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Biomedical subjects

Robert C Gorman

Publications and source records attributed to Robert C Gorman.

At least 19 recordsLinked to original sources
PubMed2006

Mechanisms of the in vivo inhibition of calcification of bioprosthetic porcine aortic valve cusps and aortic wall with triglycidylamine/mercapto bisphosphonate.

Heart valve replacements fabricated from glutaraldehyde (Glut)-crosslinked heterograft materials, porcine aortic valves or bovine pericardium, have been widely used in cardiac surgery to treat heart valve disease. However, these bioprosthetic heart valves often fail in long-term clinical implants due to pathologic calcification of the bioprosthetic leaflets, and for stentless porcine aortic valve bioprostheses, bioprosthetic aortic wall calcification also typically occurs. Previous use of the epoxide-based crosslinker, triglycidyl amine (TGA), on cardiac bioprosthetic valve materials demonstrated superior biocompatibility, mechanics, and calcification resistance for porcine aortic valve cusps (but not porcine aortic wall) and bovine pericardium, vs. Glut-prepared controls. However, TGA preparation did not completely prevent long-term calcification of cusps or pericardium. Herein we report further mechanistic investigations of an added therapeutic component to this system, 2-mercaptoethylidene-1,1-bisphosphonic acid (MABP), a custom synthesized thiol bisphosphonate, which has previously been shown in a preliminary report to prevent bioprosthetic heterograft biomaterial calcification when used in combination with initial TGA crosslinking for 7 days. In the present studies, we have further investigated the effectiveness of MABP in experiments that examined: (1) The use of MABP after optimal TGA crosslinking, in order to avoid any competitive interference of MABP-reactions with TGA during crosslinking; (2) Furthermore, recognizing the importance of alkaline phosphatase (ALP) in the formation of dystrophic calcific nodules, we have investigated the hypothesis that the mechanism by which MABP primarily functions is through the reduction of ALP activity. Results from cell-free model systems, cell culture studies, and rat subcutaneous implants, show that materials functionalized with MABP after TGA crosslinking have reduced ALP activity, and in vivo have no significant calcification in long-term implant studies. It is concluded that bioprosthetic heart valves prepared in this fashion are compelling alternatives for Glut-prepared bioprostheses.

Alkaline Phosphatase↗
PubMed2006

Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is known to cause ascending thoracic aortic aneurysms (ATAAs). Transforming growth factor beta (TGF-beta) has recently been implicated in this process. Imbalances between the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) have also been shown to contribute to aneurysm formation. Whether and to what degree MMP, TIMP, and TGF-beta signaling profiles are altered in ATAAs in MFS compared with non-MFS patients remains unknown. METHODS AND RESULTS: ATAA samples taken during aortic replacement from age-matched MFS (n=9) and non-MFS (n=18) patients were assessed for representative subtypes of all MMP classes, all 4 known TIMPs, and type 2 TGF-beta receptors (TGFBR2). Results were expressed as a percentage (mean+/-SEM) of reference control samples (100%; n=18) obtained from patients without ATAA. In MFS, decreased MMP-2 (76+/-7; P<0.05 versus control), increased MMP-12 (161+/-27% versus control; P<0.05), and increased MT1-MMP (248+/-64% versus 91+/-21 non-MFS and control; P<0.05) were observed. TIMP-3 (74+/-23%) was reduced compared with control values (P<0.05) and TIMP-2 was elevated (128+/-31%) compared with non-MFS (73+/-19%; P<0.05). In non-MFS samples, MMP-1 (70+/-16%), MMP-3 (77+/-18%), MMP-8 (75+/-11%), MMP-9 (69+/-14%), and MMP-12 (85+/-15%) were decreased compared with control (P<0.05). TIMPs 1 to 3 were reduced in non-MFS compared with control values (P<0.05). TGFBR2 were increased in MFS (193+/-32%) compared with non-MFS (95+/-16%) and controls (P<0.05). CONCLUSIONS: A unique MMP and TIMP portfolio was observed in ATAAs from MFS compared with non-MFS patients. In addition, MFS samples showed evidence of increased TGF-beta signaling. These differences suggest disparate mechanisms of extracellular matrix remodeling between these 2 groups of patients.

Adult↗
PubMed2006

Assessment of left ventricular viscoelastic components based on ventricular harmonic behavior.

BACKGROUND: Assessment of left ventricular (LV) function with an emphasis on contractility has been a challenge in cardiac mechanics during the recent decades. The LV function is usually described by the LV pressure-volume (P-V) relationship. Based on this relationship, the ratio of instantaneous pressure to instantaneous volume is an index for LV chamber stiffness. The standard P-V diagrams are easy to interpret but difficult to obtain and require invasive instrumentation for measuring the corresponding volume and pressure data. In the present study, we introduce a technique that can estimate viscoelastic properties, not only the elastic component but also the viscous properties of the LV based on oscillatory behavior of the ventricular chamber and it can be applied non-invasively as well. MATERIALS AND METHODS: The estimation technique is based on modeling the actual long axis displacement of the mitral annulus plane toward the cardiac base as a linear damped oscillator with time-varying coefficients. Elastic deformations resulting from the changes in the ventricular mechanical properties of myocardium are represented as a time-varying spring while the viscous components of the model include a time-varying viscous damper, representing relaxation and the frictional energy loss. To measure the left ventricular axial displacement ten healthy sheep underwent left thoracotomy and sonomicrometry transducers were implanted at the apex and base of the LV. The time-varying parameters of the model were estimated by a standard Recursive Linear Least Squares (RLLS) technique. RESULTS: LV stiffness at end-systole and end-diastole was in the range of 61.86-136 dyne/gxcm and 1.25-21.02 dyne/gxcm, respectively. Univariate linear regression was performed to verify the agreement between the estimated parameters, and the measured values of stiffness. The averaged magnitude of the stiffness and damping coefficients during a complete cardiac cycle were estimated as 58.63+/-12.8 dyne/gxcm and 0 dynexs/gxcm, respectively. CONCLUSION: The results for the estimated elastic coefficients are consistent with the ones obtained from force-displacement diagram. The trend of change in the estimated parameters is also in harmony with the previous studies done using P-V diagram. The only input used in this model is the long axis displacement of the annulus plane, which can also be obtained non-invasively using tissue Doppler or MR imaging.

Animals↗
PubMed2006

In-vivo dynamic deformation of the mitral valve anterior leaflet.

BACKGROUND: Surgical techniques have been developed for mitral valve repair for a wide range of pathologies. However, excessive tissue stress and damage have been identified as etiologic factors limiting long-term durability. Before computational models to optimize valve repair can be realistically developed, in-vivo dynamic mitral valve leaflet strain data are required. However, these data do not presently exist. In the present study, a sheep model and sonomicrometry were used to compute the in-surface Eulerian strain tensor of the anterior leaflet over the cardiac cycle at varying afterloads. METHODS: The anterior leaflet of nine Dorsett sheep (35 kg to 45 kg) was instrumented with nine 1-mm hemispherical piezoelectric transducers in a 15-mm square array. Three-dimensional crystal spatial positions were recorded at 250 Hz over several cardiac cycles, with peak left ventricular pressures varying from 90 mm Hg to 200 mm Hg. The in-surface Eulerian strain tensor was computed from the crystal displacements. RESULTS: The mitral valve anterior leaflet experiences large anisotropic strains and peak strain rates of 400%/s, followed by an absolute cessation of any deformation during systole. Increasing left ventricular pressure also increased the effective leaflet stiffness but not the peak strains. CONCLUSIONS: We report the first data on the dynamic in-vivo strain tensor of a functioning mitral valve anterior leaflet, which indicated large anisotropic strains and very high strain rates. Our observations also suggest that changes in left ventricular pressure and annular geometry result in altered effective leaflet stiffness, and may be an important factor in reducing leaflet stress and as such potentially affect mitral valve repair longevity.

Animals↗
PubMed2006

Effects of hemodynamic alterations on anterior mitral leaflet curvature during systole.

OBJECTIVES: The application of repair techniques to treat mitral valve incompetence has increased progressively during the past 20 years. Unfortunately, recent reports have demonstrated the longevity of these repairs to be less than previously believed. Most repair failures are stress related. Computational models to optimize valve repair are in development, but to be brought to fruition, a better understanding of dynamic leaflet geometry is necessary. In this study, sonomicrometry was used in an ovine model to compute systolic leaflet curvature at varying afterloads and states of contractility. METHODS: The anterior leaflet of 12 sheep was instrumented with 5 piezoelectric transducers in a cruciate array. Systolic blood pressure ranged from 90 to 200 mm Hg with increasing phenylephrine hydrochloride infusion. Epinephrine was used to vary contractile state. Leaflet curvature was calculated continuously (200 Hz) during systole. RESULTS: Anterior leaflet curvature in the septolateral direction was double that in the intercommisural direction. There were also significant changes in leaflet curvature during systole. Curvature in neither direction was affected by afterload. Epinephrine augmented intercommisural curvature in a dose-independent fashion, whereas it had no effect on curvature in the septolateral direction. CONCLUSIONS: Dynamic mitral anterior leaflet geometry was found to be amazingly constant over a wide range of hemodynamic conditions. These data provide information about leaflet geometry that will aid in the construction of realistic computational models. Such models may facilitate the design of annuloplasty rings and surgical techniques that minimize leaflet stress and increase mitral valve repair longevity.

Animals↗
PubMed2006

The emerging role of three-dimensional echocardiography in mitral valve repair.

Although three-dimensional (3D) echocardiography is still in its evolution, cutting edge advances that allow quantifiable images of cardiac structures to be created in real-time will begin to increase its use drastically. One of the most promising uses of the technology is in the planning, optimization, and postoperative surveillance of mitral valve repair techniques and devices. This article reviews the development of 3D echocardiography and presents illustrations of how it may be applied to improving mitral valve repair techniques. It is conceivable in the near future that mitral repair procedures will be designed and customized for each patient preoperatively using data obtained from 3D echo images and computerized virtual surgery techniques. Such tools will allow the surgeon to design operations that thoroughly analyze valve geometry and stress distribution before ever entering the operating room.

Echocardiography, Three-Dimensional↗
PubMed2006

Mitral valve surgery for heart failure: a failed innovation?

Five million Americans suffer from heart failure. Despite innovative new pharmacologic and device therapy, the 5-year mortality rate for these patients remains near 50%. Conservatively, 300,000 patients with heart failure also have severe functional mitral regurgitation. Over the past decade the surgical approach to these patients has become more aggressive as the extent of the problem has become widely recognized and surgeon familiarity with annuloplasty techniques has increased. There are, however, few data to support that such interventions improve longevity, reduce heart size, or limit symptoms. In fact the best available data support the conclusion that surgery for functional mitral regurgitation has no effect on survival. We present a review of the existing data on the efficacy of mitral valve surgery in heart failure patients. These data are sobering but confirm the need for evidence-based decision-making in cardiac surgery no matter how intuitively beneficial a procedure may initially seem.

Comorbidity↗
PubMed2006

Role of acetaminophen in acute myocardial infarction.

Acetaminophen, the active ingredient in Tylenol, is a widely used drug that is well known for its analgesic and antipyretic properties. Acetaminophen is a commonly used alternative to nonsteroidal anti-inflammatory drugs, which have recently been demonstrated to increase mortality after acute myocardial infarction (AMI). The safety and potential cardioprotective properties of acetaminophen in the setting of AMI have recently been investigated; however, the results from these studies have been inconclusive. Using both large (ovine) and small (rabbit) collateral-deficient animal models, we studied the effects of acetaminophen in the setting of reperfused AMI. In both species we studied the effects of acetaminophen on myocardial salvage and ventricular function. Additionally, we studied the effects of acetaminophen on myocardial perfusion in sheep and on myocyte apoptosis in rabbits. Sixteen sheep and twenty-two rabbits were divided into two groups and administered acetaminophen or a vehicle before undergoing ischemia and reperfusion. The ischemic period was 60 min in sheep and 30 min in rabbits. All animals were reperfused for 3 h. There were no significant differences observed in myocardial perfusion, myocyte apoptosis, or infarct size in acetaminophen-treated animals. Acetaminophen increased cardiac output and mean arterial pressure before ischemia in sheep but had no effect on any other hemodynamic parameter. In rabbits, no effect on cardiac output or blood pressure was detected. These results support the role of acetaminophen as a safe drug in the postmyocardial infarction setting; however, no significant cardioprotective effect of the drug could be demonstrated.

Acetaminophen↗
PubMed2005

Cardiac support device modifies left ventricular geometry and myocardial structure after myocardial infarction.

BACKGROUND: Whether mechanical restraint of the left ventricle (LV) can influence remodeling after myocardial infarction (MI) remains poorly understood. This study surgically placed a cardiac support device (CSD) over the entire LV and examined LV and myocyte geometry and function after MI. METHODS AND RESULTS: Post-MI sheep (35 to 45 kg; MI size, 23+/-2%) were randomized to placement of the CorCap CSD (Acorn Cardiovascular, Inc) (MI+CSD; n=6) or remained untreated (MI only; n=5). Uninstrumented sheep (n=10) served as controls. At 3 months after MI, LV end-diastolic volume (by MRI) was increased in the MI only group compared with controls (98+/-8 versus 43+/-4 mL; P<0.05). In the MI+CSD group, LV end-diastolic volume was lower than MI only values (56+/-7 mL; P<0.05) but remained higher than controls (P<0.05). Isolated LV myocyte shortening velocity was reduced by 35% from control values (P<0.05) in both MI groups. LV myocyte beta-adrenergic response was reduced with MI but normalized in the MI+CSD group. LV myocyte length increased in the MI group and was reduced in the MI+CSD group. Relative collagen content was increased and matrix metalloproteinase-9 was decreased within the MI border region of the CSD group. CONCLUSIONS: A CSD beneficially modified LV and myocyte remodeling after MI through both cellular and extracellular mechanisms. These findings provide evidence that nonpharmacological strategies can interrupt adverse LV remodeling after MI.

Actins↗
PubMed2005

Recommendations of the National Heart, Lung, and Blood Institute Working Group on Future Direction in Cardiac Surgery.

New surgical procedures, imaging modalities, and medical devices have improved therapy for many patients and made treatment possible for others who have had few options in the past. In February 2004, the National Heart, Lung, and Blood Institute's (NHLBI) Advisory Council proposed that the institute evaluate the status and future directions in cardiac surgery. In response to this recommendation, the NHLBI convened a working group of cardiac surgeons on May 7 and 8, 2004, to assess the state of cardiac surgery research, identify critical gaps in current knowledge, determine areas of opportunity, and obtain specific recommendations for future research activities. The working group discussed surgical revascularization, novel surgical approaches, valvular research directions, biotechnology and cell-based therapy, heart failure, imaging modalities, and barriers to clinical research and presents its recommendations here.

Cardiac Surgical Procedures↗
PubMed2005

Infarct size reduction and attenuation of global left ventricular remodeling with the CorCap cardiac support device following acute myocardial infarction in sheep.

BACKGROUND: Whether mechanical restraint of the left ventricle (LV) can influence remodeling following myocardial infarction (MI) remains poorly understood. The following discussion details three studies examining the effects of surgically placing a cardiac support device (CSD) over the entire epicardial surface, on infarct expansion, global cardiac function and myocyte geometry and function post-MI. METHODS: The effects of passive constraint on infarct expansion and global cardiac function/myocardial energetics were investigated in 10 sheep (5 MI only; 5 MI + CSD) using pressure-volume analysis and magnetic resonance imaging (MRI). Additionally, 11 sheep (5 MI only; 6 MI + CSD) were used to study the effects of passive restraint on myocyte geometry and function post-MI, with 10 additional uninstrumented sheep serving as controls. Baseline data was collected followed by the creation of an anterior infarct. 1 week post-infarct the animals underwent a second set of data collection studies followed by placement of the CSD in the experimental groups. Additional data was collected at 2 and 3 months post-MI. The animals in the myocyte function group underwent additional studies immediately following the 3 month time point. RESULTS: Infarct expansion was diminished as a result of the CSD. At 1 week post-MI the akinetic area was similar in both groups. At the terminal time-point, the akinetic area in the control group was similar to the 1-week time-point whereas, in the CSD group, the area of akinesis decreased (P = 0.001). A comparison of the two groups at the terminal time-point demonstrates a significantly diminished area of akinesis in the CSD group (P = 0.004). The relative area of akinesis followed a similar pattern. The CSD group also exhibited a decrease in end-diastolic volume (control 110.3 +/- 19.8 mL vs. CSD 67.6 +/- 4.7 mL, P = .006) and an improved ejection fraction (control 15.5% +/- 5.7% vs. CSD 29.46% +/- 4.42%, P = .008) relative to the control group. Myocardial energetics were also enhanced in the CSD group as evidenced by significant improvements in potential energy (control 2,015 +/- 503 mL x mm Hg/beat vs. CSD 885 +/- 220 mL x Hg/beat, P = .006), efficiency (control 39.4% +/- 13.6% vs. CSD 59.8% +/- 8.5%, P = .044), and oxygen consumption (control 0.072 +/- 0.013 mL O(2)/beat vs. CSD 0.052 +/- 0.007 mL O(2)/beat, P = .034). Isolated LV myocyte shortening velocity was reduced by 35% from control values (P < 0.05) in both MI groups. LV myocyte beta-adrenergic response was reduced with MI, but normalized in the MI + CSD group. Relative collagen content was increased and matrix metalloproteinase-9 was decreased within the MI border region of the CSD group. CONCLUSIONS: The CorCap cardiac support device retarded infarct expansion, improved global and regional cardiac function and beneficially modified LV and myocyte remodeling post-MI. These findings provide evidence that non-pharmacological strategies can interrupt adverse LV remodeling post-MI.

Animals↗
PubMed2005

Early ventricular restraint after myocardial infarction: extent of the wrap determines the outcome of remodeling.

BACKGROUND: Early infarct expansion initiates adverse remodeling, leads to left ventricular dilatation and portends a poor long-term outcome. Early mechanical prevention of infarct expansion has been proposed as a method to improve remodeling, but the extent of ventricular restraint necessary to optimize the salutary effect is not known. We tested the hypothesis that left ventricular restraint (wrap) is superior to infarct stiffening (patch). METHODS: Infarction of 20% to 25% of the left ventricle was induced by coronary ligation in 69 sheep. Infarcts were either anteroapical (n = 33) or posterobasal (n = 36). Animals with each infarct received either no treatment (anteroapical, n = 26; posterobasal, n = 17), infarct stiffening with a localized Marlex mesh patch (posterobasal, n = 9) or left ventricular wrapping with Merseline mesh (anteroapical, n = 7; posterobasal, n = 10). End-systolic volume, end-diastolic volume, end-systolic muscle to cavity area ratio, left ventricular sphericity, ejection fraction, and degree of mitral regurgitation as determined by quantitative echocardiography were assessed before infarction and at 2, 5, and 8 weeks after infarction to evaluate the extent of left ventricular remodeling. RESULTS: Control animals in both groups experienced adverse remodeling. Anteroapical infarct animals developed large left ventricular aneurysms and the posterobasal infarct animals developed severe mitral regurgitation. Early infarct stiffening did not significantly improve any aspect of remodeling due to the posterobasal infarct. Early left ventricular wrapping significantly improved remodeling after both types of infarctions. CONCLUSIONS: Early left ventricular wrapping attenuates infarct expansion and has a salutary effect on remodeling. Simple infarct stiffening alone is not effective.

Animals↗
PubMed2005

Effect of ventricular size and patch stiffness in surgical anterior ventricular restoration: a finite element model study.

BACKGROUND: Surgical anterior ventricular restoration (SAVER) has been proposed for dilated ischemic cardiomyopathy with an akinetic distal anterior left ventricular wall. We tested the hypothesis that SAVER increases stroke volume, reduces mean myofiber stress and achieves optimal results without a patch. METHODS: A finite element model of the left ventricle (LV) with an akinetic but contractile anteroapical LV wall segment was used. Separate versions of the model with normal and dilated LV sizes were developed and used to simulate the SAVER operation with and without a patch of varying stiffness from 10 to 100 kilopascals. RESULTS: The SAVER operation reduced myofiber stress in the akinetic infarct and infarct borderzone, but caused a reduction in the Starling relationship. In all cases, stroke volume decreased while ejection fraction increased after SAVER. The SAVER operation was more beneficial in dilated ventricles, and the reduction in stroke volume after SAVER without patch was minimal. The effect of patch stiffness was mixed as stiffer material causes a greater reduction in stress yet has the greatest negative effect on stroke volume. CONCLUSIONS: These simulations support the use of SAVER in dilated hearts without a patch.

Animals↗
PubMed2005

Is the myofibrillarlytic myocyte a forme fruste apoptotic myocyte?

BACKGROUND: Myofibrillarlytic (MFL) cells are commonly observed in subendocardial myocardium in myocardial infarction. Because ischemic damage to myocytes is also known to induce apoptosis, we evaluated the prevalence of apoptosis in MFL cells in nine ischemic cardiomyopathic hearts explanted during transplantation. METHODS: Myocytes with partial or complete clearing of cytoplasm, observed commonly in the subendocardium, were recognized as MFL cells. Prevalence of apoptosis was defined by TUNEL and ISOL staining and further characterized by immunohistochemical staining for caspase-3, Bcl2, BCL-X(L), Bax, proliferating cell nuclear antigen (PCNA), and Ki67. RESULTS: Of 4131 MFL cells examined, 1305 (32%) possessed nuclei in a given histologic section; 1140 (88%) of the nucleated myocardial cells were TUNEL positive. Of 842 cells with normal appearance, 257 (31%) cells demonstrated nuclei in the given histologic section. TUNEL staining was observed in 5 (1.9%) in these control areas. All MFL cells stained positive for caspase 3. The antiapoptotic proteins, Bcl2 and BCL-X(L), demonstrated intense upregulation within and surrounding MFL cells, whereas pro-apoptotic protein Bax expression was only seen at control level. The MFL cells had Ki67 negative and PCNA positive nuclei. CONCLUSIONS: The present study demonstrates that the majority of MFL cells are apoptotic and are associated with upregulation of caspase 3. Simultaneous upregulation of Bcl2 represents a survival effort in these myocytes. This is consistent with the review of the literature that MFL cells are viable, persist in myocardium for long time and may be functionally reversible. Evidence for concurrent apoptosis and survival instinct represent a conceptual paradox and suggests that myocytes undergoing apoptosis should be amenable to reconstitution of function.

Apoptosis↗