Endomyocardial biopsy in hemochromatosis: clinicopathologic correlates in six cases.

Clinical and pathologic features of cardiac hemochromatosis diagnosed by endomyocardial biopsy in six men, aged 32 to 75 years (mean 52), are described. Echocardiography demonstrated left ventricular enlargement and marked global systolic dysfunction in five. Cardiac catheterization demonstrated normal coronary arteries, increased left ventricular end-diastolic pressure and decreased left ventricular systolic function in all five so studied. Stainable iron was present in all endomyocardial biopsy specimens from the five patients with decreased left ventricular systolic function. Histologically, iron was detected only within the sarcoplasm, and its extent varied inversely with ventricular function. Thus, cardiac hemochromatosis represents a storage rather than an infiltrative disease. These results indicate that stainable iron is consistently observed in endomyocardial biopsy specimens from patients with impaired left ventricular systolic function. Iron staining is recommended for endomyocardial biopsy specimens from patients with idiopathic cardiac dysfunction.

Laser angioplasty of totally occluded coronary arteries and vein grafts: preliminary report on a current trial.

CLINICAL PERSPECTIVE: Among the various laser angioplasty systems and atherectomy devices currently in clinical trials, the Lastac system appears to be particularly suitable for treating totally occluded coronary arteries and vein grafts. Preliminary results of a clinical trial in more than 35 patients show a recanalization rate of 92% and no complications attributable to the laser. Restenosis has occurred in five cases; in three of these, the arteries were reopened with laser or conventional angioplasty.

Role of the bZIP transcription factor IREBF1 in the NGF induction of stromelysin-1 (transin) gene expression in PC12 cells.

Stromelysin-1 (ST-1) is one of the most nerve growth factor-(NGF) responsive gene products expressed in PC12 cells. In previous work, we identified a novel NGF-responsive element in the proximal promoter region of the ST-1 gene that participates in this induction, and showed that it bound a protein present in the nuclei of PC12 cells. Here, we identify a transcription factor that specifically recognizes this regulatory element-the interferon-response element binding factor-1 (IREBF1), a member of the basic leucine zipper gene family. We show that IREBF1 is constitutively expressed in PC12 cells and that overexpression of IREBF1 augments NGF-responsive ST-1 gene regulation, but does not affect basal levels of expression. On the other hand, expression of a mutated form of this transcription factor lacking the DNA binding domain attenuated NGF responsiveness, without affecting basal levels of expression. These data suggest that IREBF1 is part of the NGF-responsive transcriptional machinery necessary for the expression of ST-1 in PC12 cells.

The effect of lidoflazine on exercise tolerance in patients with angina pectoris.

The effect of therapy with lidoflazine on maximal exercise in the upright position was evaluated in 21 patients with angina pectoris. The study consisted of the following three consecutive periods: (1) a three-month period of receving placebo; (2) six months of therapy with lidoflazine; and (3) a six-month period in which patients were randomized to either therapy with lidoflazine or placebo. Functional status was monitored by multistage tests of exercise capacity and the amount of nitroglycerin consumed. From period 1 to period 2, the mean maxial exercise time increased from 4.4 to 6.5 minutes (48 percent; P less than 0.001), and the external workload increased by 68 percent (P less than 0.001). the mean heart rate at two minutes of exercise decreased from 114 to 101 beats per minute (P less than 0.001) but was unchanged at symptom-tolerated maximal exercise. During period 3, the patients receiving therapy with liodflazine maintained their improved exercise tolerance, and the reduction in mean heart rate at two minutes of exercise persisted. Patients receiving placebo during period 3 had a decrease in exercise tolerance, and the mean heart rate at two minutes of exercise increased to control values. Lidoflazine in effective as an antianginal medication, in part due to suppression of the heart rate during exercise.

Effect of propranolol on respiratory function and exercise tolerance in patients with chronic obstructive lung disease.

Ten patients with chronic obstructive lung disease (COLD) (group 1) and five patients with combined COLD and cardiac disease (group 2) were studied at rest and during exercise after an intravenous (IV) slaine control followed by IV propranolol (0.2 mg/kg). During rest propranolol did not alter significantly measurements of lung volume in groups 1 or 2. Following propranolol the mean airway resistance (AR) in group 1 increased from 4.49 to 5.2 cm H2O/L/sec (P smaller than 0.02) and airway conductance (Gaw) decreased from 0.28 to 0.24 L/sec-1 cm. H2O1 (P smaller than 0.02). In group 2 following propranolol, the mean AR increased from 3.60 to 4.67 cm H2O1 (P smaller than 0.05), and Gaw decreased from 0.30 to 0.23 L/sec-1/cm H2O1 (P smaller than 0.05). During exercise, from control to propranolol, the heart rate (HR), blood pressure (BP), and heart rate blood pressure (HR x BP) decreased significantly for both groups 1 and 2 except for the systolic pressure in group 2. The duration of exercise and exercising PO2 were not significantly altered from control to propranolol in groups 1 and 2, indicating that the small but statistically significant changes in AR and Gaw did not interfere with symptom tolerated maximal exercise in these patients and were therefore not clinically important.

Experimental background preceding direct laser-assisted angioplasty in the human coronary anatomy.

The central question that faces coronary laser investigators is whether interaction between laser energy and target tissues can be controlled in a dynamic in vivo environment. In considering this question, the author reviews the in vitro and in vivo experiments that his center carried out before it began using laser angioplasty for clinical coronary applications. The in vitro experiments were undertaken to enable coaxial delivery of argon laser energy; to monitor the fluorescence of the lens assembly; to determine the effect of a saline infusion on the conduction of thermal energy; to evaluate the potential risk posed by embolization of debris; and to analyze the effects of increased beam divergence. The in vivo experiments were undertaken to examine the results of coaxial alignment of the laser beam in a rabbit model and to test the complete delivery system in dogs. The author also discusses his institution's 1st clinical trials of laser angioplasty in peripheral arteries, and its initial use of the laser technique in human coronary vessels.

Nitrate therapy for congestive heart failure.

A randomized double-blind crossover trial included 16 patients with severe congestive heart failure who received isosorbide dinitrate or placebo for eight weeks, and then the opposite treatment for eight more weeks. All patients received their usual maintenance therapy with digitalis and diuretics. Seven morbid events occurred during 85 patient-weeks of isosorbide dinitrate therapy compared with 17 during 76 patient-weeks of placebo. Severity of congestive heart failure improved in all eight patients who received isosorbide dinitrate compared with two patients who showed improvement and five whose symptoms became worse with placebo. No significant differences in physical findings, cardiac dimensions, or resting hemodynamics were observed. Maximal exercise duration increased significantly by 2.54 minutes with isosorbide dinitrate therapy, and rose insignificantly by 1.24 minutes with placebo. This preliminary trial suggests that long-term vasodilator therapy may be clinically beneficial in congestive heart failure.

The metalloproteinase stromelysin-1 (transin) mediates PC12 cell growth cone invasiveness through basal laminae.

Matrix metalloproteinases have been implicated in various extracellular matrix remodeling events that occur during normal development and in a number of pathologies. In previous work with PC12 rat pheochromocytoma cells, we found that the matrix metalloproteinase stromelysin-1 (ST1) was highly induced by nerve growth factor (NGF), but not by epidermal growth factor (EGF). Here, we show that ST1 immunoreactivity is present in growth cones of NGF-treated PC12 cells, but not EGF-treated or untreated cells. To determine whether ST1 expression confers neurite invasiveness, three lines of PC12 cells were produced that constitutively express ST1 antisense mRNA. These lines expressed and secreted significantly reduced levels of ST1 protein, as determined by immunoblot and immunocytochemical methods, but otherwise responded normally to NGF-treatment by elaborating neurites. We found, however, that the neurites of these ST1 antisense cells showed a significantly reduced ability to penetrate a Matrigel reconstituted basal lamina, as compared to the parental cells, suggesting that ST1 confers neurite invasiveness. Finally, we show that ST1 is also expressed in vivo in sections through Embryonic Day 15 rat embryos, including neurons of both the peripheral and central nervous systems. These data indicate that ST1 may play a role in axonal growth in vivo, including a role in growth cone invasiveness.

A complex array of double-stranded and single-stranded DNA-binding proteins mediates induction of the ovalbumin gene by steroid hormones.

The transcriptional induction of the chicken ovalbumin gene by steroid hormones is abolished by inhibitors of protein synthesis such as cycloheximide, suggesting that a labile protein mediates this process. A steroid-dependent regulatory element (SDRE) has been identified in the 5'-flanking region of the gene between -900 and -780 that is required for induction by steroids. Additional transfection experiments limit the 5'-border of the SDRE to the region between -892 and -864. To investigate whether any of the proteins binding to the SDRE are affected by estrogen or cycloheximide, protein binding was investigated using DNase I and exonuclease III footprinting and gel mobility shift assays. These experiments demonstrate that labile proteins bind to the sequences between -900 and -860 and between -810 and -820. Four oviduct nuclear proteins, including one of the labile proteins, binding to the SDRE prefer single-stranded DNA (ssDNA) in a sequence-specific manner. The binding activity of three of these ssDNA-binding proteins is increased in oviduct nuclear protein extracts from estrogen-treated chicks. These data suggest that induction of the ovalbumin gene is mediated by a complex collection of ssDNA- and double-stranded DNA-binding proteins whose activities are in turn regulated by their short half-lives or by estrogen.

Direct argon laser exposure for recanalization of peripheral arteries: early results.

Direct laser light, in combination with percutaneous transluminal angioplasty (PTA), was used to recanalize atherosclerotic peripheral arteries. Argon laser energy was controlled with an optical assembly and aligned with a special centering/dilation balloon so that plaque tissue absorbed laser energy directly and was vaporized. A channel was thereby created with multiple 10-W laser exposures (2-10 seconds), and conventional angioplasty was then performed. Recanalization was achieved in 33 of 36 procedures (92%), in 23 femoropopliteal (mean length, 9 cm) and three iliac total occlusions and ten femoropopliteal high-grade stenoses, with the three failures occurring in the first group. Complications included two emboli, six moderate groin hematomas, and one laser perforation. While these results are preliminary (mean follow-up, 3 months), direct laser angioplasty appears to be a useful adjunct to PTA for treating atherosclerotic arteries.

Peripheral arterial obstructions: analysis of patency 1 year after laser-assisted transluminal angioplasty.

Sixty-eight peripheral angioplasty procedures were augmented with direct argon laser energy in 63 non-consecutive patients. Technical success was achieved in 100% of femoropopliteal stenoses, 88% of femoropopliteal occlusions (mean length, 9 cm), and 71% of occluded iliac segments (mean length, 6 cm). In femoropopliteal arteries, the primary success rate was 83% (15 of 18) for occlusions longer than 7 cm and 92% (22 of 24) for occlusions 7 cm or shorter (P = .63). Complications included three thermal perforations and two emboli. The 1-year patency rate was 75% overall and 91% for femoropopliteal stenoses; iliac and femoropopliteal occlusions had patency rates of 79% and 60%, respectively. Disease severity was predictive of 1-year patency (85% for claudication vs 23% for limb-threatening ischemia; P = .0003), while distal run-off and femoropopliteal lesion length was not (P = .30 and .69, respectively). For patients with claudication who had femoropopliteal occlusions, a 1-year patency rate of 84% was obtained in short lesions versus 68% in long lesions (P = .36). For patients with limb-threatening ischemia, similar stratifications yielded patency rates of 21% and 33% (P = .38).

Coronary artery surgery for recurrent ventricular arrhythmias in patients with variant angina.

Two patients with Prinzmetal's variant angina had recurrent episodes of resting chest pain, ST segment elevation, QRS widening, ventricular tachycardia, and ventricular fibrillation. These eqisodes were unresponsive to medical therapy including lidocaine, procaine amide, and quinidine sulfate. Coronary arteriography revealed severe obstructive coronary artery disease, involving more than one coronary artery, in both patients. Aorticocoronary saphenous vein grafts were utilized to bypass significant disease in each patient. In one patient blood flow through the grafts was measured at 90 and 65 ml per minute, respectively, at operation and patent grafts were demonstrated six months postoperatively. Neither patient has had recurrence of chest pain or evidence of ventricular tachycardia at one year or 2 1/2 years postoperatively. Postoperative resting and maximal exercise ECG's are normal. Coronary artery surgery may be an effective method of therapy for ischemic ventricular tachycardia when medical therapy fails.

The pathophysiology of angina pectoris and the effect of lidoflazine.

Angina pectoris results from a deficiency in myocardial oxygen supply. The rate-pressure product is an important predictor of myocardial oxygen requirements in patients with ischemic heart disease and in normal persons. The rate-pressure product at the onset of angina pectoris is reproducible under a variety of circumstances with a suitable protocol. In some patients, coronary artery spasm may reduce myocardial blood flow and contribute to the development of angina pectoris. Lidoflazine is a synthetic drug that appears to be a calcium-entry blocker and results in symptomatic improvement in patients with angina pectoris. Lidoflazine reduces the exercising rate-pressure product by its effect on heart rate and by decreasing systemic vascular resistance. It decreases coronary vascular resistance and antagonizes processes leading to an increase in coronary vasomotor tone.

Laser angioplasty: controlled delivery of argon laser energy.

A laser catheter system that integrates balloon and fiberoptic technologies was evaluated. In vitro tissue studies were conducted to compare the tissue response to laser irradiation from a bare optical fiber (undiverged light beam) and from a fiber with an optical assembly (diverged light beam). An in vivo study of occluded and unoccluded canine femoral arteries examined coaxial alignment of the diverged light beam and the resultant thermal effects. In the in vitro studies, a diverged laser light beam effected maximum tissue ablation (mean crater diameter, 1.81 mm +/- 0.44) at a distance of only 3 mm from the optical fiber tip. The in vivo study demonstrated the ability of a specially designed balloon catheter to align the diverged laser beam coaxially within the arterial lumen. This laser catheter system successfully avoids the risks of inadequate tissue removal and perforation.