Marcel Borgers

Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function.

BackgroundStudies done in potential donors for heart transplantation and in experimental animals have suggested that brain death can have major histopathological and functional effects on the myocardium. Methods and ResultsWe developed experimental models of brain death using dogs to study the hemodynamic and catecholamine changes, the extent of myocardial structural damage, and the recovery potential of donor hearts obtained from brain-dead donors. Brain death was caused by increasing the intracranial pressure (ICP) suddenly or gradually by injecting saline in an epidural Foley catheter. In a first series of experiments, dogs given a sudden rise in ICP (n=5) showed a hyperdynamic response and a 1,000-fold increase in the level of epinephrine after brain death. Histology revealed 93±2% of the myocardium to be severely ischemic. Dogs given a gradual rise in ICP (n=6) showed a lesser hyperdynamic response, almost 200-fold increase in the level of epinephrine after brain death, and mild ischemic damage to the myocardium (23±1%). In a second series, hearts obtained from brain-dead and non-brain-dead donors were transplanted in recipients, and the weaning and recovery potential were studied. All four recipients with hearts from non-brain-dead donors were weaned with good functional recovery. Also, all four recipients with hearts from brain-dead dogs given a gradual rise in ICP were weaned with only moderate functional recovery. However, only two of four recipients with hearts from donors given a sudden rise in ICP were weaned and showed poor functional recovery. ConclusionsOur results indicate that a sudden rise in ICP can cause irreversible myocardial damage.

Histological alterations in chronically hypoperfused myocardium. Correlation with PET findings.

BackgroundIn patients with chronic coronary artery disease (CAD) and left ventricular dysfunction, flow/metabolic studies of the myocardium with positron emission tomography (PET) are able to distinguish viable but dysfunctional myocardium from irreversible ischemic injury and scar tissue. In this study, PET findings of blood flow and metabolism in chronically hypoperfused myocardium were correlated with histology. Methods and ResultsWe studied 33 patients suffering from CAD. In each patient, myocardial blood flow and metabolism were measured with PET 1 or 2 days before revascularization. During surgery, transmural biopsies were taken from the left ventricular anterior wall and planimetrically scored for the degree of myolysis (sarcomere loss). The amount of connective tissue was calculated using morphometric techniques. Contrast ventriculography demonstrated abnormal wall motion in 23 patients. Fourteen patients with a mismatch pattern (decreased flow with preserved metabolism) in the biopsy region after quantitative analysis of the PET data showed 11±6 vol% fibrosis and 25±13% cells with sarcomere loss. The space formerly occupied by sarcomeres was mainly replaced by glycogen and mitochondria. A significant wall motion improvement was noted 3 months after surgery. Nine patients showed a match pattern (concordant flow/metabolism defects). The biopsies revealed 35±25% fibrosis and 24±15% glycogen-storing cells. The biopsies of the 10 patients with normal anterior wall motion showed 8±4% fibrosis and 12±8% glycogen-accumulating cells. ConclusionsIt can be concluded that areas with impaired wall motion and a PET match pattern show extensive fibrosis. Regions with reduced flow and preserved FDG metabolism, however, contain predominantly viable cells. In these regions, significant recovery of wall motion is found after revascularization. Regions with normal wall motion contain predominantly viable cells. Cells with reduced contractile material and increased glycogen content are mainly found in areas with wall motion impairment but are also present in areas with normal wall motion and a severe stenosis of the coronary vessel.

Relation between coronary artery stenosis and myocardial purine metabolism, histology and regional function in humans

In 54 patients undergoing elective or emergency aortocoronary bypass grafting, angiographic and electrocardiographic changes were studied. Five patients with unstable angina and five patients with evolving myocardial infarction were included. High energy phosphate metabolism and the histologic appearance of the myocardium were analyzed in transmural biopsy specimens acquired at the time of surgery. In patients without anterior infarction on the electrocardiogram, severe stenosis of the left anterior descending coronary artery resulted in a reduction of anterior wall motion that was associated with a partial depletion of the adenylate pool. Mitochondrial function, however, remained intact: the adenosine diphosphate/adenosine triphosphate ratio, the energy charge and the creatine phosphate/adenosine triphosphate ratio were in the normal range. Histologic assessment demonstrated viable myocardium with a high incidence of atrophic cells. In evolving myocardial infarction, 170 minutes of acute coronary artery obstruction resulted in anterior wall akinesia associated with a decrease of the sum of the adenylates to 52% and of creatine phosphate to 16% of their normal value (p less than 0.05). The nucleosides accumulated; their major fraction (91%) was inosine. The adenosine diphosphate/adenosine triphosphate ratio increased from 0.14 +/- 0.04 to 0.49 +/- 0.20 (p less than 0.01) and the energy charge decreased from 0.924 +/- 0.021 to 0.660 +/- 0.169 (p less than 0.01). Ultrastructure examination revealed irreversible cell damage in at least the subendocardial layer. These results suggest that the energetic base of reduced contractility due to severe coronary artery stenosis is different from that in acute coronary obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Pityriasis versicolor and Pityrosporum ovale. Morphogenetic and ultrastructural considerations.

ABSTRACT: Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) have been performed on skin material of patients with pityriasis versicolor who were orally treated with itraconazole. Before an well as after therapy, variously sized spherical structures were observed on the surface of the keratinocytes with SEM. TEM examination revealed Pityrosporum ovale, predominantly in its mycelial phase, inside keratinocytes. The spherules as observed by SEM appeared to be amorphous, lipid‐like droplets originating from the inside of the keratinocytes. The cytoplasm of the keratinocytes was at least partly occupied by the same amorphous material. It is therefore suggested that P. ovale penetrates the keratinocyte where degradation of the normal keratinous content to amorphous material takes place. This newly formed lipidic substrate may be an essential nutritive factor. The lipidified Stale of the stratum corneum persisted for at least 3 weeks after eradication of the fungus by itraconazole. It is speculated that the presence of large quantities of this lipid‐like material might be the cause of hypopigmentation because it may constitute an ultraviolet light block.

Calcium uptake by the sarcoplasmic reticulum, high energy content and histological changes in ischemic cardiomyopathy

OBJECTIVES Sarcoplasmic reticulum (SR) Ca2+ uptake, myocardial high energy content and histology were examined in different zones of hearts from patients with ischemic cardiomyopathy. METHODS AND RESULTS Unfractionated homogenates were prepared from left ventricular samples obtained in three zones of each heart: an infarct-remote zone, an outer peri-infarct zone, and an inner peri-infarct zone. Oxalate-supported 45Ca2+ uptake was measured at 37 degrees C using a filtration method. Maximum rate (Vmax) of uptake in absence or in presence of ryanodine was lower in inner peri-infarct (7.4 +/- 0.7 and 9.5 +/- 0.8 nmol min-1 mg-1 of protein, respectively; mean +/- SEM) and outer peri-infarct tissues (8.8 +/- 0.8 and 12.0 +/- 0.8 nmol min-1 mg-1) than in infarct-remote myocardium (12.7 +/- 2.1 and 15.8 +/- 2.2 nmol min-1 mg-1). The apparent affinity constants for Ca2+ (KCa) as well as the Hill coefficients were not different. Homogenate DNA (1.6 +/- 0.1, 1.6 +/- 0.1 and 1.7 +/- 0.1 mg/g of remote, inner peri-infarct and outer peri-infarct myocardium, respectively) and adenine nucleotides contents (ATP: 15 +/- 1.3, 14 +/- 0.8 and 15 +/- 1.0 mumol/g dry weight, respectively) were similar in all tissues. Fibrosis was increased in inner peri-infarct tissue (37 +/- 6%; vs. 13 +/- 2% and 12 +/- 2% in both remote and outer peri-infarct tissues, respectively), but the number of abnormal cells was not significantly different. CONCLUSION The decrease of Ca2+ uptake in ischemic cardiomyopathy is not homogeneous in the ventricular wall, and reflects a decreased number/activity of SR Ca(2+)-ATPase, without altered Ca(2+)-affinity or increased Ca2+ leakage through ryanodine receptors.

Myocardial Viability: Stunning and Hibernation

Myocardial stunning is defined as a transient postischemic myocardial dysfunction, occurring during full reperfusion after a short episode of non-lethal ischemia. This phenomenon was first recognized by Heyndrickx et al.1 and termed “myocardial stunning” by Braunwald and Kloner.2 The initial description of stunning i.e. a total coronary occlusion of only 5 to 15 minutes that was not associated with detectable myocardial necrosis, resulted in impairment of ventricular systolic function that lasted for several hours following reperfusion. Since then, myocardial stunning has been demonstrated experimentally under a variety of conditions and in many different animal species. Several of these conditions become extremely important for a better understanding of the clinical relevance of myocardial stunning. At first there is the problem of “peri-infarction stunning”. It has been well established that during prolonged coronary artery occlusion only a variable fraction of the area at risk will become necrotic.3 A “border zone” of myocardial tissue, adjacent to necrotic myocardium will survive mainly due to collateral flow, and myocardial stunning can be demonstrated in this border zone after delayed reperfusion of the blocked vessel.4Therefore, the akinetic area related to infarction can easy be overestimated in the early reperfusion phase: at this stage differentiation between viable and necrotic tissue cannot be made on the basis of regional function studies alone. Second, not only regional ischemia will result in stunning upon reperfusion but also global ischemia or anoxia. This finding has important implications because it explains why hearts of patients undergoing cardiac surgery are very often dysfunctional in the early period of reperfusion after cross clamping of the aorta despite cardioplegic protection. A third important circumstance under which stunning can be demonstrated is that stunning also occurs in the presence of partial coronary stenosis instead of complete occlusion followed by reperfusion.5 Obviously relative ischemia due to imbalance between oxygen supply and demand can induce stunning as well as a complete occlusion of the coronary vessel. This observation is important because it explains why transient coronary spasm may result in regional myocardial dysfunction.