Richard L. Varco

Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia: Report of the program on the surgical control of the hyperlipidemias (posch)

BACKGROUND AND METHODS The Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized clinical trial, was designed to test whether cholesterol lowering induced by the partial ileal bypass operation would favorably affect overall mortality or mortality due to coronary heart disease. The study population consisted of 838 patients (417 in the control group and 421 in the surgery group), both men (90.7 percent) and women, with an average age of 51 years, who had survived a first myocardial infarction. The mean follow-up period was 9.7 years. RESULTS When compared with the control group at five years, the surgery group had a total plasma cholesterol level 23.3 percent lower (4.71 +/- 0.91 vs. 6.14 +/- 0.89 mmol per liter [mean +/- SD]; P less than 0.0001), a low-density lipoprotein cholesterol level 37.7 percent lower (2.68 +/- 0.78 vs. 4.30 +/- 0.89 mmol per liter; P less than 0.0001), and a high-density lipoprotein cholesterol level 4.3 percent higher (1.08 +/- 0.26 vs. 1.04 +/- 0.25 mmol per liter; P = 0.02). Overall mortality and mortality due to coronary heart disease were reduced, but not significantly so (deaths overall [control vs. surgery], 62 vs. 49, P = 0.164; deaths due to coronary disease, 44 vs. 32, P = 0.113). The overall mortality in the surgery subgroup with an ejection fraction greater than or equal to 50 percent was 36 percent lower (control vs. surgery, 39 vs. 24; P = 0.021). The value for two end points combined--death due to coronary heart disease and confirmed nonfatal myocardial infarction--was 35 percent lower in the surgery group (125 vs. 82 events; P less than 0.001). During follow-up, 137 control-group and 52 surgery-group patients underwent coronary-artery bypass grafting (P less than 0.0001). A comparison of base-line coronary arteriograms with those obtained at 3, 5, 7, and 10 years consistently showed less disease progression in the surgery group (P less than 0.001). The most common side effect of partial ileal bypass was diarrhea; others included occasional kidney stones, gallstones, and intestinal obstruction. CONCLUSIONS Partial ileal bypass produces sustained improvement in the blood lipid patterns of patients who have had a myocardial infarction and reduces their subsequent morbidity due to coronary heart disease. The role of this procedure in the management of hypercholesterolemia remains to be determined. These results provide strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression.

Intraarterial infusion chemotherapy for hepatic carcinoma using a totally implantable infusion pump.

Intraarterial infusion chemotherapy has several theoretical advantages over conventional therapy for the treatment of unresectable malignancies. However, the catheter problems and patient restriction to the hospital associated with its use have resulted in infrequent application and a notable lack of progress in this field of oncology. This paper describes the use of a totally implantable, percutaneously refillable infusion pump in 5 patients with primary or metastatic carcinoma of the liver. The infusion cannulae were placed into the hepatic arteries under direct vision at laparotomy, and the pumps were placed in subcutaneous pockets. Four patients received infusions of 5‐fluorodeoxyuridine at rates of 0.2–0.5 mg/kg/day for periods of three to 29 weeks; the pump in the fifth patient was defective and was removed. The implanted pumps were well tolerated in these subjects, who received chemotherapy as outpatients; the only adverse effects noted were related to FUDR toxicity. This implantable infusion pump appears to be a practical means of delivering long‐term intraarterial infusion chemotherapy to outpatients.

AN INVESTIGATION OF HODGKIN'S DISEASE WITH RESPECT TO THE PROBLEM OF HOMOTRANSPLANTATION *

Homograft rejection is believed to be an immune phenomenon that in its general details most closely resembles that group of immune reactions commonly termed delayed hypersensitivity or allergy of the bacterial variety.l Our interest in Hodgkin’s disease was aroused by the reports of Schier and his co-workers*J that patients with Hodgkin’s disease are deficient in their ability to manifest this type of immune response. As a first step, experiments were carried out to attempt to confirm Schier’s observations; this work has been reported in detail el~ewhere.4.~ Skin testing was carried out in patients with histologically proved Hodgkin’s disease and in hospitalized controls, employing a standard battery of 7 antigens prepared from commonly encountered microorganisms to which the majority of individuals would be expected to react. The following materials were used: (1) dipththeria toxoid (Schick control solution), (2) streptokinase-streptodornase (SK-SD) , (3) mumps skin-testing antigen, (4) mumps control solution, (5) Trichophyton gypseum extract, ( 6 ) Candida albicans extract, and (7) purified protein derivative (PPD) of tubercle bacilli, intermediate strength. Testing was carried out in the conventional manner, injecting 0.1 ml. of suitable dilutions intradermally and noting the immediate reaction, if any, as well as the response a t 24 and 48 hours. A positive response was recorded if indurtion was present and if the reaction exceeded 5 mm. in diameter. To date 43 patients with Hodgkin’s disease have been tested; all but 1 of these patients were ambulatory a t the time of testing. None were receiving steroids or chemotherapy, although many were receiving regional X-ray therapy. The controls consisted of 208 hospitalized patients, excluding all individuals with malignancies or acute illness, as well as persons receiving treatment with steroids. The result of this testing is shown in TABLES 1 and 2. I t is apparent that patients with Hodgkin’s disease manifest a high incidence of nonreactivity or anergy in contrast to the controls. Our observations therefore confirm those reported by Schier and his co-workers. It then seemed logical to test the possibility that patients in whom delayed hypersensitivity is deficient might be anticipated to show tolerance or at least altered behavior to skin hornografts, since homograft rejection seems to resemble delayed hypersensitivity in respect to many details of the immune process. Accordingly, permission was obtained from a group of 17 patients with Hodgkin’s disease to carry out the placement of small skin homografts. These patients were all in fair to good general condition a t the time of grafting

The first open heart corrections of tetralogy of Fallot: a 26-31 year follow-up of 106 patients

Tetralogy of Fallot became a correctable malformation on August 31, 1954, and from that date through 1960, 106 patients (ages 4 months-45 years) who underwent open repairs at the University of Minnesota and were discharged, have been followed (99% complete) until death or for 26–31 years (mean: 23.7 years, 2424 patient years). The purposes of this study were to determine survival, morbidity, hemodynamics, educational/employment attainments, and relation of these to surgical technics. Operations were done by cross circulation (6 patients) and bubble oxygenator (100 patients). This group had the first uses of patch ventricular septal defect closure, outflow root, infundibuloplasty, atresia correction, ischemic arrests, and pacemakers among other innovations. Twenty-one (of 105 patients) have died during the followup: eight deaths in the first 10 years, 12 between 10 and 20 years, and 1 >20 years. The causes of death were sudden (5), accidental (4), congestive failure (2), reoperation (2), suicide (2), and other (2). Actuarial survival at 30 years was 77%. Late complications were ten reoperations, five arrhythmias, and one endocarditis. Actuarial freedom from reoperations at 30 years was 91%. Cardiac recatheterizations in 62 patients disclosed only 10 with residual shunts. Peak right ventricular systolic pressures were < 40 mmHg (34 patients), 41–60 mm (2 patients), 61–70 mm (4 patients), >71 mm (4 patients). Thirty-four patients (32%) completed college, ten of these completed graduate school (5 masters degrees, 2 M.D.S, 2 Ph.D.s, 1 lawyer). Fifteen others attended college, and nine received technical school diplomas. Forty patients (18 men, 22 women) had progeny, with 82 (93%) live births and six major cardiac defects (7.3%). In summary, complete repair gave excellent late results in this group cared for very early in the open heart era. Survivors led productive lives without restrictions in education and employment. Many of the deaths/complications that occurred are now easily preventable, which augurs extremely well for this generation.

TRANSPLANTATION STUDIES IN PATIENTS WITH AGAMMAGLOBULINEMIA

The discovery of agammaglobulinemia in 1952l provided a new and clear-cut opportunity to gain insight into the nature and significance of the immune response in man. The initial studies2-’ established that patients with agammaglobulinemia have a disease featured by increased susceptibility to infection, absence of gamma globulin from the blood and tissues, and failure of antibody production in response to the most intensive antigenic stimulation. This form of agammaglobulinemia is an isolated defect in protein metabolism. Extreme hypogammaglobulinemia, or even agammaglobulinemia, however, may occur as a part of several diseases featured by more general abnormalities in protein metabolism, such as nephrosis,8 multiple myeloma,g nutritional failure,10 and failure of general protein fabrication.”-14 Since we believe that the isolated forms of agammaglobulinemia offer an unusual opportunity to study the nature of the immune response and its relationship to other biological phenomena in man, we shall limit this discussion to this form of gamma-globulin dysmetabolism. During the past 2 years we have had the opportunity of discovering and studying 12 cases of isolated agammaglobulinemia. Brief summaries of these cases included in TABLE 1 describe the clinical manifestations of the disease observed therein. The purpose of this report is threefold: (1) to summarize briefly general studies carried out on patients with agammaglobulinemia that serve to define the disorder; (2) to report efforts involving various forms of transplantation in patients with agammaglobulinemia; and (3) to record briefly observations made during the course of pregnancy of an agammaglobulinemic patient and throughout the first year in the child born of the agammglobulinemic mother. A detailed study of this “experiment of nature” will be reported elsewhere.16 General considerations of agammaglobulinemia. Although agammaglobulinemia is probably still to be considered an uncommon disease, it is by no means rare. To date, 56 cases have been reported in the literature,l6 and the rate at which reports from. every country are appearing in the medical journals indicates that available accounts describe only a sampling of the existing number of these patients. Isolated agammaglobulinemia occurs in at least 3 distinct forms. Perhaps the most common variety is transient agammaglobulinemia of infancy. This self-limited form of agammaglobulinemia occurs in both sexes and does not appear to have a significant familial distribution. In a sense, this form represents a variety of the normal relationships. Normally, the newborn infant * These studies were aided by rants from the Helen Hay Whitney Foundation New York N . Y . the United States Public Health Service Bedesda Md: the Minnesota Division of the Ame&an C a d So& S t Paul Minn.: the Minnesota Heart kssociatiod, St. kaul, Minn.; and the American Heart Association, New Ybrk; N. Y:

Surgical Treatment of Ruptured Aneurysms of the Sinus of Valsalva

Aneurysms of the sinus of Valsalva are usu- ally congenital in origin. When they rupture, it is generally into the right atrium or the right ventricle. Signs of a left- to-right shunt, aortic runoff, and cardiac decompensation are the cardinal features. Early diagnosis and surgical cor- rection result in cure. We report our experience with 28 patients. In all patients, we used a combined aortocameral approach, and we recommend a sandwich patch for the repair. Aortic valve replacement is needed only in patients with severe degenerative changes. The overall operative mortality was 21.4%, but in the last 10 years, mortality was only 11.7%. The causes of operative and late mortality are discussed. Ruptured aneurysms of the sinus of Valsalva represent a form of arteriovenous communication that is challenging to the surgeon and potentially lethal for the patient. Sur- gical closure of the fistula offers the only form of perma- nent cure. Although ruptured aneurysms of the sinus of Valsalva may be congenital or acquired in origin, most of them are the result of a congenital defect. Edwards and Bur- chell (l) attributed the congenital variety to a discon- tinuity between the aortic media and the annulus fibrosis of the aortic valve. The coexistence of a ventricu- lar septa1 defect (VSD) in a significant percentage of pa- tients with this malformation further substantiates the congenital nature of the condition.

Late results (30 to 35 years) after operative closure of isolated ventricular septal defect from 1954 to 1960.

This study was designed to determine the clinical status, cause of death, and effects of pulmonary vascular disease and conduction abnormalities 30 to 35 years after surgery in 296 consecutive surviving patients of closure of ventricular septal defect. Of the 296 patients, current status was determined by contact with patient and physician in 290 cases, with 6 (2%) lost to follow-up (7,912 patient years are included). Cardiac catheterization after surgery in 168 patients showed complete closure of the defect in 80%. Death occurred in 59 patients (20%), with higher mortality rates in those operated on after the age of 5 years, those with pulmonary vascular resistance greater than 7 units (51%), and those with complete heart block (78%). Of 37 patients with transient heart block after surgery, 8 (22%) have died (3 pulmonary vascular disease, 2 sudden death, 2 unknown causes and 1 complete heart block). Twenty other patients had a dysarrhythmia after surgery, and none of these died. Nine episodes of endocarditis occurred (11.4/10,000 patient years). Nine of 296 (3%) offspring had cardiac malformation. Most patients are in New York Heart Association class I, 57% attended college and 15% received an advanced degree. The data show good results for this group of patients operated on during an early era (1954 to 1960) of open cardiac surgery. They support the current trend toward operation in patients with ventricular septal defects at an early age and with low pulmonary vascular resistance.

The First Open-Heart Repairs of Ventricular Septal Defect, Atrioventricular Communis, and Tetralogy of Fallot Using Extracorporeal Circulation by Cross-Circulation: A 30-Year Follow-up

From March 26, 1954, to July 19, 1955, 45 patients with major cardiac malformations not previously correctable underwent open repair utilizing cross-circulation between patient and donor without donor deaths. All operations were carried out at normothermia with lowered flow rates based on azygos flow studies. Twenty-seven patients, more than half of them infants, had ventricular septal defects closed. There were 8 hospital deaths, and there have been only 2 late deaths in 30 years. Fourteen (87.5%) of 16 who underwent recatheterization have closed defects. The 17 30-year-survivors are all in New York Heart Association Functional Class I. Five patients 4 months to 10 years old were operated on for atrioventricular canal (complete form). All had intractable failure, and 4 had pulmonary hypertension. Two of the 3 hospital deaths were due to heart block. The long-term survivor, a 15-month-old infant at the time of operation (severe pulmonary hypertension, 90/50 mm Hg), underwent repair 31 years ago and is now married with 3 children. Recatheterization disclosed normal pulmonary pressure (20/4 mm Hg), no shunts, and mild mitral regurgitation. Ten cyanotic tetrads 13 months to 14 years old were operated on with 5 hospital deaths. Of the 3 late deaths, 1 was accidental at 17 years, 1 occurred suddenly at home 13 years after operation in infancy for atresia, and the third occurred at reoperation 10 years later. The 2 remaining patients (1 the first patient operated on) are in excellent health. The surgical methods used and the physiological advantages of cross-circulation (temporary placenta) that made these results possible at a time when surgical knowledge was primitive are described.

Anomalous Muscle Bundle of the Right Ventricle Hemodynamic Consequences and Surgical Considerations

Seven examples of anomalous muscle bundles of the right ventricle have been presented. In one patient having an associated ventricular septal defect, spaces between the anomalous muscle were confused surgically with the ventricular septal defect. In the remaining six cases, the anomalous muscle bundle caused obstruction within the right ventricular cavity. Five of these patients had associated ventricular septal defect, with a clinical picture resembling that of the cyanotic or acyanotic tetralogy of Fallot. The cases served to demonstrate that the surgeon who exposes the right ventricle to relieve an obstructive lesion in the right ventricular infundibulum or in the pulmonary valve, may find no such lesions in these locations but instead may be dealing with an obstruction more proximal than these areas. Relief of the obstruction within the right ventricle may be attained by resecting the anomalous muscle mass. In one patient having intact ventricular septum and pulmonary valvular stenosis, an anomalous muscle bundle within the right ventricle which lay proximal to the infundibulum was responsible for persistent right ventricular obstruction after pulmonary valvotomy. Anomalous muscle bundles in the right ventricle may be suspected when, in the angiocardiogram, they cause filling defects within the right ventricle.

Prolongation of Skin Homograft Survival in Rabbits by 6-Mercaptopurine.

Summary 6-MP, a powerful metabolic antagonist to nucleic acid synthesis, prolongs survival time of skin homografts in rabbits when administered after grafting. Treatment must be given continuously to maintain graft viability. However, toxicity of 6-MP limits the length of time treatment may be given.