Biomedical subjects
Publications and source records attributed to Craig H Selzman.
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Although heart transplantation remains the gold standard for patients who remain in advanced heart failure despite optimal medical therapy, limited donor supplies allows for just >2000 transplant each year in the United States. Recent enthusiasm has developed for the role of mechanical circulatory support for this ever-growing population of sick patients. Although much attention has been directed toward ventricular assist devices, less information is available regarding the role of the total artificial heart. Indeed, efforts in this latter technology have allowed the relatively recent deployment of a variety of complete circulatory assist devices. The purpose of this article is to review the historical development, current use, and future role of total artificial hearts.
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Mitochondrial diseases represent a heterogeneous group of disorders associated with a wide array of clinical manifestations. The presentation of patients with mitochondrial pathology largely depends upon the dysfunction of organ systems with large metabolic/energy requirements, including cardiac, neurologic, and musculoskeletal. In particular, mitochondrial myocardial disease can be progressive resulting in congestive heart failure and end-stage heart disease. This article reviews the role of heart transplantation for a particular variant of mitochondrial disorder, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, and discusses perioperative management issues related to transplantation for mitochondrial cardiomyopathies.
BACKGROUND: The inflammatory response to vascular injury is characterized by expression of cytokines, growth factors, and chemokines that conspire to promote vessel remodeling and intimal hyperplasia (IH). Interleukin-10 (IL-10) is a multifunctional cytokine that has several anti-inflammatory properties in vitro. Few studies have evaluated the effects of IL-10 in experimental atherosclerosis. The purpose of the present study was to determine the influence of IL-10 on vascular inflammation and IH following mechanical injury. METHODS: Wire carotid injury was performed in wild-type (WT) mice with and without IL-10 treatment. Immunohistochemistry, PCR, and ELISA assays were used to examine vessel production of basic fibroblast growth factor (bFGF), monocyte chemotactic protein-1 (MCP-1), and nuclear factor kappa B (NFkappaB). Vessels were morphometrically analyzed for IH. RESULTS: Carotid injury induced early expression of MCP-1 and bFGF that was abrogated in mice treated with IL-10. Similarly, injury-induced expression of NFkappaB message and protein was attenuated in mice receiving exogenous IL-10. Compared to untreated mice, IL-10 markedly decreased levels of IH. Interestingly, carotid injury in IL-10-deficient mice resulted in an augmented IH response compared to injured WT mice. CONCLUSIONS: In an in vivo model of direct vascular injury, IL-10 decreased expression of the pro-inflammatory transcription factor, NFkappaB, and the mitogenic chemokine and growth factor, MCP-1 and bFGF, respectively. These observations were associated with IL-10-induced attenuation of IH. Furthermore, endogenous IL-10 appeared to suppress the injury response. In conclusion, exogenously delivered IL-10 may represent a clinically relevant anti-inflammatory strategy for post-injury intimal hyperplasia.
Tumor necrosis factor-alpha (TNF-alpha) is an important mediator in the inflammatory response to vascular injury. The present study sought to determine the relative contribution of each TNF-alpha receptor subtype (p55 and p75) to intimal hyperplasia (IH) and characterize the mechanisms of transcriptional regulation after vascular injury. A murine model of wire carotid arterial injury was employed to induce IH in wild-type (WT), p55-deficient (p55-/-), and p75-deficient (p75-/-) mice. Compared with injured WT and p75-/- animals, p55-/- mice demonstrated a twofold reduction in IH. Additionally, p55-/- mice demonstrated a decrease in expression of nuclear factor-kappaB mRNA and protein. These observations suggest an important role for the p55 receptor in IH after mechanical endoluminal injury. Suppression of the transcriptional activator nuclear factor-kappaB may provide a mechanism by which p55-mediated IH is attenuated.
An elevated level of C-reactive protein (CRP), an acute phase protein, is one of many downstream indicators of inflammation. Physiologically, CRP enhances cell-mediated immunity by promoting phagocytosis, accelerating chemotaxis, and activating platelets. The purposes of this article are (1) to review the clinical data implicating serum CRP level as a systemic marker of focal inflammation and (2) to explore serum CRP level as a reflection of the inflammatory component of atherogenesis. Our findings indicate that CRP levels serve as an early marker of the magnitude of inflammation in events as dissimilar as appendicitis and myocardial infarction. The level of circulating CRP correlates with endovascular disease and may serve to identify otherwise asymptomatic patients at sufficient cardiovascular risk to warrant aggressive therapy. Determining whether CRP has a direct pathologic role in the vascular wall itself may have the most clinical relevance.
OBJECTIVE: Serologic evidence of Chlamydia pneumoniae infection and atherosclerosis was first demonstrated in patients with ischemic heart disease in 1988. Subsequently, the organism has been detected in several cardiovascular lesions. Outside of observational reports, few studies mechanistically link vascular infection with C. pneumoniae and atherogenesis. To better define its pathophysiologic role, we examined the influence of C. pneumoniae infection of human vascular smooth muscle cells on vascular smooth muscle cell proliferation, cell-cycle protein expression, and inflammatory cytokine release. METHODS: Human aortic vascular smooth muscle cells were inoculated with C. pneumoniae in culture. Proliferation was assessed by mitochondrial activity, direct cell counting, and immunohistochemical staining for proliferating cell nuclear antigen. Electromobility gel shift assays probed for the antiproliferative cell-cycle protein p53. Supernatants were assayed for the mitogens interleukin-6 and interleukin-8 by enzyme-linked immunosorbent assay. RESULTS: After C. pneumoniae inoculation, vascular smooth muscle cell proliferation increased 2-fold by mitochondrial activity and more than 3-fold by cell numbers. C. pneumoniae infection promoted a 3-fold increase in proliferating cell nuclear antigen expression, which was associated with decreased nuclear binding of p53. Compared with control, C. pneumoniae inoculation resulted in a 2.5-fold increase in released interleukin-6 and interleukin-8. In each experiment, the influence of C. pneumoniae was abrogated by concomitant treatment with the macrolide antibiotic azithromycin. CONCLUSIONS: C. pneumoniae induced human vascular smooth muscle cell proliferation and proliferating cell nuclear antigen expression, down-regulated p53, and promoted release of prototypical atherogenic cytokines. These in vitro findings indicate that C. pneumoniae is more than an innocent bystander, rather it is a pathophysiologic participant in atherogenesis warranting elimination.
Although monocyte chemotactic protein-1 (MCP-1) is best known for its ability to recruit mononuclear cells, few studies have examined the effects of this chemokine on other events in the vascular response to injury. The purpose of the present study was to determine the influence of MCP-1 on human vascular smooth muscle (VSMC) proliferation. MCP-1 induced concentration-dependent VSMC proliferation as measured by bromodeoxyuridine (BrdU) uptake. Direct cell counting demonstrated a twofold increase in VSMC after stimulation with MCP-1. This mitogenic effect was similar to that observed with the prototypical atherogenic cytokine platelet-derived growth factor. Immunohistochemistry and Western blot analysis revealed that MCP-1 increased both proliferating nuclear cell antigen and cyclin A expression. Whereas MCP-1 did not promote nuclear factor-kappaB activation, MCP-1-induced VSMC proliferation appeared to be dependent on phosphotidylinositol 3-kinase activation. In conclusion, MCP-1 directly induces VSMC growth, which is associated with activation of cell cycle proteins and intracellular proliferative signals. Within the inflammatory paradigm of vascular remodeling, these data suggest that MCP-1 is more than simply a chemokine but also a potent mitogen for VSMC proliferation.
HYPOTHESIS: The selective estrogen receptor modulator raloxifene hydrochloride inhibits intimal hyperplasia. DESIGN: Controlled laboratory experiment. SETTING: Experimental animal model. INTERVENTION AND MAIN OUTCOME MEASURES: Forty-three senile female sheep were randomized to sham operation, ovariectomy, or ovariectomy followed by treatment with 17beta-estradiol or raloxifene. Six months after initial operation, we performed necropsy with histological assessment of the aortic bifurcation and bone mineral densitometry and assayed serum lipids. RESULTS: After 6 months, serum triglyceride and total and high-density lipoprotein cholesterol levels were similar among groups and within the reference range. Ovarian ablation alone resulted in intimal hyperplasia, which was attenuated with estradiol and raloxifene therapy. Furthermore, estradiol and raloxifene therapy reversed ovariectomy-induced decreases in bone mineral density measured using spine morphometry. CONCLUSIONS: Raloxifene attenuates ovariectomy-induced aortic intimal hyperplasia independent of serum lipid levels. These data suggest that raloxifene, in addition to its beneficial influence on bone density, has direct, beneficial cardiovascular effects.
Interleukin (IL)-11 is a growth factor for megakaryocytes, osteoclasts, and intestinal mucosa. IL-11 is also an anti-inflammatory agent, mediating many of its effects by inhibition of the transcriptional activator nuclear factor (NF)-kappa B. The purposes of this study were to examine the effects of IL-11 on human vascular smooth muscle cell (VSMC) proliferation and NF-kappa B activity. VSMC were cultured from human transplant donor aortas, stimulated with basic fibroblastic growth factor (bFGF), and treated with IL-11. VSMC stimulated with bFGF demonstrated an increase in cell number by direct cell counting and mitochondrial activity. IL-11 caused a concentration-dependent decrease in bFGF-induced VSMC proliferation. Furthermore, IL-11 attenuated bFGF-induced increases in cytoplasmic and intranuclear unbound NF-kappa B p65. Similarly, IL-11 attenuated VSMC expression of two NF-kappa B-dependent cytokines, IL-8 and IL-6. Stimulated VSMC did not secrete IL-11, suggesting that endogenous IL-11 did not account for our observations. In conclusion, IL-11 inhibits human VSMC proliferation in vitro and is associated with suppression of NF-kappa B.
This study sought to determine the influence of tumor necrosis factor-alpha (TNF-alpha) on intimal hyperplasia (IH) and characterize the mechanisms of transcriptional regulation after vascular injury. A murine model of wire carotid artery injury was employed to induce IH in wild-type (WT) and TNF-alpha-deficient [TNF(-/-)] animals. Three days after injury, TNF-alpha and nuclear factor-kappaB (NF-kappaB) protein expression was markedly increased in the injured WT carotid artery compared to control. Injury increased TNF-alpha and NF-kappaB mRNA expression 100- and 7.5-fold, respectively. Compared with WT specimens, injury in TNF(-/-) animals decreased both NF-kappaB mRNA and protein nearly 7.5- and 4-fold, respectively. Expression of the NF-kappaB-dependent cytokine monocyte chemotactic protein 1 was markedly diminished in injured TNF(-/-) animals. Finally, TNF(-/-) animals demonstrated a sevenfold reduction in IH compared with WT animals. Cumulatively, these data mechanistically link TNF-alpha and NF-kappaB in vivo and suggest an important influence of TNF-alpha on postinjury IH.
Vasopressin is a vital homeostatic protein which regulates fluid balance via its antidiuretic effects and vascular tone via its vasoconstrictive effects. Endogenous vasopressin deficiency has been implicated in several disease states resulting in vasodilatory shock. In particular, vasopressin levels are low in patients following cardiac surgery and in those with ventricular dysrhythmias. Several recent studies have demonstrated the effectiveness of exogenous vasopressin in providing haemodynamic support in patients with postcardiopulmonary bypass vasodilatory shock and refractory ventricular fibrillation. This manuscript reviews the pathophysiological and clinical basis for vasopressin replacement in patients with cardiovascular collapse.
Although nearly 10% of patients experience profound vasodilatory shock after cardiopulmonary bypass, some patients remain refractory to traditional resuscitation. Among this subset are patients who have inappropriately low levels of endogenous vasopressin. Thus, vasopressin replacement is an intuitively attractive intervention. The purposes of this review are to outline the pathophysiology of vasodilatory shock after cardiopulmonary bypass, to discuss the physiological role of endogenous vasopressin, to explore the clinical basis for vasopressin replacement, and to review the pharmacology and dosing guidelines.
Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is the most common congenital coronary artery defect. Left uncorrected, nearly 90% of patients will die within one year. Without surgical repair, surviving patients are subjected to risks of myocardial ischemia with global cardiomyopathy, chronic mitral regurgitation, and sudden death. We report a case of ALCAPA in a 23-year-old female with completely preserved left ventricular function. This article reviews the mechanism of this unusual presentation as well as the therapeutic options for adults presenting with ALCAPA.
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