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Biomedical subjects

E Loh

Publications and source records attributed to E Loh.

At least 55 records · Page 3Linked to original sources
PubMed1997

Ventricular dysfunction and the risk of stroke after myocardial infarction.

BACKGROUND: In patients who have had a myocardial infarction, the long-term risk of stroke and its relation to the extent of left ventricular dysfunction have not been determined. We studied whether a reduced left ventricular ejection fraction is associated with an increased risk of stroke after myocardial infarction and whether other factors such as older age and therapy with anticoagulants, thrombolytic agents, or captopril affect long-term rates of stroke. METHODS: We performed an observational analysis of prospectively collected data on 2231 patients who had left ventricular dysfunction after acute myocardial infarction who were enrolled in the Survival and Ventricular Enlargement trial. The mean follow-up was 42 months. Risk factors for stroke were assessed by both univariate and multivariate Cox proportional-hazards analysis. RESULTS: Among these patients, 103 (4.6 percent) had fatal or nonfatal strokes during the study (rate of stroke per year of follow-up, 1.5 percent). The estimated five-year rate of stroke in all the patients was 8.1 percent. As compared with patients without stroke, patients with stroke were older (mean [+/-SD] age, 63+/-9 years vs. 59+/-11 years; P<0.001) and had lower ejection fractions (29+/-7 percent vs. 31+/-7 percent, P=0.01). Independent risk factors for stroke included a lower ejection fraction (for every decrease of 5 percentage points in the ejection fraction there was an 18 percent increase in the risk of stroke), older age, and the absence of aspirin or anticoagulant therapy. Patients with ejection fractions of < or = 28 percent after myocardial infarction had a relative risk of stroke of 1.86, as compared with patients with ejection fractions of more than 35 percent (P=0.01). The use of thrombolytic agents and captopril had no significant effect on the risk of stroke. CONCLUSIONS: During the five years after myocardial infarction, patients have a substantial risk of stroke. A decreased ejection fraction and older age are both independent predictors of an increased risk of stroke. Anticoagulant therapy appears to have a protective effect against stroke after myocardial infarction.

Adult↗
PubMed1997

Development of donor-derived prostate cancer in a recipient following orthotopic heart transplantation.

OBJECTIVE: To report the development of metastatic prostate cancer in a heart transplant recipient without a primary focus in the recipient prostate gland; to present genetic evidence suggesting transplantation of the malignancy from the donor. DESIGN: Histological analysis of donor prostate and recipient prostate and rib. Molecular genetic analysis of prostate and kidney tissue from the donor and peripheral blood leukocytes and rib tissue from the transplant recipient. SETTING: University of Pennsylvania Medical Center. RESULTS: Multiple biopsies of recipient prostate were negative for malignancy but recipient rib contained prostatic adenocarcinoma with osteoblastic bone response. Molecular genetic analysis of recipient rib specimen, which contained both histologically normal and neoplastic cells, was shown to contain a combination of alleles from the donor and recipient at 4 loci. CONCLUSION: Although this is a single case report of an uncommon event, genotyping of polymorphic dinucleotide repeat elements from 4 different chromosomal regions provides strong evidence that the tumor cells arose from donor tissue and were transplanted along with the cardiac allograft.

Adenocarcinoma↗
PubMed1996

Effect of cytoplasmic domain mutations on the agonist-stimulated ligand binding activity of the platelet integrin alphaIIbbeta3.

Function of the platelet integrin alphaIIbbeta3 is regulated by agonist-generated signals interacting with its cytoplasmic tails. When alphaIIbbeta3 is expressed in Epstein-Barr virus-transformed B lymphocytes, stimulation of the cells with phorbol 12-myristate 13-acetate results in alphaIIbbeta3-mediated lymphocyte adherence to immobilized fibrinogen, as well as soluble fibrinogen binding to alphaIIbbeta3, indicating that agonists increase the affinity of alphaIIbbeta3 for fibrinogen in these cells. To address the contribution of the alphaIIb and beta3 cytoplasmic tails to this process, we mutated each tail and expressed the mutants in B lymphocytes. Truncation of the alphaIIb tail did not impair unstimulated or stimulated lymphocyte adherence to fibrinogen, regardless whether the truncation was proximal or distal to the conserved GFFKR sequence. However, deleting GFFKR or replacing it with alanines markedly reduced alphaIIbbeta3 expression due to impaired intracellular assembly of alphaIIbbeta3 heterodimers, probably due to a mutation-induced change in the conformation of alphaIIb. Introducing beta3 mutations known to impair alphaIIbbeta3 function in platelets into the cytoplasmic tail of beta3 in lymphocytes also impaired alphaIIbbeta3 function in these cells. These studies demonstrate that the cytoplasmic tail of alphaIIb is not required for alphaIIbbeta3 function in lymphocytes, although the presence of GFFKR in the alphaIIb tail is required for alphaIIb to interact with beta3. Additionally, they indicate that signals interacting with the beta3 cytoplasmic tail are responsible for the ability of agonists to stimulate alphaIIbbeta3 function.

Amino Acid Sequence↗
PubMed1996

Heart transplantation-associated perioperative ischemic myocardial injury. Morphological features and clinical significance.

BACKGROUND: The frequency and clinical significance of perioperative ischemic myocardial injury (PIMI) after heart transplantation and the diagnostic features distinguishing PIMI from rejection are not well defined. METHODS AND RESULTS: We evaluated PIMI in the first four weekly endomyocardial biopsies and/or autopsy myocardium from 140 consecutive orthotopic heart transplantation recipients (1984 to 1991) by grading the severity of coagulative myocyte necrosis (CMN) as absent, 0; mild-focal, 1; moderate-multifocal, 2; or severe-confluent, 3, and determining the evolution of morphological features of its healing. CMN (often with contraction bands) was noted in 124 patients (89%); 24 patients (17%) had grade 3 CMN, of which 4 died within 30 days of transplantation. Nevertheless, at 1 year after surgery, survival was similar in patients with and without severe injury. Increased cold ischemic time but neither donor age nor intensity of inotropic support correlated with more severe early ischemic injury. PIMI inflammation was characterized by a predominantly polymorphonuclear/histiocytic infiltrate that contained lymphocytes and plasma cells, expanding the interstitium but not encroaching upon and separable from adjacent viable myocytes. Histological features of PIMI developed and resolved more slowly than those of typical myocardial infarct necrosis in nonimmunosuppressed patients; at 4 weeks, CMN persisted in 20% of patients and residual healing in nearly half. Diagnostic rejection was observed concurrently with PIMI in 54 of 533 biopsies (10%). CONCLUSIONS: Diagnosed by conventional histological criteria, PIMI is prevalent early after heart transplantation and has a protracted healing phase that can mimic or coexist with rejection. Extensive PIMI has deleterious impact on short-term survival, but the long-term impact of PIMI remains to be established.

Adolescent↗
PubMed1996

Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans.

OBJECTIVES: This investigation sought to determine whether endothelium-derived nitric oxide contributes to hypoxia-induced systemic vasodilation and pulmonary vasoconstriction in humans. BACKGROUND: Endothelium-derived nitric oxide contributes to basal systemic and pulmonary vascular resistance. During hypoxia, systemic vasodilation and pulmonary vasoconstriction occur. There are some data indicating that endothelium-derived nitric oxide mediates changes in vascular resistance during hypoxia, but much of it is contradictory, and none has been derived from normal humans. METHODS: The hemodynamic effects of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, were studied in healthy volunteers under normoxic and hypoxic conditions. A Swan-Ganz catheter and radial artery cannula were inserted to measure right atrial, pulmonary artery, pulmonary capillary wedge and systemic blood pressures. Cardiac output was measured by thermodilution. Systemic vascular resistance and pulmonary vascular resistance were calculated. The pharmacokinetics of L-NMMA (300 mg intravenously) was studied during normoxia in six subjects. Hypoxia was induced in eight subjects who inspired a mixture of nitrogen and oxygen through a gas blender adjusted to reduce the partial pressure of oxygen from (mean +/- SE) 98 +/- 4 to 48 +/- 1 mm Hg. RESULTS: During normoxia, L-NMMA increased systemic vascular resistance from 1,108 +/- 74 to 1,705 +/- 87 dynes-s-cm-5 and increased pulmonary vascular resistance from 60 +/- 5 to 115 +/- 9 dynes-s-cm-5 (p < or = 0.01 for each). Peak effects occurred within 10 min of L-NMMA administration. Acute hypoxia alone decreased systemic vascular resistance from 1,209 +/- 78 to 992 +/- 58 dynes-s-cm-5 (p < or = 0.05) and increased pulmonary vascular resistance from 92 +/- 11 to 136 +/- 4 dynes-s-cm-5 (p < or = 0.01). While hypoxic conditions were maintained, infusion of L-NMMA increased systemic vascular resistance (to 1,496 +/- 97 dynes-s-cm-5, p < or = 0.01) and increased pulmonary vascular resistance further (to 217 +/- 25 dynes-s-cm-5, p < or = 0.01). CONCLUSIONS: Endothelium-derived nitric oxide contributes to systemic vasodilation and serves as a counterregulatory mechanism to attenuate pulmonary vasoconstriction during acute hypoxia in healthy human subjects.

Acute Disease↗
PubMed1996

Effect of bolus milrinone on hemodynamic variables and pulmonary vascular resistance in patients with severe left ventricular dysfunction: a rapid test for reversibility of pulmonary hypertension.

OBJECTIVES: To examine the feasibility of using milrinone to test pulmonary vascular reactivity in patients before heart transplantation, we tested the hypothesis that milrinone would lower pulmonary vascular resistance (PVR) in patients with severe heart failure. BACKGROUND: Fixed pulmonary hypertension is a risk factor for right heart failure and death after orthotopic heart transplantation. Sodium nitroprusside, the agent used most commonly to test for reversibility of pulmonary hypertension before transplantation, requires dose titration and is frequently limited by hypotension. Milrinone is an intravenously active phosphodiesterase inhibitor that acts rapidly and exerts both positive inotropic and direct vasodilator effects in patients with heart failure. The ability of milrinone to lower PVR in patients with heart failure has not been tested. METHODS: In 27 patients with New York Heart Association functional class III or IV heart failure referred for heart transplantation with a PVR > or = 200 dynes-s-cm-5, we measured the hemodynamic response to a single intravenous bolus of milrinone (50 micrograms/kg body weight) infused over 1 min. RESULTS: Milrinone decreased PVR in all patients. The effect was maximal 5 to 10 min after the bolus and persisted for at least 20 min. The reduction in PVR at 5 min ([mean +/- SEM] 31 +/- 4%) was associated with a 42 +/- 4% increase in cardiac output and decreases of 12 +/- 4% and 16 +/- 5% in mean pulmonary artery and pulmonary artery wedge pressures, respectively, but no change in transpulmonary pressure gradient. Milrinone had no effect on heart rate or systemic arterial pressure. The magnitude of the decrease in PVR correlated inversely with the milrinone-induced increase in cardiac output. CONCLUSIONS: Bolus milrinone consistently decreases PVR in patients with pulmonary hypertension secondary to severe heart failure. This effect is rapid in onset and well tolerated, even by patients with low systemic arterial pressure. An intravenous bolus of milrinone can be used to test for the reversibility of pulmonary hypertension in patients with heart failure undergoing evaluation for heart transplantation.

Adult↗
PubMed1996

Myocardial viability in patients with coronary artery disease and left ventricular dysfunction: transplantation or revascularization?

Coronary artery bypass surgery performed in patients with coronary artery disease and left ventricular dysfunction improves survival compared with antianginal therapy alone. The mechanisms for this survival advantage with revascularization therapy have not been systematically elucidated. Many of these patients have "hibernating" myocardium secondary to chronic ischemia with the potential for substantial improvement in left ventricular function and heart failure symptoms following revascularization therapy. Nevertheless, as survival with cardiac transplantation continues to improve, a significantly larger number of patients with coronary artery disease and left ventricular dysfunction are being referred for cardiac transplantation in lieu of revascularization surgery. Recently developed imaging modalities, which include positron emission tomography, thallium imaging, and dobutamine echocardiography, can reliably predict recovery of regional myocardial dysfunction after revascularization in these areas of hibernating heart. New modalities to detect hibernating myocardium include 99mTc-sestamibi, contrast echocardiography, nuclear magnetic resonance spectroscopic imaging, and ultrasonic tissue characterization. In an era of medicine characterized by increased concern for cost containment and the judicious application of expensive technology, the choice of the most appropriate tests to detect viability is a growing challenge and is essential in the choice between transplantation and revascularization.

Algorithms↗
PubMed1996

Cortical blindness secondary to cyclosporine after orthotopic heart transplantation: a case report and review of the literature.

Cyclosporine neurotoxicity has been described after liver, kidney, and bone marrow transplantation and has been associated with a number of risk factors, including hypomagnesemia and low serum cholesterol levels. Reports in heart transplant recipients are less common. We present a patient with cortical blindness secondary to cyclosporine after orthotopic heart transplantation. The patient had confusion, focal visual field defects, and bilateral occipital lobe lesions shown on magnetic resonance imaging. Although he had significant clinical improvement with decreasing cyclosporine levels, residual computerized visual field defects and magnetic resonance imaging abnormalities were documented several months later.

Blindness↗
PubMed1995

Nitric oxide inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular dysfunction.

BACKGROUND: Nitric oxide (NO) attenuates the contractile response to beta-adrenergic stimulation in cultured cardiac myocytes in vitro and in myocardium in vivo. We tested the hypothesis that NO synthesized in the heart inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular (LV) dysfunction. METHODS AND RESULTS: Patients with various degrees of LV dysfunction and free from epicardial coronary artery disease were instrumented with an infusion catheter in the left main coronary artery and a high-fidelity micromanometer-tipped catheter in the LV. Measurements included LV pressure, aortic pressure, heart rate, and LV peak +dP/dt. In eight subjects, dobutamine was infused via the left main coronary artery (25 or 50 micrograms/min) before and concurrent with intracoronary infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 20 mumol/min for 10 minutes). In six other subjects, dobutamine was infused (6, 10, or 15 micrograms.kg-1.min-1) via a peripheral vein. Intracoronary (n = 8) dobutamine infusions increased LV peak +dP/dt by an average of 33 +/- 3%. The intracoronary infusion of L-NMMA had no effect on baseline LV peak +dP/dt, LV systolic or end-diastolic pressures, aortic pressure, or heart rate. The intracoronary infusion of L-NMMA, concurrent with a second infusion of dobutamine, potentiated the +dP/dt response to dobutamine by 30 +/- 10% (P < .04 versus dobutamine alone). The intracoronary infusion of L-NMMA likewise potentiated the +dP/dt response to the peripheral infusion of dobutamine by 37 +/- 18%. CONCLUSIONS: Nitric oxide produced in the heart attenuates the positive inotropic response to beta-adrenergic stimulation in humans with LV dysfunction. NO may contribute to beta-adrenergic hyporesponsiveness in patients with LV dysfunction.

Adrenergic beta-Agonists↗
PubMed1995

Agonist-stimulated ligand binding by the platelet integrin alpha IIb beta 3 in a lymphocyte expression system.

The ligand binding activity of the platelet integrin alpha IIb beta 3 is initiated by agonist-generated intraplatelet signals. We studied this process in vitro by expressing recombinant alpha IIb beta 3 in Epstein-Barr virus-immortalized B lymphocytes. We found that phorbol ester stimulation induced the adhesion of lymphocytes expressing alpha IIb beta 3 to immobilized fibrinogen. Moreover, replacement of the transmembrane and cytoplasmic domains of the alpha and beta subunits of alpha IIb beta 3 with those of alpha L beta 2 significantly increased adherence, whereas replacement of only the cytoplasmic domains significantly decreased adherence. This suggests that transmembrane segments are involved in the agonist-induced modulation of alpha IIb beta 3 activity. Similar results were seen when the alpha IIb beta 3 activation-dependent monoclonal antibody PAC-1 was substituted for immobilized fibrinogen. We also found that the adherence of lymphocytes expressing beta 3 with either of the two alpha IIb/alpha L chimeras was similar to that of cells expressing alpha IIb beta 3, whereas the adherence of cells expressing alpha IIb with either of the two beta 3/beta 2 chimeras was substantially decreased, suggesting that the identity of the cytoplasmic domain of beta 3, but not of alpha IIb, is critical for alpha IIb beta 3 function. This report indicates that B lymphocytes contain signal transduction pathways involving protein kinase C that can increase the ligand binding activity of alpha IIb beta 3 and demonstrates the utility of these cells as an expression system for the study of agonist-stimulated alpha IIb beta 3 function.

Amino Acid Sequence↗
PubMed1995

Natural history of focal moderate cardiac allograft rejection. Is treatment warranted?

BACKGROUND: The rate of progression and potential long-term consequences of isolated foci of moderate acute rejection (FMR) on endomyocardial biopsy (EMB) have not been defined; therefore, whether FMR necessitates augmented immunosuppression remains controversial. METHODS AND RESULTS: At our institution, recipients with EMBs having FMR, defined as one or two isolated foci of cellular infiltrates with associated myocyte damage (International Society for Heart and Lung Transplantation [ISHLT] grade 2 and a subset of grade 3A), do not routinely receive intensified immunosuppression. Accordingly, to determine the outcome of untreated FMR, we reviewed 4398 EMBs (mean, 4.4 samples each) obtained after orthotopic heart transplantation in 208 consecutive recipients maintained on triple immunosuppressive therapy. The incidence of progression versus resolution of FMR, the time interval after transplantation when FMR was detected, and the relation of untreated FMR to recipient survival were analyzed. FMR categorized as one (n = 312) or two (n = 89) foci was present in 401 EMBs (9% of total) obtained 10 days to 7.5 years after transplantation from 149 recipients (72%). EMBs with FMR resolved without treatment in 341 of 401 (85%), and only 60 of 401 (15%) progressed to higher grade rejection. EMBs that progressed occurred 7.5 +/- 7.9 months (mean +/- SD) after transplantation compared with 14.0 +/- 16.5 months after transplantation for those that resolved (P < .005). Of the 60 EMBs that progressed, 55% occurred within the first 6 months, 78% within the first year, and 97% within the first 2 years after transplantation. EMBs with two foci of FMR were no more likely to progress than those with one focus. Thirty-nine recipients experienced one (n = 25), two (n = 9), three (n = 3), or four (n = 2) episodes of FMR that progressed. One or more episodes of FMR that did not progress occurred in 110 recipients. By Kaplan-Meier analysis, survival at 1 and 5 years was similar in recipients with and those without FMR progression. CONCLUSIONS: First, untreated FMR consisting of either one or two foci has a low rate of progression. Second, progression of FMR decreases with increasing postoperative interval and becomes rare after 2 years. Last, FMR progression did not identify recipients with decreased survival.

Azathioprine↗
PubMed1995

Effect of nitric oxide synthase inhibition on bleeding time in humans.

Endothelium-derived nitric oxide (NO) is a potent in vitro inhibitor of platelet adhesion and aggregation, but its role in regulating platelet reactivity in vivo and in humans in particular is undefined. Our primary objective was to determine whether the in vivo inhibition of NO production shortens template bleeding time (BT). The hemodynamic and platelet effects of NG-mono-methyl-L-arginine (L-NMMA), an NO synthase inhibitor, were studied in 12 normal volunteers. Forearm template BT was determined before and 15 min after the intravenous (i.v.) infusion of 4.3 mg/kg L-NMMA. L-NMMA infusion increased mean arterial pressure from 88 +/- 4 to 99 +/- 3 mm Hg (p = 0.0001). Plasma NO levels, determined by chemiluminescence, decreased 65 +/- 10% from basal values (p < 0.05), confirming inhibition of endogenous NO production. Intravenous L-NMMA shortened BT from 5.5 +/- 0.9 to 4.0 +/- 0.6 min (p = 0.026), or by 24 +/- 8% (p = 0.008). L-NMMA infusion did not significantly change ex vivo platelet aggregation. To determine whether vasoconstriction affected BT, we investigated forearm blood flow (FBF; determined by venous occlusion plethymography), and template BT in 3 subjects after the local infusion of L-NMMA (2-4 mg/min intraarterially, i.a.). Intraarterial administration of L-NMMA caused a 39 +/- 3% (p = 0.006) reduction in FBF in the infused arm but did not change BT. These data show that systemic inhibition of NO production shortens BT in humans. However, the precise mechanism by which L-NMMA shortens BT is not completely defined.

Adult↗
PubMed1995

Decreased adenylate cyclase activity and expression of Gs alpha in human myocardium after orthotopic cardiac transplantation.

We studied several aspects of guanine nucleotide-stimulated adenylate cyclase function in patients after orthotopic cardiac transplantation. In 28 patients, adenylate cyclase activity was measured in endomyocardial biopsy samples obtained just before and at monthly intervals after cardiac transplantation. In biopsies obtained > or = 6 months after transplantation, basal adenylate cyclase activity was decreased by 67% (n = 12; P < .05), GTP gamma S-stimulated adenylate cyclase activity was decreased by 78% (n = 12; P < .05), Mn+2+forskolin-stimulated adenylate cyclase activity was decreased by 80% (n = 8; P < .05), and Mn+2-stimulated adenylate cyclase activity (a measure of activity of the catalytic subunit of adenylate cyclase) was decreased by 83% (n = 8, P < .05). Western blot analysis demonstrated that 6 months after cardiac transplantation, the level of Gs alpha protein was decreased by 61 +/- 12% (n = 8; P < .001). There was no change in the level of Gi alpha as assessed by pertussis toxin-catalyzed ADP-ribosylation (n = 4; P = NS). With the use of the quantitative polymerase chain reaction, a 50 +/- 10% (n = 6; P < .001) reduction in the steady-state level of Gs alpha mRNA was observed. There was no change in the level of mRNA for Gi-3 alpha. Thus, after orthotopic cardiac transplantation in humans, guanine nucleotide-stimulated adenylate cyclase activity is decreased in parallel with decreased levels of Gs alpha protein and mRNA.

Adenylyl Cyclases↗