THE DESIGN AND ANALYSIS OF EXPERIMENTS. By Oscar Kempthorne. New York, John Wiley and Sons, Inc., 1952. 631 pp. $8.50. This book by a teacher of statistics (as well as a consultant for \"experimenters\") is a comprehensive study of the philosophical background for the statistical design of experiment. It is necessary to have some facility with algebraic notation and manipulation to be able to use the volume intelligently. The problems are presented from the theoretical point of view, without such practical examples as would be helpful for those not acquainted with mathematics. The mathematical justification for the techniques is given. As a somewhat advanced treatment of the design and analysis of experiments, this volume will be interesting and helpful for many who approach statistics theoretically as well as practically. With emphasis on the \"why,\" and with description given broadly, the author relates the subject matter to the general theory of statistics and to the general problem of experimental inference. MARGARET J. ROBERTSON

The Design and Analysis of Experiments

Background. Left ventricular dilatation and dysfunction after myocardial infarction are major predictors of death. In experimental and clinical studies, long-term therapy with the angiotensin-converting—enzyme inhibitor captopril attenuated ventricular dilatation and remodeling. We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infarction. Methods. Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive double-blind treatment with either placebo (1116 patients) or captopril (1115 patients) and were followed for an average of 42 months. Results. Mortality from all causes was significantly reduced in the captopril group (228 deaths, or 20 percent) as compared with the placebo group (275 deaths, or 25 percent); the reduction in risk was 19 percent (95 percent conf...

Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. results of the survival and ventricular enlargement trial

To evaluate the influence of the angiotensin-converting enzyme inhibitor, enalapril (2.5 to 40 mg/day), on the prognosis of severe congestive heart failure, defined as New York Heart Association functional class IV, a double-blind study was undertaken in which 253 patients were randomized to receive either placebo (n = 126) or enalapril (n = 127) in addition to conventional treatment, including vasodilators. Follow-up averaged 188 days (range 1 day to 20 months). The reduction in crude mortality within 6 months (primary objective) was 40% in the enalapril-treated group (from 44 to 26%, p = 0.002) and within 1 year 31% (p = 0.001). By the end of the study, 68 subjects in the placebo group and 50 in the enalapril group had died--a reduction of 27% (p = 0.003). The entire reduction in total mortality (50%) was found in patients dying from progressive heart failure, whereas no difference was seen in the incidence of sudden cardiac death. There was a significant improvement in New York Heart Association classification in the enalapril group, together with a reduction in heart size and a reduced requirement for other heart failure medication. It is concluded that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The effect seems to be due to a reduction in death from progression of heart failure.

Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)

An acute myocardial infarction, particularly one that is large and transmural, can produce alterations in the topography of both the infarcted and noninfarcted regions of the ventricle. This remodeling can importantly affect the function of the ventricle and the prognosis for survival. In the early period, infarct expansion has been recognized by echocardiography as a lengthening of the noncontractile region. The noninfarcted region also undergoes an important lengthening that is consistent with a secondary volume-overload hypertrophy and that can be progressive. The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival. The process of ventricular enlargement can be influenced by three interdependent factors, that is, infarct size, infarct healing, and ventricular wall stresses. A most effective way to prevent or minimize the increase in ventricular size after infarction and the consequent adverse effect on prognosis is to limit the initial insult. Acute reperfusion therapy has been consistently shown to result in a reduction in ventricular volume. The reestablishment of blood flow to the infarcted region, even beyond the time frame for myocyte salvage, has beneficial effects in attenuating ventricular enlargement. The process of scarification can be interfered with during the acute infarct period by the administration of glucocorticosteroids and nonsteroidal antiinflammatory agents, which result in thinner infarcts and greater degrees of infarct expansion. Modification of distending or deforming forces can importantly influence ventricular enlargement. Even short-term augmentations in afterload have deleterious long-term effects on ventricular topography. Conversely, judicious use of nitroglycerin seems to be associated with an attenuation of infarct expansion and long-term improvement in clinical outcome. Long-term therapy with an angiotensin converting enzyme inhibitor can favorably alter the loading conditions on the left ventricle and reduce progressive ventricular enlargement as demonstrated in both experimental and clinical studies. With the former therapy, this attenuation of ventricular enlargement was associated with a prolongation in survival. The long-term clinical consequences of long-term angiotensin converting enzyme inhibitor therapy after myocardial infarction is currently being evaluated. Although studies directed at attenuating left ventricular remodeling after infarction are in the early stages, it does seem that this will be an important area in which future research might improve long-term outcome after infarction.

Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications.

Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension and fibrous replacement. Here we show that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction. The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition and sustained improvement in cardiac function. The use of cytokine-mobilized autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium (alone or in conjunction with currently used therapies) has the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling.

Neovascularization of ischemic myocardium by human bone-marrow–derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function

To define the relationship between infarct size and ventricular performance, we performed hemodynamic studies in rats 21 days after left coronary artery occlusion. Ventricular performance was assessed under ether anesthesia by measurements of baseline hemodynamics and stressed performance as determined by the peak cardiac output and stroke volume obtained during intravenous volume loading and by the peak left ventricular developed pressure obtained during occlusion of the ascending aorta. Infarct size was determined by planimetry of the endocardial circumference of each of four histological slices of the left ventricle. Rats with small (4-30%) myocardial infarctions had no discernible impairment in either baseline hemodynamics or peak indices of pumping and pressure-generating ability when compared to the sham-operated, noninfarcted rats. Rats with moderate (31-46%) infarctions had normal baseline hemodynamics but reduced peak flow indices and developed pressure. Rats with infarctions greater than 46% had congestive heart failure, with elevated filling pressures, reduced cardiac output, and a minimal capacity to respond to pre- and after load stresses. The entire spectrum of postinfarction ventricular function was observed, from no detectable impairment to congestive failure. In this model of histologically healed myocardial infarction, the impairment of left ventricular function was directly related to the loss of myocardium.

Myocardial infarct size and ventricular function in rats.

To determine whether the relationship between infarct size and ventricular performance, volume, and compliance could be altered favorably, captopril was administered to rats for 3 months following coronary artery ligation. Baseline left and right ventricular and systemic arterial pressures and aortic blood flow, and maximal stroke volume and cardiac indices attained during a volume loading, were measured. Passive pressure-volume relations of the left ventricle were determined, and the slopes of segments of this relation were analyzed to characterize ventricular chamber stiffness. In untreated rats, left ventricular end-diastolic pressure progressively rose (from 5-28 mm Hg) as a function of infarct size, whereas, in captopril-treated rats, filling pressure remained within normal limits (5 +/- 1 mm Hg) in all but those with extensive infarcts. Chronic captopril therapy reduced baseline mean arterial pressure and total peripheral resistance, yet maintained cardiac and stroke outputs in rats both with and without infarcts. In untreated rats, maximal pumping ability progressively declined with increasing infarct size, whereas, in captopril-treated rats, peak stroke volume index remained within normal limits in all but those with extensive infarcts. The in vitro left ventricular volumes of captopril-treated rats were significantly less than those of untreated rats. The maintenance of forward output from a lesser dilated left ventricle yielded an index of ejection fraction for treated rats with moderate and large infarcts that was significantly elevated compared with that of untreated rats with infarcts of comparable size. Left ventricular chamber stiffness, which fell as infarct size increased in untreated rats, was normalized by chronic captopril therapy. Thus, captopril attenuated the left ventricular remodeling (dilation) and deterioration in performance that were observed in rats with chronic myocardial infarction.

Influence of chronic captopril therapy on the infarcted left ventricle of the rat.

Although vasodilator therapy has been shown to improve functional capacity in patients with congestive heart failure, there is no evidence that such therapy can prolong survival. Coronary artery ligation in the rat was used to produce a wide range of myocardial infarct sizes and a resultant spectrum of left ventricular dysfunction. To determine the relationship between size of myocardial infarction and long-term survival and to test the hypothesis that long-term therapy with captopril could improve survival after myocardial infarction, 302 rats were randomly assigned to either placebo or captopril therapy 14 days after coronary artery ligation. The animals were kept in a laminar flow unit and followed daily for a 1 year period or until spontaneous death. Size of myocardial infarction was determined by planimetry of serial histologic sections of the left ventricle. One year survival in placebo-treated rats decreased markedly in direct relation to increasing size of infarction (from 71% in noninfarcted rats to only 8% in rats with large infarcts). Long-term captopril therapy prolonged the survival of rats with infarcts (p less than .02). The most marked improvement in survival was noted in the animals with infarcts of moderate size, in which 1 year survival was 21% in the placebo-treated rats and 48% in the captopril-treated rats. Thus, in this experimental preparation of myocardial infarction and left ventricular dysfunction, survival was inversely related to size of infarction. Long-term therapy with captopril, which we had previously shown to improve left ventricular function and lessen dilatation in the chronic phase of infarction, also had a pronounced effect on prolonging survival in this preparation of chronic infarction.

Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril.

Ventricular dilatation may have important prognostic implications for the survival of patients with left ventricular (LV) dysfunction. To determine the manner and extent to which the left ventricle of the rat remodels and dilates after myocardial infarction, we obtained the passive pressure-volume relationships, chamber stiffness constants, and mass during both the early and late phases. In moderate and large infarcts as inflammation and edema developed, LV weight increased then progressively decreased as a thin scar formed, returning to normal values as a result of compensatory hypertrophy of the residual myocardium. LV dilatation occurred in all rats with infarcts but to different extents depending on infarct size and duration. In the early postinfarction phase, pressure-volume relationship was relatively unchanged in all infarct-size groups, except for significant rightward shift in low pressure range for rats with moderate and large infarcts and significant leftward shift in high pressure range for rats with small infarcts. During resolution of the inflammatory response, LV dilatation occurred in all infarct groups in relation to infarct size. As scar formation became complete, LV enlargement did not progress in rats with small infarcts but did so in rats with moderate and large infarcts. LV chamber stiffness remained within the range of normal values during the early phase in all rats with infarcts but decreased significantly during the late phase in rats with moderate and large infarcts in association with the extent of ventricular enlargement. Alterations in the volume-to-mass ratio (V/Vwt) were most marked in the late postinfarction phase, wherein both volume (increased) and mass (decreased, then increased) changed dramatically and V/Vwt progressively increased in rats with large infarcts.

Progressive ventricular remodeling in rat with myocardial infarction.

To determine the effects of healed myocardial infarction on the diastolic compliance of the left ventricle, we studied 36 rats 26 days after left coronary artery ligation. Peak cardiac output and stroke volume were measured under ether anesthesia during volume loading, and peak left ventricular developed pressure was determined during occlusion of the ascending aorta. During a slow infusion of saline into the potassium-arrested left ventricle, diastolic pressure and volume were measured continuously over the pressure range -5 to 30 mm Hg. Infarct size was determined by planimetry of serial sections taken from each heart at 1-mm intervals from apex to base. In rats with healed infarcts, left ventricular volume was increased in proportion to infarct size and the diastolic pressure-volume relationship was shifted so that at pressures below 2.5 mm Hg volume was increased, resulting in an increased ventricular compliance in this low pressure range. Above this pressure, the slopes of the pressure-volume curves were similar in rats with and without infarctions. Peak cardiac output and pressure-generating capacity were impaired in proportion to infarct size. This impairment of cardiac performance correlated with the infarct size-related increase in diastolic volume, which served to offset the reduction in flow generating capacity caused by systolic dysfunction, while contributing directly to the impairment of pressure generating capacity.

Janice M. Pfeffer

Papers

Myocardial infarct size and ventricular function in rats.

Influence of chronic captopril therapy on the infarcted left ventricle of the rat.

Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril.

Progressive ventricular remodeling in rat with myocardial infarction.

Left ventricular diastolic pressure-volume relations in rats with healed myocardial infarction. Effects on systolic function.