Vittorio Fineschi

Sudden cardiac death during anabolic steroid abuse: morphologic and toxicologic findings in two fatal cases of bodybuilders.

We report two cases of sudden cardiac death (SCD) involving previously healthy bodybuilders who were chronic androgenic–anabolic steroids users. In both instances, autopsies, histology of the organs, and toxicologic screening were performed. Our findings support an emerging consensus that the effects of vigorous weight training, combined with anabolic steroid use and increased androgen sensitivity, may predispose these young men to myocardial injury and even SCD.

Correlation between cardiac oxidative stress and myocardial pathology due to acute and chronic norepinephrine administration in rats

Background: To investigate the cardiotoxic role of reactive oxygen species (ROS) and of products derived from catecholamines auto‐oxidation, we studied: (1) the response of antioxidant cardiac cellular defence systems to oxidative stress induced by norepinephrine (NE) administration, (2) the effect of NE administration on cardiac β1‐adrenergic receptors by means of receptor binding assay, (3) the cellular morphological alterations related to the biologically cross‐talk between the NE administration and cytokines [tumor necrosis factor‐alpha (TNF‐α), monocyte chemotactic protein‐1 (MCP‐1), interleukins IL6, IL8, IL10]Methods and Results: A total of 195 male rats was used in the experiment. All animals underwent electrocardiogram (EKG) before being sacrificed. The results obtained show that NE administration influences the antioxidant cellular defence system significantly increasing glutathione peroxidase (GPx) activity, glutathione reductase (GR) and superoxide dismutase (SOD). The oxidized glutathione (GSH/GSSG) ratio significantly decreases and malondialdehyde (MDA) levels increase showing a state of lipoperoxidation of cardiac tissue. We describe a significant apoptotic process randomly sparse in the damaged myocardium and the effect of ROS on the NE‐mediated TNF‐α, MCP‐1, and IL6, IL8, IL10 production. Conclusions: Our results support the hypothesis that catecholamines may induce oxidative damage through reactive intermediates resulting from their auto‐oxidation, irrespective of their interaction with adrenergic receptors, thus representing an important factor in the pathogenesis of catecholamines‐induced cardiotoxicity. The rise of the cardioinhibitory cytokines may be interpreted as the adaptive response of jeopardized myocardium with respect to the cardiac dysfunction resulting from NE injection.

Myocardial contraction bands

Abstract Pathological contraction bands affecting myocardial cells are observed in many different human conditions and in different experimental models. Their morphology was defined long ago but we need to understand the pathogenesis and functional meaning. A distinction between different histological forms of contraction bands and their quantification in a large spectrum of human diseases (262 cases) and a normal population sample where death was due to various types of accidental death (170 cases) produced the following conclusions: 1) The term “contraction band necrosis”, as used presently, is ambiguous and should be reserved for a specific morpho-functional entity induced experimentally by intravenous catecholamine infusion and seen in equivalent human cases with pheochromocytoma. 2) In human pathology it may represent a sign of adrenergic stress linked with malignant arrhythmia/ventricular fibrillation. 3) Beyond a histological threshold of 37 ± 7 foci and 322 ± 99 myocells/100 mm2, the lesion may indicate sympathetic overdrive in the natural history of a disease and associated arrhythmogenic supersensitivity. 4) The detection of few pathological contraction bands in normal subjects in some types of accidental death correlates with the survival time, suggesting an agonal adrenergic stimulation to promote the cardiac pump.

Side effects of cocaine abuse: multiorgan toxicity and pathological consequences.

Cocaine is a powerful stimulant of the sympathetic nervous system by inhibiting catecholamine reuptake, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine (NE). It is known, from numerous studies, that cocaine causes irreversible structural changes on the brain, heart, lung and other organs such as liver and kidney and there are many mechanisms involved in the genesis of these damages. Some effects are determined by the overstimulation of the adrenergic system. Most of the direct toxic effects are mediated by oxidative stress and by mitochondrial dysfunction produced during the metabolism of noradrenaline or during the metabolism of norcocaina, as in cocaine-induced hepathotoxicity. Cocaine is responsible for the coronary arteries vasoconstriction, atherosclerotic phenomena and thrombus formation. In this way, cocaine favors the myocardial infarction. While the arrhythmogenic effect of cocaine is mediated by the action on potassium channel (blocking), calcium channels (enhances the function) and inhibiting the flow of sodium during depolarization. Moreover chronic cocaine use is associated with myocarditis, ventricular hypertrophy, dilated cardiomyopathy and heart failure. A variety of respiratory problems temporally associated with crack inhalation have been reported. Cocaine may cause changes in the respiratory tract as a result of its pharmacologic effects exerted either locally or systemically, its method of administration (smoking, sniffing, injecting), or its alteration of central nervous system neuroregulation of pulmonary function. Renal failure resulting from cocaine abuse has been also well documented. A lot of studies demonstrated a high incidence of congenital cardiovascular and brain malformations in offspring born to mothers with a history of cocaine abuse.

Markers of cardiac oxidative stress and altered morphology after intraperitoneal cocaine injection in a rat model

Abstract This study was designed to assess the parameters of myocardial oxidative stress and related cardiac morphological changes following intraperitoneal cocaine exposure in rats. The cardiac levels of reduced glutathione(GSH), oxidised glutathione(GSSG), ascorbic acid (AA), and the production of malondialdehyde (MDA) were measured, as well as the variations of activity in the enzyme systems involved in cell antioxidant defence, glutathione peroxidase (GSH-Px), glutathione reductase (GR) and superoxide dismutase (SOD). After chronic cocaine administration for 30 days GSH was significantly depleted in the heart from 30 min (P < 0.001) to 24 h (P < 0.001) after exposure, and GSSG was increased for a similar time (P < 0.05 at 30 min and P < 0.01 at 24 h). SOD increased during the first hour (P < 0.001), GR and GSH-Px both increased from 30 min to 24 h, and these increases were statistically significant (P < 0.01 and P < 0.001 at 30 min and P < 0.01 and P < 0.001 at 24 h, respectively). The AA levels increased after 1 h (P < 0.01), remaining significantly so for 24 h (P < 0.001) and MDA increased from 30 min to 24 h, all values being highly significant (P < 0.001). The body weight was significantly (P < 0.001) reduced in both cocaine groups (40 mg/kg × 30 days and 40 mg/kg × 10 days + 60 mg/kg × 20 days). The heart weight (P < 0.01) and its percentage of the body weight (P < 0.001) were significantly higher in these two groups than in the controls. Similarly, in the noradrenaline 4 mg/ kg × 30 days group, the body weight was significantly (P < 0.001) reduced and the heart weight (P < 0.01) and its percentage of body weight (P < 0.001) were significantly higher than in the controls. In comparing the cocaine and noradrenaline experiments, the frequency and extent of cardiac lesions obtained with 40 mg/kg × 10 days + 60 mg/kg × 20 days of cocaine were similar to those with 8 mg/kg of noradrenaline at 24 h. In this experimental model, cocaine administration compromised the antioxidant defence system of the heart associated with a significant increase of heart weight and the percentage of body weight.

Histological age determination of venous thrombosis: A neglected forensic task in fatal pulmonary thrombo-embolism

The histological age determination of venous thromboses in fatal pulmonary embolism cases is an important task of forensic medicine and requires thorough knowledge of the general and specific pathology of pulmonary thromboembolism (PTE). The aim of our investigation was to carry out a chronological evaluation of the deep venous thrombosis (DVT) phenomenon, to assess the chronological transformation of the thrombus and to determine the causal relationship with PTE as cause of death. The clinical data and the autopsy records of the 2843 autopsies performed over the period 1 November 1998 to 31 December 2007 were retrospectively evaluated, and 140 cases in which PTE was pointed out as cause of death were selected. The dissection of the deep veins of the legs has been performed systematically to search for the starting point of venous embolism. 4.5% of pulmonary embolisms originated in the in iliac veins, 20.7% in the femoral veins, and 74.8% in the deep crural veins. In the venous sites of thrombosis, the histological assessment has been performed in conjunction with the surrounding vascular wall of uncut blood vessel with at least three to six different transverse incisions. Histological assessment of the embolus samples was also performed in conjunction with the venous sites of thrombosis. In our selected 140 cases of PTE, the DVT was classified as phase 1 in 48 cases (34.29%), as phase 2 in 70 cases (50%), and 22 cases (15.71%) were evaluated as older than 2 months (phase 3). The observed transformation of the thrombus by organization is suitable for a forensically utilizable age determination. However, only three chronological stages can be distinguished with any degree of certainty using immunohistochemistry and CLSM.

Insight into stress-induced cardiomyopathy and sudden cardiac death due to stress. A forensic cardio-pathologist point of view.

Emotional, physiological and physical stress is associated with increased rates of cerebrovascular events and sudden deaths. The pathophysiology of stress-induced cardiomyopathy is not well understood. Proposed mechanisms for catecholamine-mediated stunning in stress cardiomyopathy include epicardial vasospasm, microvascular dysfunction, hyperdynamic contractility with midventricular or outflow tract obstruction, and direct effects of catecholamines on cardiomyocytes. Studies show evidence of significant heritable influences on individual responses to adrenergic stimulation. Data from such studies may be of help for a more accurate comprehension of clinical and morphological alterations of the heart. Irrespective of the cause, patients with the classic stress-induced cardiomyopathy morphology deserve special attention because this extensive distribution of wall motion abnormalities has implications for potential associated complications. Cardiac response may be significantly coupled to genetic differences at candidate loci that encode components of catecholamine biosynthesis, storage, and metabolic pathway. Given the role of the sympathetic nervous system in responses to acute stress, it is reasonable to explore whether genetically determined alterations in catecholamine system functions contribute to acute and chronic cardiovascular disorders such as stress-induced cardiomyopathy.

Cardiac pathology in death from electrocution

To better characterize the morphologic changes in electrocution, morphologic changes in the hearts of 21 subjects, who died instantaneously of electrocution, were compared to the hearts of decedents with different types of death. Sixteen myocardial samples per heart were processed for histological examination, and sections were prepared with a variety of specific stains. The frequency, location and extent of myocellular segmentation (stretching and/or rupture) of intercalated discs and associated changes of myocardial bundles and single myocells [myofibre break-up (MFB)] were recorded, quantitatively analysed and statistically evaluated. The frequency of MFB was maximal in cases of electrocution (90%). The findings show that MFB is an ante-mortem change and may be a distinct finding in electrocution.

MDMA Toxicity and Pathological Consequences: A Review About Experimental Data and Autopsy Findings

Studies conducted in humans or in animals explored the presence, nature and potential causes of 3,4-methylenedioxymethamphetamine (MDMA) toxicity. According to literature, there are four principal types of such serious toxicity: hepatic, cardiovascular, cerebral and hyperpyrexic. The molecular mechanisms involved in the genesis of these toxic effects are not yet fully clarified, but the oxidative stress, excitotoxicity, and mitochondrial dysfunction appear to be causal events that converge to mediate MDMA-induced toxicity. Studies conducted on animals demonstrated that the acute administration of MDMA elicits cardiovascular responses that are similar to those elicited by d-amphetamine, and that these responses appear to involve catecholaminergic and non-catecholaminergic-dependent mechanisms. Although there is undeniable evidence of MDMA-induced cardiac toxicity, the mechanism responsible remains to be clarified. While many reports both in humans and in animals have demonstrated MDMA-induced liver damage, the underlying mechanism accounting for hepatic toxicity is poorly understood. Various mechanisms may contribute to MDMA-induced liver toxicity, including the metabolism of MDMA, the increased efflux of neurotransmitters, the oxidation of biogenic amines, and hyperthermia. The molecular mechanisms involved in the genesis of these toxic effects are not yet fully clarified, but the oxidative stress, excitotoxicity, and mitochondrial dysfunction appear to be causal events that converge to mediate MDMA-induced neurotoxicity, as measured by loss of various markers of dopaminergic and serotonergic terminals. The evidence is overwhelming that MDMA produces acute and long-lasting toxic anatomic effects in animals and humans. Anatomical and functional MDMA consequences must be better understood.

Complement C3a expression and tryptase degranulation as promising histopathological tests for diagnosing fatal amniotic fluid embolism.

To date, the most recent specific diagnostic investigations for amniotic fluid embolism have been unable to conclusively identify any mechanism of disease other than a physical block to the circulation. We selected eight fatal cases in previously healthy women with uneventful singleton term pregnancies who presented to tertiary care centers in Italy for delivery. Pathologic features were assessed immunohistochemically using anti-fibrinogen, anti-tryptase, anti-C3a, and anti-cytokeratin antibodies. AE1/AE3 cytokeratin stains proved positive, and tryptase-positive material was documented outside pulmonary mast cells. In all studied cases, expression of complement C3a was twofold lower than in the control group, suggesting a possible complement activation in AFE, initiated by fetal antigen leaking into the maternal circulation.