Nifedipine: a myocardial protective agent.

The effectiveness of the calcium antagonist nifedipine in preserving postischemic myocardial function and structural integrity was experimentally demonstrated in isolated rabbit hearts, in conscious dogs subjected to myocardial infarction, in open chest anesthetized dogs with normothermic regional ischemia induced for 1 to 2 hours and in dogs undergoing hypothermic global ischemia for 2 hours followed by 2 hours of reperfusion. Nifedipine had a beneficial effect on postischemic myocardial stiffness and mitochondrial calcium accumulation, which were correlated. Administration of nifedipine at the onset of myocardial infarction increased blood flow to ischemic zones of myocardial infarction and resulted in less loss of creatine kinase. It reduced by two- to three-fold the volume of the ischemia-reperfusion injury induced by left anterior descending coronary arterial occlusion and release and preserved indexes of hemodynamic function. Nifedipine was found effective in protecting myocardial performance and structure after 2 hours of global ischemia during hypothermic cardiopulmonary bypass. It is suggested that this agent may be useful as an adjunct to cold cardioplegia in man for enhanced myocardial protection during cardiac surgery.     

Distinct protein components from Torpedo marmorata membranes carry the acetylcholine receptor site and the binding site for local anesthetics and histrionicotoxin.

Highly purified subsynaptic membrane fragments prepared from Torpedo marmorata electric organ (specific activity, greater than 4 mumol of Naja nigricollis alpha-[3H]toxin per mg of protein) exhibit, on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, two major protein bands of apparent molecular weight 40,000 and 43,000, respectively. Dissolution of these membranes by the nondenaturing detergents Triton X-100 and Berol 043 followed by standard fractionation yielded (i) the 9S acetylcholine-receptor protein which still binds the alpha-[3H]toxin and after further purification yielded, in the presence of sodium dodecyl sulfate, the 40,000-dalton component, covalently labeled by the affinity reagent 4-(N-maleimido)phenyl[3H]trimethylammonium; only serine was found as the NH2-terminal amino acid of this protein; and (ii) a high molecular weight aggregate named 43,000 protein which was resolved in denaturing gels almost exclusively as the 43,000-dalton band, In the absence of detergents, the 43,000 protein binds compounds known to interact with the acetylcholine ionophore: a fluorescent local anesthetic quinacrine and histrionicotoxin (apparent dissociation constant, 7 +/- 1 X 10(-7) M). The regulation of quinacrine fluorescennce by carbamylcholine, observed in the intact membrane, no longer occurs with the isolated 43,000 component.     

Influence of nifedipine on left ventricular systolic and diastolic function: Relationships to manifestations of ischemia and congestive failure

In addition to the favorable effects of calcium antagonists on symptoms related to coronary spasm, we recently documented preclusion of ergonovine-induced coronary spasm angiographically in four patients with proved Prinzmetal's angina.To determine whether nifedipine has similar “relaxing” or negative inotropic actions on left ventricular myocardial function, we studied 19 patients with various degrees of left ventricular dysfunction before and after nifedipine (20 mg sublingually) during cardiac catheterization. Left ventricular afterload was reduced, with a significant (13 percent) decline in arterial pressure; left ventricular diastolic pressures were unchanged. Left ventricular ejection function was augmented, with significant increases in ejection fraction (14 percent), mean velocity of circumferential fiber shortening (41 percent), systolic ejection rate (25 percent), and end-systolic $\text{pressure}\text{volume}$ ratio (19 percent). Cardiac index increased significantly by 16 percent. Early diastolic relaxation, diastolic pressure-volume relations and end diastolic stiffness remained unchanged after nifedipine. When patients were categorized (Group I: left ventricular end-diastolic volume ≤ 90 ml/m², end-diastolic pressure ≤ 20 mm Hg; Group II: end-diastolic volume > 90 ml/m², end-diastolic pressure > 20 mm Hg), highly pertinent differences were apparent. Nifedipine significantly reduced left ventricular preload and end-diastolic pressures in Group II but not in Group I patients. Enhancement of left ventricular ejection function in Group II patients was significantly more prominent than that in patients with normal baseline function. Although diastolic properties were insignificantly changed overall, the left ventricular diastolic pressure-volume relation was displaced downward by nifedipine in Group II, but not in Group I patients. Both systemic and pulmonary vascular resistance declined significantly more in Group II patients, whereas cardiac index was increased 25 percent compared with a negligible change in group I patients. These results indicate beneficial effects of nifedipine on myocardial oxygen requirements, particularly in patients with impaired left ventricular function in whom left ventricular preload and afterload were both significantly reduced, cardiac index augmented and the pressure-volume relation shifted downward.To confirm predicted symptomatic benefits in 13 other patients with fixed coronary, disease, incremental atrial pacing to anginal threshold was performed before and 30 minutes after nifedipine (20 mg sublingually). Mean paced heart rate at onset of angina increased 19.3 percent after nifedipine. Concomitantly, aortic pressure decreased significantly by 22.1 percent at the onset of angina; double product was unchanged at the anginal threshold. Thus, although left ventricular afterload was reduced by nifedipine, the anginal threshold was unchanged in terms of myocardial oxygen requirements.In concert, these results indicate that therapeutically effective influences of nifedipine in patients with fixed coronary disease are attributable basically to hemodynamic alterations consequent upon left ventricular afterload reduction. Nevertheless, such effects imply therapeutic benefit, the reduced afterload concomitantly permitting greater exercise-induced tachycardia before the anginal threshold is reached.     

Leiomyoblastoma associated with intractable hypercalcemia and elevated 1,25-dihydroxycholecalciferol levels. Treatment by hepatic enzyme induction

A 42-year-old woman, with a previously resected jejunal leiomyoblastoma, was first seen with liver metastases 31/2 years after the tumor resection. Intractable malignant hypercalcemia appeared eight months later, together with renal insufficiency. No osteolytic lesions were detected. Levels of parathyroid hormone, cyclic adenosine monophosphate, and 1,25-dihydroxycholecalciferol (1,25[OH]2D) were not useful in distinguishing between the hypercalcemia of malignancy and concurrent hyperparathyroidism. Despite renal insufficiency, hypercalcemia, and subtotal parathyroidectomy, the 1,25(OH)2D levels remained elevated, consistent with the speculation that a tumor product stimulated 1-alpha-hydroxylation of 25-hydroxycholecalciferol. Phenytoin and phenobarbital (enzyme induction therapy), in combination with phosphorus and glucocorticoids, appeared to be useful in controlling the hypercalcemia.     

Improvement of regional myocardial metabolism after coronary thrombolysis induced with tissue-type plasminogen activator or streptokinase

To assess the effects on the heart itself of coronary thrombolysis induced with either tissue-type plasminogen activator (t-PA) or streptokinase (SK), we performed positron emission tomography with 11C-palmitate in 19 patients with initial transmural myocardial infarction immediately after admission and again within 48 to 72 hr after intracoronary administration of t-PA (n = 2) or SK (n = 17). Clots were persistent in eight patients treated with SK despite an average dose of 336,000 IU, sufficient to markedly deplete fibrinogen. In the absence of lysis, favorable tomographic changes did not occur. In contrast, in each of the 11 patients in whom lysis was induced (two with t-PA and nine with SK) myocardial accumulation of 11C-palmitate improved by an average of 29% in late compared with early studies (p less than .001). Results were comparable in patients with anterior and those with inferior infarction. Thus clot lysis induced with either t-PA or SK led to improved regional myocardial metabolism.     

Differential regulation by troglitazone of plasminogen activator inhibitor type 1 in human hepatic and vascular cells

Troglitazone, a novel oral insulin sensitizer, normalizes increased plasma activity of plasminogen activator inhibitor type 1 (PAI-1) in hyperinsulinemic patients such as women with polycystic ovary syndrome and patients with type 2 diabetes mellitus. However, underlying mechanisms have not yet been fully elucidated. Human hepatic and vascular cells, the main sources of circulating PAI-1, were studied in cell culture. In human hepatic cells, PAI-1 accumulated in conditioned medium by 23% within 24 h after exposure to 3 microg/mL troglitazone (P = 0.001). The accumulation depended on the concentration of troglitazone, but not that of insulin (known to stimulate PAI-1 synthesis). By contrast, in human aortic smooth muscle cells, 3 microg/mL troglitazone decreased basal PAI-1 expression by 23% (P = 0.037) and decreased transforming growth factor-beta-induced expression by 34% (P = 0.026). Concomitant insulin had no effect. Tissue-type plasminogen activator was decreased by 38% (P = 0.002). In human endothelial cells, PAI-1 was diminished by 32% (P < 0.001), whereas tissue-type plasminogen activator was unaffected. The results suggest that the reduction in plasma activity of PAI-1 induced by troglitazone in patients may reflect both directly mediated diminution of its elaboration from vessel walls and indirectly mediated reduction of its hepatic synthesis secondary to attenuation of hyperinsulinemia (known to increase the hepatic synthesis of PAI-1).     

Predicting Hip Fracture Type With Cortical Bone Mapping (CBM) in the Osteoporotic Fractures in Men (MrOS) Study

Hip fracture risk is known to be related to material properties of the proximal femur, but fracture prediction studies adding richer quantitative computed tomography (QCT) measures to dual‐energy X‐ray (DXA)‐based methods have shown limited improvement. Fracture types have distinct relationships to predictors, but few studies have subdivided fracture into types, because this necessitates regional measurements and more fracture cases. This work makes use of cortical bone mapping (CBM) to accurately assess, with no prior anatomical presumptions, the distribution of properties related to fracture type. CBM uses QCT data to measure the cortical and trabecular properties, accurate even for thin cortices below the imaging resolution. The Osteoporotic Fractures in Men (MrOS) study is a predictive case‐cohort study of men over 65 years old: we analyze 99 fracture cases (44 trochanteric and 55 femoral neck) compared to a cohort of 308, randomly selected from 5994. To our knowledge, this is the largest QCT‐based predictive hip fracture study to date, and the first to incorporate CBM analysis into fracture prediction. We show that both cortical mass surface density and endocortical trabecular BMD are significantly different in fracture cases versus cohort, in regions appropriate to fracture type. We incorporate these regions into predictive models using Cox proportional hazards regression to estimate hazard ratios, and logistic regression to estimate area under the receiver operating characteristic curve (AUC). Adding CBM to DXA‐based BMD leads to a small but significant (p < 0.005) improvement in model prediction for any fracture, with AUC increasing from 0.78 to 0.79, assessed using leave‐one‐out cross‐validation. For specific fracture types, the improvement is more significant (p < 0.0001), with AUC increasing from 0.71 to 0.77 for trochanteric fractures and 0.76 to 0.82 for femoral neck fractures. In contrast, adding DXA‐based BMD to a CBM‐based predictive model does not result in any significant improvement. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.     

B-cell lymphoma after angioimmunoblastic lymphadenopathy: a case with oligoclonal gene rearrangements associated with Epstein-Barr virus

We describe a patient with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), who subsequently developed large-cell immunoblastic lymphoma of B-cell immunophenotype. At the time of the initial diagnosis, histologic examination of an inguinal lymph node showed typical features of AILD, and there was no evidence of a monoclonal B-cell population by immunohistochemical analysis. In situ hybridization and Southern blot analysis for Epstein-Barr virus (EBV) were negative. At autopsy 2 years later, the patient had widespread lymph node and organ involvement by large-cell immunoblastic lymphoma of B-cell immunophenotype. Southern blot analysis performed on DNA extracted from lymph nodes, liver, and spleen showed two patterns of Ig heavy chain and kappa light chain gene rearrangements. The T-cell receptor beta chain gene was in the germline configuration. Analysis with an EBV terminal repeat region probe showed two clonal populations that paralleled the Ig gene rearrangement studies. Double-labeling immunohistochemistry and in situ hybridization confirmed the presence of EBV within the neoplastic B cells. The data support the hypothesis that EBV was not etiologically related to AILD in this case, and that EBV proliferation may occur after the onset of the disease. Further, the data suggest that some B-cell lymphomas that arise in the setting of AILD resemble EBV-associated B-cell lymphomas that arise in other immunodeficiency states.