Edmond A. Murphy

Progression of Aortic Dilatation and the Benefit of Long-Term β-Adrenergic Blockade in Marfan's Syndrome

BACKGROUND The aortic root enlarges progressively in Marfans syndrome, and this enlargement is associated with aortic regurgitation and dissection. Long-term treatment with beta-adrenergic blockade, by reducing the impulse (i.e., the rate of pressure change in the aortic root) of left ventricular ejection and the heart rate, may protect the aortic root. METHODS We conducted an open-label, randomized trial of propranolol in adolescent and adult patients with classic Marfans syndrome (32 treated and 38 untreated [control] patients). Aortic-root dimensions and clinical end points (aortic regurgitation, aortic dissection, cardiovascular surgery, congestive heart failure, and death) were monitored for an average of 9.3 years in the control group and 10.7 years in the treatment group. All 70 patients were included in the analysis according to the intention-to-treat principle. RESULTS The dose of propranolol was individualized; the mean (+/- SE) dose was 212 +/- 68 mg per day. The mean slope of the regression line for the aortic-root dimensions, which reflect the rate of dilatation, was significantly lower in the treatment group than in the control group (0.023 vs. 0.084 per year, P < 0.001). Clinical end points were reached in five patients in the treatment group and nine in the control group. The Kaplan-Meier survival curve for the treatment group differed significantly from that for the control group during the middle years of the trial and remained better for the treatment group throughout the study. CONCLUSIONS Prophylactic beta-adrenergic blockade is effective in slowing the rate of aortic dilatation and reducing the development of aortic complications in some patients with Marfans syndrome.

A prospective longitudinal evaluation of pregnancy in the Marfan syndrome.

OBJECTIVE We undertook a prospective evaluation of the outcomes of pregnancy, both maternal and fetal, and the long-term impact of pregnancy on Marfan syndrome in a series of consecutive, unselected patients. STUDY DESIGN Forty-five pregnancies in 21 Marfan syndrome patients were prospectively observed in one institution between 1983 and 1992. During pregnancy, patients were monitored with serial echocardiograms and close attention to symptoms. Maternal and fetal outcomes were monitored with serial echocardiographic data were analyzed by least-squares regression. Eighteen of the patients were followed up for 15 months to 13 years after the completion of their last pregnancy for investigation of the long-term impact of pregnancy on the cardiovascular manifestations of Marfan syndrome. RESULTS Aortic dissection occurred in two patients, both with increased risk for dissection established before pregnancy. The incidence of obstetric complications otherwise did not exceed that in the general population. Echocardiographic data demonstrated little to no change in aortic root diameter throughout pregnancy in most patients. Long-term follow-up showed no apparent worsening of cardiovascular status attributable to pregnancy in comparison with a group of 18 women with Marfan syndrome who were of similar age, had a similar degree of disease severity, and underwent no pregnancies. CONCLUSIONS Patients with Marfan syndrome in whom cardiovascular involvement is minor and aortic root diameter is < 40 mm usually tolerate pregnancy well, with favorable maternal and fetal outcomes, and without subsequent evidence of aggravated aortic root dilatation over time.

Further studies on cholesterol levels in the Johns Hopkins medical students: the effect of stress at examinations.

1. 1. Serum cholesterol determinations on 52 male medical students were carried out at admission to medical school (Test I), at final anatomy examination (Test II), and during a period of regular academic work (Test III). 2. 2. The mean cholesterol levels at Tests I and II were significantly higher than at Test III. 3. 3. The cholesterol levels of two additional subjects showed a similar pattern when the values at final biochemistry examination (Text IV) were compared with Test III. 4. 4. For certain students, Test III fell close to the final biochemistry examination; the fall from Test II to Test III was less marked in these subjects. 5. 5. The total eosinophil count was significantly lower at Test II than Test III. 6. 6. There was no significant difference in body weight between Tests I, II, and III. 7. 7. The findings are consistent with the hypothesis that stress such as accompanies the first few weeks of medical school or important final examinations is accompanied by a significant mean rise in cholesterol level.

One cause? Many causes?

Abstract The use of bimodality in the distribution curve of a sample as evidence bearing on the existence of a single main factor in the production of a characteristic is discussed. It is pointed out that bimodality (double peaking) can arise through a number of different mechanisms other than the operation of a single factor of overwhelming importance. Conversely one cannot deny the existence of such a major factor simply from the absence of bimodality. The conditions which regulate the separation of a mixed population into two peaks are discussed in some detail. The existence of two populations should be deduced from bimodality only with the greatest circumspection; the cleanness of the segregation is in practice rarely good. The use of arbitrary dividing lines is deplored because of the risk of creating fictitious problems.

The normal range--a common misuse.

Abstract The conventional ‘normal range’ is an unsatisfactory yardstick for decisions. The best dividing lines between the ‘normal’ and the ‘diseased’ or between ‘those who need not be investigated farther’ and ‘those who do’ depend on the disease under consideration, and must be determined by taking account of the distributions and sizes of the normal and diseased groups, and the costs of making the wrong decision. No simple solution is proposed, but in practice it is evident that the ‘normal range’ provides information which is mostly irrelevant, and is largely ignored by the experienced clinician. The proposed quantitative approach has limitations (though usefulness of information which can neither be quantitated nor classified has probably been exaggerated), but the subject does call for exploration and the collection of the necessary data particularly in view of the growing promise of the value of computers as adjuvants to diagnosis especially in the realms of data retrieval and discriminant analysis.

Familial aggregation in Alzheimer dementia--I. A model for the age-dependent expression of an autosomal dominant gene.

An autosomal dominant genetic etiology has been proposed for Alzheimer Dementia (AD), but many cases appear to be sporadic. Evaluation of the possible genetic transmission of AD from its familial aggregation requires consideration of (1) the proportion of index cases with genetic disease, and (2) the consequences of typically very late onset. To investigate these factors, a provisional biomathematical genetic model was developed from the empirical age-specific incidence of AD in relatives. Based upon the premise of an autosomal dominant AD gene in proband families, the modeling technique provides estimates of the proportion of genetic index cases (as opposed to phenocopies) and the parameters of age-dependent gene expression. With appropriate parameters the model accurately reflects the age-specific familial risk of AD, suggesting the appropriateness of its underlying assumptions. The estimated proportions of genetic index cases suggest that heritable disease constitutes a majority of AD. In cases ascertained by the presence of aphasia or apraxia the estimated proportion of genetic cases is 100%. The greatest likelihood of gene expression is in the ninth decade, however, suggesting that most genetically predisposed relatives will die from other causes before developing AD.

Kinetics and Distribution of 111Indium-Labeled Platelets in Patients with Homocystinuria

Homocystinuria is an inborn error of metabolism involving a high incidence of thromboembolism. It sometimes improves with large doses of pyridoxine. We investigated the kinetics and distribution of 111Indoxine-labeled platelets in 11 normal volunteers and 12 patients with homocystinuria, none of whom had clinical evidence of acute thrombosis at the time of the study. Six of the patients were resistant to pyridoxine and had homocystinemia. There were no statistical differences in mean platelet-survival times between pyridoxine responders and nonresponders or between normal subjects and pyridoxine responders or nonresponders, regardless of whether a linear, exponential, or multiple-hit model was used to analyze the kinetic data. Plasma homocystine levels had no apparent effect on mean platelet-survival time. There was no abnormal accumulation of platelets in any of the patients, and the distribution of platelets in liver and spleen was similar to that in normal subjects. Our results suggest that the kinetics and distribution of platelets in patients with homocystinuria who have no clinical evidence of thromboembolism are normal. Thus, the data do not provide evidence for disordered platelet function or for an ongoing interaction of platelets with vessel walls in this condition.

Genetics of Longevity in Man

In this chapter, we shall consider three major topics: the evolutionary implications of the length of life, the light that genetics may throw on the nature of longevity, and the empirical evidence that there is a heritable component. It is wise to perceive at the start not only that these topics are elusive but also that they are posed inside an arbitrary conceptual framework. There is a priori no reason to believe that the terms of the question, or even the question itself, have any meaning; it may be that we think the questions are sound simply because, as reflecting animals, we are interested in prolonging life. Superficially, it appears a simple problem to explore, but the more we try to crystallize it with scientific investigation in mind, the more it becomes eroded by elimination of aspects that prove to be irrelevant.

Genetics and congenital heart disease: Perspectives and prospects

Elucidating the role of genes in the ontogenesis of the cardiovascular system is a task that involves many fields of inquiry. Recent dramatic advances in the molecular biology of transcription and its variations and the prospects for sequencing the entire human genome must not induce complacency; the major task of determining how a one-dimensional code specifies a three-dimensional structure demands an understanding of biologic systems considerably beyond the current level. The study of pathologic cardiovascular ontogeny is equally in need of new insight and fresh approaches. Although all clinicians might agree that genes are important contributors to both the etiology and the pathogenesis of congenital heart defects, with the exception of a few Mendelian conditions, this knowledge cannot be put to practice beyond crude statements of empirically determined probabilities. In this review, we selectively examine studies that are addressing what we perceive as provocative issues and suggest some areas, such as chaos theory, in which new ideas might be found.

Quantitative genetics: a critique.

Abstract The quantitative aspects of human genetics have hitherto been confined to (1) Mendelian categorization of qualities, which is enumerative and best applied to single‐locus conditions; and (2) Galtonian analysis, which is an examination of the first and second moments of quantities and best applied to multiple‐locus conditions. The latter analysis throws no light on the details of the genotype or how they shape the phenotype; and even as a descriptive device it is adequate only where narrowly restrictive assumptions (equality, additivity, and independence of the component contributions) are met. The utility of such general models as approximate describers, provided that they are tempered by explicit empirical inquiry, is illustrated by familiar analogies. Several examples are discussed where neither Mendelian nor Galtonian analysis is appropriate. Many mechanisms do not even fulfill the assumption of monotonicity. Heritability in the conventional sense is briefly discussed