[Do we die from myocardial apoptosis? Fashion and reality of different types of cell death in cardiovascular diseases].
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Biomedical subjects
Publications and source records attributed to G Baroldi.
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BACKGROUND: Focal myocardial necrosis reported in patients who died of brain lesions and in donor hearts soon after insertion has been attributed to catecholamine-related injury induced before operation, or in the perioperative period. Interpretation of the morphofunctional type of myocardial injury observed and its quantification may help understand both its pathophysiology and clinical relevance. METHODS: In 27 patients without heart disease who died of intracranial brain hemorrhage after berry aneurysm rupture, terminal clinical signs were correlated with the presence of absence of myocardial injury. All hearts were systematically examined, and the total histologic area was measured in square millimeters, with both the number of foci and myocardial cells showing necrosis, normalized to 100 mm2. Forty-five cases of fatal head trauma (26 "instantaneous" and 19 "rapid" deaths) in normal subjects and 38 cases of acquired immunodeficiency syndrome with (14 cases) or without (24 cases) severe brain damage were used as control subjects. RESULTS: Contraction band necrosis was the only form of myocardial necrosis found in 89% of patients with acute brain hemorrhage. Its extent was 26 +/- 34 foci and 67 +/- 104 necrotic myocardial cells x 100 mm2. In patients with acquired immunodeficiency syndrome, its frequency was 58% in those without and 78.5% with severe brain lesions, with foci and myocardial cell values of 1 +/- 1.5 and 10 +/- 22 and 7 +/- 16 and 17 +/- 32, respectively. In head trauma cases with instantaneous death, the frequency was 4% (one case only with foci 0.5 and myocardial cells 35), whereas with a rapid death it was 40% (foci 12 +/- 18 and myocardial cells 21 +/- 33). CONCLUSIONS: The observed myocardial injury was present in all groups examined, being maximal in patients with intracranial brain hemorrhage with longer survival and minimal in patients with head trauma who died instantaneously. In this setting, this lesion is typical of catecholamine myotoxicity and may express a sympathetic overstimulation either in the agonal period and independent of therapy or be caused by brain injury, especially intracranial brain hemorrhage. However, the extent of myocardial injury observed was minimal and should not jeopardize cardiac function if hearts from such subjects are transplanted.
To determine the morphological bases of thallium-201 myocardial distribution in chronic cardiac dysfunction and their relation to myocardial blood flow, myocardial slices from ten excised hearts of five chronic ischaemic heart disease patients and five idiopathic dilated cardiomyopathy patients, were imaged on a gamma camera to quantitate the uptake of thallium-201, injected 4 h before surgery, and myocardial blood flow from distribution of technetium-99m-labelled human albumin microspheres injected during surgery. Tracer distribution was correlated with histologically assessed myocardial fibrosis and myocytolysis. Thallium-201 uptake was inversely related to fibrosis (r = -0.73, in ischaemic heart disease, r = -0.65 in idiopathic dilated cardiomyopathy). In ischaemic heart disease, myocardial blood flow was related neither to thallium-201 uptake (r = 0.41) nor to the extent of fibrosis (r = -0.48). In this group, segments with normal or mildly reduced thallium-201 uptake showed significantly lower fibrosis than those with moderate or severe uptake defects (5 +/- 7% and 7 +/- 11% vs 33 +/- 14% and 42 +/- 12%, respectively, P < 0.0001. In a clinical model of chronic ischaemic dysfunction, despite severely depressed myocardial blood flow, extensive areas of myocardium devoid of significant structural impairment are present. Thallium-201 uptake effectively discriminates regions with preserved viability from those with relevant myocardial damage.
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Lysosomal glycogen storage in muscle with normal acid maltase activity is a rare inherited condition characterized by cardiomyopathy, mental retardation and mild myopathy in males, but generally only cardiomyopathy in females. Three cases (index case, his sister and her son) are described in a family with at least two other affected members. The index case underwent a successful heart transplant. The sister has cardiac involvement, myopathic changes and mental impairment--to our knowledge the first report of multisystem involvement in a female. We propose that skeletal muscle should be examined in young patients with hypertrophic cardiomyopathy. Furthermore, female relatives of males with the disease should be investigated for cardiomyopathy; they would be excellent candidates for life-saving heart transplant, since myopathy and mental retardation, if clinically evident, are mild.
Clinical and laboratory findings were compared in 65 women and 238 men with invasively documented idiopathic dilated cardiomyopathy. Women had more severe symptoms (New York Heart Association class > or = III in 48 vs 39%; p < 0.05), presented more frequently with heart failure signs (63 vs 41%; p < 0.01), and had a higher cardiothoracic ratio (0.56 +/- 0.06 vs 0.53 +/- 0.06; p < 0.05) and higher frequency of left bundle branch block (41 vs 29%; p < 0.05). Echocardiographic measurements in women showed significantly greater left ventricular (LV) end-diastolic (42 +/- 7 vs 39 +/- 6 mm/m2; p < 0.0001) and end-systolic (36 +/- 7 vs 33 +/- 6 mm/m2; p < 0.001) diameters, and mean myocardial thickness (11 +/- 2 vs 10 +/- 2 mm; p < 0.05). Exercise duration was shorter in women than in men (7 +/- 3 vs 10 +/- 4 minutes; p < 0.001). After 18 +/- 16 months, 9 women and 27 men died, and 7 and 17, respectively, received transplants. Transplant-free survival was not significantly different according to gender. By Cox multivariate analysis, LV ejection fraction was a significant independent predictor of cardiac death or heart transplantation in both sexes (p < 0.05 in men, and p < 0.005 in women), together with left atrial diameter index (p < 0.01) in women, and mean pulmonary artery pressure (p < 0.001) in men. In conclusion, women with idiopathic dilated cardiomyopathy present a more advanced phase of the disease with greater LV dilation, but do not have a different prognosis.
This mortality study deals with the 1068 heart transplants (1054 patients) performed in Italian Units from November 1985 to April 1992. The death rate was 19.7% and the actuarial survival was 89% at 1 month, 83% at 1 year and 74% at 6.5 years. Recipients who died had been less often transplanted for dilated cardiomyopathy, were older (44.1 vs. 41.7 years) and more often male (84.5 vs. 72.7%). Analysis of the causes of death was restricted to orthotopic transplantations (1029/1068 procedures, 195/208 deaths). Deaths were grouped within four intervals: peri-operative (< or = 1 month, 50.0% of deaths), early (> 1 month < or = 3 months, 17.2%), intermediate (> 3 months < or = 2 years, 22.6%) and late (> 2 years, 10.2%). The prime causes of death were mostly postoperative graft failure (whose effects brought about 64% of peri-operative deaths, 28% of early and 7% of intermediate deaths), post-operative complications (10% of peri-operative deaths), acute rejection (10% of total deaths, distributed in all the periods), graft arteriopathy (6% of early, 36% of intermediate and 58% of late deaths), infections (17% of deaths, occurring in all periods but late) and malignant tumours (7% of deaths), lymphomas being the first to occur and Kaposi's sarcoma occurring only in the intermediate period. Repeat transplantation had a poor outcome (death rate 71.4%), two-thirds of the re-transplanted patients' deaths being due to early graft failure and a third to late relapsing graft vasculopathy.
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All the transplantation units within the Italian Heart Transplantation Project are supported by a section of pathology, devoted to the study of the recipient's heart, to patient monitoring by means of a schedule of endomyocardial biopsies, and, if that was the case, to examine the donor's heart and to analyse the causes of death. When successes and failures of the first five years of the Project's activity are weighed up, good results are observed: of the 847 operations performed (orthotopic, heterotopic and heart-lung transplants, and re-transplants) an actuarial survival rate of 77% at 5 years has been achieved. The sections of pathology believe to have contributed significantly to these results, examining as many as 10,446 endomyocardial biopsies. The indications for transplantation were: dilated cardiomyopathy (48.5%); ischemic (35.3%); valvular (5.9%) and congenital (2.4%) heart disease; hypertrophic cardiomyopathy (2.2%); endocardial fibroelastosis (1.7%); restrictive cardiomyopathy (1.4%); anthracycline cardiotoxicity (0.8%); myocarditis (0.8%); cardiac tumours (0.5%) and arrhythmogenic cardiomyopathy (0.2%). Distribution of recipients by sex and age varied according to the indications for transplantation: males were more common among the patients transplanted for ischemic (97%) and valvular (84%) heart disease, as well as for dilated (82%) and hypertrophic (78%) cardiomyopathy, whereas the opposite was true for endocardial fibroelastosis (males constituting 21%) and cardiac tumours (25%). Mean age at transplantation ranged from 49 years (ischemic heart disease) to 6 years (endocardial fibroelastosis). In the follow-up period, a 17.5% death rate was recorded; the main causes of death were the early failure of the transplanted heart (27 pts), postoperative complications (16), hyperacute rejection (4), acute rejection (18), infections (the singular most frequent cause of death, 35 pts), the proliferative endoarteritis of coronary branches (the so-called chronic rejection, that caused 21 deaths and required 14 re-transplants) and the development of neoplasms (11). The actuarial survival curve drops to 89% after the first postoperative month, abates to 82% at the end of the first year, and progressively decreases to 77% at the end of the fifth follow-up year. Rejection monitoring required an average number of 12.5 endomyocardial biopsies per recipient, and allowed 1.7 rejection episodes per patient to be diagnosed. The fewer were the rejection episodes occurring in a unit, the higher was the percentage of deaths due to infections.(ABSTRACT TRUNCATED AT 400 WORDS)
In 34 hearts, obtained at autopsy in consecutive AIDS cases, leukocytic phenotype and presence of viral antigens were investigated in paraffin-embedded (34 cases) and frozen myocardial sections (10 cases) by different monoclonal antibodies. The total frequency of focal lymphocytic infiltrates with and without myocell necrosis was 26.4 and 32.3%, respectively. In six control cases (HIV-negative i.v. drug abusers dying from acute fulminating hepatitis), these infiltrates were absent. In AIDS patients, the number of infiltrative foci per section, their wall distribution (subendocardial, middle layer, subepicardial), number of leukocytes per focus, and cell phenotype (prevalence of CD8+ suppressor/cytotoxic T-lymphocytes with CD4/CD8 ratio of 0.6 +/- 0.09 SE, absence of B-cells and granulocytes) were similar in cases with and without myocell necrosis. Significant differences were not observed between homosexual and i.v. drug abuser patients. In inflammatory foci associated with myocell necrosis CD45+/CD68+ monocytes prevailed, as a possible manifestation of nonspecific reparative process. In addition, in both AIDS patients and HIV-negative drug abusers, a population of CD68+ dendritic monocytes (histiocytes) characterized by a restricted CD45 expression (PanLeu-/9.4+) was found dispersed in the interstitium, with a significant higher frequency in the subendocardial layer. Histologic evidences of myocardial virus infections were not observed. Cytomegalovirus (CMV) antigens, however, were found in frozen sections of five of the six cases with lymphocytic infiltrates, supporting the view that this virus can be one of the possible causes of myocarditis in AIDS. Moreover, in two of these CMV-positive cases, a concomitant expression of HIV1 antigens in isolated intramyocardial leukocytes was also observed.(ABSTRACT TRUNCATED AT 250 WORDS)
A 45-year-old man with unstable angina developed persistent ECG changes of myocardial ischemia during coronary angiography. Occlusion of the left anterior descending branch (LAD) was documented 20 minutes after these changes. Intracoronary nitrate, Ca antagonist, urokinase, removal by percutaneous transluminal coronary angioplasty (PTCA) of atherosclerotic obstructions, and emergency bypass surgery failed to restore myocardial perfusion. Only short periods of reflow were obtained by urokinase and PTCA. The repeated coronary injections demonstrated a progressive disappearance of the left anterior descending artery (LAD) starting from the distal portion and progressing retrogradely up to the origin of the vessel. The patient developed a transmural anterolateral myocardial infarction and 12 months later underwent cardiac transplantation for untractable failure. His heart was examined and the infarct confirmed. Analysis of this case suggests that coronary occlusion in acute myocardial infarction can be an event secondary to increased intramyocardial resistance rather than the cause of reduced coronary blood flow in subepicardial coronary arteries.
Based on the working hypothesis that coronary atherosclerosis begins in childhood, a histologic study was carried out on the subepicardial coronary arterial tree of 100 young persons (1-20 years), who had died from causes unrelated to the cardiovascular system. These subjects were natives of a well-defined geographic area in northern Italy, namely the region of Veneto. Intimal proliferations (musculo-elastic and fibro-elastic layers) were observed in 95.3% of the coronary arterial segments in the age group between one and five years. The more distal the coronary segments examined, the lesser was the intimal thickening. Raised mature fibrous plaques were detected in 23 segments from 15 patients (2 from subjects aged between six and 10 years; 4 between 11 and 15 years, and 9 between 16 and 20 years). Single vessel disease was present in 9, double vessel disease in 4 and triple vessel disease in 2 cases. The site most involved by plaques was the proximal part of the left anterior descending coronary artery. Only one plaque was of sufficient dimensions to be considered stenotic (50% luminal reduction). Plaques were rarely sudanophilic, and all seemed to arise in relation to previous intimal thickening. No qualitative nor quantitative sexual differences were observed. These data give rise to much concern, and one consistent with a recently observed occurrence of sudden coronary death in young people from the same geographic area.
Discontinuous density sucrose gradient centrifugation was used to isolate membrane vesicles from the left ventricle of three normal subjects (one prospective organ donor and two traffic victims whose hearts were obtained 1 hour after death) and nine patients undergoing cardiac transplantation as a consequence of idiopathic dilated cardiomyopathy. Sarcolemma-enriched subcellular fractions, detected in the interface between 8.55% and 25% sucrose, were identified by the increased activity of Na+,K+-ATPase and by enrichment in beta-adrenergic receptor density. The density of beta-adrenergic receptors was lower in vesicles from diseased hearts (610 +/- 71 fmol/mg protein) than in vesicles from normal hearts (1,410 +/- 226 fmol/mg protein; p less than 0.01). alpha 1-Adrenergic receptors were identified in these membrane vesicles by [3H]prazosin binding. Specific binding of [3H]prazosin was about 50% of the total binding at 1 nM, and alpha 1-adrenergic binding sites were saturable at approximately 3 nM. Scatchard analysis revealed 58 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.08 nM) in pathological hearts and 30 +/- 5 fmol/mg protein (KD = 0.90 +/- 0.03 nM) in normal hearts (p less than 0.01). The displacement curve of (-)-norepinephrine in membrane vesicles from normal hearts delineated one subpopulation of alpha 1-adrenergic receptors; the addition of 0.1 mM GTP did not cause right shift. In membrane vesicles from diseased heart, the displacement curve of (-)-norepinephrine disclosed two subpopulations of alpha 1-adrenergic receptors. A right shift that occurred after addition of GTP showed that in this case alpha 1-adrenergic receptors were functionally coupled with GTP-binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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