Influence of surgery on the natural history of rheumatic mitral and aortic valve disease

The rate of survival, the evolution of functional cardiac status and the incidence of major complications during a 5 year period were studied in 410 patients with rheumatic mitral or aortic valve disease, of whom 200 were treated medically and 210 by surgery. The 5 year survival rates in patients with various types of rheumatic mitral valve disease were similar (45 percent for those with mitral stenosis and 46 percent for those with mitral insufficiency or mixed mitral insufficiency and stenosis). The survival rate in patients with aortic valve disease was somewhat more favorable (64 percent).Mitral valvulotomy had the most positive influence on mortality. The 85 percent 5 year survival rate of patients who underwent this procedure was significantly higher than that of patients with medically treated mitral stenosis. In patients submitted to mitral and aortic valve replacement, the survival rate was also improved in comparison with data in the corresponding medically treated groups, but to a lesser degree (70 percent for aortic valve replacement and 60 percent for mitral valve replacement). In all surgically treated groups, initial operative mortality was the primary determinant of the rate of survival at the end of 5 years.Survivors of all surgical groups had appreciable improvement in cardiac functional classification and a remarkable reduction in the incidence of heart failure and atrial fibrillation. The incidence of infectious endocarditis was significantly reduced after mitral valvulotomy, as compared with the incidence in patients with medically treated mitral stenosis. Mitral and aortic valve replacement did not reduce the incidence of infectious endocarditis. The incidence of thromboembolic phenomena was favorably influenced by mitral valvulotomy and aortic valve replacement, but not by mitral valve replacement.     

Influence of pacemaker-induced tachycardia with A-V block on left ventricular blood velocity in man.

Phasic instantaneous left ventricular blood velocity was measured by radiotelemetry in 28 subjects with a Doppler ultrasonic flowmeter catheter during atrial pacing and induced A-V block Type I Wenckebach A-V block with conduction ratios of 9:8 or lower generally produced a stepwise reduction of peak left ventricular blood velocity in relation to shortened R-R intervals. Longer Wenckebach periods resulted in little or no blood velocity alteration during 1:1 A-V conduction. Those beats following a blocked atrial depolarization were associated with augmented blood velocities. In three subjects, bigeminal periods of 3:2 A-V block resulted in larger left ventricular blood velocities when compared with 2:1 A-V block, despite identical R-R intervals following the blocked P wave. This latter phenomenon was attributed to diastolic augmentation of left ventricular contraction following the second and hemodynamically ineffective beat during 3:2 A-V block. Three patients manifested true blood velocity alternation during second-degree A-V block and changing R-R intervals. The variations in peak left ventricular blood velocity observed during atrial pacing and A-V block are related to changing inotropic state and cycle length dependent alterations of left ventricular diastolic filling.     

Effects of intravenous verapamil on cardiac arrhythmias and on the electrocardiogram.

The effects of intravenous verapamil on the electrocardiogram in 15 patients with heart disease in sinus rhythm and in 44 patients with supraventricular and ventricular tachyarrhythmias were evaluated. Verapamil prolonged the P-R interval without effect on the QRS duration or the Q-Tc interval. In patients with atrial flutter and fibrillation, A-V block was increased, with slowing of the ventricular rate, in almost all cases but sinus rhythm was restored in only 1 of 12 patients in atrial fibrillation and in 2 of the 11 patients with flutter. Verapamil had no effect in 3 patients with atrial fibrillation complicating WPW syndrome; in 1 of 5 patients with ventricular tachycardia it caused reversion to sinus rhythm. Sinus rhythm was restored promptly by verapamil in 13 of 17 patients with paroxysmal supraventricular tachycardias; in 2 others, sinus rhythm became established 1 to 2 hours after administration of the drug. Transient hypotension, not requiring treatment, was the only side effect noted but not in the patients with supraventricular tachycardias, in whom blood pressure generally increased after reversion to sinus rhythm by verapamil.     

Geometric and functional abnormalities of the left ventricle with a chronic localized noncontractile area

Thirty-one patients with coronary artery disease, 25 of whom had a chronic localized noncontractile area in the anteroapical region of the left ventricle, were studied at rest by means of left heart catheterization, left cineventriculography and selective coronary arteriography. The left ventricular volume, stroke volume, ejection fraction, left ventricular end-diastolic pressure, cardiac output and the surface area of the noncontractile area were measured.

The patients with a noncontractile area were classified in 4 groups according to the size of the noncontractile area relative to the end-diastolic left ventricular surface area. The relative size of the non-contractile area ranged from 5 to 47 percent. Six patients with uncomplicated coronary artery disease comprised the control group.

The critical size of the noncontractile area beyond which significant functional derangement occurred appeared to be 20 to 30 percent of the left ventricular internal surface area. The end-diastolic volume increased significantly and the ejection fraction was reduced to less than half of normal when the regional noncontractile area was larger than the critical size. Neither the cardiac output nor the left ventricular end-diastolic pressure correlated closely with size of the noncontractile area. In contrast, the ejection fraction was a more sensitive indicator and correlated well with the extent of regional contraction abnormality. In this study, double vessel disease was most common, followed by single vessel disease. Obstruction of the left anterior descending coronary artery was significant in the formation of anteroapical noncontractile regions.     

Central and regional hemodynamic effects and neurohumoral consequences of minoxidil in severe congestive heart failure and comparison to hydralazine and nitroprusside

Minoxidil is a potent oral vasodilator of potential value in patients with congestive heart failure (CHF), although preliminary studies show that it causes fluid retention. To test whether minoxidil acts primarily as an arterial vasodilator in CHF, it was compared with hydralazine and nitroprusside. To evaluate its chronic efficacy and mechanism of fluid retention, the effects of minoxidil (7 patients) were compared, in a double-blind manner, with those of hydralazine (8 patients) on central and regional hemodynamics and the renin-angiotensin-aldosterone and sympathetic nervous systems. There was no demonstrable difference in the central hemodynamic effects of minoxidil and hydralazine in the dosages used. After 6 hours both drugs increased cardiac index (minoxidil group, from 1.65 ± 0.29 to 2.26 ± 0.40 liters /min/m², p < 0.0001; hydralazine group, from 1.88 ± 0.61 to 2.34 ± 0.90 liters/min/m², p < 0.0001), decreased systemic vascular resistance and increased heart rate without change in pulmonary arterial, pulmonary capillary wedge or right atrial pressures. Nitroprusside effects differed from those of minoxidil and hydralazine with respect to heart rate (p < 0.005) and mean pulmonary arterial (p < 0.007) and right atrial (p < 0.009) pressures. Nitroprusside also decreased relative hepatomesenteric flow compared with the other 2 agents (p < 0.005). Neither renal blood flow, glomerular filtration rate, filtration fraction, nor urinary sodium excretion were significantly altered acutely by any of the 3 drugs. Minoxidil and hydralazine did not differ in their neurohumoral effects: Both agents produced an increase in plasma norepinephrine concentration (p < 0.003) and plasma renin activity (p < 0.04), but no change in plasma epinephrine or aldosterone concentrations. After 1 week of double-blind therapy, fluid retention was a greater problem with minoxidil than with hydralazine. Thus, minoxidil behaves primarily as an arterial vasodilator in CHF, fluid retention is a severe adverse effect, and the greater degree of fluid retention with minoxidil than hydralazine is not attributable to differing acute effects on total renal blood flow or function, or differing effects on the renin-angiotensin-aldosterone or sympathetic nervous systems.     

Radionuclide analysis of right and left ventricular response to exercise in patients with atrial and ventricular septal defects

In patients with ventricular or atrial septal defect, the ventricle which is chronically volume overloaded might not appropriately respond to increased demand for an augmentation in output and thereby might limit total cardiac function. In this study we simultaneously measured right and left ventricular response to exercise in 10 normal individuals, 10 patients with ventricular septal defect (VSD), and 10 patients with atrial septal defect (ASD). The normal subjects increased both right and left ventricular ejection fraction, end-diastolic volume, and stroke volume to achieve a higher cardiac output during exercise. Patients with VSD failed to increase right ventricular ejection fraction, but increased right ventricular end-diastolic volume and stroke volume. Left ventricular end-diastolic volume did not increase in these patients but ejection fraction, stroke volume, and forward left ventricular output achieved during exercise were comparable to the response observed in healthy subjects. In the patients with ASD, no rest-to-exercise change occurred in either right ventricular ejection fraction, end-diastolic volume, or stroke volume. In addition, left ventricular end-diastolic volume failed to increase, and despite an increase in ejection fraction, left ventricular stroke volume remained unchanged from rest to exercise. Therefore, cardiac output was augmented only by the heart rate increase in these patients. Right ventricular function appeared to be the major determinant of total cardiac output during exercise in patients with cardiac septal defects and left-to-right shunt.     

Efficient transposition of the Tol2 transposable element from a single-copy donor in zebrafish

The Tol2 transposable element is a powerful genetic tool in model vertebrates and has been used for transgenesis, insertional mutagenesis, gene trapping, and enhancer trapping. However, an in vivo transposition system using Tol2 has not yet been developed. Here we report the in vivo Tol2 transposition system in a model vertebrate, zebrafish. First, we constructed transgenic zebrafish that carried single-copy integrations of Tol2 on the genome and injected transposase mRNA into one-cell stage embryos. The Tol2 insertions were mobilized efficiently in the germ lineage. We then mobilized an insertion of the Tol2 gene trap construct in the nup214 gene, which caused a recessive lethal mutant phenotype, and demonstrated that this method is applicable to the isolation of revertants from a transposon insertional mutant. Second, we constructed transgenic fish carrying the transposase cDNA under the control of the hsp70 promoter. Double-transgenic fish containing the transposase gene and a single-copy Tol2 insertion were treated with heat shock at the adult stage. We found that transposition can be induced efficiently in the male germ cells. We analyzed new integration sites and found that the majority (83%) of them were mapped on chromosomes other than the transposon donor chromosomes and that 9% of local hopping events mapped less than 300 kb away from the donor loci. Our present study demonstrates that the in vivo Tol2 transposition system is useful for creating genome-wide insertions from a single-copy donor and should facilitate functional genomics and transposon biology in vertebrates.     

Comparison of effectiveness of thyrotropin-suppressive doses of d- and l-thyroxine in treatment of hypercholesterolemia

In an attempt to compare the cholesterol-lowering effects of equivalent doses of d- and l-thyroxine, 10 euthyroid, hypercholesterolemic subjects were treated with graded doses of each medication in a cross-over design using thyrotropin suppression following thyrotropin-releasing hormone administration as the end-point. The mean thyrotropin-suppressive dose of d-thyroxine was 2.4 ± 0.66 mg per day, which resulted in mean reductions of 10 percent in total plasma cholesterol, 10 percent in plasma low-density lipoprotein cholesterol, and 11 percent in plasma high-density lipoprotein cholesterol. The mean thyrotropin-suppressive dose of l-thyroxine was 135 ± 46 μg per day, which resulted in mean reductions of 7 percent in total plasma cholesterol, 6 percent in plasma low-density lipoprotein cholesterol, and 14 percent in plasma high-density lipoprotein cholesterol. The reductions in total, low-density, and high-density cholesterol achieved with d-thyroxine were not significantly different from those achieved with l-thyroxine. Neither medication produced a significant increase in heart rate or ventricular ectopy as determined by Holter monitoring. These data do not support the belief that d-thyroxine has a preferential cholesterol-lowering effect in humans when compared with equivalent doses of l-thyroxine. In addition, both d- and l-thyroxine reduced plasma high-density lipoprotein cholesterol.     

Changes in the microvasculature with age

The microvasculature of various organs of the rat and of the mesentery of the cat were examined for histochemical changes as a function of age, using the periodic acid-Schiff (PAS) reaction. Arterioles, minute arteries, and nonmuscular venules were histochemically unchanged to approximately 17 months of age in the rat and 8 years in the cat. Subsequently, focal areas of PAS-positive material developed in the media of arterioles and small arteries and increased in extent and severity with age. The adventitia of nonmuscular venules normally stains slightly positive due to the mucopolysaccharide coating of collagen fibers. With age this adventitial layer becomes more intensely PAS-positive. In the 26-month-old rat and 19-year-old cat, the media of arterioles and small arteries were extensively hyalinized. Lesions of arteriosclerosis were not present. These observations, in consort with prior observations of others in various mammals, indicate that there is a regular systematic alteration of various elements of the microcirculation with age. A possible relationship between these anatomical changes and tissue exchange is considered.     

T cell subsets and cellular immunity in end-stage renal disease

The T lymphocyte population was studied by immunofluorescent staining with monoclonal antibodies and laser flow cytometry in the blood of 50 patients with end-stage renal disease undergoing long-term maintenance intermittent hemodialysis. The absolute number of T cells was lower in patients receiving dialysis for more than one year (p less than 0.001), as was the absolute count of helper T cells (p less than 0.005). In patients under 30 years of age, the absolute number of helper T cells was markedly reduced, whereas the number of suppressor/cytotoxic T lymphocytes was not changed. In patients between the ages of 30 and 60 years, both helper and suppressor cells were significantly reduced. In patients over 60 years of age, only the number of helper T cells was reduced. The in vitro response of patients' lymphocytes was reduced both in the mixed lymphocyte reaction (p less than 0.01) and after phytohemagglutinin stimulation (p less than 0.001). Natural killer cytotoxicity of patients' peripheral blood mononuclear cells, however, was unaffected.