The mechanism by which the cytosolic protein Zap70 physically interacts with and phosphorylates its substrate, the transmembrane protein LAT, upon T cell receptor (TCR) stimulation remains largely obscure. In this study, we found that the pharmacological inhibition of formins, a major class of actin nucleators, suppressed LAT phosphorylation by Zap70, despite TCR stimulation-dependent phosphorylation of Zap70 remaining intact. High-resolution imaging and three-dimensional image reconstruction revealed that localization of phosphorylated Zap70 to the immune synapse (IS) and subsequent LAT phosphorylation are critically dependent on formin-mediated actin polymerization. Using knockout mice, we identify mDia1 and mDia3, which are highly expressed in T cells and which localize to the IS upon TCR activation, as the critical formins mediating this process. Our findings therefore describe previously unsuspected roles for mDia1 and mDia3 in the spatiotemporal control of Zap70-dependent LAT phosphorylation at the IS through regulation of filamentous actin, and underscore their physiological importance in TCR signaling.

Excerpt Dr. Andrew G. Morrow: In spite of the efforts of our colleagues in the field of preventive medicine, rheumatic mitral valve disease continues to be one of the commonest and most important c...

IN PATIENTS with ventricular septal defect who are more than 3 or 4 years of age, an open corrective operation may be carried out with minimal risk if the lesion is not complicated by the presence of severe pulmonary hypertension. With surgical technics presently available, however, the closure of a ventricular septal defect in an infant or very young child is associated with considerable hazard. In 41 children under the age of 2 operated upon by Cooley' the mortality was 39 per cent and in Kirklin's experience in 1956, quoted by Keith,2 70 per cent of children in this age group died after open repair. Thus, it seems clear that elective operations for ventricular septal defect should, whenever possible, be deferred until the child has reached optimal age and size. Although isolated ventricular septal defect is generally considered to be one of the more benign congenital cardiovascular malformations, a certain proportion of infants with this lesion develop severe symptomatology and in this group the early mortality is high. Keith, for example, observed a series of 111 symptomatic children with ventricular septal defect; more than one third died in the first year of life.2 Seventeen patients who evideneed heart failure were reported by Morgan et al.3 and, of these, 10 died before the age of 1 year. Marquis4 found that ventricular septal defect was the most common cause of death from congenital heart disease among children less than 3 years of age. It is thus apparent that a large number of infants with ventricular septal defect will tiot survive with nonoperative management and yet should not be subjected to corrective operation because of the prohibitive risk asso-

The clinical and morphologic features of tunnel subaortic stenosis, an unusual form of obstruction to left ventricular outflow, are described in 11 patients. Although patients with tunnel subaortic stenosis demonstrate a variety of cardiovascular malformations, the most characteristic anatomic feature is fibromuscular tubular narrowing of the outflow tract that remains relatively unchanged during the cardiac cycle. The aortic anulus was abnormally small in six of the 11 patients, including one who also had a hypoplastic ascending aorta. Evidence of a small mitral orifice was present

Instantaneous ascending aortic blood flow was recorded at operation in five patients with severe, pure mitral regurgitation, and in nine dogs in which mitral regurgitation was produced experimentally under controlled conditions. In both the patients and the experimental animals, the pattern of aortic flow was abnormal during mitral regurgitation: peak flow occurred early, the percentage of total forward flow

Patients who underwent operations in which cardiopulmonary bypass was used had elevations of plasma fibrinopeptide A which did not return to normal during bypass despite conventional heparin anticoagulation, suggesting inadequate heparin dosage and continued thrombin activity during the operation. Patients who underwent aortocoronary artery grafting had high plasma thromboxane B2 levels and a rapid fall in platelet count at the onset of extracorporeal circulation. Thromboxane elevations were less marked in patients who underwent valve replacement. Platelet aggregation and coronary artery constriction secondary to thromboxane production may contribute to the morbidity of cardiopulmonary bypass.

THE DIRECT MORTALITY associated with operations upon the heart and great vessels has steadily declined as surgeons have become more familiar with the operative management of various congenital and acquired malformations, and as improvements have been made in methods of preoperative preparation, the conduct of cardiopulmonary bypass, and in postoperative management. Nevertheless, complications secondary to the operation, usually occurring in the early postoperative period, may still represent serious threats to the patient's survival. These complications involve disturbances in the cardiac rhythm and contractile state, electrolyte balance, as well as in the functions of the renal, pulmonary, gastrointestinal, hematopoietic, or central nervous systems. Because of the nature of these complications, they are managed most effectively by the combined efforts of internist or cardiologist and the cardiovascular surgeon, and are frequently termed the "<medical" complications of cardiac operations. Some of these complications are seen only in postoperative patients; although others may also occur in patients who have not been operated upon, their manifestations and methods of management may be quite different

THE ABOLITION of effective ventricular contraction facilitates many intracardiac operative procedures and also reduces the risk of systemic air embolism. It is now recognized that severe impairment of cardiac performance may follow a period of cardiac arrest produced by the infusion of a potassium salt into the coronary circulation or by myocardial hypoxia.14 On the other hand, the induction of ventricular fibrillation with maintenance of the coronary circulation has been considered a safe and effective technique.5-" When ventricular fibrillation was utilized during operations in patients, it became apparent that fibrillation would not always persist in the human heart after the arrhythmia was induced by a single shock, and spontaneous defibrillation with return of effective contractions often occurred when the risk of air embolization remained high. To obviate this danger, a technique was developed by which fibrillation was induced and maintained by the constant application of a small a-c current to the ventricle,'2 13 and this method is now commonly employed during open cardiac operations. The effects of such stimulation on subsequent cardiac performance and on the metabolism of the heart were determined in the experiments described in the following report.

T HE PATHOLOGICAL anatomy and clinical manifestations of aortic regurgitation have been familiar to physicians for nearly 150 years, and over this period of time considerable progress has been made in elucidating the circulatory alterations which result from aortic regurgitant flow. However, a definitive hemodynamic characterization of the disease in man has been impossible until recently because the most important variable, the magnitude of retrograde flow through the aortic valve, could not be measured directly. Instantaneous aortic blood flow can now be determined with accuracy, and the opportunity to make such observations in man is provided when patients with aortic valvular disease are operated on. In the present study, detailed hemodynamic observations were made at the time of operation in 14 patients with varying degrees of aortic regurgitation. The volumes of forward and regurgitant blood flow were measured with an electromagnetic flowmeter, and by means of simultaneous determinations of left ventricular and central aortic pressure, left ventricular work and its kinetic component were calculated. The effects of aortic regurgitation on the performance of the left ventricle were further defined by comparing the results of studies carried out before and after total replacement of the diseased aortic valve.

Although many studies of juxtaductal coarctation of the aorta have been reported, none has correlated clinical, hemodynamic, angiographic, anatomic, and operative findings. Of 84 patients (62 male and 22 female; age range, 1 to 49 years [mean 17]), all had murmurs; 76 had absent, diminished, or delayed femoral pulsations; 50 had cuff systolic blood pressures in the arm greater than 140 mm Hg, and 30 had diastolic pressures greater than 90 mm Hg. The average pressure gradients (mm Hg) by direct measurements above and below the coarctation in 35 patients were peak systolic, 45; mean, 17; and diastolic, 5. Rib notching, visible in chest roentgenograms in 43 patients, correlated directly with age and inversely with the diameter of the coarctation. Moderate or marked cardiomegaly by radiograph was present in only 1 of 48 patients with isolated coarctation and in 17 of 36 with associated cardiovascular malformations. Electrocardiograms were abnormal in more than two thirds of patients with associated anomalies, but were normal in more than three fourths of those with isolated coarctation. In 70 excised, serially sectioned coarctations the aortic lumens were completely occluded in 4 patients, up to 0.5 mm in internal diameter in 22 patients, from 0.6 to 2 mm in 26 patients, from 2.1 to 5 mm in 14, and greater than 5 mm in 4, and correlated directly with lumens measured angiographically. The most significant anatomic factor causing the coarctation was invagination of the media from the posterior aortic wall, but intimal proliferation (jet lesion) at and immediately distal to the invagination contributed to the narrowing. Three (each with associated anomalies) of 70 patients died early after coarctation repair. Systolic or diastolic blood pressures decreased early postoperatively in 58 (87%) of 67 surviving patients, and both pressures decreased in 42 (63%). Late postoperatively (mean follow-up, 4.7 years), the systolic blood pressure remained elevated in 25% of patients.

Since 1960, at the National Institutes of Health, ventricular septal myotomy and myectomy has been the mode of treatment for severely symptomatic patients with hypertrophic cardiomyopathy and obstruction to left ventricular outflow who do not respond to medical therapy. Our long-term results of operation for hypertrophic cardiomyopathy are reviewed in 240 patients operated upon prior to 1980. Postoperatively, most patients had improved symptomatically (i.e. 70%) and manifested marked reduction or abolition of the basal left ventricular outflow gradient (i.e. 98%). However, 8% of the patients died of causes related to operation, 9% had persistent or recurrent severe functional limitation, and 7% died up to 19 years postoperatively due to the underlying cardiomyopathy. Of 17 late postoperative deaths, eight were sudden and nine were due to chronic heart failure. In particular, postoperative atrial fibrillation was a significant contributing factor to poor clinical outcome. Hence, while ventricular septal myotomy-myectomy is not always a curative procedure for obstructive hypertrophic cardiomyopathy, the vast majority of patients who survive operation experience long-lasting clinical improvement.

The late results were evaluated of operations for the relief of left ventricular outflow tract obstruction in young patients, 1 to 18 years old, from the National Heart Institute who were followed up for at least 5 years and from recently reported studies with an average follow-up duration of 5 or more years. The operative mortality rate for the combined series was low: 1.9 percent of 522 patients with valvular aortic stenosis, 6.0 percent of 222 patients with fixed subvalvular aortic stenosis and 5.5 percent of 18 patients with hypertrophic subaortic stenosis. From the National Heart Institute series, gradients early postoperatively were decreased to less than 50 mm Hg in 88 percent (30 of 34) of patients with valvular, in 68 percent (15 of 22) of patients with subvalvular and in 88 percent (8 of 9) of patients with hypertrophic subaortic stenosis. Late survival rates for patients in the combined series were 90 percent (472 of 522), 86 percent (190 of 222), and 82 percent (14 of 17) in the three respective groups after mean follow-up periods of 5 to 14.4 years. All late survivors in the current series have had symptomatic improvement; 95 percent (58 of 61) are asymptomatic. However, actuarial analysis in these patients predicts that 50 ± 8 percent of those with valvular and 44 ± 10 percent of those with subvalvular aortic stenosis after 10 years will be free from the adverse postoperative events of residual or recurrent left ventricular outflow tract obstruction, clinically significant aortic regurgitation, reoperation, endocarditis or late death.

For many years rheumatic heart disease was considered the major cause of mitral regurgitation (MR) severe enough to necessitate mitral valve replacement (MVR). In most past studies of patients with mitral valvular disease, patients were subdivided on the basis of predominant mitral stenosis (MS) or predominant MR. This type of subdivision, however, does not provide as much information about etiology as can be obtained by dividing patients with mitral valve dysfunction into two groups based on the presence or absence of mitral valve obstruction. MS of any degree is recognized as usually having a rheumatic etiology. Likewise, most patients who have combined dysfunction of both mitral and aortic valves usually have a rheumatic etiology of their valvular lesions. The present study examines the etiology of the valvular disease in 97 patients over the age of 30 years in whom MVR was carried out for severe, chronic, pure MR unassociated with MS or aortic valve dysfunction.

Certain clinical and morphologic features are described in a patient with severe bioprosthetic obstruction 9 years after mitral valve replacement. At reoperation, severe inward bending of the stent-posts was found without significant bioprosthetic cuspal abnormalities. “Polymer creep” is considered responsible for the stent-post deformity.

Since 1960, at the National Institutes of Health, ventricular septal myotomy and myectomy has been the mode of treatment for severely symptomatic patients with hypertrophic cardiomyopathy and obstruction to left ventricular outflow who do not respond to medical therapy. Our long-term results of operation for hypertrophic cardiomyopathy are reviewed in 240 patients operated upon through 1979. Postoperatively, most patients (70%) had improved symptomatically with marked reduction in left ventricular outflow gradient at rest. However, 8% of the patients died of causes related to operation. 9% had persistent or recurrent severe functional limitation, and 7% died up to 19 years postoperatively due to underlying cardiomyopathy. Of 17 late postoperative deaths, eight were sudden and nine were due to chronic heart failure. In particular, atrial fibrillation appeared to be a significant contributing factor to poor clinical outcome. Long-lasting clinical improvement occurred in most patients who survived operation for hypertrophic cardiomyopathy. However: (1) 10% of patients deteriorated clinically over the 5-year average follow-up; and (2) there is a continued, small annual postoperative mortality.

Described herein are clinical and necropsy findings in a 61-year-old woman with fatal left ventricular diastolic failure secondary to massive calcific deposits primarily within the left ventricular cavity. At age 3, an isthmic aortic coarctation was resected, and at age 44, a stenotic congenitally bicuspid aortic valve was replaced. The cause of the intracavitary calcific deposits remains unclear, but surgical resection of the deposits has been an effective form of therapy.