. Morphological progression of cell death in myocardial infarction, from apoptosis to necrosis, may depend upon exceeding the local capacity for phagocytosis of apoptotic cells. However, cells dying by either apoptosis or necrosis are equally dead. There is a need for better definition of the role of apoptosis in myocardial hibernation (or stunning), in ischemic preconditioning and in the pathogenesis of silent angina, and post-myocardial infarction remodeling.

Intracellular distribution of adenylate cyclase in human cardiocytes determined by electron microscopic cytochemistry.

Subcellular localization of adenylate cyclase (AC) in human cardiocytes was studied by electron microscopic cytochemistry using ventricular biopsies from various diseased hearts. In addition to the weak enzyme activity on the sarcolemma, the intense reaction products of AC were demonstrated within distinctive morphologic components of sarcoplasmic reticulum, nuclear envelope, and other internal membranes such as parallel lamellar structures and interlaced tubular structures in the perinuclear regions and stacked membranous structures beneath sarcolemma in cardiocytes. The distribution and intensity of cytochemical activity within different organelles was variable among biopsy cases. The reaction products of AC cytochemistry within the sarcoplasmic reticulum could be related to signal transduction targeting Ca2+ handling by the organella. Cytochemical activity within the nuclear envelope and perinuclear internal membranes possibly reflects AC participation in a signal function to regulate nuclear activity, such as gene expression. Cytochemical distribution of the enzyme in membranous structures beneath the sarcolemma is most likely related to hormone receptors and the linked activity of AC. The subcellular distribution of AC on various internal membrane structures in cardiocytes may reflect compartmentalization of the enzyme at individual intracellular sites to regulate a preferential specific signal function among multiple potential signal transductions by a cascade of AC, cyclic AMP, and cyclic AMP-dependent protein kinase. Alternatively, subcellular localization of the reaction products may reflect local enzyme synthesis or represent sites of enzyme transport, e.g., to terminal localization beneath the sarcolemma.

Normal and abnormal consequences of apoptosis in the human heart.

Knowledge about apoptosis has become essential for understanding many aspects of cardiac structure and function. In the human heart there are major periods of morphogenesis that begin only after birth, and some of these processes recur intermittently for many years. Although the exact mechanisms by which these events are initiated or terminated remain poorly understood, it is clear that their benefits may be mirrored in destructive effects. In this review, selected examples include normal morphogenesis of the cardiac conduction system and the normal postnatal involution of the right ventricle, both of which are mediated by apoptosis. Destructive counterparts include familial heart block ending in fatal arrhythmias, similar results in the long QT syndrome, and the pathogenesis of both Uhl's anomaly and arrhythmogenic right ventricular dysplasia; in each apoptosis is an important factor.

Complex causes of fatal myocardial infarction.

It is too often deduced that myocardial infarction is due to coronary occlusion and that subsequent death needs no other explanation. But the great majority of myocardial infarctions are not fatal, whether treated or untreated. There is, of course, some relation to the size of the infarct and the presence or absence of complicating conditions such as diabetes mellitus or hypertension, but little attention has been directed at the myriad of other events and processes influencing the clinical course. Examples include the exact anatomic territory infarcted and whether it includes the sinus node or AV node or important neuroreceptors; whether many small arteries are occluded (especially downstream of narrowed main coronary branches); whether the heart is hypertrophied, dilated, infected, or infiltrated; and whether there may be intracardiac, extracardiac, or intracranial neuropathological conditions that could destabilize cardiac electrical activity. It is now known that apoptosis plays a major role in myocardial infarction or ischemia, but it also occurs within the heart completely independently of infarction. There is also the vexing dilemma that an effective coronary collateral circulation, which is determined primarily by transanastomotic pressure gradient, is made less effective by exactly those treatments that reestablish flow in an occluded coronary artery. Since thrombolysis and angioplasty are automatically considered urgent treatment for an occluded coronary artery, it is prudent to remember the complex causes that determine whether the patient lives or dies.

Apoptotic myocardial degeneration in thrombotic thrombocytopenic purpura.

The objective of this study was to determine whether the known myocardial degeneration in TTP is due to apoptosis. In TTP the heart is often involved, including the cardiac conduction system. Despite many platelet occlusions of small coronary arteries, there is little myocardial necrosis. Why the intermittent clinical episodes begin or end is unknown. Six hearts of patients dying with TTP were examined with routine and immunohistochemical stains. In addition to ventricular and atrial myocardium we examined the cardiac conduction system and coronary chemoreceptor. Numerous small coronary arteries were occluded with platelet thrombi in all these sites, including especially the sinus node, AV node and His bundle. The myocardial degeneration we found was conspicuously devoid of inflammation and the myocytes were relatively intact. These characteristics combined with TUNEL-positivity in the degenerating cells are typical of apoptosis. The focal degeneration in TTP is primarily apoptotic. Because circulating serotonin is carried by platelets and is released during aggregation, and because serotonin can cause a powerful cardiogenic hypertensive chemoreflex, we suggest that such a response may dislodge early platelet aggregations. Lessons from TTP may have special relevance for better understanding of myocardial reperfusion problems associated with angioplasty, thrombolysis and ischemic preconditioning.

Spontaneous death of isolated adult rat cardiocytes in culture in association with internucleosomal cleavage of genomic DNA.

Many isolated adult cardiocytes do not survive beyond the early days of culture, but why they die has not been defined. We examined the possibility of apoptosis as the mechanism of death in cultured atrial and ventricular rat cardiocytes. Calcium-tolerant cardiocytes isolated by enzymatic dissociation were cultured with a medium containing FBS. Nucleosomal DNA fragmentation was detected by electrophoresis of DNA extracted from the cardiocytes, by immunohistochemical in situ DNA nick-end labelling of single cells, and by enzyme immunoassay for in vitro quantification in cytoplasmic fraction. Electrophoresis on the 5th to 14th day of culture revealed the ladder appearance characteristic of internucleosomal DNA cleavage in apoptosis with a consistent single peak of increased cytoplasmic DNA fragments. After the 14th day, the cytoplasmic DNA fragments decreased, and the ladder appearance could no longer be detected by electrophoresis. Cardiocytes positive with nick-end labelling were seen by the 5th day, and then increased in number over the remaining days. These results indicate that many isolated cardiocytes die spontaneously by apoptosis within the first 2 weeks of culture, suggesting a possible signal dependence for survival of adult cardiocytes. In addition to chemical signal depletion in culture, other possible explanations for this apoptosis include the absence of an electric signal during culture, lack of contractile activity, and initial loss of intercellular connections.

Apoptosis in congenital heart disease.

Morphogenesis in the human body is mediated to an important, but not exclusive, extent by apoptosis. That this is true in the heart is illustrated by primary pulmonary hypertension, which includes medial degeneration in both coronary and pulmonary arteries, normal and abnormal postnatal involution of the right ventricle, familial progressive heart block ending in fatal arrhythmias, and the long QT syndrome. Apoptosis occurs in ventricular myocardium, specialized myocytes of the conduction system, endothelium and medial smooth muscle of small arteries, cardiac nerves and ganglia and fibroblasts. The normal onset, duration and termination of apoptosis act beneficially. If apoptosis fails to occur or is too long continued, the result is harmful. Little is known of the signals controlling apoptosis in the human heart. Future research into these questions may radically change many of our present concepts of congenital heart disease.

Long reflections on the QT interval: the sixth annual Gordon K. Moe Lecture.

This review of accumulated knowledge about the long QT syndromes begins with an iteration of the original papers and then proceeds to a broader historic reflection that includes my personal work as well as many studies by others. Next come reflections upon the current status of knowledge on the subject, combined with comments about remaining challenges and questions grouped as follows: (1) morphologic abnormalities of the cardiac conduction system and their pathophysiologic significance in the long QT syndromes; (2) cardioneuropathy in the pathogenesis of long QT syndromes; (3) variability of QT prolongation, including consideration of peripheral and central dysautonomic conditions with certain diagnostic and therapeutic implications; (4) some caveats about the popular use of left cervical sympathectomy to treat symptomatic individuals with long QT syndrome, emphasizing hazards for future electrical instability of the heart; (5) consideration of genetic influences in the long QT syndromes, a field holding great promise as well as fraught with many puzzling dilemmas; and (6) apoptosis and the pathogenesis of the long QT syndromes, based upon personal observations previously made with electron microscopic studies of the sinus node and now including new immunohistochemical evidence expanding the relevance of this novel view-point. These intentionally provocative presentations are made to stimulate physicians and other scientists to consider these several different perspectives in planning future studies aimed at better understanding of one of the most challenging medical entities facing cardiology today.

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.

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.

Generation of new intercellular junctions between cardiocytes. A possible mechanism compensating for mechanical overload in the hypertrophied human adult myocardium.

Intercellular dehiscence is a common cardiocytic response to pathological conditions. However, little consideration has been given to the possibility of new intercellular junctions developing between cardiocytes within developed myocardium. To examine this possibility as it may relate to useful compensation for hemodynamic overloads, changes in cardiocytic connection were evaluated by scanning electron microscopy in hypertrophied myocardium of adult human hearts. Transmural myocardium of left ventricle was obtained at autopsy from five hearts with concentric hypertrophy, five hearts with eccentric hypertrophy, and five control hearts (noncardiac death). After formalin fixation, the number of cardiocytes connected to an individual cardiocyte was counted in tissues from the middle portion of the transmural samples by scanning electron microscopy. Cardiocytic diameter and connective tissue volume fraction were measured on the transmural sections by light microscopy. In concentrically hypertrophied hearts present both increased cardiocytic diameter and connective tissue volume fraction, the number of other cardiocytes connected to an individual cardiocyte (4.60 +/- 0.10 [mean +/- SE] was significantly increased (P < .05) compared with control hearts (4.19 +/- 0.12) or eccentrically hypertrophied hearts (4.11 +/- 0.10). The increase in junctions per cardiocyte in concentrically hypertrophied hearts suggests that new connections had been generated. More junctions developing during hypertrophy could add another structural advantage to those of cardiocytic hypertrophy and connective tissue proliferation as compensatory adjustments to hemodynamic overload in concentrically hypertrophied hearts.