Steven Goldfine - Academia.edu (original) (raw)
Papers by Steven Goldfine
Cardiology, 1998
Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic r... more Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic regurgitation (AR), and may be related to the pathophysiology of congestive heart failure (CHF) in this disease. To define the relationship between myocardial histopathologic variations and CHF in chronic AR, we performed gross and microscopic evaluations of postmortem tissue from a rabbit model of chronic AR manifesting left ventricular (LV) responses to AR similar to those in humans. Moderate-to-severe chronic AR (echocardiographic regurgitant fraction = 52 ± 13%) was induced by closed-chest aortic valve perforation in 11 New Zealand White rabbits; 5 control rabbits were sham operated. Six of the 11 AR rabbits died 1.5 ± 0.8 years (range 0.6–2.8 years) after AR induction; all 6 had gross and histologic anatomic evidence of CHF at necropsy. The remaining 5 AR rabbits survived until sacrifice at 2.9 ± 0.1 years of AR; none had pathologic evidence of CHF. Cardiac hypertrophy and the extent of LV fibrosis and myocyte necrosis all were greatest among the 6 AR CHF rabbits. No inflammatory response was apparent in any animal. Moderate-to-severe chronic experimental AR frequently results in CHF which is strongly associated with myocardial fibrosis and necrosis, without evidence of inflammation. These histopathologic variations may be pathophysiologically related to CHF development.
Springer eBooks, Nov 22, 2007
ABSTRACT Regurgitant valvular heart diseases and, most particularly, insufficiency of the aortic ... more ABSTRACT Regurgitant valvular heart diseases and, most particularly, insufficiency of the aortic and/or mitral valves (AR, MR), are among the more common, and most predictable, causes of congestive heart failure. Current data suggest that these conditions also confer a proclivity for sudden death, even among asymptomatic or minimally symptomatic patients (1,2,3).
ABSTRACT The authors have developed a 3-compartment model for determining the distribution of lab... more ABSTRACT The authors have developed a 3-compartment model for determining the distribution of label derived from L-[l-/sup 14/C]leucine (LEU) in myocardial tissue. The 3 compartments are the pools of tissue precursor (i.e. free) LEU, protein-incorporated leucine (P-LEU), and the leucine metabolite /spl alpha/-ketoisocaproate (KIC). To apply this model to positron emission tomography (PET) of the heart with /sup 11/C labeled LEU, the portion of image activity within the protein pool must be determined. The authors have determined experimentally the kinetic rate coefficients for LEU metabolism in heart protein and used them to calculate the distribution of activity in the tissue LEU, P-LEU and KIC pools from the plasma LEU activity. The authors then applied these results in simulation studies modeling PET image acquisition using L-[1-/sup 11/C]LEU. Their findings indicate that PET imaging of protein metabolism with L-[l-/sup 11/C]LEU is feasible.< >
ABSTRACT We have previously shown that left ventricular (LV) shape transformation (from ellipsoid... more ABSTRACT We have previously shown that left ventricular (LV) shape transformation (from ellipsoid toward spherical) may modulate abnormal myocardial wall stresses occurring as a result of chronic severe aortic regurgitation (AR). If so then the extent of spherical shape change in AR may be inversely related to myocyte injury. To test this hypothesis, we compared the endocardial/epicardial antimyosin antibody uptake ratio in hearts from rabbits with early-AR and late-AR and from controls. The endocardial/epicardial antimyosin antibody activity ratio was increased in ellipsoid shaped late-AR hearts (vs control, p<.001), but not in early-AR or spherically shaped late-AR hearts. Thus, spherical shape is associated with less endocardial injury than ellipsoidal shape in the late AR LV
In severe, chronic aortic regulation (AR) in man, systolic pressure time interval and diastolic p... more In severe, chronic aortic regulation (AR) in man, systolic pressure time interval and diastolic pressure time interval measurements suggest an abnormal load-to-endocardial blood flow relationship. To better define this relationship, the authors extended their previously reported model for determining myocardial wall stress in include radial stress from endocardial (ENDO) to epicardium (EPI), a factor believed to influence distribution of coronary blood flow. Estimates of radial, circumferential and meridional stresses were compared with axial and transmyocardial blood flow measured from the base to apex and ENDO to EPI in normal rabbits and rabbits with severe, chronic AR. The authors' results suggest that blood flow is uniform from base to apex but not from ENDO to EPI near the apex where radial wall stress may influence blood flow.<<ETX>>
Journal of Nuclear Cardiology, 1997
Fiber dropout and myocyte necrosis precede heart failure in experimental aortic regurgitation (AR... more Fiber dropout and myocyte necrosis precede heart failure in experimental aortic regurgitation (AR). The current study aimed to determine whether this process can be detected by noninvasive scintigraphic imaging. 111In-labeled antimyosin antibody Fab fragment (1 to 1.5 mCi) (Myoscint) was administered to each of 34 New Zealand White rabbits: 11 early (3 to 5 weeks) after surgical AR induction; 9 late (98 to 128 weeks) after AR induction; 5 normal and 3 sham-operated age-matched with early AR; and 3 normal and 3 sham-operated age-matched with late AR. Echocardiographic fractional shortening was indistinguishable among control, early AR, and late AR groups. In vivo gamma camera imaging 24 and 48 hours after isotope administration, post-mortem heart activity determination (percentage injected dose per gram), and autoradiography were performed. At 24 and 48 hours, heart-to-lung counts-per-pixel ratios from in vivo images were greater (p < 0.05) in the late AR rabbits than in each of the three other groups. No significant differences were found when early AR and older or younger control rabbits were compared. Heart activity (percentage injected dose per gram) in late AR rabbits trended toward higher values than in age-matched control rabbits (p = 0.057), but in early AR it was indistinguishable from that in the corresponding control (p = 0.413, difference not significant). The autoradiographic endocardial/epicardial activity ratio in late AR rabbits was greater than in control and early AR rabbits (1.27 +/- 0.13 vs 1.06 +/- 0.09 and vs 1.13 +/- 0.10, respectively, p < 0.02). Whereas isotope uptake in late AR rabbits differed from that in control and early AR rabbits, systolic function was indistinguishable. Thus 111In-labeled antimyosin antibody imaging may permit noninvasive detection of AR-induced myocardial damage before functional deterioration.
Virology, Jun 1, 1978
ABSTRACT Antisera used previously to assay SV40 T antigen have been produced in tumor-bearing ham... more ABSTRACT Antisera used previously to assay SV40 T antigen have been produced in tumor-bearing hamsters. This report describes the production and characterization of antiserum produced by injection of rabbits with denatured large-T antigen (Ag) purified by immunoprecipitation and electrophoresis. The resulting antiserum reacts with native large-T Ag as determined by indirect immunofluorescence, complement fixation, and indirect immunoprecipitation assays and binds to species such as “small-T Ag” and previously described proteolytic fragments of large-T Ag.
De Gruyter eBooks, Dec 31, 1990
Journal of the American College of Cardiology, Feb 1, 1995
The impact of regional wall stress (WS) abnormalities on regional coronary flow (CBF) in aortic r... more The impact of regional wall stress (WS) abnormalities on regional coronary flow (CBF) in aortic regurgitation (AR) is not known. However, the existence of such a relation is of potential importance since it might account in part for LV dysfunction and myocardial fibrosis seen in AR, and could suggest therapeutic strategies. We have previously developed and validated a method for calculating regional WS in the radial, circumferential and meridional directions from mid wall (MW) to apex (AP) and endocardium (ENDO) to epicardium (EPI) using a 4000 element model of the LV To define the relation of regional WS and CSF in AR, we applied our LV model in 5 normal (NL) and 4 AR rabbits in which regional CBF was measured using fluorescent microspheres. CBF and radial WS were as follows: CBF (ml/min/gm) Radial WS (× 103dynes/cm2) MW AP MW AP NL EPI 2.49 1.30 83 29* ENDO 2.09 0.74 133 133* AR EPI 1.82 1.82* 86 38* ENDO 1.41 0.77* 133 133* *= p l 0.001 (EPI vs ENDO for CSF, EPI to ENDO gradient in AR vs NL for radial WS) Thus, in AR, transmural CBF distribution varies significantly at the apex, while this tendency is less marked and less consistent in NL. No discernable transmural variation was apparent elsewhere in either group. These differences paralleled inversely the transmural variations in radial WS in AR vs NL. In contrast, meridional WS and circumferential WS were uniformly and significantly higher in AR than NL at apex and base (all p l 0.001), a pattern which bore no relation to regional CSF pattern. Thus, regional radial WS influences regional transmural CBF pattern in AR. The importance of this relation to regional LV function and regional myocardial fibrosis in AR now must be assessed.
Journal of Cell Science, Aug 1, 1981
Attached, spread, chick heart fibroblasts were induced to shorten by treatment with the ionophore... more Attached, spread, chick heart fibroblasts were induced to shorten by treatment with the ionophore, A23187. The shortening resulted from the retraction of the leading lamellae and other major cell processes. The response was dependent on external calcium with a threshold close to, and a maximal effect at, physiological concentrations. The shortening was also induced in Colcemid-treated cells and therefore did not involve a depolymerization of microtubules. Indirect evidence indicates that the shortening was preceded by an increase in tension in the spread cell. The response is consistent with the effect of an increase in the cytoplasmic concentration of free calcium on a calcium-sensitive actomyosin system in the spread fibroblast. Although the retraction of non-spreading processes mimicked the intermittent retraction of similar trailing processes during normal movement of fibroblasts, the response to the ionophore differed in that the leading lamellae were also induced to retract. This difference implies that a general increase in the cytoplasmic concentration of free calcium alone cannot account for the intermittent shortening that occurs in normal movement.
Journal of Muscle Research and Cell Motility, Apr 1, 1991
Although a substantial literature exists on the in vitro polymerization of purified myosin, littl... more Although a substantial literature exists on the in vitro polymerization of purified myosin, little is known about native thick filament assembly, remodeling or turnover. We have recently described a cell-free system (Bouche et al., 1988) fo examine the interactions between thick filaments and soluble, newly synthesized myofibrillar proteins. In the present manuscript we describe our studies on myosin heavy (MHC) and light chain (LC) incorporation into myofibrils or native and synthetic thick filaments. 3 87 myofibrillar proteins or myosin subunits were synthesized in a reticulocyte lysate translation system after which myofibrils or myofilaments were added and incubated with these proteins in the lysate. The added filaments were then sedimented and analyzed by SDS-PAGE and fluorography fo establish which of the labeled protein subuni~ were co-pelleted. Operationally, this co-sedimentation of labeled proteins with myofilaments has been termed 'protein incorporation'. We observed that newly synthesized MHC, LCs 1, 2 and 3 all incorporated into the thick filaments. However, the quantity and specificity of LC incorporation depended upon the structure or composition of the filaments. LCs 1 and 3 were preferentially incorporated into myofibrils and native thick filaments, whereas LC2 was selectively taken up by synthetic filaments prepared from purified myosin. These results suggest that soluble MHCs and LCs interact independently with myofilaments. This hypothesis is supported by the observation that selective removal of soluble MHCs, or of a single LC, did not alter the incorporation of the remaining myosin subunits. Similarly, MHCs synthesized in the absence of LCs also incorporated into myofilaments or myofibrils. We propose that myosin subunits are capable of independent incorporation into and exchange from myofilaments.
American Journal of Therapeutics, Nov 1, 1998
Cardiovascular Pathology, 1999
Intercellular conduction in the working myocardium of the mammalian heart is mediated by gap junc... more Intercellular conduction in the working myocardium of the mammalian heart is mediated by gap junctions composed of connexin43 or 45. Recently, it has been shown that myocardial connexin expression is malleable and may be altered with disease. To better understand myocardial conduction in left ventricular hypertrophy resulting from volume overload, we used indirect immunofluorescence microscopy to examine cardiac connexin43 expression in 10 New Zealand white rabbits with surgically induced aortic regurgitation (AR) and in 10 age-matched sham-operated controls. Animals were sacrificed at approximately 1 month or у 2.5 years after operation. All AR animals developed eccentric hypertrophy; none evidenced heart failure. The heart-to-body weight ratios for the 1 month AR and control groups were 2.9 Ϯ 0.8 vs 1.8 Ϯ 0.2 g/kg (p р 0.01) while ratios for the у 2.5 year AR and control groups were 2.4 Ϯ 0.3 vs 1.9 Ϯ 0.3 (p р 0.05). No significant differences in posterior wall thickness were found among any of the groups. Although the overall pattern of connexin43-like immunoreactivity was similar for all four groups, staining in the 1 month AR animals tended to be less than that of age-matched controls; staining was increased in the у 2.5 year AR animals and was greater than control (p Ͻ 0.05), in which staining did not change with animal age. This disease duration-related increase differs from the long-term decrease in connexin43 expression associated with other forms of heart disease and suggests that alterations in connexin expression may play a role in the rhythm abnormalities commonly seen in AR.
Journal of Nuclear Medicine 36(5 Suppl. ), Apr 3, 1995
Computers in Cardiology 1995, 1995
... supplied Myoscint 8 antimyosin antibody for our use, and The Howard Gilman Foundation, New Yo... more ... supplied Myoscint 8 antimyosin antibody for our use, and The Howard Gilman Foundation, New York, NY, and by stipends from The Daniel and Elaine ... 1. Borer JS, Herrold E, Hochreiter C, Roman M, Supino P, Devereux RB, Kligfield P, Nawaz H. Natural history of lett ventricular ...
Journal of Muscle Research and Cell Motility, 1991
Cardiology, 1998
Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic r... more Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic regurgitation (AR), and may be related to the pathophysiology of congestive heart failure (CHF) in this disease. To define the relationship between myocardial histopathologic variations and CHF in chronic AR, we performed gross and microscopic evaluations of postmortem tissue from a rabbit model of chronic AR manifesting left ventricular (LV) responses to AR similar to those in humans. Moderate-to-severe chronic AR (echocardiographic regurgitant fraction = 52 +/- 13%) was induced by closed-chest aortic valve perforation in 11 New Zealand White rabbits; 5 control rabbits were sham operated. Six of the 11 AR rabbits died 1.5 +/- 0.8 years (range 0.6-2.8 years) after AR induction; all 6 had gross and histologic anatomic evidence of CHF at necropsy. The remaining 5 AR rabbits survived until sacrifice at 2.9 +/- 0.1 years of AR; none had pathologic evidence of CHF. Cardiac hypertrophy and the extent of LV fibrosis and myocyte necrosis all were greatest among the 6 AR CHF rabbits. No inflammatory response was apparent in any animal. Moderate-to-severe chronic experimental AR frequently results in CHF which is strongly associated with myocardial fibrosis and necrosis, without evidence of inflammation. These histopathologic variations may be pathophysiologically related to CHF development.
American Journal of Therapeutics, 1996
I-125 labeled SP4 is a synthetic oligopeptide derived from apolipoprotein B of low-density lipopr... more I-125 labeled SP4 is a synthetic oligopeptide derived from apolipoprotein B of low-density lipoprotein that has been shown to localized in atherosclerotic plaques in experimental animals. However, its biodistribution and mechanism of localization need to be further elucidated. Twenty-four cholesterol-fed (CF) and 20 normal (NL) New Zealand White rabbits were injected with I-125-SP4 and killed 15 to 30 min (6 NL; 6 CF) or 2 h (14 NL; 18 CF) later. We obtained aortic autoradiograms and activity concentrations (% injected dose/gm) in aortic segments and other tissues. The uptake of I-125-SP4 was higher in CF than in NL rabbits in all aortic segments (p &amp;lt; 0.05). I-125-SP4 was cleared rapidly in both CF and NL rabbits with 60 to 70% of the injected dose cleared from the blood by 1 h. No statistically significant differences in radiotracer biodistribution were observed between NL and CF rabbits although activity tended to be higher in the liver, gallbladder, and intestine in NL rabbits and in the kidney and spleen in CF rabbits. Silver grains were distributed mainly on foam cells of the fatty streaks in aortic microautoradiograms from two additional rabbits that had been injected with I-125-SP4. There were 23,518 plus minus 15,878 (SD) grains/mm(2) in fatty plaques but only 14,669 plus minus 11,035 grains/mm(2) in media muscle (p &amp;lt; 0.0001 [9 sections, 17 areas evaluated] in an atherosclerotic animal) in injected animals and 13,439 plus minus 5,565 grains/mm(2) in media muscle (two sections, four areas) in the normal control animals (NS versus media of atherosclerotic animal). I-125-SP4 specifically localizes in aortic atherosclerotic plaques in CF rabbits. There is no significant difference in tissue distribution between normal and CF rabbits except in the aorta. Preliminarily, it appears that the site of tracer uptake is on foam cells and this suggests the possibility of relative specificity for fatty plaque.
American Journal of Therapeutics, 1998
Myocardial fibrosis and abnormal myocardial collagen content are common in many forms of patholog... more Myocardial fibrosis and abnormal myocardial collagen content are common in many forms of pathological cardiac hypertrophy, including that mediated by pressure overload. Recently, in an experimental animal model of chronic aortic regurgitation (AR), we found a strong relation between myocardial fibrosis and congestive heart failure development. To determine if these fibrotic lesions are composed of collagen, as they are in pressure overload, and to determine if potential preventive therapies should be developed similarly in both diseases, we assessed left ventricular collagen content at three time points after AR induction. Moderate to severe AR was induced in 19 New Zealand White rabbits by inserting a catheter through the carotid artery to perforate the aortic valve leaflets. Animals were killed (1) when they showed echocardiographically discernible systolic dysfunction or (2) if normal cardiac function continued, either early (1 month) or late (>3 years) after operation. Fourteen age-matched, sham-operated controls and seven normal unoperated rabbits also were studied. Collagen concentrations were determined biochemically by hydroxyproline measurement. Fibrosis was measured histologically using Mason's trichrome stain and the fibrous collagen-specific stain, Picro-Sirius Red. Our results show an age-related increase in left ventricular collagen concentration with no specific increase among animals with evidence of fibrosis. We conclude that, unlike pressure overload, volume overload produces fibrotic lesions not composed predominantly of excess collagen and that the therapy needed to prevent fibrosis may be different in these conditions. Further study is needed to define the chemical characteristics of the fibrous lesions and the pathophysiological importance of this finding.
Cardiology, 1998
Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic r... more Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic regurgitation (AR), and may be related to the pathophysiology of congestive heart failure (CHF) in this disease. To define the relationship between myocardial histopathologic variations and CHF in chronic AR, we performed gross and microscopic evaluations of postmortem tissue from a rabbit model of chronic AR manifesting left ventricular (LV) responses to AR similar to those in humans. Moderate-to-severe chronic AR (echocardiographic regurgitant fraction = 52 ± 13%) was induced by closed-chest aortic valve perforation in 11 New Zealand White rabbits; 5 control rabbits were sham operated. Six of the 11 AR rabbits died 1.5 ± 0.8 years (range 0.6–2.8 years) after AR induction; all 6 had gross and histologic anatomic evidence of CHF at necropsy. The remaining 5 AR rabbits survived until sacrifice at 2.9 ± 0.1 years of AR; none had pathologic evidence of CHF. Cardiac hypertrophy and the extent of LV fibrosis and myocyte necrosis all were greatest among the 6 AR CHF rabbits. No inflammatory response was apparent in any animal. Moderate-to-severe chronic experimental AR frequently results in CHF which is strongly associated with myocardial fibrosis and necrosis, without evidence of inflammation. These histopathologic variations may be pathophysiologically related to CHF development.
Springer eBooks, Nov 22, 2007
ABSTRACT Regurgitant valvular heart diseases and, most particularly, insufficiency of the aortic ... more ABSTRACT Regurgitant valvular heart diseases and, most particularly, insufficiency of the aortic and/or mitral valves (AR, MR), are among the more common, and most predictable, causes of congestive heart failure. Current data suggest that these conditions also confer a proclivity for sudden death, even among asymptomatic or minimally symptomatic patients (1,2,3).
ABSTRACT The authors have developed a 3-compartment model for determining the distribution of lab... more ABSTRACT The authors have developed a 3-compartment model for determining the distribution of label derived from L-[l-/sup 14/C]leucine (LEU) in myocardial tissue. The 3 compartments are the pools of tissue precursor (i.e. free) LEU, protein-incorporated leucine (P-LEU), and the leucine metabolite /spl alpha/-ketoisocaproate (KIC). To apply this model to positron emission tomography (PET) of the heart with /sup 11/C labeled LEU, the portion of image activity within the protein pool must be determined. The authors have determined experimentally the kinetic rate coefficients for LEU metabolism in heart protein and used them to calculate the distribution of activity in the tissue LEU, P-LEU and KIC pools from the plasma LEU activity. The authors then applied these results in simulation studies modeling PET image acquisition using L-[1-/sup 11/C]LEU. Their findings indicate that PET imaging of protein metabolism with L-[l-/sup 11/C]LEU is feasible.< >
ABSTRACT We have previously shown that left ventricular (LV) shape transformation (from ellipsoid... more ABSTRACT We have previously shown that left ventricular (LV) shape transformation (from ellipsoid toward spherical) may modulate abnormal myocardial wall stresses occurring as a result of chronic severe aortic regurgitation (AR). If so then the extent of spherical shape change in AR may be inversely related to myocyte injury. To test this hypothesis, we compared the endocardial/epicardial antimyosin antibody uptake ratio in hearts from rabbits with early-AR and late-AR and from controls. The endocardial/epicardial antimyosin antibody activity ratio was increased in ellipsoid shaped late-AR hearts (vs control, p<.001), but not in early-AR or spherically shaped late-AR hearts. Thus, spherical shape is associated with less endocardial injury than ellipsoidal shape in the late AR LV
In severe, chronic aortic regulation (AR) in man, systolic pressure time interval and diastolic p... more In severe, chronic aortic regulation (AR) in man, systolic pressure time interval and diastolic pressure time interval measurements suggest an abnormal load-to-endocardial blood flow relationship. To better define this relationship, the authors extended their previously reported model for determining myocardial wall stress in include radial stress from endocardial (ENDO) to epicardium (EPI), a factor believed to influence distribution of coronary blood flow. Estimates of radial, circumferential and meridional stresses were compared with axial and transmyocardial blood flow measured from the base to apex and ENDO to EPI in normal rabbits and rabbits with severe, chronic AR. The authors' results suggest that blood flow is uniform from base to apex but not from ENDO to EPI near the apex where radial wall stress may influence blood flow.<<ETX>>
Journal of Nuclear Cardiology, 1997
Fiber dropout and myocyte necrosis precede heart failure in experimental aortic regurgitation (AR... more Fiber dropout and myocyte necrosis precede heart failure in experimental aortic regurgitation (AR). The current study aimed to determine whether this process can be detected by noninvasive scintigraphic imaging. 111In-labeled antimyosin antibody Fab fragment (1 to 1.5 mCi) (Myoscint) was administered to each of 34 New Zealand White rabbits: 11 early (3 to 5 weeks) after surgical AR induction; 9 late (98 to 128 weeks) after AR induction; 5 normal and 3 sham-operated age-matched with early AR; and 3 normal and 3 sham-operated age-matched with late AR. Echocardiographic fractional shortening was indistinguishable among control, early AR, and late AR groups. In vivo gamma camera imaging 24 and 48 hours after isotope administration, post-mortem heart activity determination (percentage injected dose per gram), and autoradiography were performed. At 24 and 48 hours, heart-to-lung counts-per-pixel ratios from in vivo images were greater (p < 0.05) in the late AR rabbits than in each of the three other groups. No significant differences were found when early AR and older or younger control rabbits were compared. Heart activity (percentage injected dose per gram) in late AR rabbits trended toward higher values than in age-matched control rabbits (p = 0.057), but in early AR it was indistinguishable from that in the corresponding control (p = 0.413, difference not significant). The autoradiographic endocardial/epicardial activity ratio in late AR rabbits was greater than in control and early AR rabbits (1.27 +/- 0.13 vs 1.06 +/- 0.09 and vs 1.13 +/- 0.10, respectively, p < 0.02). Whereas isotope uptake in late AR rabbits differed from that in control and early AR rabbits, systolic function was indistinguishable. Thus 111In-labeled antimyosin antibody imaging may permit noninvasive detection of AR-induced myocardial damage before functional deterioration.
Virology, Jun 1, 1978
ABSTRACT Antisera used previously to assay SV40 T antigen have been produced in tumor-bearing ham... more ABSTRACT Antisera used previously to assay SV40 T antigen have been produced in tumor-bearing hamsters. This report describes the production and characterization of antiserum produced by injection of rabbits with denatured large-T antigen (Ag) purified by immunoprecipitation and electrophoresis. The resulting antiserum reacts with native large-T Ag as determined by indirect immunofluorescence, complement fixation, and indirect immunoprecipitation assays and binds to species such as “small-T Ag” and previously described proteolytic fragments of large-T Ag.
De Gruyter eBooks, Dec 31, 1990
Journal of the American College of Cardiology, Feb 1, 1995
The impact of regional wall stress (WS) abnormalities on regional coronary flow (CBF) in aortic r... more The impact of regional wall stress (WS) abnormalities on regional coronary flow (CBF) in aortic regurgitation (AR) is not known. However, the existence of such a relation is of potential importance since it might account in part for LV dysfunction and myocardial fibrosis seen in AR, and could suggest therapeutic strategies. We have previously developed and validated a method for calculating regional WS in the radial, circumferential and meridional directions from mid wall (MW) to apex (AP) and endocardium (ENDO) to epicardium (EPI) using a 4000 element model of the LV To define the relation of regional WS and CSF in AR, we applied our LV model in 5 normal (NL) and 4 AR rabbits in which regional CBF was measured using fluorescent microspheres. CBF and radial WS were as follows: CBF (ml/min/gm) Radial WS (× 103dynes/cm2) MW AP MW AP NL EPI 2.49 1.30 83 29* ENDO 2.09 0.74 133 133* AR EPI 1.82 1.82* 86 38* ENDO 1.41 0.77* 133 133* *= p l 0.001 (EPI vs ENDO for CSF, EPI to ENDO gradient in AR vs NL for radial WS) Thus, in AR, transmural CBF distribution varies significantly at the apex, while this tendency is less marked and less consistent in NL. No discernable transmural variation was apparent elsewhere in either group. These differences paralleled inversely the transmural variations in radial WS in AR vs NL. In contrast, meridional WS and circumferential WS were uniformly and significantly higher in AR than NL at apex and base (all p l 0.001), a pattern which bore no relation to regional CSF pattern. Thus, regional radial WS influences regional transmural CBF pattern in AR. The importance of this relation to regional LV function and regional myocardial fibrosis in AR now must be assessed.
Journal of Cell Science, Aug 1, 1981
Attached, spread, chick heart fibroblasts were induced to shorten by treatment with the ionophore... more Attached, spread, chick heart fibroblasts were induced to shorten by treatment with the ionophore, A23187. The shortening resulted from the retraction of the leading lamellae and other major cell processes. The response was dependent on external calcium with a threshold close to, and a maximal effect at, physiological concentrations. The shortening was also induced in Colcemid-treated cells and therefore did not involve a depolymerization of microtubules. Indirect evidence indicates that the shortening was preceded by an increase in tension in the spread cell. The response is consistent with the effect of an increase in the cytoplasmic concentration of free calcium on a calcium-sensitive actomyosin system in the spread fibroblast. Although the retraction of non-spreading processes mimicked the intermittent retraction of similar trailing processes during normal movement of fibroblasts, the response to the ionophore differed in that the leading lamellae were also induced to retract. This difference implies that a general increase in the cytoplasmic concentration of free calcium alone cannot account for the intermittent shortening that occurs in normal movement.
Journal of Muscle Research and Cell Motility, Apr 1, 1991
Although a substantial literature exists on the in vitro polymerization of purified myosin, littl... more Although a substantial literature exists on the in vitro polymerization of purified myosin, little is known about native thick filament assembly, remodeling or turnover. We have recently described a cell-free system (Bouche et al., 1988) fo examine the interactions between thick filaments and soluble, newly synthesized myofibrillar proteins. In the present manuscript we describe our studies on myosin heavy (MHC) and light chain (LC) incorporation into myofibrils or native and synthetic thick filaments. 3 87 myofibrillar proteins or myosin subunits were synthesized in a reticulocyte lysate translation system after which myofibrils or myofilaments were added and incubated with these proteins in the lysate. The added filaments were then sedimented and analyzed by SDS-PAGE and fluorography fo establish which of the labeled protein subuni~ were co-pelleted. Operationally, this co-sedimentation of labeled proteins with myofilaments has been termed 'protein incorporation'. We observed that newly synthesized MHC, LCs 1, 2 and 3 all incorporated into the thick filaments. However, the quantity and specificity of LC incorporation depended upon the structure or composition of the filaments. LCs 1 and 3 were preferentially incorporated into myofibrils and native thick filaments, whereas LC2 was selectively taken up by synthetic filaments prepared from purified myosin. These results suggest that soluble MHCs and LCs interact independently with myofilaments. This hypothesis is supported by the observation that selective removal of soluble MHCs, or of a single LC, did not alter the incorporation of the remaining myosin subunits. Similarly, MHCs synthesized in the absence of LCs also incorporated into myofilaments or myofibrils. We propose that myosin subunits are capable of independent incorporation into and exchange from myofilaments.
American Journal of Therapeutics, Nov 1, 1998
Cardiovascular Pathology, 1999
Intercellular conduction in the working myocardium of the mammalian heart is mediated by gap junc... more Intercellular conduction in the working myocardium of the mammalian heart is mediated by gap junctions composed of connexin43 or 45. Recently, it has been shown that myocardial connexin expression is malleable and may be altered with disease. To better understand myocardial conduction in left ventricular hypertrophy resulting from volume overload, we used indirect immunofluorescence microscopy to examine cardiac connexin43 expression in 10 New Zealand white rabbits with surgically induced aortic regurgitation (AR) and in 10 age-matched sham-operated controls. Animals were sacrificed at approximately 1 month or у 2.5 years after operation. All AR animals developed eccentric hypertrophy; none evidenced heart failure. The heart-to-body weight ratios for the 1 month AR and control groups were 2.9 Ϯ 0.8 vs 1.8 Ϯ 0.2 g/kg (p р 0.01) while ratios for the у 2.5 year AR and control groups were 2.4 Ϯ 0.3 vs 1.9 Ϯ 0.3 (p р 0.05). No significant differences in posterior wall thickness were found among any of the groups. Although the overall pattern of connexin43-like immunoreactivity was similar for all four groups, staining in the 1 month AR animals tended to be less than that of age-matched controls; staining was increased in the у 2.5 year AR animals and was greater than control (p Ͻ 0.05), in which staining did not change with animal age. This disease duration-related increase differs from the long-term decrease in connexin43 expression associated with other forms of heart disease and suggests that alterations in connexin expression may play a role in the rhythm abnormalities commonly seen in AR.
Journal of Nuclear Medicine 36(5 Suppl. ), Apr 3, 1995
Computers in Cardiology 1995, 1995
... supplied Myoscint 8 antimyosin antibody for our use, and The Howard Gilman Foundation, New Yo... more ... supplied Myoscint 8 antimyosin antibody for our use, and The Howard Gilman Foundation, New York, NY, and by stipends from The Daniel and Elaine ... 1. Borer JS, Herrold E, Hochreiter C, Roman M, Supino P, Devereux RB, Kligfield P, Nawaz H. Natural history of lett ventricular ...
Journal of Muscle Research and Cell Motility, 1991
Cardiology, 1998
Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic r... more Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic regurgitation (AR), and may be related to the pathophysiology of congestive heart failure (CHF) in this disease. To define the relationship between myocardial histopathologic variations and CHF in chronic AR, we performed gross and microscopic evaluations of postmortem tissue from a rabbit model of chronic AR manifesting left ventricular (LV) responses to AR similar to those in humans. Moderate-to-severe chronic AR (echocardiographic regurgitant fraction = 52 +/- 13%) was induced by closed-chest aortic valve perforation in 11 New Zealand White rabbits; 5 control rabbits were sham operated. Six of the 11 AR rabbits died 1.5 +/- 0.8 years (range 0.6-2.8 years) after AR induction; all 6 had gross and histologic anatomic evidence of CHF at necropsy. The remaining 5 AR rabbits survived until sacrifice at 2.9 +/- 0.1 years of AR; none had pathologic evidence of CHF. Cardiac hypertrophy and the extent of LV fibrosis and myocyte necrosis all were greatest among the 6 AR CHF rabbits. No inflammatory response was apparent in any animal. Moderate-to-severe chronic experimental AR frequently results in CHF which is strongly associated with myocardial fibrosis and necrosis, without evidence of inflammation. These histopathologic variations may be pathophysiologically related to CHF development.
American Journal of Therapeutics, 1996
I-125 labeled SP4 is a synthetic oligopeptide derived from apolipoprotein B of low-density lipopr... more I-125 labeled SP4 is a synthetic oligopeptide derived from apolipoprotein B of low-density lipoprotein that has been shown to localized in atherosclerotic plaques in experimental animals. However, its biodistribution and mechanism of localization need to be further elucidated. Twenty-four cholesterol-fed (CF) and 20 normal (NL) New Zealand White rabbits were injected with I-125-SP4 and killed 15 to 30 min (6 NL; 6 CF) or 2 h (14 NL; 18 CF) later. We obtained aortic autoradiograms and activity concentrations (% injected dose/gm) in aortic segments and other tissues. The uptake of I-125-SP4 was higher in CF than in NL rabbits in all aortic segments (p &amp;lt; 0.05). I-125-SP4 was cleared rapidly in both CF and NL rabbits with 60 to 70% of the injected dose cleared from the blood by 1 h. No statistically significant differences in radiotracer biodistribution were observed between NL and CF rabbits although activity tended to be higher in the liver, gallbladder, and intestine in NL rabbits and in the kidney and spleen in CF rabbits. Silver grains were distributed mainly on foam cells of the fatty streaks in aortic microautoradiograms from two additional rabbits that had been injected with I-125-SP4. There were 23,518 plus minus 15,878 (SD) grains/mm(2) in fatty plaques but only 14,669 plus minus 11,035 grains/mm(2) in media muscle (p &amp;lt; 0.0001 [9 sections, 17 areas evaluated] in an atherosclerotic animal) in injected animals and 13,439 plus minus 5,565 grains/mm(2) in media muscle (two sections, four areas) in the normal control animals (NS versus media of atherosclerotic animal). I-125-SP4 specifically localizes in aortic atherosclerotic plaques in CF rabbits. There is no significant difference in tissue distribution between normal and CF rabbits except in the aorta. Preliminarily, it appears that the site of tracer uptake is on foam cells and this suggests the possibility of relative specificity for fatty plaque.
American Journal of Therapeutics, 1998
Myocardial fibrosis and abnormal myocardial collagen content are common in many forms of patholog... more Myocardial fibrosis and abnormal myocardial collagen content are common in many forms of pathological cardiac hypertrophy, including that mediated by pressure overload. Recently, in an experimental animal model of chronic aortic regurgitation (AR), we found a strong relation between myocardial fibrosis and congestive heart failure development. To determine if these fibrotic lesions are composed of collagen, as they are in pressure overload, and to determine if potential preventive therapies should be developed similarly in both diseases, we assessed left ventricular collagen content at three time points after AR induction. Moderate to severe AR was induced in 19 New Zealand White rabbits by inserting a catheter through the carotid artery to perforate the aortic valve leaflets. Animals were killed (1) when they showed echocardiographically discernible systolic dysfunction or (2) if normal cardiac function continued, either early (1 month) or late (>3 years) after operation. Fourteen age-matched, sham-operated controls and seven normal unoperated rabbits also were studied. Collagen concentrations were determined biochemically by hydroxyproline measurement. Fibrosis was measured histologically using Mason's trichrome stain and the fibrous collagen-specific stain, Picro-Sirius Red. Our results show an age-related increase in left ventricular collagen concentration with no specific increase among animals with evidence of fibrosis. We conclude that, unlike pressure overload, volume overload produces fibrotic lesions not composed predominantly of excess collagen and that the therapy needed to prevent fibrosis may be different in these conditions. Further study is needed to define the chemical characteristics of the fibrous lesions and the pathophysiological importance of this finding.