Biomedical subjects

M Borgers

Publications and source records attributed to M Borgers.

At least 73 records · Page 4Linked to original sources

PubMed1997

Correlation of functional recovery with myocardial blood flow, glucose uptake, and morphologic features in patients with chronic left ventricular ischemic dysfunction undergoing coronary artery bypass grafting.

OBJECTIVE: Our objective was to investigate the influence of preoperative myocardial ultrastructure and metabolism on recovery of contractile function after coronary artery bypass grafting in patients with coronary artery disease and left ventricular dysfunction. METHODS: Dynamic positron emission tomography with 13N-ammonia and 18F-deoxyglucose was used to assess myocardial perfusion and glucose uptake in 53 patients scheduled for coronary revascularization because of coronary artery disease and left ventricular dysfunction. The degree of tissue fibrosis and the presence of potentially reversible alterations of cardiomyocytes (loss of myofilaments and accumulation of glycogen) were quantified from transmural biopsy specimens. These were harvested from the center of the dysfunctional area during the operation and analyzed with a light microscope. The recovery of contractile performance was assessed from the changes in left ventricular function at contrast ventriculography or echocardiography before and 6 months after the operation. RESULTS: According to postoperative changes in regional wall motion, left ventricular function was considered to have improved in 34 patients, whereas dysfunction persisted in 19 patients. In patients with improved wall motion, ejection fraction rose by 12% and end-systolic volume decreased by 28%. By contrast, in patients with persistent dysfunction, ejection fraction decreased by 6% and end-systolic volume increased by 25%. Before revascularization, myocardium with reversible dysfunction displayed higher levels of absolute myocardial blood flow, higher myocardial glucose uptake, less tissue fibrosis, and more altered cardiomyocytes than myocardium with persistent dysfunction. Significant correlations were found between regional blood flow and the surface of the biopsy specimen covered by fibrosis, as well as between glucose uptake and the density of altered cardiomyocytes. CONCLUSION: In patients with left ventricular ischemic dysfunction, the recovery of regional and global left ventricular function after surgical revascularization is associated with higher preoperative blood flow and glucose uptake, with less tissue fibrosis and a higher amount of viable cardiomyocytes in the dysfunctional area. The current study thus confirms the value of noninvasive preoperative metabolic imaging for identification of residual viable myocardium and for prediction of the functional outcome after revascularization.

Adult↗

PubMed1997

Intrahepatocellular erythrocyte inclusions and increased calcium precipitation in canine endotoxic shock.

AIMS: To investigate the electron microscopic localization of membrane-bound and exchangeable calcium with specific calcium precipitation techniques during endotoxic shock in the dog. METHODS: Ten pentobarbital anesthetized, mechanically ventilated, and paralyzed dogs were studied. Six dogs received 2 mg/kg E. coli endotoxin i.v. followed by a continuous 0.9% saline infusion to restore and maintain baseline cardiac filling pressures. Four dogs served as time-matched controls. Each experiment lasted for 3 h. After the completion of study, the livers of four endotoxic and two control dogs were fixed by perfusion of 3% glutaraldehyde via the portal vein. Liver sections were then prepared for electron microscopy and calcium localization studies. RESULTS: Hepatocytes of endotoxic animals completely lost their plasma membrane-bound calcium. The most severely damaged cells showed extensive "blebbing" of the plasma membrane and contained numerous cytoplasmic erythrocyte inclusions. Endotoxin administration also caused excessive calcium precipitation inside hepatocytes in areas with pronounced sinusoidal damage. CONCLUSIONS: In this acute model of fluid-resuscitated endotoxic shock in dogs, the use of specific calcium localization techniques enables the demonstration of disturbances in hepatocellular calcium handling, which appear to be closely related to structural alterations of the hepatocyte cell membrane. Erythrocyte uptake by hepatocytes is a previously undescribed phenomenon in canine endotoxic shock and may serve as an additional histologic marker of ultrastructural cell (membrane) damage.

Animals↗

PubMed1997

125I-Tyr0-hCRH labelling characteristics of corticotropin-releasing hormone receptors: differences between normal and adenomatous corticotrophs.

The presence of corticotropin-releasing hormone (CRH) receptors has been previously demonstrated in corticotrophs from normal pituitaries using a method combining immunocytochemistry and liquid emulsion autoradiography. The aim of this study was to compare the characteristics of the 125I-Tyr0-hCRH binding in corticotrophs from normal pituitaries (three obtained at autopsy and one obtained at surgery) with corticotrophs from pituitary adenomas (six corticotroph adenomas responsible for Cushing's disease and two silent corticotroph adenomas secreting a biologically inactive ACTH molecule). In normal corticotrophs, the larger part of the 125I-Tyr0-hCRH binding was localised in patchy conglomerates at the centre of the cell and, to a much lesser degree, in a diffuse pattern at the cell periphery. In adenomatous corticotrophs, CRH receptor expression is disturbed both quantitatively and qualitatively. Except for a minority of cells in one adenoma, all adenomatous corticotrophs showed only peripherally bound 125I-Tyr0-hCRH and no centrally localised binding. Furthermore, adenomatous corticotrophs revealed a statistically significant lower signal intensity when compared to normal corticotrophs and a strongly negative correlation was found between the labelling area in adenomatous corticotrophs and both the basal and CRH-stimulated plasma ACTH levels. These findings suggest defective processing of CRH receptors and could be relevant to the sustained ACTH secretion by adenomatous corticotrophs in Cushing's disease and, more generally, provide an explanation to its pathology. The silent corticotrophs secreting a biologically inactive ACTH molecule were characterised by a very faint signal intensity, although present on almost every cell.

Adenoma↗

PubMed1997

Assessment of myocardial viability in chronic coronary artery disease using technetium-99m sestamibi SPECT. Correlation with histologic and positron emission tomographic studies and functional follow-up.

OBJECTIVES: The value of 99mTc-sestamibi (2-methoxy-isobutyl isonitrile [MIBI]) as a viability tracer was investigated in patients undergoing coronary artery bypass graft surgery. BACKGROUND: Initial studies claim that rest MIBI single-photon emission computed tomographic (SPECT) studies can be used to assess myocardial viability. METHODS: Thirty patients with a severely stenosed left anterior descending coronary artery and wall motion abnormalities were prospectively included. The patients underwent a MIBI rest study, a positron emission tomographic (PET) flow (13NH3) and metabolism (18F-deoxyglucose) study and nuclear angiography before undergoing bypass surgery. A preoperative transmural biopsy specimen was taken from the left ventricular anterior wall. Morphometry was performed to assess percent fibrosis. After 3 months, radionuclide angiography was repeated. RESULTS: Statistically significant higher MIBI values were found in the group with myocardial viability as assessed by PET than in the group with PET-assessed nonviability (p < 0.01). Significantly higher MIBI values were found in the group with enhanced contractility at 3 months (76 +/- 13% vs. 53 +/- 22%, p < 0.01). A linear relation was found between MIBI uptake and percent fibrosis in the biopsy specimen (r = 0.78, p < 0.00001). When maximizing the threshold for assessment of viability with MIBI by using functional improvement as the reference standard, a cutoff value of 50% was found, with positive and negative predictive values of 82% and 78%, respectively. CONCLUSIONS: 99mTc MIBI uptake was significantly higher in PET-assessed viable areas and in regions with enhanced contractility at 3 months. A linear relation was found between percent fibrosis and MIBI uptake. An optimal threshold of 50% was found for prediction of functional recovery.

Ammonia↗

PubMed1997

Protection with lubeluzole against delayed ischemic brain damage in rats. A quantitative histopathologic study.

BACKGROUND AND PURPOSE: Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vulnerable brain areas. Lubeluzole is not an N-methyl-D-aspartate antagonist but prevents postischemic increase in extracellular glutamate concentrations. The present study examined whether lubeluzole, administered after global incomplete ischemia in rats, is capable of preserving the structural integrity of CA1 hippocampus. METHODS: Ischemia was induced by bilateral carotid artery occlusion and severe hypotension for a duration of 9 minutes. Delayed neuronal cell death was histologically evaluated 7 days later. This was done by scoring acidophilic cell change and coagulative necrosis and by counting the number of surviving neurons in the CA1 subfield. Experiments were performed according to a paired design (13 animals per treatment group). RESULTS: Posttreatment with lubeluzole (0.31 mg/kg i.v. bolus at 5 minutes and 0.31 mg/kg i.v. infusion during 1 hour) resulted in significant neuroprotection. Whereas in the untreated rats there were 42 (median) viable neurons per millimeter CA1 layer in the left and 69 in the right hemisphere, in the drug-treated rats 99 viable neurons per millimeter were found in the left (P = .002) and 113 in the right hemisphere (P = .013). Histological scores, reflecting altered staining properties of the hippocampal cells, correlated strongly with the quantitative data, reflecting the structural integrity of CA1 pyramidal neurons. CONCLUSIONS: Lubeluzole, when administered after an ischemic insult in rats, protects vulnerable brain regions against delayed structural injury. The results support the potential clinical use of this new drug in stroke treatment.

Animals↗

PubMed1997

Fluorescein-labeled tyramide strongly enhances the detection of low bromodeoxyuridine incorporation levels.

Immunocytochemical detection of bromodeoxyuridine (BrdU) labeling can be hampered by low BrdU incorporation levels. We describe here an amplification method for weak BrdU immunosignals. The tyramide signal amplification method based on catalyzed reporter deposition (CARD) uses fluorescein-labeled tyramide as a substrate for horseradish peroxidase. The enzyme catalyzes the formation of highly reactive tyramide radicals with a very short half-life, resulting in the binding of fluorescein-conjugated tyramide only at the site of the enzymatic reaction. MCF-7 cells were grown in vitro in medium containing charcoal-stripped fetal bovine serum supplemented by growth factors. Under these culture conditions, the BrdU immunosignal was hard to detect but could be enhanced specifically by the tyramide signal amplification system, resulting in clear-cut differences between BrdU-negative and BrdU-positive cells. This enabled rapid and objective quantification of the BrdU labeling index without the risk of underestimating the number of cells in S-phase. Therefore, this amplification of BrdU immunosignals might also prove valuable for in vivo cancer prognosis, cell kinetics studies, and computer-assisted image analyses.

Breast Neoplasms↗

PubMed1997

Dedifferentiation of atrial cardiomyocytes as a result of chronic atrial fibrillation.

Chronic atrial fibrillation was induced in goats by electrical pacing. After 9 to 23 weeks of sustained atrial fibrillation, the morphology of the atrial structures was examined. The majority of the cardiomyocytes exhibited marked changes in their cellular substructures, with the replacement of sarcomeres by glycogen as the main characteristic. Using immuno-histochemical staining procedures, we assessed the expression and organization of contractile and cytoskeletal proteins in these cases and compared them with the expression and organization of these proteins in normal atria. Part of the atrial cardiomyocytes acquired a dedifferentiated phenotype, as deduced from the re-expression of alpha-smooth muscle actin, the disappearance of cardiotin, and the staining patterns of titin, which resembled those of embryonic cardiomyocytes. From these results we conclude that chronic atrial fibrillation induces myocardial dedifferentiation. This model of chronic atrial fibrillation in goats offers the possibility to study the time course of changes in cardiac structure during sustained atrial fibrillation and after cardioversion.

Animals↗

PubMed1996

Only hibernating myocardium invariably shows early recovery after coronary revascularization.

BACKGROUND: The aims of this study were to identify hibernating myocardium (hypocontractile, hypoperfused viable myocardium that regains contractility after revascularization) in the clinical setting and to predict functional outcome in patients with coronary artery disease after coronary revascularization. METHODS AND RESULTS: Preoperative data related to the anterior free wall of the left ventricle were collected in 50 coronary bypass surgery candidates (positron emission tomography [PET], [13N]NH3 for flow, and [18F]FDG for metabolism [MET]; equilibrium-gated nuclear angiography [EGNA] for regional ejection fraction [REF]; and histological data from myocardial biopsies for percentage fibrosis and viable myocytes). Three months after surgery, the patients had follow-up PET and EGNA investigations. A principal-components analysis identified four patient clusters. Cluster 1 (n = 9) had normal viable myocardium. Cluster 2 (n = 18) had viable hypocontractile myocardium (REF, 39 +/- 12%) showing a PET mismatch pattern. Cluster 3 (n = 16) had viable hypocontractile myocardium associated with morphological myocyte injury showing a matched moderate decrease in flow (66 +/- 11%) and MET (70 +/- 11%). Cluster 4 (n = 7) had hypocontractile myocardium with mainly scar tissue (fibrosis, 74 +/- 12%). After surgery, only cluster 2, with hibernating myocardium, showed significant improvement in REF (from 39 +/- 12% to 50 +/- 13%, P < .05). Cluster 3, with sites of morphological myocyte injury, showed no recovery. The stepwise logistic regression showed a combination of low preoperative REF and high MET to be the best predictor of functional recovery (P < .008). CONCLUSIONS: Multivariate analysis identifies hibernating myocardium showing early postrevascularization recovery, as opposed to viable but myolytic myocardium with no early recovery. Postrevascularization recovery can be predicted (combination of low REF and high MET) by noninvasive techniques.

Adult↗

PubMed1996

Nuclear lamin expression in chronic hibernating myocardium in man.

Cardiomyocytes of chronic hibernating myocardium are known to undergo structural changes, indicative of dedifferentiation. Amongst these are changes in nuclear shape and chromatin distribution. Nuclear A-type lamins are known to be expressed in a differentiation-related fashion and to contribute to nuclear integrity and chromatin organization. Lamin expression was investigated with immunocytochemical staining procedures in biopsies from patients with chronic hibernating myocardium. The expression of A-type (lamin A and C) were shown to be downregulated during hibernation, while lamin B2 remained present in hibernating cardiomyocytes in a way similar to embryonic muscle cells. All heart muscle cells were shown to be negative for lamin B1. The absence of A-type lamins in chronic hibernating cardiomyocytes could be taken as an additional argument for the dedifferentiation state of these cells. The absence of A-type lamins was accompanied by dispersion of the nuclear heterochromatin, in a way similar to nuclei of embryonic cardiomyocytes.

Biopsy↗

PubMed1996

Calcium homeostasis in cardiomyocytes isolated from heat-shocked rats.

The cellular mechanism of heat shock-mediated cardioprotection is still under debate. Because heat pretreatment negatively affects the normoxic left ventricular contractile performance in vitro when the extracellular Ca2+ concentration ([Ca2+]o) is relatively low (0.65-1.25 mM), the intracellular Ca2+ homeostasis was studied in more detail in cardiomyocytes isolated from adult rats 24 h after heat stress (42 degrees C for 15 min) or anesthesia (control). Sensitivity to Ca2+ overload was assessed by exposure to veratridine (quiescent cells) or to [Ca2+]o ranging from 0.125 to 20 mM in quiescent and paced cardiomyocytes. The fraction of irreversibly hypercontracted cells was not different between groups. The fura-2 fluorescence ratio (I340/I380), which was used as a measure for cytoplasmic Ca2+ concentration ([Ca2+]i) in quiescent cells after exposure to [Ca2+]o (0.5-10 mM), was also not different between groups. Myofilament Ca2+ sensitivity was assessed in paced (0.5 Hz) cells by simultaneous measurement of [Ca2+]i transients and cell shortening. At stepwise increases of [Ca2+]o from 1 to 10 mM, these parameters were comparable between groups. The diastolic cell length shortened progressively and equally in both groups after increasing [Ca2+]o. However, within 2 min of return from 10 to 1 mM [Ca2+]o, cells from heat-shocked rats retained the same length, whereas cells from control rats contracted further (P = 0.05). These data suggest that heat stress improves relaxation after challenge with high [Ca2+]o.

Animals↗

PubMed1996

Liarozole potentiates the all-trans-retinoic acid-induced structural remodelling in human breast carcinoma MCF-7 cells in vitro.

Liarozole inhibits cytochrome P-450-dependent enzymes that play a key role in all-trans-retinoic acid (ATRA) catabolism. In MCF-7 cells, liarozole potentiates the antiproliferative effects of ATRA. The present study demonstrates this synergistic effect on cell differentiation of MCF-7 cell cultures as measured by immunocytochemistry for cytokeratins 8, 18, and 19, actin, E-cadherin, desmoglein and desmoplakins I & II. ATRA concentration-dependently (10(-8) M-10(-6) M) induced changes in actin stress fibers and cytokeratin intermediate filaments. These changes were accompanied by a more obvious interaction of these filaments with junctional complexes. Surface area and volume of the MCF-7 cells increased markedly after ATRA exposure, with extensive filopodia formation. Liarozole (10(-6) M) alone had no effect on cell morphology, cytokeratin or actin organization, or on cellular junctions. In combination with ATRA (10(-9) M and 10(-8) M), liarozole potentiated the ATRA-induced effects. The MCF-7 cell cultures used showed morphological heterogeneity, consisting of at least two cellular subpopulations. This was reflected in the staining for E-cadherin, desmoglein and desmoplakins I & II. ATRA increased E-cadherin staining at cell-cell contact sites, but had no influence on the staining patterns of desmoglein and desmoplakins I & II. Similar to what has been observed for the cytoskeletal differentiation parameters, liarozole alone had no influence on E-cadherin, desmoglein or desmoplakins I & II expression, but in combination with ATRA again intensified the effects on E-cadherin distribution. These effects on MCF-7 cells agree with previously obtained observations concerning the inhibition of ATRA catabolism by liarozole. Furthermore, our data support the hypothesis that the antiproliferative properties of the drug are accompanied by induction of differentiation.

Antineoplastic Agents, Hormonal↗

PubMed1995

Liarozole, an antitumor drug, modulates cytokeratin expression in the Dunning AT-6sq prostatic carcinoma through in situ accumulation of all-trans-retinoic acid.

Liarozole showed antitumoral activity in the Dunning AT-6sq, an androgen-independent rat prostate carcinoma. To investigate its potential mechanism of action, the effects of the drug doses (ranging from 3.75 to 80 mg/kg b.i.d.) on endogenous plasma and tissue all-trans-retinoic acid levels and on the differentiation status of the tumor cells were evaluated. To follow modulation of differentiation, cytokeratins were localized in the (un)treated tumors by immunocytochemistry and quantitatively determined by immunoblotting. Results showed that liarozole statistically significantly reduced tumor weight from 30 mg/kg upwards and induced accumulation of all-trans-retinoic acid both in plasma and tumors. In the tumors, a statistically significant accumulation was already noted from 7.5 mg liarozole/kg upwards. Concomitantly, the differentiation status shifted from a keratinizing towards a non-keratinizing squamous carcinoma, which was further confirmed by the cytokeratin profile of the carcinoma (presence of CK 8, 10, 13, 14, 18, 19). Immunoblotting revealed an overall decrease in cytokeratin content, except for CK 8. These findings suggest that the antitumoral properties of liarozole might be related to an increase in the degree of tumor differentiation through accumulation of all-trans-retinoic acid.

Animals↗

PubMed1995

Regional myocardial blood flow, glucose utilization and contractile function before and after revascularization and ultrastructural findings in patients with chronic coronary artery disease.

In patients with chronic coronary artery disease, follow-up measurements of myocardial blood flow, metabolism and function were correlated with histology. In 41 patients with chronic coronary artery disease and a severely stenosed left anterior descending coronary artery, a positron emission tomographic (PET) flow/metabolism study and nuclear angiography were performed immediately before and 3 months after bypass surgery. Biopsies were taken from the left ventricular anterior wall at the time of surgery. Control biopsies were taken from donor hearts for cardiac transplantation and from hearts of patients with a defect of the atrial septum. A significant improvement of flow (P<0.01) and regional contractile function (P<0.01) was observed in the mismatch group. Glucose utilization was significantly lower (P<0.001) as compared to preoperative values. The group with preserved flow and the PET match group revealed no significant changes in flow, metabolism or function. Control biopsies revealed significantly less myolytic cells as compared to biopsies taken from both match and mismatch groups (P<0.01) and less fibrosis as compared to biopsies taken from the match group (P<0.01). Postoperatively, linear relationships were found between flow and both % fibrosis (r = 0.71, P<0.001) and regional anterior ejection fraction (r = 0.7, P<0.001). Only mismatch areas revealed significant recovery of both flow and function after revascularization with a disappearance of enhanced glucose uptake. The better linear correlation between flow and % fibrosis after surgery as compared to preoperatively was probably due to improvement of flow values in the mismatch group.

Coronary Artery Bypass↗

PubMed1995

Molecular changes of titin in left ventricular dysfunction as a result of chronic hibernation.

Cardiomyocytes of chronic hibernating myocardium are affected by partial to complete loss of sarcomeres, accumulation of glycogen, adaptations in size and shape of mitochondria, reorganisation of nuclear chromatin and depletion of sarcoplasmic reticulum. The nature of these changes, which from a purely morphologic viewpoint are akin to dedifferentiation, needed further clarification at the molecular level. For this purpose we have studied the expression and reorganization of titin, one of the earliest markers of cardiomyocytes differentiation. By use of monoclonal antibodies, recognizing different epitopes distributed over the whole length of the titin molecule, we were able to detect changes in its molecular organization as a result of chronic hibernation. The epitopes of the titin molecule attached to the Z-disc and those present close to the M-line remained detectable at all stages of hibernation, while epitopes at the A-I junction and parts of the myosin anchoring region of the molecule became masked or were lost. A fragmented or punctuated appearance of the titin staining pattern with antibodies to A-I junction related epitopes is found in cells which we consider to represent a more advanced stage of dedifferentiation. Changes in the distribution of the titin molecule or its molecular environment in hibernating myocardium resemble at least in part changes occurring during muscle cell differentiation, although in reversed order.

Animals↗

PubMed1995

Annexin V in the adult rat heart: isolation, localization and quantitation.

Annexins are a family of proteins with calcium- and phospholipid-binding properties. The present study was performed to identify which members of the annexin family are present in rat heart and to determine the cellular and subcellular distribution of annexin V, the most prominent annexin in rat cardiac tissue, in isolated ventricular myocytes and cultured endothelial and fibroblast-like cells. The presence of annexin I plus II, III, IV, V and VI in rat cardiac tissue was positively established with western blot analysis. Immunohistochemistry and western blot analysis revealed that annexin V is present in both cardiomyocytes and non-myocytal cells of the heart. In endothelial cells and fibroblast-like cells annexin V is predominantly localized in the cytoplasm and in cardiac myocytes in close vicinity of the sarcolemma. This last finding is confirmed by electron microscopy. Northern blot analysis demonstrated that all cell types investigated showed expression of annexin V. Annexin V mRNA levels were highest in the fibroblast-like cells, followed by the endothelial cells, and a weak signal was observed in the cardiomyocytes. By means of a sandwich-type enzyme-linked immunosorbent assay (ELISA) annexin V content in intact adult rat heart, isolated myocytes, cultured cardiac endothelial cells and fibroblast-like cells was found to be 0.70, 0.17, 1.63 and 3.84 micrograms/mg total protein, respectively. The differences in subcellular localization of annexin V in myocytes and non-myocytes suggest differences in biological function of annexin V in the various cell types.

Animals↗

PubMed1995

Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans.

Assessment of regional myocardial perfusion and glucose uptake with positron emission tomography (PET) identifies dysfunctional myocardium that shows improvement in function after revascularization. Yet little is known about the ultrastructural patterns of ischemic injury in myocardium with and without postoperative functional improvement in relation to residual perfusion and metabolism. Therefore dynamic PET with [13N]ammonia and 18F-labeled deoxyglucose was performed in 24 patients with coronary artery disease and anterior wall dysfunction undergoing bypass surgery. Transmural biopsies were obtained from the dysfunctional area during surgery and analyzed by optical and electron microscopy to quantify the presence of fibrosis and cardiomyocytes. As judged from the postoperative changes in contraction, left ventricular function improved in 16 patients. In myocardium that showed improved function after revascularization, preoperative flow and glucose uptake were higher by PET than in persistently dysfunctional myocardium. In tissue samples from myocardium that improved postoperatively, there were more cardiomyocytes, including a larger proportion of cells with excess glycogen stores (35 vs. 21%), and there was less fibrosis (24 vs. 49%) than in tissue samples from myocardium that did not improve functionally. Preoperative perfusion and postoperative wall motion were inversely correlated with the amount of tissue fibrosis, whereas preoperative 18F-labeled deoxyglucose uptake correlated positively with the amount of cardiomyocytes showing excess glycogen stores.

Adult↗

PubMed1994

ALCAPA syndrome: an example of chronic myocardial hypoperfusion?

OBJECTIVES: The purpose of this study was to evaluate functional variables and morphologic correlates of chronically hypoperfused myocardium before and after revascularization. BACKGROUND: Neonates with congenital anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA syndrome) develop some myocardial necrosis shortly after birth. The survivors of this event are left with a localized infarction and an almost entirely collateral circulation-dependent perfusion of the left ventricle that results in poor global left ventricular function. Survival beyond infancy is uncommon because of severe left heart failure. Revascularization, however, brings about functional recovery with good clinical outcome. The ALCAPA syndrome is thus characterized by chronic collateral circulation-dependent low perfusion, low contraction matching and potential revivability. METHODS: Five patients with ALCAPA syndrome are presented, with preoperative and postoperative clinical findings and histologic data obtained from intraoperative transmural biopsy specimens. RESULTS: The angiographically assessed preoperative ejection fraction was 33 +/- 19% (mean +/- SD). Postoperative echocardiographic follow-up revealed normal left ventricular function in all patients. Histologic study of the biopsy specimens taken from the region perfused by the anomalous artery showed a variable degree of fibrosis (51 +/- 32%). The ultrastructure of the remaining myocytes revealed viable characteristics, but a substantial percent (46 +/- 26%) showed a markedly reduced fraction of contractile material. CONCLUSIONS: These ultrastructural studies suggest delayed subcellular adaptive responses in the chronically hypoperfused myocardium of patients with ALCAPA syndrome.

Adolescent↗

PubMed1994

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

BACKGROUND: In 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 RESULTS: We 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. CONCLUSIONS: It 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.

Biopsy↗