Reconstitution of virus-mediated expression of interferon alpha genes in human fibroblast cells by ectopic interferon regulatory factor-7.

Type I interferons constitute an important part of the innate immune response against viral infection. Unlike the expression of interferon (IFN) B gene, the expression of IFNA genes is restricted to the lymphoid cells. Both IFN regulatory factor 3 and 7 (IRF-3 and IRF-7) were suggested to play positive roles in these genes expression. However, their role in the differential expression of individual subtypes of human IFNA genes is unknown. Using various IFNA reporter constructs in transient transfection assay we found that overexpression of IRF-3 in virus infected 2FTGH cells selectively activated IFNA1 VRE, whereas IRF-7 was able to activate IFNA1, A2, and A4. The binding of recombinant IRF-7 and IRF-3 to these VREs correlated with their transcriptional activation. Nuclear proteins from infected and uninfected IRF-7 expressing 2FTGH cells formed multiple DNA-protein complexes with IFNA1 VRE, in which two unique DNA-protein complexes containing IRF-7 were detected. In 2FTGH cells, virus stimulated expression of IFNB gene but none of the IFNA genes. Reconstitution of IRF-7 synthesis in these cells resulted, upon virus infection, in the activation of seven endogenous IFNA genes in which IFNA1 predominated. These studies suggest that IRF-7 is a critical determinant for the induction of IFNA genes in infected cells.

Atrial septal defect resulting from mitral balloon valvuloplasty: relation of defect morphology to transseptal balloon catheter delivery.

Percutaneous balloon mitral valvuloplasty has been shown to be an effective means of reducing mitral valve gradient and increasing mitral valve area in patients with mitral stenosis. Most techniques currently employed for performing this procedure involve delivery of one or two balloon valvuloplasty catheters through the interatrial septum en route to the mitral valve orifice. To determine the morphology of the resultant atrial septal defect (ASD), particularly as a function of the technique employed, we performed a series of in vitro experiments designed to simulate a variety of technical approaches. Ninety-eight experiments in total were performed in 19 normal adult hearts obtained in the fresh, nonpreserved state at necropsy. Transseptal delivery and withdrawal of two conventional, elliptical balloon catheters through two, individual septostomy sites was found to produce the largest ASD (combined area of two defects = 21.4 +/- 2.2 mm2). The defect resulting from transseptal delivery and tandem withdrawal of two elliptical balloon catheters through a single septostomy site measured 14.8 +/- 1.1 mm2, significantly (p = 0.0043) smaller than that produced by two septostomies. Transseptal delivery and withdrawal of a single, segmentally inflating (Inoue) balloon catheter produced a defect of intermediate size (17.5 +/- 1.2 mm2). ASD size was exacerbated by improper balloon withdrawal compared with tandem withdrawal of two completely deflated balloon catheters. Simultaneous withdrawal of two completely deflated balloon catheters through the same septostomy site increased ASD size from 14.8 +/- 1.1 mm2 to 23.6 +/- 2.3 mm2 (p = 0.0004). Simultaneous withdrawal of two incompletely deflated balloon catheters further increased ASD size to 45.8 +/- 2.6 mm2 (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Atherosclerotic Yucatan microswine: an animal model with high-grade, fibrocalcific, nonfatty lesions suitable for testing catheter-based interventions.

A new breed of swine, the Yucatan microswine, that was derived from repetitive inbreeding of selected, small Yucatan swine, was investigated as an animal model of advanced vascular atherosclerosis. Nineteen animals were fed an atherogenic diet for 9.9 +/- 1.5 (mean +/- SEM) weeks before and 19.9 +/- 1.8 weeks after balloon endothelial denudation of all four iliac arteries. In 18 (94.7%) of the 19 microswine, angiography performed at 33 to 87 weeks of age disclosed some degree of luminal diameter narrowing: six animals (33.3%) had one-vessel, six (33.3%) had two-vessel, four (22.2%) had three-vessel, and two (11.1%) had four-vessel disease. In 38 (50%) of 76 denuded arteries, angiographically apparent luminal diameter narrowing was observed as follows: three arteries (7.9%) were narrowed less than 50%; 10 arteries (26.3%) were narrowed 50% to 75%; seven arteries (18.4%) were narrowed 76% to 99%; and 18 arteries (47.3%) were occluded. Sixty-four arteries were harvested from 16 of the 18 microswine with angiographically apparent luminal narrowing, which yielded 748 histologic sections. Maximum cross-sectional area narrowing from atherosclerotic plaque exceeded 90% in 135 (18%) of the sections examined, while 65 sections (9%) were narrowed 76% to 90%, and 127 sections (17%) were narrowed 51% to 75%. Atherosclerotic plaque in these animals appeared histologically similar to the so-called "complex" lesion that is typical of human atherosclerosis, which consists predominantly of collagen with focal calcific deposits and a minor lipid component. The smaller size and lower weight of these animals, in comparison with full-size farm pigs and "minipigs," facilitated transportation, handling, and instrumentation. These findings establish the Yucatan microswine as a useful, representative, and economical atherosclerotic animal model for the evaluation of novel interventional techniques.

Clinical and noninvasive hemodynamic results after aortic balloon valvuloplasty for aortic stenosis.

Balloon valvuloplasty has been shown to be an effective treatment for adults with aortic stenosis, typically providing a 50 to 80% increase in aortic valve area and marked improvement in exertional dyspnea, angina and syncope. However, the duration of this hemodynamic and clinical improvement is uncertain. Forty-two patients were followed for 10.2 +/- 0.5 months. Balloon valvuloplasty caused dramatic immediate reduction in the number of patients with moderate or severe dyspnea (80 to 14%), moderate or severe angina (39 to 2%) and syncope (30 to 2%). Furthermore, this improvement in symptoms continued for the duration of the follow-up period in most patients. Echocardiographic aortic valve mean gradient and area determined at 3-month intervals, however, showed a trend toward or return to prevalvuloplasty levels by 9 months' follow-up in 13 of 25 patients (52%), whereas 12 of 25 patients showed no deterioration in their hemodynamic parameters. This trend toward restenosis was accompanied by symptomatic deterioration in 5 of 13 patients (38%). This tendency toward restenosis in greater than 50% of patients by 9 months underscores the need for further technical improvements if balloon valvuloplasty is to be widely applied. Even with these limitations, however, balloon valvuloplasty seems to provide a significant improvement in actuarial survival compared with the natural history of elderly patients with severe aortic stenosis.

Laser therapy in the treatment of cardiovascular disease.

Percutaneous laser angioplasty has now become a clinical reality, consisting chiefly of applications of thermal angioplasty in conjunction with balloon angioplasty for the recanalization of peripheral vascular obstructions. In conjunction with this development, various aspects of laser-tissue interactions, fibreoptic transmission and delivery catheter design pertinent to the cardiovascular system have come under closer scrutiny, resulting in the emergence of both noteworthy concepts and clinical achievements.

Balloon valvuloplasty in adults.

Aortic and mitral balloon valvuloplasty are procedures recently introduced for treatment of aortic and mitral stenosis. Current techniques and applications are described in detail in this discussion.

"Quinidine syncope" without lengthening of Q-Tc interval in the presence of left bundle branch block. Role of programmed ventricular stimulation studies.

Idiosyncratic and proarrhythmic reactions to antiarrhythmic drugs are a well-recognized phenomenon and appear to correlate poorly with Q-T prolongation or with the serum concentration of the drug. It therefore becomes difficult to identify patients clinically with an underlying electrophysiologic substrate for ventricular tachycardia which was made manifest by an antiarrhythmic drug, or to determine whether the drug is causing an idiosyncratic reaction (the classic "long Q-T syndrome"). We recently studied a patient with ischemic heart disease and a prolonged corrected Q-T interval (Q-Tc) due to chronic left bundle-branch block. She developed "quinidine syncope," and the Q-Tc was unchanged despite stopping administration of the drug; however, electrophysiologic studies demonstrated reproducibly inducible "torsade de pointes" while the patient was being rechallenged with quinidine, while no inducible arrhythmia was seen during control studies. We conclude that electrophysiologic studies are of clinical value in the clarification of possible drug-induced arrhythmias.

Dual balloon technique for valvuloplasty of aortic stenosis in adults.

A dual balloon technique was studied in 16 patients with aortic stenosis in whom results with a single balloon (up to 20 mm, 5.5 cm or 25 mm, 3.0 cm in diameter and length, respectively) were judged to be suboptimal. Dual balloon valvuloplasty was performed using 2 balloons advanced and inflated simultaneously across the stenotic aortic valve orifice. For the group as a whole, the average peak transvalvular gradient was reduced from 79 +/- 8 to 57 +/- 7 mm Hg (mean +/- standard error) using a single balloon (p less than 0.0005), and reduced further to 36 +/- 4 mm Hg using dual balloons (p less than 0.0005 compared with single balloon results). Similarly, calculated aortic valve orifice area was increased from 0.45 +/- 0.04 to 0.57 +/- 0.05 cm2 using a single balloon (p less than 0.0005), and further increased to 0.77 +/- 0.06 cm2 using dual balloons (p less than 0.0005). Dual balloon dilation caused no complications directly attributable to the use of 2 balloons, including no exacerbation of aortic regurgitation. These results suggest that dual balloon valvuloplasty is safe and efficacious in selected patients with aortic stenosis.

Mechanism of aortic balloon valvuloplasty: fracture of valvular calcific deposits.

Balloon valvuloplasty has been shown to acutely reduce the hemodynamic and symptomatic severity of calcific aortic stenosis. The mechanism by which this improvement is accomplished is not known. At necropsy, three patients who died after hemodynamically successful aortic balloon valvuloplasty were found to have aortic valve calcific deposits fractured at one or more sites. These findings suggest that fracture of leaflet calcium represents the basis for successful aortic balloon valvuloplasty.

Cardiorespiratory efficiency at submaximal work in young and middle-aged women.

Seventeen middle-aged women and 26 younger women were studied while walking at 3 mph and a 5% grade on a motorized treadmill. This was submaximal work for all subjects and is equivalent to the intensity of everyday activity. The middle-aged women had a significantly greater oxygen uptake, ventilatory equivalent, and heart rate, suggesting a relative cardiorespiratory inefficiency at this submaximal work intensity. This phenomenon is most likely a function of body size, however, since dividing the submaximal oxygen uptake by body weight rendered the mean difference between the two groups statistically insignificant. The age-associated reduction in cardiorespiratory efficiency at submaximal exercise is thus due primarily to weight gain rather than to actual systems degeneration. Maximal oxygen uptake, that associated with maximal physical effort, was significantly reduced in the older subjects, and this is probably due to a combination of previous life-style habits and aging.