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Biomedical subjects

P Anversa

Publications and source records attributed to P Anversa.

At least 73 records · Page 4Linked to original sources
PubMed1997

Coronary constriction impairs cardiac function and induces myocardial damage and ventricular remodeling in mice.

To establish whether coronary artery narrowing (CAN) in mice was accompanied by depressed ventricular function, tissue injury, and modifications in cardiac anatomy, the left coronary artery was constricted in FVB/N mice and the animals were killed 7 days later. CAN consisted of a 53% reduction in luminal diameter, which resulted in a twofold increase in left ventricular end-diastolic pressure. Left ventricular systolic pressure and left ventricular + and -dP/dt decreased 15, 21, and 11%, respectively. Left ventricular weight-to-body weight ratio increased 33%. This hypertrophic adaptation was characterized by a 9 and 20% increase in the longitudinal and transverse cavitary diameters, which provoked a 1.5-fold expansion in chamber volume. In contrast, wall thickness decreased 15%. These anatomic and functional changes induced a threefold elevation in diastolic stress. Foci of reparative fibrosis were found in the endomyocardium and epimyocardium, involving 2-3% of the tissue. Finally, myocyte loss in the ventricle was 15%, and myocyte hypertrophy was 38%. Impaired ventricular function, diastolic Laplace overloading, myocyte loss, and decompensated eccentric hypertrophy in mice after CAN mimic the ischemic cardiomyopathic heart in humans.

Animals↗
PubMed1996

Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice.

Transgenic mice were generated in which the cDNA for the human insulin-like growth factor 1B (IGF-1B) was placed under the control of a rat alpha-myosin heavy chain promoter. In mice heterozygous for the transgene, IGF-1B mRNA was not detectable in the fetal heart at the end of gestation, was present in modest levels at 1 day after birth, and increased progressively with postnatal maturation, reaching a peak at 75 days. Myocytes isolated from transgenic mice secreted 1.15 +/- 0.25 ng of IGF-1 per 10(6) cells per 24 hr versus 0.27 +/- 0.10 ng in myocytes from homozygous wild-type littermates. The plasma level of IGF-1 increased 84% in transgenic mice. Heart weight was comparable in wild-type littermates and transgenic mice up to 45 days of age, but a 42%, 45%, 62%, and 51% increase was found at 75, 135, 210, and 300 days, respectively, after birth. At 45, 75, and 210 days, the number of myocytes in the heart was 21%, 31%, and 55% higher, respectively, in transgenic animals. In contrast, myocyte cell volume was comparable in transgenic and control mice at all ages. In conclusion, overexpression of IGF-1 in myocytes leads to cardiomegaly mediated by an increased number of cells in the heart.

Animals↗
PubMed1996

Programmed myocyte cell death affects the viable myocardium after infarction in rats.

To determine whether apoptotic and necrotic myocyte cell death occur acutely and chronically after infarction, the formation of DNA strand breaks and the localization of myosin monoclonal antibody labeling were analyzed in the surviving myocardium from 20 min to 1 month. DNA strand breaks in myocyte nuclei were detected as early as 3 h following coronary artery occlusion and were still present at 1 month. This cellular process was characterized biochemically by internucleosomal DNA fragmentation which produced DNA laddering on agarose gel electrophoresis. Quantitatively, 155 myocyte nuclei per 10(6) cells exhibited DNA strand breaks in the portion adjacent to the infarcted tissue at 3-12 h. This parameter increased to 704 at 1-2 days and subsequently decreased to 364 at 7 days, 188 at 14 days, and 204 at 1 month. In the remote myocardium, the number of myocyte nuclei with DNA strand breaks was 84 per 10(6) at 3-12 h and remained essentially constant up to 1 month. Programmed myocyte cell death was accompanied by a decrease in the expression of bcl-2 and an increase in the expression of bax. The changes in the expression of these genes were present at 1 and 7 days after coronary artery occlusion. In conclusion, the mechanical load produced by myocardial infarction and ventricular failure may affect the regulation of bcl-2 and bax in the viable myocytes, triggering programmed cell death and the remodeling of the ventricular wall.

Animals↗
PubMed1996

Myocardial infarction is coupled with activation of cyclins and cyclin-dependent kinases in myocytes.

To determine whether the molecular components implicated in the regulation of the cell cycle are activated in myocytes after infarction, the expression of cyclins E, A, and B and the levels of their associated kinase activity were measured at 1 and 7 days following surgery. The quantity of cdk2 and cdc2 and the level of their kinase activity were also determined. Myocardial infarction was characterized by an increase in cyclins E, A, and B and cdc2 proteins in the surviving myocytes at 1 and 7 days. Cyclin E, A, and B and cdk2 and cdc2 kinase activity also increased. The quantity of cyclins E and A and the level of cyclin E-associated kinase activity in myocytes after infarction were comparable with those measured in neonatal myocytes. Moreover, cdc2 protein and cdc2 kinase activity in myocytes reached levels after infarction which were similar to those in neonatal myocytes. Thus, myocytes react to myocardial infarction by activating cyclins and cyclin-dependent kinases which may be coupled with the regeneration of muscle mass and recovery of ventricular function.

Animals↗
PubMed1996

Myocardial Infarction Is Coupled with the Activation of Cyclins and Cyclin-Dependent Kinases in Myocytes

To determine whether the molecular components implicated in the regulation of the cell cycle are activated in myocytes after infarction, the expression of cyclins E, A, and B and the levels of their associated kinase activity were measured at 1 and 7 days following surgery. The quantity of cdk2 and cdc2 and the level of their kinase activity were also determined. Myocardial infarction was characterized by an increase in cyclins E, A, and B and cdc2 proteins in the surviving myocytes at 1 and 7 days. Cyclin E, A, and B and cdk2 and cdc2 kinase activity also increased. The quantity of cyclins E and A and the level of cyclin E-associated kinase activity in myocytes after infarction were comparable with those measured in neonatal myocytes. Moreover, cdc2 protein and cdc2 kinase activity in myocytes reached levels after infarction which were similar to those in neonatal myocytes. Thus, myocytes react to myocardial infarction by activating cyclins and cyclin-dependent kinases which may be coupled with the regeneration of muscle mass and recovery of ventricular function.

Journal Article↗
PubMed1996

Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart.

The current investigation was designed to evaluate whether the proportion of mononucleated binucleated, trinucleated and tetranucleated myocytes varies in the left ventricle, interventricular septum and right ventricular free wall with aging, cardiac hypertrophy and ischemic cardiomyopathy. In addition, the number and dimensional properties of myocytes were measured to determine whether a relationship existed between myocyte size and number, and organ hypertrophy. For this purpose, 72 normal hearts were obtained from individuals who died from causes other than cardiovascular disease and compared with 81 hypertrophied hearts and 95 with ischemic cardiomyopathy. The age interval examined varied from 26 to 93 years. The analysis of enzymatically dissociated myocytes in control left ventricles demonstrated that mononucleated, binucleated, trinucleated, trinucleated and tetranucleated myocytes comprised 74%, 25.5%, 0.4% and 0.1% of the entire myocyte population. Similarly, mononucleated myocytes constituted the prevailing cell population of the interventricular septum and right ventricular free wall. Aging, myocardial hypertrophy and ischemic cardiomyopathy did not change the percentage of mononucleated and multinucleated myocyte in the ventricular myocardium. Cardiac hypertrophy and ischemic cardiomyopathy were characterized by comparable increase in myocyte size in spite of a significant difference in the magnitude of myocardial hypertrophy. Myocyte number was increased in hypertrophied hearts, whereas myocyte cell loss occurred in ischemic cardiomyopathy. In conclusion, aging, cardiac hypertrophy and ischemic cardiomyopathy do not alter the fractions of mononucleated and multinucleated myocytes in the myocardium.

Adult↗
PubMed1996

Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart.

Conditions of diastolic overload associated with increases in filling pressure trigger apoptosis. Moreover, ischemia alone and ischemia followed by reperfusion induce programmed cell death in myocytes in vitro. On this basis, the possibility was raised that apoptotic myocyte cell death may occur in the surviving myocardium acutely after infarction. Myocardial samples were obtained from the region adjacent to and remote from infarction in patients who died within 10 days from the initial clinical symptoms. Apoptosis was measured quantitatively by the terminal deoxynucleotidyl transferase assay and confirmed biochemically by DNA extraction and agarose gel electrophoresis. This analysis included 20 infarcted and ten control hearts. DNA strand breaks in myocyte nuclei were observed in all 20 infarcted hearts in both the regions bordering on and distant from the necrotic myocardium. However, the number of apoptotic nuclei was greater in the peri-infarcted region than in that away from infarction. Quantitatively, 12% of myocytes in the border zone showed DNA strand breaks, whereas 1% of cells were undergoing apoptosis in the remote myocardium. Moreover DNA laddering was detected biochemically in these two regions of the heart. Thus, apoptosis appears to be a significant complicating factor of acute myocardial infarction increasing the magnitude of myocyte cell death associated with coronary artery occlusion.

Adult↗
PubMed1996

Myocyte death in heart failure.

Decompensated eccentric ventricular hypertrophy characterizes the transition from compensated pressure or volume over-load hypertrophy to myocardial dysfunction and failure. Myocyte loss is the major etiologic factor of wall thinning and chamber dilation and may condition the progression of the cardiac myopathy. Myocyte death can occur by apoptosis or necrosis, but the activation of the suicide program of myocytes exceeds necrotic cell death in the pathologic heart of ischemic origin. Whether reactive fibrosis constitutes a primary event in the initiation of ventricular dysfunction or a secondary reaction to myocyte death is an important unanswered question.

Animals↗
PubMed1996

Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats.

To determine the effects of aging on myocyte cell death, Fischer 344 rats at 3, 7, 12, 16, and 24 mo of age were injected with myosin monoclonal antibody for the localization and quantification of necrotic myocyte cell death in the left ventricle, interventricular septum, and right ventricle. Conversely, the presence of DNA strand breaks in myocyte nuclei, indicative of programmed cell death, was evaluated by the terminal deoxynucleotidyl transferase assay and confirmed by DNA laddering. Myocyte necrosis, which involved nearly 1,000 myocytes in the left ventricular free wall at 3 mo, progressively increased with aging, reaching a value of 13,600 myocytes at 24 mo. Corre- sponding values in the interventricular septum were 300 and 9,400 myocytes. In the right ventricle, there were 270 necrotic myocytes at 3 mo and 9,000 at 24 mo. Programmed myocyte cell death was restricted to the left ventricular free wall and included 140 cells at 3 mo. This form of myocyte cell death increased at the subsequent age intervals, resulting in the involvement of 874 cells at 24 mo. The combination of necrosis and apoptosis in the left ventricular free wall was associated with 1,150 cells dying at 3 mo and 14,500 at 24 mo. In conclusion, myocyte cell death, apoptotic and necrotic in nature, constitutes an important determinant of the aging process, possibly mediating the occurrence of ventricular dysfunction and failure in the old heart.

Aging↗
PubMed1996

Aging does not affect the activation of the myocyte insulin-like growth factor-1 autocrine system after infarction and ventricular failure in Fischer 344 rats.

To determine whether the attenuation in the growth capacity of myocytes in the overloaded aging heart is associated with an impairment in the activation of insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) in the stressed cells, large myocardial infarcts were produced in Fischer 344 rats at 4 and 16 months of age, and the animals were killed 6 hours, 3 days, and 7 days later. After the documentation of cardiac failure, the unaffected myocytes were enzymatically dissociated, and the expression of IGF-1 and IGF-1R was measured at these three time points after surgery. The level of expression of IGF-1R mRNA increased at 3 days and remained elevated at 7 days in both age groups. In addition, an increase in IGF-1R protein in these cells was found, with no apparent difference with age. This phenomenon was coupled with an upregulation of IGF-1 mRNA of comparable magnitude in the younger and older animals. In contrast, the increases in the dimensional properties of myocytes were delayed and of smaller magnitude in the older infarcted rats. Moreover, the expression of atrial natriuretic factor, used as a molecular marker of myocyte cellular hypertrophy, was greater at 3 days in 4-month-old rats and at 7 days in 16-month-old rats. Thus, aging may affect the hypertrophic response of myocytes after infarction but has no impact on the ability of the cells to enhance the expression of IGF-1 and IGF-1R, which may sustain only in part the growth reserve mechanisms of the pathological heart.

Aging↗
PubMed1996

Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats.

Programmed cell death in the myocardium has been linked to ischemia reperfusion injury as well as to excessive mechanical forces associated with increases in ventricular loading. Moreover, hypoxia activates the suicide program of cardiac myocytes in vitro. Because the supplied portion of the ventricular wall is ischemic and subjected to high levels of systolic and diastolic stresses (acutely after coronary artery occlusion), apoptosis and necrosis may contribute independently to myocyte cell death after infarction. Therefore, myocardial infarction was produced in rats, and, after the determination of ventricular hemodynamics, the contribution of apoptotic and/or necrotic myocyte cell death to infarct size was measured quantitatively from 20 minutes to 7 days after coronary artery occlusion. Programmed cell death was assessed by the terminal deoxynucleotidyl transferase assay and by the electrophoretic detection of DNA laddering. Myocyte necrosis was evaluated by myosin monoclonal Ab labeling. Moreover, the expression of Bcl-2, Bax, and Fas proteins in myocytes was examined by immunocytochemistry. Myocyte cell death by apoptosis and necrosis comprised nearly 3 million myocytes at 2 hours. Apoptotic cell death involved 2.8 million cells and necrotic cell death only 90,000 myocytes. Apoptosis continued to represent the major independent form of myocyte cell death, affecting 6.6 million myocytes at 4.5 hours. Myocyte necrosis peaked at 1 day, including 1.1 million myocytes. DNA electrophoretic analysis confirmed these observations by showing nucleosomal ladders at 2-3 hours, 4.5 hours, 1 day, and 2 days after coronary artery occlusion. Myocytes showing both DNA strand breaks and myosin labeling were a prominent aspect of myocardial damage only after 6 hours. Finally, the expression of Bcl-2 and Fas in myocytes increased 18-fold and 131-fold, respectively. In conclusion, programmed myocyte cell death is the major form of myocardial damage produced by occlusion of a major epicardial coronary artery, whereas necrotic myocyte cell death follows apoptosis and contributes to the progressive loss of cells with time after infarction. The enhanced expression of Fas may be implicated in the activation of apoptosis in spite of the increase in Bcl-2, which tends to preserve cell survival.

Animals↗
PubMed1995

The cellular basis of pacing-induced dilated cardiomyopathy. Myocyte cell loss and myocyte cellular reactive hypertrophy.

BACKGROUND: Rapid ventricular pacing leads to a cardiac myopathy consisting of an increase in chamber dimension, mural thinning, elevation in ventricular wall stress, and congestive heart failure, mimicking dilated cardiomyopathy in humans. However, contrasting results have been obtained concerning the mechanisms of ventricular dilation and the existence of myocardial hypertrophy. Moreover, questions have been raised regarding the occurrence of myocardial damage and cell loss in the development of the experimental myopathy. METHODS AND RESULTS: The functional and structural characteristics of the heart were studied in conscious dogs subjected to left ventricular pacing at 210 beats per minute for 3 weeks and 240 beats per minute for an additional week. At the time the animals were killed, measurements of myocardial structural integrity and myocyte shape, size, and number were determined by morphometric analysis of the myocardium in situ and enzymatically dissociated cells. The experimental protocol used was associated with overt cardiac failure documented by an increase in left ventricular end-diastolic pressure and a decrease in left ventricular systolic pressure and +dP/dt in combination with tachycardia, ascites, and pulmonary congestion. Although cardiac weights were not altered, cavitary diameter was increased and wall thickness was decreased from the base to the apex of the heart. Multiple foci of replacement fibrosis, comprising 6% of the myocardium, were detected across the left ventricular wall. Measurements of myocyte size and number documented a 39% loss of cells in the entire ventricle and a 61% increase in volume of the remaining viable myocytes. Myocyte hypertrophy was characterized by a 33% increase in cell length and a 23% increase in transverse area, resulting in a 23% increase in the cell length-to-cell diameter ratio. Pacing did not alter the relative proportion of mononucleated, binucleated, and multinucleated myocytes in the myocardium. CONCLUSIONS: Myocyte cell loss and myocyte reactive hypertrophy are the major components of ventricular remodeling in pacing-induced dilated cardiomyopathy.

Animals↗
PubMed1995

Programmed cell death and expression of the protooncogene bcl-2 in myocytes during postnatal maturation of the heart.

To determine whether programmed myocyte cell death is a major component of the differential growth adaptation of the right and left ventricle during development, the formation of DNA strand breaks in myocyte nuclei was identified and quantitated in hearts of rats at the end of gestation and at 1, 5, 11, and 21 days after birth. Incorporation of BrdU in left and right ventricular myocytes was also evaluated. Moreover, the expression of bcl-2 in myocytes was determined. Programmed myocyte cell death was absent in the fetal heart but affected the myocardium postnatally. This phenomenon was no longer detectable at 21 days. DNA strand breaks in nonmyocyte nuclei were present at all time intervals. Quantitatively, 10.4, 6.1, and 2.5 myocyte nuclei/10,000 nuclei exhibited DNA degradation at 1 day in the right ventricle, interventricular septum, and left ventricule, respectively. Corresponding values at 5 days were 3.7, 3.5, and 2.0 myocyte nuclei/10,000 nuclei. At 11 days, programmed cell death involved 1.2, 1.5, and 0.53 myocyte nuclei/10,000 nuclei in these three regions of the heart. The 4.2-fold, 1.9-fold, and 2.3-fold greater magnitude of programmed cell death in the right ventricle at 1, 5, and 11 days was statistically significant. In contrast, BrdU incorporation in myocytes decreased in a comparable manner in the left and right ventricles with maturation. Importantly, bcl-2 mRNA levels were high in fetal myocytes, decreased markedly at 1 and 5 days, and progressively increased at 11 and 21 days. The expression of bcl-2 was lower in right than in left ventricular myocytes. In conclusion, programmed myocyte cell death is inversely related to bcl-2 expression and affects the right ventricle more than the left ventricle during postnatal development. This phenomenon may be crucial in the modulation of the number of myocytes in the two ventricles during the transition from the fetal to the adult circulatory system.

Aging↗
PubMed1995

Gender differences and aging: effects on the human heart.

OBJECTIVES: This study investigated the changes in myocyte size and number in the left and right ventricles that occur with aging in the female and male heart. BACKGROUND: Differences in life span between women and men may be related to a better preservation of myocardial structure in the female heart with aging. On this basis, the hypothesis was advanced that the aging process has a different impact on the integrity of the myocardium in the two genders. METHODS: Morphometric methodologies were applied to analyze the changes in number and size of ventricular myocytes in the hearts of 53 women and 53 men. The changes in mononucleated and binucleated myocytes with age were determined in enzymatically dissociated cells. The age interval examined varied from 17 to 95 years. RESULTS: Aging was associated with a preservation of ventricular myocardial mass, aggregate number of mononucleated and binucleated myocytes, average cell diameter and volume in the female heart. In contrast, nearly 1 g/year of myocardium was lost in the male heart, and this phenomenon accounted for the loss of approximately 64 million cells. This detrimental effect involved the left and right sides of the heart. In the remaining cells, myocyte cell volume increased at a rate of 158 microns3/year in the left and 167 microns3/year in the right ventricle. CONCLUSIONS: Aging does not lead to myocyte cell loss and myocyte cellular reactive hypertrophy in women, indicating that gender differences may play a significant role in the detrimental effects of the aging process on the heart.

Adolescent↗
PubMed1995

The cellular basis of dilated cardiomyopathy in humans.

The present investigation was designed to evaluate whether end-stage cardiac failure in patients affected by dilated cardiomyopathy (DC) was dependent upon extensive myocyte cell death with reduction in muscle mass or was the consequence of collagen accumulation in the myocardium independently from myocyte cell loss. In addition, the mechanisms of ventricular dilation were analysed in order to determine whether the changes in cardiac anatomy were important variables in the development of intractable congestive heart failure. DC is characterized by chamber dilation, myocardial scarring and myocyte hypertrophy in the absence of significant coronary atherosclerosis. However, the relative contribution of each of these factors to the remodeling of the ventricle is currently unknown. Moreover, no information is available concerning the potential etiology of collagen deposition in the myocardium and the changes in number and size of ventricular myocytes with this disease. Morphometric methodologies were applied to the analysis of 10 DC hearts obtained from patients undergoing cardiac transplantation. An identical number of control hearts was collected from individuals who died from causes other than cardiovascular diseases. DC produced a 2.2-fold and 4.2-fold increase in left ventricular weight and chamber volume resulting in a 48% reduction in mass-to-volume ratio. In the right ventricle, tissue weight and chamber size were both nearly doubled. Left ventricular dilation was the result of a 59% lengthening of myocytes and a 20% increase in the transverse circumference due to slippage of myocytes within the wall. Myocardial scarring represented by segmental, replacement and interstitial fibrosis occupied approximately 20% of each ventricle, and was indicative of extensive myocyte cell loss. However, myocyte number was not reduced and average cell volume increased 2-fold in both ventricles. In conclusion, reactive growth processes in myocytes and architectural rearrangement of the muscle compartment of the myocardium appear to be the major determinants of ventricular remodeling and the occurrence of cardiac failure in DC.

Autopsy↗