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Papers by Jonathan Palma

Research paper thumbnail of Improved Exercise Capacity and Reduced Systemic Inflammation After Adenoviral-Mediated SERCA-2a Gene Transfer

Journal of Surgical Research, 2008

Background. We hypothesized that sarcoplasmic reticulum Ca 2؉ ATPase pump (SERCA-2a) gene deliver... more Background. We hypothesized that sarcoplasmic reticulum Ca 2؉ ATPase pump (SERCA-2a) gene delivery would have beneficial effects upon exercise capacity and markers of inflammation in the setting of heart failure.

Research paper thumbnail of Massive right atrial myxoma presenting with syncope

Heart and Vessels, 2006

A 65-year-old man presented to the emergency room following an episode of syncope. His vital sign... more A 65-year-old man presented to the emergency room following an episode of syncope. His vital signs and physical examination were unremarkable. A chest X-ray and an ECG were also normal. He was admitted to the hospital for further work-up. A computed tomography scan of his brain did not reveal any evidence of stroke, hemorrhage, or mass effect. A transesophageal echocardiogram, however, revealed tricuspid regurgitation and a right atrial mass with finger-like projections, which appeared to originate from the tricuspid valve. Left heart catheterization was performed, showing a 99% proximal right coronary artery stenosis. The patient was scheduled to undergo atrial mass resection, tricuspid valve annuloplasty, and coronary bypass. During the procedure, a large myxoma was found to be adherent to the right side of the atrial septum, adjacent to the fossa ovalis. The mass was friable and was attached to the endocardium by a pedicle. Following resection of the atrial mass and tricuspid valve annuloplasty, a single saphenous vein graft bypass to the right coronary artery was performed. The patient's postoperative course was unremarkable and he was discharged home on postoperative day 6.

Research paper thumbnail of Intra-coronary adenoviral-mediated sarcoplasmic reticulum Ca2+ATPase gene transfection during experimental heart failure improves exercise capacity and hemodynamic, inflammatory, and apoptotic profiles

Journal of The American College of Surgeons, 2004

Research paper thumbnail of Reverse remodeling is associated with changes in extracellular matrix proteases and tissue inhibitors after mesenchymal stem cell (MSC) treatment of pressure overload hypertrophy

Journal of Tissue Engineering and Regenerative Medicine, 2009

Changes in ventricular extracellular matrix (ECM) composition of pressure overload hypertrophy de... more Changes in ventricular extracellular matrix (ECM) composition of pressure overload hypertrophy determine clinical outcomes. The effects of mesenchymal stem cell (MSC) transplantation upon determinants of ECM composition in pressure overload hypertrophy have not been studied. Sprague–Dawley rats underwent aortic banding and were followed by echocardiography. After an absolute decrease in fractional shortening of 25% from baseline, 1 × 106 MSC (n = 28) or PBS (n = 20) was randomly injected intracoronarily. LV protein analysis, including matrix metalloproteinases (MMP-2, MMP-3, MMP-6, MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3), was performed after sacrifice on postoperative day 7, 14, 21 or 28. Left ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 were demonstrated to be decreased in the MSC group compared with controls after 28 days. Expression of MMP-2 and TIMP-2 remained relatively stable in both groups. Successful MSCs delivery was confirmed by histological analysis and visualization of labelled MSCs. In this model of pressure overload hypertrophy, intracoronary delivery of MSCs during heart failure was associated with specific changes in determinants of ECM composition. LV reverse remodeling was associated with decreased ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3, which were upregulated in the control group as heart failure progressed. These effects were most significant at 28 days following injection. Copyright © 2008 John Wiley & Sons, Ltd.

Research paper thumbnail of Congenital heart disease manifested as acute abdominal pain

International Journal of Cardiology, 2007

We present a case of a 53-year-old man with complaints of severe abdominal pain and nausea. Emerg... more We present a case of a 53-year-old man with complaints of severe abdominal pain and nausea. Emergency department abdominal workup was non-diagnostic. Physical examination revealed signs of right-and left-heart failure. A past medical history of dysrhythmias and chronic abdominal complaints prompted hospital admission. Subsequent right heart catheterization revealed a significant left-to-right shunt. CT scan of the chest and angiography confirmed the diagnosis of an abnormal ascending vein between the innominate vein and the left superior pulmonary vein. After the anomalous vein was ligated, the patient's abdominal pain resolved.

Research paper thumbnail of Novel Experimental Model of Pressure Overload Hypertrophy in Rats

Journal of Surgical Research, 2009

Background. We studied a novel animal model of pressure overload hypertrophy in transition to hea... more Background. We studied a novel animal model of pressure overload hypertrophy in transition to heart failure following ascending aortic constriction. We sought to assess chronologic changes in hemodynamic parameters, echocardiographic signs of left ventricular (LV) remodeling, exercise tolerance, and profiles of systemic and local inflammation.

Research paper thumbnail of Right ventricular beneficial effects of beta adrenergic receptor kinase inhibitor ( βARKct ) gene transfer in a rat model of severe pressure overload

Biomedicine & Pharmacotherapy, 2009

Heart failure is associated with abnormalities in betaAR cascade regulation, calcium cycling, exp... more Heart failure is associated with abnormalities in betaAR cascade regulation, calcium cycling, expression of inflammatory mediators and apoptosis. Adenoviral mediated gene transfer of betaARKct has beneficial indirect effects on these pathologic processes upon the left ventricular myocardium. The concomitant biochemical changes that occur in the right ventricle have not been well characterized. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in fractional shortening of 25% from baseline, intracoronary injection of adenoviral-betaARKct (n=14) or adenoviral-beta-galactosidase (control, n=13) was performed. Rats were randomly euthanized on post-operative day 7, 14 or 21. Protein analysis including RV myocardial levels of betaARKct, betaARK1, SERCA(2a), inflammatory tissue mediators (IL-1, IL-6 and TNF-alpha), apoptotic markers (bax and bak), and MAP kinases (jnk, p38 and erk) was performed. ANOVA was employed for group comparison. Adenoviral-betaARKct treated animals showed increased expression of betaARKct and decreased levels of betaARK1 compared with controls. This treatment group also demonstrated normalization of SERCA(2a) expression and decreased levels of the inflammatory markers IL-1, IL-6 and TNF-alpha. The pro-apoptotic markers bax and bak were similarly improved. Ventricular levels of the MAP kinase jnk were increased. Differences were most significant 7 days after gene transfer, but the majority of these changes persisted at 21 days. These results suggest that attenuation of the pathologic mechanisms of beta adrenergic receptor desensitization, SERCA(2a) expression, inflammation and apoptosis, not only occur in the left ventricle but also in the right ventricular myocardium after intracoronary gene transfer of betaARKct during heart failure.

Research paper thumbnail of Improvement in hemodynamic performance and exercise capacity after mesenchymal stem cell transplantation in an experimental model of cardiomyopathy

Indian Journal of Thoracic and Cardiovascular Surgery, 2006

Research paper thumbnail of Right ventricular effects of intracoronary delivery of mesenchymal stem cells (MSC) in an animal model of pressure overload heart failure 1

Biomedicine & Pharmacotherapy, 2009

In a rat model of left ventricular pressure overload hypertrophy with biventricular failure, we s... more In a rat model of left ventricular pressure overload hypertrophy with biventricular failure, we studied the effects of intracoronary delivery of mesenchymal stem cells (MCS) upon right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in left ventricular fractional shortening of 25% from the baseline (relative 50% reduction), animals were randomized to an intracoronary injection of MSC (n=28) or PBS (n=20). Right ventricular hemodynamic assessment and measurement of local inflammatory markers, proapoptotic factors, and determinants of extracellular matrix remodeling were performed on post-transplantation day 7, 14, 21 or 28. MSC injection improved right ventricular systolic function in the MSC group compared to the control group (mean+/-SD, max dP/dt 772+/-272 mm Hg/s vs. 392+/-132 at 28 days, P<0.01). Diastolic function was similarly improved (mean+/-SD, max -dP/dt -558+/-171 mm Hg/s vs. -327+/-131 at 28 days, P<0.05). Right ventricular levels of IL-1, IL-6, TNF-alpha, bax, bak and p38 were significantly decreased in the MSC treated animals. Expression of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 declined in the MSC group compared with controls after 28 days. In this model of left ventricular pressure overload hypertrophy and biventricular failure, intracoronary delivery of MSC was associated with an improvement in the right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling.

Research paper thumbnail of Adenoviral β-Adrenergic Receptor Kinase Inhibitor Gene Transfer Improves Exercise Capacity, Cardiac Contractility, and Systemic Inflammation in a Model of Pressure Overload Hypertrophy

Cardiovascular Drugs and Therapy, 2008

Objective We hypothesized that intracoronary adenoviral-mediated delivery of βARKct would improve... more Objective We hypothesized that intracoronary adenoviral-mediated delivery of βARKct would improve heart failure associated pathophysiologic abnormalities related to exercise capacity, cardiac contractility, systemic inflammation and volume overload. Methods After aortic banding, a cohort of Sprague–Dawley rats was followed by echocardiography. When an absolute decline of 25% in fractional shortening was detected, animals were randomized to intracoronary delivery of Ad.ßARKct (n = 14), Ad.β-Gal (n = 13), or followed without any other further intervention (n = 18). Assessment of exercise tolerance and hemodynamic profile and measurement of markers of systemic inflammation and volume overload was performed at 7, 14, and 21 days after gene delivery. Data were analyzed using ANOVA. Results Animals receiving Ad.ßARKct showed improved exercise tolerance compared to Ad.Gal-treated animals at 14 days (507 ± 26 s vs. 408 ± 19 s, P = 0.01) and 21 days (526 ± 55 s vs. 323 ± 19 s, P < 0.001) following injection. Animals receiving Ad.ßARKct demonstrated improved +dP/dtmax (mean ± SD, 5,581 ± 960 mmHg/s vs. 3,134 ± 438 mmHg/s, P < 0.01) and -dP/dtmax (mean ± SD, −3,494 ± 1,269 mmHg/s vs. −1,925 ± 638 mmHg/s, P < 0.01) compared to Ad.Gal-treated animals at 7 days. These differences were observed up to 21 days following injection. Serum levels of IL-1, IL-6, and TNF-alpha, as well as ANP were also decreased in animals receiving Ad.βARKct. Conclusions Genetic modulation of heart failure using the βARKct gene was associated with improved exercise capacity and cardiac function as well as amelioration in heart failure-associated profiles of systemic inflammation and volume overload.

Research paper thumbnail of Improvement in hemodynamic performance, exercise capacity, inflammatory profile, and left ventricular reverse remodeling after intracoronary delivery of mesenchymal stem cells in an experimental model of pressure overload hypertrophy

Journal of Thoracic and Cardiovascular Surgery, 2008

In a rat model of pressure overload hypertrophy, we studied the effects of intracoronary delivery... more In a rat model of pressure overload hypertrophy, we studied the effects of intracoronary delivery of mesenchymal stem cells on hemodynamic performance, exercise capacity, systemic inflammation, and left ventricular reverse remodeling. Sprague-Dawley rats underwent aortic banding and were followed up by echocardiographic scanning. After a decrease in fractional shortening of 25% from baseline, animals were randomized to intracoronary injection of mesenchymal stem cells (MSC group; n = 28) or phosphate-buffered saline solution (control group; n = 20). Hemodynamic and echocardiographic assessment, swim testing to exhaustion, and measurement of inflammatory markers were performed before the rats were humanely killed on postoperative day 7, 14, 21, or 28. Injection of mesenchymal stem cells improved systolic function in the MSC group compared with the control group (mean +/- standard deviation: maximum dP/dt 3048 +/- 230 mm Hg/s vs 2169 +/- 97 mm Hg/s at 21 days and 3573 +/- 741 mm Hg/s vs 1363 +/- 322 mm Hg/s at 28 days: P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001). Time to exhaustion was similarly increased in the MSC group compared with controls (487 +/- 35 seconds vs 306 +/- 27 seconds at 28 days; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01). Serum levels of interleukins 1 and 6, tumor necrosis factor-alpha, and brain natriuretic peptide-32 were significantly decreased in animals treated with mesenchymal stem cells. Stem cell transplantation improved left ventricular fractional shortening at 21 and 28 days. Left ventricular end-systolic and end-diastolic diameters were also improved at 28 days. In this model of pressure overload hypertrophy, intracoronary delivery of mesenchymal stem cells during heart failure was associated with an improvement in hemodynamic performance, maximal exercise tolerance, systemic inflammation, and left ventricular reverse remodeling. This study suggests a potential role of this treatment strategy for the management of hypertrophic heart failure resulting from pressure overload.

Research paper thumbnail of Improved Exercise Capacity and Reduced Systemic Inflammation After Adenoviral-Mediated SERCA-2a Gene Transfer

Journal of Surgical Research, 2008

Background. We hypothesized that sarcoplasmic reticulum Ca 2؉ ATPase pump (SERCA-2a) gene deliver... more Background. We hypothesized that sarcoplasmic reticulum Ca 2؉ ATPase pump (SERCA-2a) gene delivery would have beneficial effects upon exercise capacity and markers of inflammation in the setting of heart failure.

Research paper thumbnail of Massive right atrial myxoma presenting with syncope

Heart and Vessels, 2006

A 65-year-old man presented to the emergency room following an episode of syncope. His vital sign... more A 65-year-old man presented to the emergency room following an episode of syncope. His vital signs and physical examination were unremarkable. A chest X-ray and an ECG were also normal. He was admitted to the hospital for further work-up. A computed tomography scan of his brain did not reveal any evidence of stroke, hemorrhage, or mass effect. A transesophageal echocardiogram, however, revealed tricuspid regurgitation and a right atrial mass with finger-like projections, which appeared to originate from the tricuspid valve. Left heart catheterization was performed, showing a 99% proximal right coronary artery stenosis. The patient was scheduled to undergo atrial mass resection, tricuspid valve annuloplasty, and coronary bypass. During the procedure, a large myxoma was found to be adherent to the right side of the atrial septum, adjacent to the fossa ovalis. The mass was friable and was attached to the endocardium by a pedicle. Following resection of the atrial mass and tricuspid valve annuloplasty, a single saphenous vein graft bypass to the right coronary artery was performed. The patient's postoperative course was unremarkable and he was discharged home on postoperative day 6.

Research paper thumbnail of Intra-coronary adenoviral-mediated sarcoplasmic reticulum Ca2+ATPase gene transfection during experimental heart failure improves exercise capacity and hemodynamic, inflammatory, and apoptotic profiles

Journal of The American College of Surgeons, 2004

Research paper thumbnail of Reverse remodeling is associated with changes in extracellular matrix proteases and tissue inhibitors after mesenchymal stem cell (MSC) treatment of pressure overload hypertrophy

Journal of Tissue Engineering and Regenerative Medicine, 2009

Changes in ventricular extracellular matrix (ECM) composition of pressure overload hypertrophy de... more Changes in ventricular extracellular matrix (ECM) composition of pressure overload hypertrophy determine clinical outcomes. The effects of mesenchymal stem cell (MSC) transplantation upon determinants of ECM composition in pressure overload hypertrophy have not been studied. Sprague–Dawley rats underwent aortic banding and were followed by echocardiography. After an absolute decrease in fractional shortening of 25% from baseline, 1 × 106 MSC (n = 28) or PBS (n = 20) was randomly injected intracoronarily. LV protein analysis, including matrix metalloproteinases (MMP-2, MMP-3, MMP-6, MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3), was performed after sacrifice on postoperative day 7, 14, 21 or 28. Left ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 were demonstrated to be decreased in the MSC group compared with controls after 28 days. Expression of MMP-2 and TIMP-2 remained relatively stable in both groups. Successful MSCs delivery was confirmed by histological analysis and visualization of labelled MSCs. In this model of pressure overload hypertrophy, intracoronary delivery of MSCs during heart failure was associated with specific changes in determinants of ECM composition. LV reverse remodeling was associated with decreased ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3, which were upregulated in the control group as heart failure progressed. These effects were most significant at 28 days following injection. Copyright © 2008 John Wiley & Sons, Ltd.

Research paper thumbnail of Congenital heart disease manifested as acute abdominal pain

International Journal of Cardiology, 2007

We present a case of a 53-year-old man with complaints of severe abdominal pain and nausea. Emerg... more We present a case of a 53-year-old man with complaints of severe abdominal pain and nausea. Emergency department abdominal workup was non-diagnostic. Physical examination revealed signs of right-and left-heart failure. A past medical history of dysrhythmias and chronic abdominal complaints prompted hospital admission. Subsequent right heart catheterization revealed a significant left-to-right shunt. CT scan of the chest and angiography confirmed the diagnosis of an abnormal ascending vein between the innominate vein and the left superior pulmonary vein. After the anomalous vein was ligated, the patient's abdominal pain resolved.

Research paper thumbnail of Novel Experimental Model of Pressure Overload Hypertrophy in Rats

Journal of Surgical Research, 2009

Background. We studied a novel animal model of pressure overload hypertrophy in transition to hea... more Background. We studied a novel animal model of pressure overload hypertrophy in transition to heart failure following ascending aortic constriction. We sought to assess chronologic changes in hemodynamic parameters, echocardiographic signs of left ventricular (LV) remodeling, exercise tolerance, and profiles of systemic and local inflammation.

Research paper thumbnail of Right ventricular beneficial effects of beta adrenergic receptor kinase inhibitor ( βARKct ) gene transfer in a rat model of severe pressure overload

Biomedicine & Pharmacotherapy, 2009

Heart failure is associated with abnormalities in betaAR cascade regulation, calcium cycling, exp... more Heart failure is associated with abnormalities in betaAR cascade regulation, calcium cycling, expression of inflammatory mediators and apoptosis. Adenoviral mediated gene transfer of betaARKct has beneficial indirect effects on these pathologic processes upon the left ventricular myocardium. The concomitant biochemical changes that occur in the right ventricle have not been well characterized. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in fractional shortening of 25% from baseline, intracoronary injection of adenoviral-betaARKct (n=14) or adenoviral-beta-galactosidase (control, n=13) was performed. Rats were randomly euthanized on post-operative day 7, 14 or 21. Protein analysis including RV myocardial levels of betaARKct, betaARK1, SERCA(2a), inflammatory tissue mediators (IL-1, IL-6 and TNF-alpha), apoptotic markers (bax and bak), and MAP kinases (jnk, p38 and erk) was performed. ANOVA was employed for group comparison. Adenoviral-betaARKct treated animals showed increased expression of betaARKct and decreased levels of betaARK1 compared with controls. This treatment group also demonstrated normalization of SERCA(2a) expression and decreased levels of the inflammatory markers IL-1, IL-6 and TNF-alpha. The pro-apoptotic markers bax and bak were similarly improved. Ventricular levels of the MAP kinase jnk were increased. Differences were most significant 7 days after gene transfer, but the majority of these changes persisted at 21 days. These results suggest that attenuation of the pathologic mechanisms of beta adrenergic receptor desensitization, SERCA(2a) expression, inflammation and apoptosis, not only occur in the left ventricle but also in the right ventricular myocardium after intracoronary gene transfer of betaARKct during heart failure.

Research paper thumbnail of Improvement in hemodynamic performance and exercise capacity after mesenchymal stem cell transplantation in an experimental model of cardiomyopathy

Indian Journal of Thoracic and Cardiovascular Surgery, 2006

Research paper thumbnail of Right ventricular effects of intracoronary delivery of mesenchymal stem cells (MSC) in an animal model of pressure overload heart failure 1

Biomedicine & Pharmacotherapy, 2009

In a rat model of left ventricular pressure overload hypertrophy with biventricular failure, we s... more In a rat model of left ventricular pressure overload hypertrophy with biventricular failure, we studied the effects of intracoronary delivery of mesenchymal stem cells (MCS) upon right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in left ventricular fractional shortening of 25% from the baseline (relative 50% reduction), animals were randomized to an intracoronary injection of MSC (n=28) or PBS (n=20). Right ventricular hemodynamic assessment and measurement of local inflammatory markers, proapoptotic factors, and determinants of extracellular matrix remodeling were performed on post-transplantation day 7, 14, 21 or 28. MSC injection improved right ventricular systolic function in the MSC group compared to the control group (mean+/-SD, max dP/dt 772+/-272 mm Hg/s vs. 392+/-132 at 28 days, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01). Diastolic function was similarly improved (mean+/-SD, max -dP/dt -558+/-171 mm Hg/s vs. -327+/-131 at 28 days, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Right ventricular levels of IL-1, IL-6, TNF-alpha, bax, bak and p38 were significantly decreased in the MSC treated animals. Expression of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 declined in the MSC group compared with controls after 28 days. In this model of left ventricular pressure overload hypertrophy and biventricular failure, intracoronary delivery of MSC was associated with an improvement in the right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling.

Research paper thumbnail of Adenoviral β-Adrenergic Receptor Kinase Inhibitor Gene Transfer Improves Exercise Capacity, Cardiac Contractility, and Systemic Inflammation in a Model of Pressure Overload Hypertrophy

Cardiovascular Drugs and Therapy, 2008

Objective We hypothesized that intracoronary adenoviral-mediated delivery of βARKct would improve... more Objective We hypothesized that intracoronary adenoviral-mediated delivery of βARKct would improve heart failure associated pathophysiologic abnormalities related to exercise capacity, cardiac contractility, systemic inflammation and volume overload. Methods After aortic banding, a cohort of Sprague–Dawley rats was followed by echocardiography. When an absolute decline of 25% in fractional shortening was detected, animals were randomized to intracoronary delivery of Ad.ßARKct (n = 14), Ad.β-Gal (n = 13), or followed without any other further intervention (n = 18). Assessment of exercise tolerance and hemodynamic profile and measurement of markers of systemic inflammation and volume overload was performed at 7, 14, and 21 days after gene delivery. Data were analyzed using ANOVA. Results Animals receiving Ad.ßARKct showed improved exercise tolerance compared to Ad.Gal-treated animals at 14 days (507 ± 26 s vs. 408 ± 19 s, P = 0.01) and 21 days (526 ± 55 s vs. 323 ± 19 s, P < 0.001) following injection. Animals receiving Ad.ßARKct demonstrated improved +dP/dtmax (mean ± SD, 5,581 ± 960 mmHg/s vs. 3,134 ± 438 mmHg/s, P < 0.01) and -dP/dtmax (mean ± SD, −3,494 ± 1,269 mmHg/s vs. −1,925 ± 638 mmHg/s, P < 0.01) compared to Ad.Gal-treated animals at 7 days. These differences were observed up to 21 days following injection. Serum levels of IL-1, IL-6, and TNF-alpha, as well as ANP were also decreased in animals receiving Ad.βARKct. Conclusions Genetic modulation of heart failure using the βARKct gene was associated with improved exercise capacity and cardiac function as well as amelioration in heart failure-associated profiles of systemic inflammation and volume overload.

Research paper thumbnail of Improvement in hemodynamic performance, exercise capacity, inflammatory profile, and left ventricular reverse remodeling after intracoronary delivery of mesenchymal stem cells in an experimental model of pressure overload hypertrophy

Journal of Thoracic and Cardiovascular Surgery, 2008

In a rat model of pressure overload hypertrophy, we studied the effects of intracoronary delivery... more In a rat model of pressure overload hypertrophy, we studied the effects of intracoronary delivery of mesenchymal stem cells on hemodynamic performance, exercise capacity, systemic inflammation, and left ventricular reverse remodeling. Sprague-Dawley rats underwent aortic banding and were followed up by echocardiographic scanning. After a decrease in fractional shortening of 25% from baseline, animals were randomized to intracoronary injection of mesenchymal stem cells (MSC group; n = 28) or phosphate-buffered saline solution (control group; n = 20). Hemodynamic and echocardiographic assessment, swim testing to exhaustion, and measurement of inflammatory markers were performed before the rats were humanely killed on postoperative day 7, 14, 21, or 28. Injection of mesenchymal stem cells improved systolic function in the MSC group compared with the control group (mean +/- standard deviation: maximum dP/dt 3048 +/- 230 mm Hg/s vs 2169 +/- 97 mm Hg/s at 21 days and 3573 +/- 741 mm Hg/s vs 1363 +/- 322 mm Hg/s at 28 days: P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001). Time to exhaustion was similarly increased in the MSC group compared with controls (487 +/- 35 seconds vs 306 +/- 27 seconds at 28 days; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01). Serum levels of interleukins 1 and 6, tumor necrosis factor-alpha, and brain natriuretic peptide-32 were significantly decreased in animals treated with mesenchymal stem cells. Stem cell transplantation improved left ventricular fractional shortening at 21 and 28 days. Left ventricular end-systolic and end-diastolic diameters were also improved at 28 days. In this model of pressure overload hypertrophy, intracoronary delivery of mesenchymal stem cells during heart failure was associated with an improvement in hemodynamic performance, maximal exercise tolerance, systemic inflammation, and left ventricular reverse remodeling. This study suggests a potential role of this treatment strategy for the management of hypertrophic heart failure resulting from pressure overload.