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Biomedical subjects

Douglas F Larson

Publications and source records attributed to Douglas F Larson.

At least 19 recordsLinked to original sources
PubMed2006

Role of T lymphocytes in hypertension-induced cardiac extracellular matrix remodeling.

Cardiac remodeling in response to pressure overload involves reorganization of the myocytes and extracellular matrix (ECM). Neurohormonal pathways have been described as effector pathways in left ventricular ECM reorganization in response to pressure overload; we now are assessing the role of the T lymphocyte in this process. Mice with defined differences in T-lymphocyte function (C57BL/6 SCID, C57BL/6 WT, and BALB/c) were treated with 50 mg/L of N(G)-nitro-l-arginine methyl ester in their drinking water for 30 days. The immune function of C57BL/6 WT mice was T-helper type 1 (TH1), BALB/c was TH2, and C57BL/6 SCID was null. The arterial blood pressure increased by 30% in all of the strains of mice. However, ventricular stiffness significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. The characterization of matrix metalloproteinase induction and activation on day 30 was associated with T-lymphocyte function. The total cardiac fibrillar collagen, percentage of fibrillar collagen cross-linking, and the activity of the cross-linking enzyme lysyl oxidase-like-3 (LOXL-3) significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. This study revealed that the LOXL-3 pathway, namely, gene expression, enzymatic activities, and LOXL-3-mediated collagen cross-linking, was associated with ventricular stiffness and incongruence with lymphocyte function. These data support the concept that the T lymphocytes may play a fundamental regulatory role in cardiac ECM composition through modulation of collagen synthesis, degradation, and cross-linking.

Amino Acid Oxidoreductases↗
PubMed2006

Macrophage migration inhibitory factor: controller of systemic inflammation.

Macrophage migration inhibitory factor (MIF) is a cytokine that is secreted by the anterior pituitary and immune cells in response to surgical stress, injury, and sepsis. This cytokine appears to be a critical regulator of the inflammatory pathways, leading to systemic inflammatory response syndrome and subsequent multiple organ dysfunction syndrome. This report provides an integrated scheme describing the manner by which MIF controls the neurohormonal response and the adaptive immune system, namely the T-helper (Th)1 and Th2 lymphocytes, which results in the release of pro-inflammatory cytokines and the anti-inflammatory cytokine interleukin-10. The development of systemic inflammatory response syndrome and subsequent development of multiple organ dysfunction syndrome appear to be related to MIF levels and the balance of Th1 and Th2 function.

Humans↗
PubMed2006

Hyperglycemia as an effect of cardiopulmonary bypass: intra-operative glucose management.

Cardiopulmonary bypass (CPB) is associated with surgical stress, hypothermia, hyperoxia, enhancement of neuroendocrine outflow, and administration of glucogenic catecholamines that are associated with glucogonolysis and glucogenesis that result in hyperglycemia. The hyperglycemic state during CPB has been associated with adverse outcomes, such as infection, neurological impairment, cardiac dysfunction, prolonged hospitalization, and higher mortality rates. This report justifies vigilant monitoring of blood glucose levels and a rational protocol for the treatment of hyperglycemia of all open heart surgical patients that may improve post-CPB surgical outcomes.

Coronary Artery Bypass↗
PubMed2005

Comparative effects of dehydroepiandrosterone sulfate on ventricular diastolic function with young and aged female mice.

The adrenal steroid hormone dehydroepiandrosterone (DHEA) and its sulfated derivative [DHEA(S)] have been extensively studied for their potential anti-aging effects. Associated with aging, DHEA levels decline in humans, whereas other adrenal hormones remain unchanged, suggesting that DHEA may be important in the aging process. However, the effect of DHEA(S) supplementation on cardiac function in the aged has not been investigated. Therefore, we administered to young and old female mice a 60-day treatment with exogenous DHEA(S) at a dose of 0.1 mg/ml in the drinking water and compared the effects on left ventricular diastolic function and the myocardial extracellular matrix composition. The left ventricular stiffness (beta) was 0.30 +/- 0.06 mmHg/mul in the older control mice compared with 0.17 +/- 0.02 mmHg/mul in young control mice. Treatment with DHEA(S) decreased left ventricular stiffness to 0.12 +/- 0.03 mmHg/mul in the older mice and increased left ventricular stiffness to 0.27 +/- 0.04 mmHg/mul in young mice. The mechanism for the DHEA(S)-induced changes in diastolic function appeared to be associated with altered matrix metalloproteinase activity and the percentage of collagen cross-linking. We conclude that exogenous DHEA(S) supplementation is capable of reversing the left ventricular stiffness and fibrosis that accompanies aging, with a paradoxical increased ventricular stiffness in young mice.

Aging↗
PubMed2005

A role for T lymphocytes in mediating cardiac diastolic function.

The induction of T helper (TH) lymphocytes by distinct TH ligands results in a differentiation to TH1/TH2 subsets based on their unique pattern of cytokine secretion and effector functions. We hypothesized that the relative proportion of TH1/TH2 directly relates to cardiac fibroblast (CF) function and thereby cardiac extracellular matrix (ECM) composition and cardiac diastolic function in the absence of injury or altered wall stress. We compared the effect of selective TH1 with TH2 inducers on cardiac gene expression, ECM composition, and diastolic function in C57BL/J mice. Twelve weeks after immune modulation, the left ventricular stiffness (beta) was significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). The TH2 group also demonstrated significantly increased end-diastolic and end-systolic volumes (P < 0.01). Cardiac gene expression patterns for pro-matrix metalloproteinase (MMP)-9 and -13 were increased by greater than fivefold in the TH2 group and significantly decreased in the TH1 group (P < 0.05). The total cardiac collagen and cross-linked collagen were significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). Coculturing lymphocytes harvested from the treated mice with naive primary CF demonstrated a direct control of the lymphocytes on CF pro-collagen, pro-MMP gene expression, and MMP activity. These results suggest that the TH phenotype differentially affects diastolic function through modulating CF pro-collagen and pro-MMP gene expression, MMP activity, and cardiac collagen cross-linking, resulting in altered ECM composition. Thus modulation of TH lymphocyte function could promote adaptive remodeling in heart failure and postmyocardial infarction.

Animals↗
PubMed2005

Inflammatory cytokine inhibition of erythropoiesis in patients implanted with a mechanical circulatory assist device.

Mechanical circulatory assist devices (MCADs) are increasingly utilized independently of cardiac transplantation in the management of heart failure. Though MCAD use incorporates inherent mechanical risks, the inevitable onset of chronic anemia, with its associated morbidity and mortality, is also a significant concern. MCAD support has been correlated with elevated plasma levels of inflammatory cytokines TNF-alpha, IL-1beta, and IL-6, which have separately been found to inhibit erythropoietin (Epo)-induced erythrocyte (RBC) maturation. Previous analysis of hematological parameters for MCAD-supported patients concluded that an amplified inflammatory response impedes RBC proliferation and recovery from hemolytic anemia. Additional analysis may bolster this assertion. Hemoglobin concentration (HC), RBC distribution width (RDW), mean cell volume (MCV), and cardiac index were retrospectively analysed for 78 MCAD-supported patients implanted for greater than 30 days at the University of Arizona Health Sciences Center from 1996 to 2002. Analysis confirms that the HC, a conventional marker for anemia, declines with MCAD placement and remains below the clinically defined, minimum normal value. Inversely, the RDW rises above maximum normal measure, signifying an increased fraction of juvenile RBCs. The MCV remains unchanged and within normal limits, demonstrating adequate substrate for RBC formation. MCAD performance also stabilizes as adequate perfusion returns. These results further support our previously published conclusion that a sufficient response of erythropoiesis occurs in reaction to the onset of anemia by an increased production of immature RBCs. However, the cells never fully mature and join circulation. The patient's inflammatory cytokine response to the implanted device most likely mediates the chronic MCAD-induced anemia by inhibition of Epo effects.

Adult↗
PubMed2005

General anesthesia in cardiac surgery: a review of drugs and practices.

General anesthesia is defined as complete anesthesia affecting the entire body with loss of consciousness, analgesia, amnesia, and muscle relaxation. There is a wide spectrum of agents able to partially or completely induce general anesthesia. Presently, there is not a single universally accepted technique for anesthetic management during cardiac surgery. Instead, the drugs and combinations of drugs used are derived from the pathophysiologic state of the patient and individual preference and experience of the anesthesiologist. According to the definition of general anesthesia, current practices consist of four main components: hypnosis, analgesia, amnesia, and muscle relaxation. Although many of the agents highlighted in this review are capable of producing more than one of these effects, it is logical that drugs producing these effects are given in combination to achieve the most beneficial effect. This review features a discussion of currently used anesthetic drugs and clinical practices of general anesthesia during cardiac surgery. The information in this particular review is derived from textbooks, current literature, and personal experience, and is designed as a general overview of anesthesia during cardiac surgery.

Anesthesia, General↗
PubMed2004

Modulation of iNOS activity in age-related cardiac dysfunction.

Based on the role of inducible nitric oxide synthase (iNOS) in heart failure, we hypothesized that the elevated expression of iNOS compared to young mice in the myocardium contributes to the age-related decline of left ventricular (LV) function. Cardiac iNOS mRNA and protein expression was singularly identified in old, wild type (WT) male mice (I6-month) and not in young WT male mice (6-month). Characterized with in vivo pressure-volume loops analysis, an age-related LV dysfunction was found in the old WT mice. The LV dysfunction of the aged mice was modified to that of the younger mice by the specific iNOS inhibitors, aminoguanidine (AMG, 10 mg/Kg, i.v. or infusion, n = 15) and S-methyl-isothiourea (MITU, 3 mg/Kg, i.v. n = 7), and declined with L-arginine (10 mg/Kg, i.v. n = 7). All three drugs had no effects on the LV function of young WT mice or old iNOS knockout (KO) mice. The NOx and cGMP levels were significantly higher only in the old WT mice (n = 6) and cGMP levels decreased to normal with AMG administration. In conclusion, these results suggested that the iNOS/NO/cGMP pathway may contribute to ventricular dysfunction during the aging process and that inhibition of iNOS activity significantly improved heart function in aged mice.

Aging↗
PubMed2004

Characterization of high-salt and high-fat diets on cardiac and vascular function in mice.

This study compared two established dietary formulations, high salt and high fat-high carbohydrate, separately or in combination on the induction cardiovascular dysfunction. One-month-old C57BL/6J mice were fed one of the following diets for 3 mo: (1) control diet consisting of a high fat-high sim-ple carbohydrate (HFHSC); (2) 8% NaCl diet (HS); or (3) HFHSC diet supplemented with 1% NaCl (HFHS). After 3 mo, the HFHSC mice demonstrated significantly increased end-diastolic volume and end-systolic volume, specifically increases of 35% and 78%, respectively (p < 0.01) and a reduction of ventricular stiffness by 27% (p = 0.015). The HS mice exhibited arterial hyper-tension with an increase of 33% in maximum end-systolic pressure (p =.024) and a decrease of 44% in arterial elastance (p = 0.020), corroborated by an increase in the heart weight to body weight ratios (p = 0.002) and vascular types I and III collagen (p = 0.03 and p = 0.0008, respectively). The HFHS group revealed a striking response of 230% to the alpha1-adrenergic challenge (p = 0.00034). These data suggest that the HFHSC diet causes dilated cardio-myopathy, whereas the HS diet produces arterial hypertension and the HFHS diet causes a vascular dysfunctional state that was highly responsive to alpha-adrenergic stimulation.

Animals↗
PubMed2004

Dilated cardiomyopathy in retrovirally infected mice: a novel model for silent viral DCM?

Dilated cardiomyopathy (DCM) is a clinically relevant disease that can occur independently or secondary to other diseases such as HIV infection and AIDS. To study this latter process, we used a model in which mice are infected with the LP-BM5 murine AIDS (MAIDS) retrovirus. Cardiac function of control and infected mice was determined through the in vivo analysis of left ventricular pressure-volume loops. Furthermore, the role of myocarditis was investigated through immunohistochemistry for T-cell, B-cell, and macrophage cardiac infiltrates and Northern blot analysis for tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS). End-systolic and end-diastolic volumes were significantly increased and ventricular stiffness was significantly decreased in infected mice, consistent with DCM; however, no staining for inflammatory cellular infiltrates or TNF-alpha and iNOS was seen. These data support the conclusion that the LP-BM5 HIV model virus causes DCM in the absence of chronic cardiac inflammation. These findings support MAIDS retroviral infection as a new model of idiopathic DCM in which myo-carditis does not occur.

Animals↗
PubMed2004

Inflammatory mediated chronic anemia in patients supported with a mechanical circulatory assist device.

It is widely accepted and clinically anticipated that the patient implanted with a mechanical circulatory assist device (MCAD) will develop a state of chronic anemia that will last throughout the duration of MCAD support. Large-scale hemolysis mediated by the high sheer stress transmitted to the erythrocytes (RBCs) from the mechanical action of most MCAD systems is the accustomed mechanism responsible for this anemic status. MCAD patients exhibiting chronic anemia require frequent blood transfusions placing the patients at a high infectious risk to maintain an acceptable hematocrit. It is also acknowledged that the biomaterial interaction of the MCAD with the immune system precipitates a chronic inflammatory state in this patient population. Taken together, we hypothesize that inflammatory mediation of the erythropoiesis pathway at multiple sites-limiting the replacement of lysed RBCs-dictates the extent of chronic anemia in MCAD patients more than mechanical trauma to the blood. Hematological parameters were retrospectively analyzed for 78 patients implanted with a mechanical circulatory assist device for greater than 30 days at the University of Arizona Health Sciences Center between the years 1996 to 2002. Analysis demonstrates that the rate of hemolysis slows after MCAD implantation, marked by a progressively decreasing plasma hemoglobin concentration. In addition, the absolute reticulocyte count, a marker of juvenile RBC production, increases and remains above maximum normal values after MCAD implantation. Furthermore, the mean cell hemoglobin concentration indicates sufficient substrate for RBC development and maturation. However, hematocrit, a conventional marker of anemia, drops and remains below minimum normal value throughout the measured time period. A state of anemia in the MCAD supported patient results initially from the effect of hemolysis associated with the mechanical action of the MCAD, then chronically persists as the result of another undetermined mechanism. Given the state of chronic inflammation in the patient population, immunological activation most likely limits the full production of RBCs to their mature state.

Adult↗
PubMed2004

TGF-beta1 overexpression: a mechanism of diastolic filling dysfunction in the aged population.

The prevalence of cardiovascular disease in the United States dramatically increases with age. A hallmark feature of the aged myocardium is increased fibrosis resulting in diastolic dysfunction. Moreover, the survival of patients subsequent to a myocardial infarction is inversely related to age because of a certain extent to maladaptive remodeling mediated by cardiac fibroblasts. Our hypothesis is that cardiac fibroblast (CF) dysfunction results in overexpressed TGF-beta1 leading to increased cardiac collagen content in the aged population. TGF-beta1 stimulates the synthesis of the extracellular matrix proteins, including collagen in the cardiac tissues. The RT-PCR analysis of mRNA expression of TGF-beta1 of the CF was increased by 43% in the aged mice as compared to the younger. The stiffness of the left ventricle is expressed with the slope of the end-diastolic pressure-volume relationship parameter, beta (mmHg/microL). In a mouse model, we demonstrated that beta was 0.30 +/- 0.05 in the young as compared to 0.52 +/- 0.10 in the aged (p < .05). The ventricular stiffness was associated with the myocardial collagen content; namely, young versus the aged was 9.5 +/- 4.0 as compared to 16.4 +/- 2.3% of total protein, respectively (p < .05). In conclusion, the gene structure-function relationships support our hypothesis that cardiac fibroblast disregulation contributes to diastolic filling dysfunction in elderly persons. These data provide a potential contributory mechanism for diastolic dysfunction that may be vital in caring for the aged open-heart surgical patient.

Age Factors↗
PubMed2004

Rationale of platelet gel to augment adaptive remodeling of the injured heart.

Cardiac pathologic events including; myocardial infarction, viral infection and hypertrophy, and aging, may trigger maladaptive remodeling of the myocardium. Maladaptive remodeling results in diastolic and systolic dysfunction, myocyte loss, and malformation of the extracellular matrix. It is proposed that platelet gel applied to the site of myocardial injury may provide the proper cytokines, growth factors, and chemokines to promote adaptive remodeling. The hypothesis is that platelet gel concentrates may provide a temporary and local hyperphysiologic concentration of platelet secretory factors that may initiate adaptive myocardial healing. Autologous platelet gel can be derived from concentrated platelets activated and induced to secrete cytokines, growth factors, and chemokines with an array of stimulating agents. This report discusses selected platelet secretory factors, including; IL-1beta, TGF-beta, TGF-alpha, FGF, EGF, PDGF, and IGF, which support the concept that platelet concentrates can mediate cardiac wound healing. In conclusion, application of platelet gel to areas of cardiac injury may offer a therapeutic means to stimulate myocyte regeneration, angiogenesis, and restoration of a normal extracellular matrix composition.

Blood Platelets↗
PubMed2004

Relationship of aging and cardiac IL-10.

Current therapies for the treatment of myocardial infarction and heart failure include medical, surgical, mechanical assist, and transplantation. These therapies have been based on the dogma that ventricular myocytes themselves are terminally differentiated and, therefore, cannot regenerate. This concept has been recently challenged with stem cell therapy. A potential problem is the ability of cardiac tissue to mobilize, recruit, and transdifferentiate adult stem cells from other tissues. We believe that there is a unique failure of the damaged myocardium to provide the appropriate molecular signals for stem cells engraftment related to age. Our hypothesis is that the overexpression of IL-10 in the aged population reduces cardiac cellular proliferation subsequent to myocardial injury. This hypothesis is supported by aging models, where elevated levels of IL-10 are associated with reduced healing response to noncardiac tissue injury. We demonstrated an increased cardiac gene expression of IL-10 that may be associated with a reduced proliferative response in the border regions of the infarcted myocardium that are proportional with age. In conclusion, myocardial infarction and heart failure has presented a significant challenge for the clinician to provide reparative therapies. The use of therapeutics to modulate IL-10 and, thereby, optimizing regenerative processes in the injured myocardium may provide a unique means for the cardiac patient.

Aging↗
PubMed2003

Heart disease, methamphetamine and AIDS.

Methamphetamine (MA) not only affects the nervous system but also has cardiac toxicity and immunosuppressive properties. This manuscript will provide support that there is a relationship between MA use and heart disease as well as immune dysfunction. The cardiovascular manifestations of acute MA use include tachycardia, atrioventricular arrhythmias, myocardial ischemia, myocardial ischemia and hypertension, resulting in cardiac lesions. Chronic use of MA causes cardiomyopathy including cellular infiltration, myocardial hypertrophy, myocardium rupture and fibrosis. The increased catecholamine levels are responsible for the cardiac lesions induced by MA. The additional problem with MA use is its potential to disrupt the immune system function leading to suppression of mitogen-stimulated lymphocyte, a reduction in circulating lymphocyte numbers and alternation T-lymphocyte cytokine secretion as well as B cell proinflammatory cytokine secretion. Concomitant MA use and Human Immunodeficiency Virus (HIV) infection not only enhances immunosuppression associated with HIV but also increases the heart disease occurrence with a coincidentally complication of AIDS or AIDS medications.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Effects of chronic methamphetamine exposure on heart function in uninfected and retrovirus-infected mice.

Methamphetamine (MA) increases catecholamine levels, which have detrimental effects on heart function through vasoconstriction, myocardial hypertrophy, and fibrosis. Murine retrovirus infection induces dilated cardiomyopathy (DCM). The present study investigated the cardiovascular effects of chronic MA treatment on uninfected and retrovirus-infected mice. C57BL/6 mice were studied after 12 weeks treatment. The four study groups were (group I) uninfected, MA placebo; (group II) infected, MA placebo; (group III) uninfected, MA treatment; and (group IV) infected and MA treatment. MA injections were given i.p. once a day for 5 days/week with a increasing dose from 15 mg/kg to 40 mg/kg. Left ventricular mechanics were measured in situ a using Millar conductance catheter system for pressure-volume loop analysis. Cardiac pathology was determined with histological analysis. In the uninfected mice, the load independent contractile parameters, pre-load recruitable stroke work (PRSW) and dP/dt(max) vs. Ved, significantly decreased by 32% and 35% in MA treated mice when compared to the saline injected mice. In retrovirus-infected mice, although there were no significant difference in Ees, PRSW, and dP/dt(max) vs. Ved due to MA treatment, they were increased 45%, 15% and 42% respectively when compared to saline treated mice. No further lowered heart function during murine AIDS may be due to the counteraction of the retroviral DCM and the MA induced myocardial fibrosis and hypertrophy (thickening of the ventricular walls). This is supported by increases in the End-diastolic volume (Ved, 38%) and End-systolic volume (Ves, 84%) in the retrovirus-infected saline injected mice, the decreases of 33% and 17% in the uninfected MA-treated mice, but no significant changes in the retrovirus-infected MA treated mice when compared to uninfected saline injected mice. These data suggest that MA induced myocardial cellular changes compensate for retrovirus induced DCM.

Animals↗
PubMed2002

Cocaethylene and heart disease during murine AIDS.

Cocaethylene is an active cocaine metabolite believed to play a causative role in the increased incidence of sudden cardiac death in individuals who co-administer alcohol and cocaine. Prolonged and excessive abuse of cocaine and alcohol will result in marked alteration of host immunity to increased susceptibility to infection. To test the chronic direct effect of cocaethylene on the heart function, a conductance catheter system (CCS) was used in vivo in this study. To test whether cocaethylene injection exacerbates coxsackievirus B3 (CVB3) or cytomegalovirus (CMV) cardiomyopathy during murine AIDS, female C57BL/6 mice were infected with LP-BM5 retrovirus and superinfected with CVB3 or CMV. Daily, mice were injected intraperitoneally with cocaethylene in 0.9% saline solution (concentration increased gradually from 15 to 25 mg/ml). Histopathology of heart tissue was analyzed in all groups, and cytokines of spleen were measured in the CMV-infected groups. Results showed there was little effect on the cardiovascular system after cocaethylene injection. Cocaethylene injection during murine retrovirus infection greatly exacerbated the pathogenesis of CVB3 or CMV infection, whereas CMV-infected mice showed relatively moderate cardiac pathology compared with CVB3 infection. Both CMV and retrovirus infection suppressed the Th1 response. Our data suggest that cocaethylene treatment shifts the cytokine balance and suppresses Th1 response particularly, facilitating increased CVB3- or CMV-induced myocarditis.

Animals↗