Furio Silvestri | Università degli Studi di Trieste (original) (raw)
Papers by Furio Silvestri
Cardiac complications are a major cause of morbidity and mortality after non-cardiac surgery, who... more Cardiac complications are a major cause of morbidity and mortality after non-cardiac surgery, whose incidence varies according to patient risk stratification and type of patient cohorts investigated. Perioperative myocardial injury may be triggered by different conditions occurring in the perioperative phase, and patient risk factors represent a favorable milieu for triggers to act. The majority of postoperative myocardial ischemia in high-risk patients tends to develop very early on the day of surgery, starting at the end of surgery and during emergence from anesthesia, or on the first postoperative day. Most of postoperative episodes of myocardial ischemia are silent, and show ST-segment depression rather than elevation. Preventive measures are aimed at improving perioperative cardiac outcome, but their identification and application in clinical practice require understanding of the pathophysiology of myocardial ischemia and infarction in non-cardiac surgery patients. Among the protective strategies, beta-blocking agents are the most investigated since 1996, when data from atenolol administration showed a protective effect against myocardial ischemia and infarction in non-cardiac surgery. Since then several clinical studies have reported encouraging results, but conflicting data on possible serious side effects have recently raised concern and doubts about routine administration of beta-blockers in patients at risk undergoing non-cardiac surgery. The aim of this manuscript is to address the main mechanisms responsible for myocardial ischemia in the perioperative phase of non-cardiac surgery and, by going through the recent literature and taking into consideration the very recent European and American recommendations, to provide a pathophysiological approach to the use of beta-blockers in such scenario.
Circulation Research, Aug 3, 2012
The controversy on the growth reserve of the adult human heart has not been resolved and the exte... more The controversy on the growth reserve of the adult human heart has not been resolved and the extent of myocyte renewal reported by different groups varies significantly. Additionally, myocyte regeneration has been claimed to decrease with aging, although cell death is markedly enhanced in the old myocardium. Thus, the effects of age and gender on the magnitude of myocyte turnover were determined. Myocyte replication, senescence and apoptosis were measured in normal female and male human hearts collected from patients 19 to 104 years of age who died from causes other than cardiovascular diseases. Myocardial aging was characterized by a time-dependent increase in the generation of amplifying cardiomyocytes in women and men. Levels of Ki67 and phospho-H3 were comparable in the young female and male heart but differed later in life. As a function of age, the pool of amplifying myocytes was 2-fold higher in women than men, pointing to enhanced myocyte renewal in the female heart. The frequency of p16 INK4a -positive myocytes was higher in men than in women. From 19 to 104 years of age, the time-dependent increase in senescent myocytes was 0.68% per year in women and 0.89% per year in men; the 31% higher rate of accumulation of old myocytes in the aging male heart was significant. Myocyte apoptosis occurred only in p16 INK4a -positive cells and was consistently higher in men than in women at all age intervals. However, the increase in myocyte apoptosis with age did not differ with gender. Based on these parameters, we measured the average age of cardiomyocytes, their age distribution, turnover rate and time to acquire the senescent phenotype to define the biology of myocardial aging as a function of lifespan. In the female heart, myocyte turnover occurs at a rate of 10%, 15% and 40% per year at 20, 60 and 100 years of age, respectively. Corresponding values in the male heart are 7%, 12% and 32% per year, documenting that cardiomyogenesis involves a large and progressively increasing number of parenchymal cells with aging. In conclusion, the human heart is a highly dynamic organ in which progressive myocyte loss is at least in part counteracted by enhanced myocyte renewal. Myocyte regeneration in the physiologically aging heart takes place at previously unexpected levels in both women and men.
From the ENT Clinic (Drs. Spanio and Varini) and Institute of Pathology (Drs. Silvestri and Bussa... more From the ENT Clinic (Drs. Spanio and Varini) and Institute of Pathology (Drs. Silvestri and Bussani), University of Trieste. Received for publication Nov. 30, 1994; revision received July 17, 1995; accepted July 21, 1995. Reprint requests: Massimo Spanio, MD, Clinica Otorinolaringoiatrica, Ospedale di Cattinara, Strada di Flume 447, 34149, Trieste, Italy. OTOLARYNGOL HEAl) NECK SURG 1996;114:642-4. Copyright © 1996 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/96/$5.00 + 0 23/4/68144 atypical lymphoid infiltrate with plasmacytoid features, consistent with Waldenstrom's macroglobulinemia, may be found in any reticuloendothelial system-containing organ. Involvement of the lower respiratory tract is not rare. 24 In this article we describe an unusual case of laryngeal involvement, which has never, as far as we know, been reported up to now.
Acta otorhinolaryngologica Italica : organo ufficiale della Società italiana di otorinolaringologia e chirurgia cervico-facciale
Primitive glandular neoplasms of the middle ear are a rare entity. Under this definition epitheli... more Primitive glandular neoplasms of the middle ear are a rare entity. Under this definition epithelial neoplasms are classified according to structure as adenomas or adenocarcinomas, with intact tympanic membrane. Review of the literature shows that four histopathological patterns can be identified among these neoplasms: adenoma, adenocarcinoma, ceruminous adenoma and ceruminous adenocarcinoma. The present work describes a case of primitive ceruminous adenoma of the middle ear (6 cases have been reported in the literature) discovered during exploratory tympanotomy performed on a presumed otitis media which had not responded to medical treatment. The case description is followed by a review of the literature on the subject. The rarity of such neoplasms arises from this review as well as the fact that the histogenesis of ceruminous neoplasms of the middle ear is not clearly defined. Further study is required and more reports need be made in order to establish the best therapeutic approac...
Otolaryngology - Head and Neck Surgery, 1996
Ultrasound in Obstetrics and Gynecology, 2004
New England Journal of Medicine, 2001
Background The scarring of the heart that results from myocardial infarction has been interpreted... more Background The scarring of the heart that results from myocardial infarction has been interpreted as evidence that the heart is composed of myocytes that are unable to divide. However, recent observations have provided evidence of proliferation of myocytes in the adult heart. Therefore, we studied the extent of mitosis among myocytes after myocardial infarction in humans. Methods Samples from the border of the infarct and from areas of the myocardium distant from the infarct were obtained from 13 patients who had died 4 to 12 days after infarction. Ten normal hearts were used as controls. Myocytes that had entered the cell cycle in preparation for cell division were measured by labeling of the nuclear antigen Ki-67, which is associated with cell division. The fraction of myocyte nuclei that were undergoing mitosis was determined, and the mitotic index (the ratio of the number of nuclei undergoing mitosis to the number not undergoing mitosis) was calculated. The presence of mitotic spindles, contractile rings, karyokinesis, and cytokinesis was also recorded. Results In the infarcted hearts, Ki-67 expression was detected in 4 percent of myocyte nuclei in the regions adjacent to the infarcts and in 1 percent of those in regions distant from the infarcts. The reentry of myocytes into the cell cycle resulted in mitotic indexes of 0.08 percent and 0.03 percent, respectively, in the zones adjacent to and distant from the infarcts. Events characteristic of cell division-the formation of the mitotic spindles, the formation of contractile rings, karyokinesis, and cytokinesis-were identified; these features demonstrated that there was myocyte proliferation after myocardial infarction. Conclusions Our results challenge the dogma that the adult heart is a postmitotic organ and raise the possibility that the regeneration of myocytes may contribute to the increase in muscle mass of the myocardium.
American Heart Journal, 1992
European Heart Journal, 2005
Unfavourable cardiac remodelling often complicates acute myocardial infarction (AMI) as a result ... more Unfavourable cardiac remodelling often complicates acute myocardial infarction (AMI) as a result of increased cardiomyocyte apoptosis. It is currently unclear whether ongoing or recurrent ischaemia is an independent determinant for increased apoptosis in peri-infarct viable myocardium. Methods and results In order to assess the link between infarct-related artery (IRA) occlusion, ischaemia, and apoptosis, 30 subjects dying 7-120 days after AMI (16 with IRA occlusion and 14 with patent IRA) and five control subjects were selected at autopsy. Cardiomyocytes were defined as apoptotic if co-expressing TUNEL and activated caspase-3. Expression of both hypoxia-inducible factor-1 and cyclo-oxygenase-2 was assessed in the peri-infarct myocardium and considered as tissue markers of ischaemia. Evidence of ischaemia was significantly more frequent in cases with IRA occlusion (53%) than in cases with patent IRA (15%) or control hearts (0%, P ¼ 0.026). The finding of IRA occlusion and markers of ischaemia identified cases with higher apoptotic rates (ARs) in the peri-infarct viable myocardium [12.2% (8.2-14.0), P , 0.001 vs. others], whereas IRA occlusion without ischaemia was associated with lower AR, not significantly different from patent IRA [3.0% (1.0-7.9) vs. 2.2% (1.0-5.8), respectively, P ¼ 0.42] Conclusion Ischaemia in the peri-infarct viable myocardium is present in over 50% of subjects dying late after AMI with IRA occlusion, and it is associated with increased apoptosis. Relief of ischaemia after AMI may prove of benefit in preventing apoptosis and its consequences.
Dilated Cardiomyopathy, 2019
ABSTRACTCOVID-19 is a deadly pulmonary disease with unique clinical features. A thorough understa... more ABSTRACTCOVID-19 is a deadly pulmonary disease with unique clinical features. A thorough understanding of the molecular and histological correlates of the disease is still missing, especially because post-mortem analysis of COVID-19-affected organs has been so far scant and often anecdotical. Here we report the results of the systematic analysis of 41 consecutive post-mortem samples from individuals who died of COVID-19. We found that the disease is characterized by extensive alveolar damage and thrombosis of the lung micro- and macro-vasculature. Thrombi were in different stages of organization, consistent with an ongoing, endogenous thrombotic process. In all the analyzed samples, in situ RNA hybridization showed that pneumocytes and vascular endothelial cells had massive presence of viral RNA even at the later stages of the disease. An additional feature of the disease was the presence, in the vast majority of patients, of a large number of dysmorphic pneumocytes, often forming l...
In Vivo
Aim: We examined evidence on infective and non-infective endocarditis obtained from a database of... more Aim: We examined evidence on infective and non-infective endocarditis obtained from a database of 50,403 clinical autopsies performed at an Italian general hospital between January 1983 and December 2006. Materials and Methods: Out of 814 endocarditis cases, 409 were of infective endocarditis (IE) and 405 non-infective (NIE). The median age at the time of death was 78 years for those with IE and 83 for those with NIE. Data were collected on gender, clinical history, comorbidities, kind of affected valve (non-prosthetic/mechanical/biological), pathological features of endocarditis, endocarditis complications and microbiological agents. Results: The diagnosis of IE was frequently missed and these conditions were often complicated by cardiovascular events. IE was more common among patients with prior valve infection or cardiovascular surgery, while malignancies were frequent comorbidities of NIE. Conclusion: In general, we found several data that differ from those generally present in the scientific literature, and this could be explained by the fact that data on IE and NIE are generally obtained from surgical and clinical databases, while we analysed only autoptic cases.
Quaderni Europei Sul Nuovo Welfare, 2012
Cardiac complications are a major cause of morbidity and mortality after non-cardiac surgery, who... more Cardiac complications are a major cause of morbidity and mortality after non-cardiac surgery, whose incidence varies according to patient risk stratification and type of patient cohorts investigated. Perioperative myocardial injury may be triggered by different conditions occurring in the perioperative phase, and patient risk factors represent a favorable milieu for triggers to act. The majority of postoperative myocardial ischemia in high-risk patients tends to develop very early on the day of surgery, starting at the end of surgery and during emergence from anesthesia, or on the first postoperative day. Most of postoperative episodes of myocardial ischemia are silent, and show ST-segment depression rather than elevation. Preventive measures are aimed at improving perioperative cardiac outcome, but their identification and application in clinical practice require understanding of the pathophysiology of myocardial ischemia and infarction in non-cardiac surgery patients. Among the protective strategies, beta-blocking agents are the most investigated since 1996, when data from atenolol administration showed a protective effect against myocardial ischemia and infarction in non-cardiac surgery. Since then several clinical studies have reported encouraging results, but conflicting data on possible serious side effects have recently raised concern and doubts about routine administration of beta-blockers in patients at risk undergoing non-cardiac surgery. The aim of this manuscript is to address the main mechanisms responsible for myocardial ischemia in the perioperative phase of non-cardiac surgery and, by going through the recent literature and taking into consideration the very recent European and American recommendations, to provide a pathophysiological approach to the use of beta-blockers in such scenario.
Circulation Research, Aug 3, 2012
The controversy on the growth reserve of the adult human heart has not been resolved and the exte... more The controversy on the growth reserve of the adult human heart has not been resolved and the extent of myocyte renewal reported by different groups varies significantly. Additionally, myocyte regeneration has been claimed to decrease with aging, although cell death is markedly enhanced in the old myocardium. Thus, the effects of age and gender on the magnitude of myocyte turnover were determined. Myocyte replication, senescence and apoptosis were measured in normal female and male human hearts collected from patients 19 to 104 years of age who died from causes other than cardiovascular diseases. Myocardial aging was characterized by a time-dependent increase in the generation of amplifying cardiomyocytes in women and men. Levels of Ki67 and phospho-H3 were comparable in the young female and male heart but differed later in life. As a function of age, the pool of amplifying myocytes was 2-fold higher in women than men, pointing to enhanced myocyte renewal in the female heart. The frequency of p16 INK4a -positive myocytes was higher in men than in women. From 19 to 104 years of age, the time-dependent increase in senescent myocytes was 0.68% per year in women and 0.89% per year in men; the 31% higher rate of accumulation of old myocytes in the aging male heart was significant. Myocyte apoptosis occurred only in p16 INK4a -positive cells and was consistently higher in men than in women at all age intervals. However, the increase in myocyte apoptosis with age did not differ with gender. Based on these parameters, we measured the average age of cardiomyocytes, their age distribution, turnover rate and time to acquire the senescent phenotype to define the biology of myocardial aging as a function of lifespan. In the female heart, myocyte turnover occurs at a rate of 10%, 15% and 40% per year at 20, 60 and 100 years of age, respectively. Corresponding values in the male heart are 7%, 12% and 32% per year, documenting that cardiomyogenesis involves a large and progressively increasing number of parenchymal cells with aging. In conclusion, the human heart is a highly dynamic organ in which progressive myocyte loss is at least in part counteracted by enhanced myocyte renewal. Myocyte regeneration in the physiologically aging heart takes place at previously unexpected levels in both women and men.
From the ENT Clinic (Drs. Spanio and Varini) and Institute of Pathology (Drs. Silvestri and Bussa... more From the ENT Clinic (Drs. Spanio and Varini) and Institute of Pathology (Drs. Silvestri and Bussani), University of Trieste. Received for publication Nov. 30, 1994; revision received July 17, 1995; accepted July 21, 1995. Reprint requests: Massimo Spanio, MD, Clinica Otorinolaringoiatrica, Ospedale di Cattinara, Strada di Flume 447, 34149, Trieste, Italy. OTOLARYNGOL HEAl) NECK SURG 1996;114:642-4. Copyright © 1996 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/96/$5.00 + 0 23/4/68144 atypical lymphoid infiltrate with plasmacytoid features, consistent with Waldenstrom's macroglobulinemia, may be found in any reticuloendothelial system-containing organ. Involvement of the lower respiratory tract is not rare. 24 In this article we describe an unusual case of laryngeal involvement, which has never, as far as we know, been reported up to now.
Acta otorhinolaryngologica Italica : organo ufficiale della Società italiana di otorinolaringologia e chirurgia cervico-facciale
Primitive glandular neoplasms of the middle ear are a rare entity. Under this definition epitheli... more Primitive glandular neoplasms of the middle ear are a rare entity. Under this definition epithelial neoplasms are classified according to structure as adenomas or adenocarcinomas, with intact tympanic membrane. Review of the literature shows that four histopathological patterns can be identified among these neoplasms: adenoma, adenocarcinoma, ceruminous adenoma and ceruminous adenocarcinoma. The present work describes a case of primitive ceruminous adenoma of the middle ear (6 cases have been reported in the literature) discovered during exploratory tympanotomy performed on a presumed otitis media which had not responded to medical treatment. The case description is followed by a review of the literature on the subject. The rarity of such neoplasms arises from this review as well as the fact that the histogenesis of ceruminous neoplasms of the middle ear is not clearly defined. Further study is required and more reports need be made in order to establish the best therapeutic approac...
Otolaryngology - Head and Neck Surgery, 1996
Ultrasound in Obstetrics and Gynecology, 2004
New England Journal of Medicine, 2001
Background The scarring of the heart that results from myocardial infarction has been interpreted... more Background The scarring of the heart that results from myocardial infarction has been interpreted as evidence that the heart is composed of myocytes that are unable to divide. However, recent observations have provided evidence of proliferation of myocytes in the adult heart. Therefore, we studied the extent of mitosis among myocytes after myocardial infarction in humans. Methods Samples from the border of the infarct and from areas of the myocardium distant from the infarct were obtained from 13 patients who had died 4 to 12 days after infarction. Ten normal hearts were used as controls. Myocytes that had entered the cell cycle in preparation for cell division were measured by labeling of the nuclear antigen Ki-67, which is associated with cell division. The fraction of myocyte nuclei that were undergoing mitosis was determined, and the mitotic index (the ratio of the number of nuclei undergoing mitosis to the number not undergoing mitosis) was calculated. The presence of mitotic spindles, contractile rings, karyokinesis, and cytokinesis was also recorded. Results In the infarcted hearts, Ki-67 expression was detected in 4 percent of myocyte nuclei in the regions adjacent to the infarcts and in 1 percent of those in regions distant from the infarcts. The reentry of myocytes into the cell cycle resulted in mitotic indexes of 0.08 percent and 0.03 percent, respectively, in the zones adjacent to and distant from the infarcts. Events characteristic of cell division-the formation of the mitotic spindles, the formation of contractile rings, karyokinesis, and cytokinesis-were identified; these features demonstrated that there was myocyte proliferation after myocardial infarction. Conclusions Our results challenge the dogma that the adult heart is a postmitotic organ and raise the possibility that the regeneration of myocytes may contribute to the increase in muscle mass of the myocardium.
American Heart Journal, 1992
European Heart Journal, 2005
Unfavourable cardiac remodelling often complicates acute myocardial infarction (AMI) as a result ... more Unfavourable cardiac remodelling often complicates acute myocardial infarction (AMI) as a result of increased cardiomyocyte apoptosis. It is currently unclear whether ongoing or recurrent ischaemia is an independent determinant for increased apoptosis in peri-infarct viable myocardium. Methods and results In order to assess the link between infarct-related artery (IRA) occlusion, ischaemia, and apoptosis, 30 subjects dying 7-120 days after AMI (16 with IRA occlusion and 14 with patent IRA) and five control subjects were selected at autopsy. Cardiomyocytes were defined as apoptotic if co-expressing TUNEL and activated caspase-3. Expression of both hypoxia-inducible factor-1 and cyclo-oxygenase-2 was assessed in the peri-infarct myocardium and considered as tissue markers of ischaemia. Evidence of ischaemia was significantly more frequent in cases with IRA occlusion (53%) than in cases with patent IRA (15%) or control hearts (0%, P ¼ 0.026). The finding of IRA occlusion and markers of ischaemia identified cases with higher apoptotic rates (ARs) in the peri-infarct viable myocardium [12.2% (8.2-14.0), P , 0.001 vs. others], whereas IRA occlusion without ischaemia was associated with lower AR, not significantly different from patent IRA [3.0% (1.0-7.9) vs. 2.2% (1.0-5.8), respectively, P ¼ 0.42] Conclusion Ischaemia in the peri-infarct viable myocardium is present in over 50% of subjects dying late after AMI with IRA occlusion, and it is associated with increased apoptosis. Relief of ischaemia after AMI may prove of benefit in preventing apoptosis and its consequences.
Dilated Cardiomyopathy, 2019
ABSTRACTCOVID-19 is a deadly pulmonary disease with unique clinical features. A thorough understa... more ABSTRACTCOVID-19 is a deadly pulmonary disease with unique clinical features. A thorough understanding of the molecular and histological correlates of the disease is still missing, especially because post-mortem analysis of COVID-19-affected organs has been so far scant and often anecdotical. Here we report the results of the systematic analysis of 41 consecutive post-mortem samples from individuals who died of COVID-19. We found that the disease is characterized by extensive alveolar damage and thrombosis of the lung micro- and macro-vasculature. Thrombi were in different stages of organization, consistent with an ongoing, endogenous thrombotic process. In all the analyzed samples, in situ RNA hybridization showed that pneumocytes and vascular endothelial cells had massive presence of viral RNA even at the later stages of the disease. An additional feature of the disease was the presence, in the vast majority of patients, of a large number of dysmorphic pneumocytes, often forming l...
In Vivo
Aim: We examined evidence on infective and non-infective endocarditis obtained from a database of... more Aim: We examined evidence on infective and non-infective endocarditis obtained from a database of 50,403 clinical autopsies performed at an Italian general hospital between January 1983 and December 2006. Materials and Methods: Out of 814 endocarditis cases, 409 were of infective endocarditis (IE) and 405 non-infective (NIE). The median age at the time of death was 78 years for those with IE and 83 for those with NIE. Data were collected on gender, clinical history, comorbidities, kind of affected valve (non-prosthetic/mechanical/biological), pathological features of endocarditis, endocarditis complications and microbiological agents. Results: The diagnosis of IE was frequently missed and these conditions were often complicated by cardiovascular events. IE was more common among patients with prior valve infection or cardiovascular surgery, while malignancies were frequent comorbidities of NIE. Conclusion: In general, we found several data that differ from those generally present in the scientific literature, and this could be explained by the fact that data on IE and NIE are generally obtained from surgical and clinical databases, while we analysed only autoptic cases.
Quaderni Europei Sul Nuovo Welfare, 2012