Recovery of left ventricular function in acute nonischemic congestive cardiomyopathy

Recovery of left ventricular function in acute nonischemic congestive cardiomyopathy The extent and time course of recovery of left ventricular function were investigated in 29 patients with no previous symptoms who had acute nonischemic congestive cardiomyopathy and left ventricular ejection fraction of 0.22 _+ 0.07. Improvement in left ventricular ejection fraction by at least 0.05 was observed in 24 of the 29 patients and was achieved within 6 months after the initial evaluation. Progressive improvement was seen, with a maximum ejection fraction of 0.45 _+ 0.17 being achieved within approximately 18 months. The degree of ejection fraction recovery was not related to the initial clinical or hemodynamic variables. However, the extent of fibrosis detected on endomyocardial biopsy correlated inversely with subsequent changes in ejection fraction (r = -0.65, p = 0.0003). Thus significant recovery is likely after an acute episode of nonischemic cardiomyopathy and may be progressive during the first year. Recovery is related to the extent of myocardial fibrosis detected on endomyocardial biopsy but cannot be predicted from the initial clinical or hemodynamic presentation. (AM HEART J 1995;129:24-30.)

Andrew M. Cross, Jr., MD, a Charles Steenbergen, MD, b and Michael B. Higginbotham, MB b Durham, N. C., and Lexington, Ky.

T h e long-term prognosis of patients with chronic congestive h e a r t failure is poor 1-7 and is d e p e n d e n t on the degree of left ventricular dysfunction and baseline h e m o d y n a m i c s and measures of n e u r o h u m o r a l activation.4, 5, s-10 In contrast, m a n y patients with an acute clinical episode achieve a significant degree of recovery. 1Ms This finding has been especially common in patients with suspected myocarditis or perip a r t u m cardiomyopathy. 12,14,17, 18 In such patients the ability to predict who will recover and the expected time period for recovery would be useful when considering eligibility for h e a r t t r a n s p l a n t a t i o n and other interventions. H e m o d y n a m i c p a r a m e t e r s obtained on initial examination have not been found to be associated with r e c o v e r y in previous studies, 11-18 although the a m o u n t of fibrosis seen on endomyocardial biopsy was modestly associated with recovery. 11 Comparison of initial hemodynamics, endomyocardial biopsy, and serial follow-up of ventric-

From the bDepartment of Medicine, Division of Cardiology and the Department of Pathology, Duke University Medical Center, Durham; and the aDepartment of Internal Medicine, Division of Cardiology, University of Kentucky Medical Center, Lexington. Supported in part by National Research Service Award grant HL07101-17 from the National Institutes of Health. Received for publication Nov. 18, 1993; accepted March 7, 1994. Reprint requests: Andrew M. Cross, Jr., MD, Division of Cardiology, Room MN 670 UKMC, 800 Rose St., Lexington, KY 40536-0084. Copyright ® 1995 by Mosby-Year Book, Inc. 0002-8703/95/$3.00 + 0 4/1/59139

24

ular function has not been r e p o r t e d in any study. We describe the e x t e n t and time course of recovery of left ventricular function in patients with recent-onset, nonischemic, nonvalve-related h e a r t failure and correlate the degree of recovery with the initial clinical, h e m o d y n a m i c , and histologic findings. METHODS

Patient population. The records of all patients referred to a university medical center heart failure service from January 1987 to June 1992 were reviewed. Entry criteria for the s,tudy were as follows: no previous history of cardiac disease, onset of heart failure symptoms <6 months, initial ejection fraction <40 % (radionuclide or contrast ventriculogram), <=25% stenosis detected on coronary angiography, no valvular heart disease, and serial follow-up with clinical evaluation and ejection fraction measurement. A database search was conducted to find all patients who had undergone cardiac catheterization at the medical center and determine which patients with acute nonischemic congestive cardiomyopathy were seen by the staffs of the general medicine and cardiology services during the time period being studied. Treatment. All patients were initially treated with angiotensin-converting enzyme inhibitors (enalapril 10 to 20 mg daily or captopril 37.5 to 75 mg daily), digoxin (0.25 mg daily), diuretics, and intravenous inotropic therapy as required (4 patients); dosing was individualized to achieve optimal clinical and hemodynamic responses. The initial clinic visit occurred from 1 to 4 months after hospitalization. Over the subsequent year, follow-up intervals were 3 to 6 months and 6 to 12 months thereafter.

Volume 129, Number 1

CF088,Steenbergen, and Higginbotham 25

American Heart Journal

Endomyocardial biopsy. Biopsies were performed at the discretion of the attending physician. Samples were evaluated for lymphocyte content, fibrosis, and myocyte myofibril volume fraction. The average number of lymphocytes per 200x field was determined by immunoperoxidase staining for the pan-T lymphocyte markers CD2 (Tll) and CD3 (Leu-4) as previously described. 19Fibrosis was assessed in Masson-stained, paraffin-embedded sections. The volume fraction of interstitial fibrosis tissue was quantified by using a grid point counting method at 130x as previously described by Weibel2°and Figulla et al.11The grid consisted of 144 points, and a minimum of 250 test points were counted per biopsy. Myocyte myofibril volume fraction was evaluated by using electron micrographs at 250x magnification. Seventeen to 20 micrographs per biopsy were examined, and a grid-point counting method was again used for quantification. This grid had 168 points, and a minimum of 2700 points were counted per biopsy. Analysis. Paired two-tailed t tests were performed to compare the maximum follow-up ejection fraction with the value obtained at the time of the initial evaluation. Reproducibility studies previously performed in our laboratory2~ determined a change in ejection fraction of 0.05 to be outside the range of variation for the test. Correlation analysis was performed to compare the maximum improvement in ejection fraction with hemodynamic and histologic measurements obtained during the initial evaluation. Analysis of variance was performed to evaluate improvement in New York Heart Association (NYHA) functional class as related to the improvement in ejection fraction. Scheff~'s F procedure was used to evaluate differences between the mean changes in ejection fraction associated with each change in NYHA class. A p value of <0.05 was considered significant.

Table I. Parameters recorded during initial evaluation

RESULTS Patient characteristics. Approximately 1100 charts were screened. Of the 33 patients who satisfied the initial clinical and hemodynamic criteria for the study, 29 (16 men and 13 women) underwent serial follow-up and were included in the analysis. Three patients were excluded because they did not have cardiac catheterization, and one was lost to followup. Table I summarizes the characteristics of the patients at the time of their initial evaluation. The range of age was 21 to 64 years (mean 41 years). The precise cause of heart failure was undetermined in the great majority of patients; no patient had biopsy-proven myocarditis, and one patient had biopsy evidence of hemochromatosis. Clinical diagnoses as determined by history and physical examination included peripartum cardiomyopathy (4 patients), hypertensive cardiomyopathy (3), alcoholic cardiomyopathy (2), hypothyroidism (1), idiopathic cardiomyopathy (6), and suspected myocarditis (12). The patient with hypothyroidism had the diagnosis verified by laboratory testing during the course of his hospital admission. The duration of symptoms ranged

from 1 day to 16 weeks (mean 5.5 weeks). The first measurement of ejection fraction was performed from I day to 6 weeks (mean 1.2 weeks) after medical therapy was started. Radionuclide ventriculography was used in 20 patients, and contrast ventriculography was used in 9. All follow-up ejection fraction measurements were done with radionuclide ventriculography. The initial ejection fraction ranged from 0.11 to 0.39 (0.22 +_ 0.07, mean + SD). The database search revealed an additional 20 patients who met the clinical criteria but who were not followed-up by the heart failure service. Only 4 of these patients had had a follow-up radionuclide measurement of ejection fraction. Therefore our sample represented approximately 55 % of the population seen by the university medical center with relatively acute nonischemic, nonvalvular congestive heart failure. Twenty-seven of 29 patients had biopsies performed. All specimens were evaluated by immunoperoxidase staining for lymphocyte content. Because of technical limitations, 24 could be evaluated by electron microscopy for myofibril volume fraction and 18 for fibrosis.

Clinical Age (yr) Sex Male Female Initial functional class Duration of symptoms (wk) Hemodynamic Initial ejection fraction Pressure (mm Hg) Mean right atrial Right ventricular systolic Right ventricular end diastolic Mean pulmonary artery Pulmonary artery systolic Pulmonary artery diastolic Mean pulmonary artery wedge Mean aortic Systolic aortic Diastolic aortic Left ventricular systolic Left ventricular end diastolic Heart rate (beats/rain) Cardiac output (L/min) Cardiac index (L/min/m 2) Stroke volume (ml) Stroke work index gm • m/m2/beat Arterial-venous oxygen difference (vol % ) Histologic Lymphocytic infiltrate (cetls/HPF) Myofibril fraction Fibrosis fraction

41 _+ 11 16 13 3.4 _+ 0.8 5.5 -- 5 0.22 +_ 0.07 7.5 38.9 9.7 26.9 38.5 20.1 19.2 88.9 112.4 76.8 112.5 20.5 91.1 4.7 2.5 59.0 28.6 5.6

_+ 5.3 + 13.2 _+ 6.1 _+ 11.3 + 13.5 _+ 9.4 _+ 11.9 _+ 14.1 _+ 20.1 _+ 11.3 _+ 20.2 _+ 10.0 _+ 22.1 _+ 1.6 +_ 0.9 L +_ 33.8 +_ 18.9 _+ 1.7

2.5 _+ 3.6 0.57 + 0.50 0.07 _+ 0.05

26

January 1995 American Heart Journal

Cross,Steenbergen, and Higginbotham .8

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Ventricular function. The ejection fraction of 24 (83 %) of the 29 patients improved by at least 0.05. Eighteen patients improved by >0.20; one patient improved by 0.10. The maximum follow-up ejection fractions were detected a mean of 12.8 + 12.8 months after the initial evaluation. For the group, ejection fraction improved from 0.22 _+ 0.07 to 0.45 _+ 0.17, p < 0.0001 (Fig. 1), with the range of maximum ejection fractions being 0.15 to 0.73. In the subgroup of patients who were initially evaluated with radionuclide ventriculography, ejection fraction improved from 0.21 +_ 0.06 to 0.43 _+ 0.04. Most of the improvement appeared to occur within the first 6 months, with a slower rate of change over the subsequent year. Because the timing of the ejection fraction measurements was not uniform, formal analysis of the rates of recovery could not be performed. Clinical outcome. Two patients died and one underwent cardiac transplantation; among these three patients, the best ejection fraction was <25%. All other patients were alive and clinically stable at the time of the last evaluation. Analysis of variance (Fig. 2) revealed that clinical improvement, as measured by the NYHA functional classification, coincided with improvement in left ventricular function. A change in NYHA class by 2 or 3 points was associated with a significantly higher improvement in ejection fraction as compared to no change in NYHA class (p = 0.04 and p = 0.002, respectively). This was also true for a change in NYHA class by 3 points compared to a change of 1 point (p = 0.008). Correlates of left ventricular recovery, None of the initial clinical or hemodynamic variables signifi-

cantly correlated with the degree of improvement in ventricular function. However, the degree of fibrosis detected on the biopsy, which ranged from a fraction of 0 to 0.15, correlated with the maximal increase in left ventricular ejection fraction (r = - 0 . 6 5 , p = 0.003; Fig. 3). The myofibril volume fraction did not significantly correlate with a change in ejection fraction. DISCUSSION

The purpose of this study was to examine the outcome of a group of patients with the relatively common and readily recognized clinical presentation of acute left ventricular dysfunction in the presence of normal coronary arteries who were treated intensively with early institution of digoxin, diuretics, and angiotensin-converting enzyme inhibitors. Eightysix percent of the patients in this study demonstrated improvement of left ventricular function within 1 year that was associated with clinical improvement. Furthermore, recovery frequently appeared to be progressive, with early recovery occurring within 6 months and continued improvement over the subsequent year. Comparison with previous studies. The improvement observed in this set of patients with nonischemic cardiomyopathy was considerably greater than had been reported previously. 11-1s Figulla et al. 11 studied 56 patients with nonischemic dilated cardiomyopathy. Fourteen of those patients died within 2 years of diagnosis and did not have follow-up evaluation. Of the remaining 42 patients, 20 had deterioration of the left ventricular ejection fraction

Volume 129, N u m b e r 1

Cross, Steenbergen, and Higginbotham

AmericanHeartJournal

27

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Fig. 2. Improvement in NYHA functional class as related to improvement in ejection fraction (EF). Error bars represent SD. *, p = 0.04 change by 2 points vs no change; **, p = 0.002 change by 3 points vs no change; §, p = 0.008 change by 3 points vs change by 1 point. No significant difference between change by 2 points and change by 1 point or no change.

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Fig, 3. Correlation between maximum change in ejection fraction (EF) during follow-up and fibrosis fraction on initial endomyocardial biopsy in 18 patients with acute nonischemic congestive heart failure. r = -0.65, p = 0.003.

a n d only 22 (52 % ) i m p r o v e d or stabilized. Still lower incidences of i m p r o v e m e n t were r e p o r t e d b y Chow et al., 16 Dec et al., 12 Francis et al., 1~ Parrillo et al., 15 a n d Quigley et al. ~4 T h e p r e s e n t s t u d y m a y differ f r o m these b y the inclusion in the o t h e r studies of p a t i e n t s who h a d s y m p t o m s of longer d u r a t i o n (often >6 m o n t h s ) . In addition, medical t h e r a p y with angioten-

sin-converting e n z y m e inhibitors was not s t a n d a r d at the t i m e previous studies were conducted. T R E A T M E N T EFFECTS

Angiotensin-converting e n z y m e inhibitors have b e e n shown to i m p r o v e survival in p a t i e n t s with congestive h e a r t failure, 6, 7 a n d d a t a also s u p p o r t their

January 1995

28

Cross,Steenbergen, and Higginbotham

beneficial effects on ventricular remodeling. 22-25 Although the effects of angiotensin-converting enzyme inhibitors on remodeling have been demonstrated primarily in models of ischemic dysfunction, they also may be applicable to nonischemic dilated cardiomyopathy. Several mechanisms have been proposed for the changes in ventricular structure associated with the progression of dilated cardiomyopathy. 26-29 One view is that myocardial hypertrophy occurs early in response to increased wall stress 2s, 30 associated with the initial left ventricular injury. Although this initial compensatory response may be effective in decreasing wall stress, further damage may then occur as the result of poor subendocardial perfusion, 26 volume overload with slippage of myocytes, 31 and increased collagen deposition. 2s Collagen may be produced in response to myocardial stretch and with increased fibroblast stimulation by angiotensin II and aldosterone. 32-34 Initiating aggressive medical therapy early in the course of dilated cardiomyopathy may prevent the damaging aspects of reactive myocardial hypertrophy, ventricular dilation, and fibrosis that contribute to remodeling. Increased sympathetic nervous system activity has been shown to be associated with congestive heart failure. 3537 Elevated levels of neurohormones are predictive of mortality in congestive heart failure 5 and may directly contribute to progressive deterioration of ventricular function. 29, 3s, 39 Improved survival with angiotensin-converting enzyme inhibitor therapy may be partially attributable to correction of some of the neuroendocrine abnormalities, 29 and early suppression of neuroendocrine activation may allow some recovery of ventricular function. Possible predictors of recovery. An effort was made

in this study to determine factors that may predict recovery of left ventricular function. Patients in whom cardiomyopathy is thought to be the result of reversible conditions such as alcohol use, pregnancy, hypertension, hypothyroidism, malnutrition, or persistent tachycardia may be expected to have a better prognosis after the underlying condition resolves. Indeed, O'Connell et al. 17 and Cole et al.ls detected recovery in 50% and 85%, respectively, of women with peripartum cardiomyopathy. In our study there was no significant difference between the incidence of improvement of any of the diagnostic subgroups. Although the initial degree of clinical decompensation was heterogeneous, there was no correlation between the initial clinical and hemodynamic variables and the magnitude of left ventricular recovery. This finding is consistent with the results of other studies in which hemodynamics were measured dur-

AmencanHeartJournal

ing the initial evaluation of congestive heart failure.ll, 12, 14-17 In the present study, the amount of fibrosis detected in the biopsy specimens was associated with the degree of ejection fraction increase, but the myofibril volume fraction was not. Figulla et al. 11 found that fibrosis was related to hemodynamic deterioration in heart failure patients, but statistical significance was barely reached. The myofibril volume fraction was significantly correlated with improvement in that study. The differences may be methodological or the result of the patients in our study having had symptoms for a much shorter period of time (<6 months vs >10 months). Ultrastructural characteristics detected later in the course of illness may differ from those present at an earlier time. The association of the degree of fibrosis and improvement in left ventricular function may be of practical importance. The early development of fibrosis may be suppressed by improvement in hemodynamics and possibly modulation of neuroendocrine activation afforded by medical therapy. The continued improvement seen later may indicate slow resolution or arrest of an active process such as inflammation, which may have caused the original myocardial injury. Limitations. Several limitations of this study must be appreciated before attempting to apply our findings to clinical practice. First, the study included only patients who could be stabilized on medical therapy and discharged from the hospital. Subjects who may not have survived their initial hospitalization or those who were unstable and required urgent cardiac transplantation were not included. However, our patient population was clinically well defined and included 29 of 33 referred patients who satisfied a predefined set of clinical criteria. A second potential limitation is that the timing of follow-up evaluation varied between subjects depending on their clinical presentation and may have affected the results. However, systematic clinical evaluations were performed during the study period, and patients continued follow-up regardless of their left ventricular function. A third consideration is that the same technique was not used in performing all of the initial ejection fraction measurements. Nine patients had contrast ventriculography on initial evaluation, and the remainder of the group had radionuclide studies. Links et al. 4° found a close correlation of 0.85 to 0.87 between radionuclide and angiographic ejection fraction measurements. 4° This finding was associated with a 4 % to 5 % difference between the two types of measurements. Because most patients in our

Volume 129, Number 1 American Heart Journal

study improved by >10 percentage points, the impact of the variation between the measurement techniques is not significant. In addition, the subgroup of patients in whom all ejection fractions were measured with radionuclide ventriculography had improvements similar to the entire study population. Therefore the inclusion of patients evaluated with contrast ventriculography does not appear to detract from the overall results. Finally, the study population was small and may not be representative of all patients with nonischemic cardiomyopathy. The nearuniform recovery of left ventricular function would tend to diminish the importance of this limitation. Conclusions. Our findings confirm that acute nonischemic cardiomyopathy occurs in a variety of clinical settings and can involve a wide range of pathologic entities but often remains unexplained despite extensive evaluation with cardiac catheterization and endomyocardial biopsy. However, despite nonspecific histologic changes, a fairly uniform and progressive improvement often occurs with intensive, individualized medical therapy. The degree of ventricutar fibrosis may be an index for the amount of recovery that can be expected after myocardial injury has occurred. Further confirmation of these findings could be obtained from a prospective study with measurement of ejection fraction at uniform intervals. Left ventricular recovery is common, and patients with acute nonischemic cardiomyopathy treated medically should be expected to demonstrate increases in their ejection fractions within 6 months after initial evaluation. If not by this time it is unlikely that significant future improvement will occur. Endomyocardial biopsy findings should be considered a prognostic variable when patients are evaluated for possible cardiac transplantation or enrollment into interventional studies. We thank Pat Shaw for his excellent technical assistance, and David Booth, MD, for his critical remarks and useful suggestions. REFERENCES

1. Fuster V, Gersh BJ, Giuliam ER, Tajik AJ. The natural history of idiopathic dilated cardiomyopathy. Am J CardioI 1981;47:525-31. 2. McKee PA, Castelh WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Frammgham Study. N Engl J Med 1971;285:1441-6. 3. Franciosa JA, Wilen M. Zmsche S, Cohn JN. Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic cardiomyopathy. Am J Cardiol 1983;51:831-6. 4. Wilson JR, Schwartz JS, Sutton MS, Ferraro N, Horowitz LN, Reichek N, Josephson ME. Prognosis in severe heart failure: relation to hemodynamic measurements and ventricular ectopic activity J Am Coli Cardiol 1983:2:403-10. 5. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311:819-23.

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6. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302. 7. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tistani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetl R, Haakenson C. A comparison of enalapril with hydralazine-lsosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 322:303-10. 8. Popma J J, Cigarron RG, Buja LM, Hfllis LD. Diagnostic and prognostic utility of right sided catheterization and endomyocardlal biopsy in idiopathic dilated cardiomyopathy. Am J Cardiol 1989:63:955-8. 9. UnverferthDV, MagorienRD, MoeshbergerML, BakerPB.Fetters JK, Leier CV. Factors influencing the one-year mortality of dilated cardiomyopathy. Am J Cardiol 1984;54:147-52. 10. Latham RD, Muh'ow JR. Virarani R, Robinowitz M, Moody JM. Recently diagnosed idiopathic dilated cardlomyopathy: incidence of myocarditis and efficacy of predmsone therapy. AM HEART J 1989; 117:876-82. 11. Figulla HR, Gunther R, Nieger M, Lulg H, Kreuzer H. Spontaneous hemodynamic improvement or stabilization and associated biopsy findings in patients with congestive cardiomyopathy. Circulation 1985; 71:1095-104. 12. Dec GW, Palacios IF, Fallon JT, Aretz HT, Mills J, Lee DC-S, Johnson A. Active myocarditis in the spectrum of acute dilated cardiomyopathies. N Engl J Med 1985;3121:885-90. 13. Francis GS, Johnson TH, Ziesche S, Berg M, Boosalis P, Cohn JN. Marked spontaneous improvement in ejection fraction in patients with congestive heart failure. Am J Med 1990;89:303-7. 14. Qulgley P J, Richardson PJ, Meany BT, Olsen EGJ, Monaghan MJ, Jackson G, Jewitt DE. Long-term follow-up of acute myocardltls. Correlation of ventricular function and outcome. Eur Heart J 1987;8(suppl J):39-42. 15. Parrillo JE, Cunnion RE, Epstein SE, Parker MM, Suffredini AF, Brenner M, Schaer GL, Palmeri ST, Cannon RO, Alling D, Wittes JT, Ferrans VJ, Rodriguez ER, Fauci AS. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 1989;321:1061-8. 16. Chow LC, Dittrich HC, Shabetal R. Endomyocardial biopsy in patients with unexplained congestive heart failure. Ann Intern Med 1988; 109:535-9. 17. O'Connell JB, Costanzo-Nordin MR, Subramanian R, Robinson JA, Wallis DE, Scanlon PJ, Gunnar RM. Peripartum cardiomyopathy: clinical, hemodynamlc, hlstologic, and prognostic characteristics. J Am Coll Cardlol 1986;8'52-6. 18. Cole P, Cook F, Plappert T, Saltzman D. Sutton MS. Longitudinal changes in left ventricular architecture and function in penpartum cardiomyopathy. Am J Cardiol 1987;60:871-6. 19. Kolbeck PC, Steenbergen C, Wolfe JA, Sanfilippo F, Jennings RB. The correlation of mononuclear cell phenotype in endomyocardial biopsies with clinical history and cardiac dysfunction. Am J Clin Pathol 1989;91:37-44. 20. Weibel ER. Practical sterological methods for biological morphometry. J Cell Biol 1966;30:23-38. 21. Morris KG, Higginbotham MB, Coleman RE, Shand DG, Cobb FR. Comparison of high-dose and medium-dose propranolol in the rehef of exercise-induced myocardial ischemia. Am J Cardiol 1983;52:7-13. 22. Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 1985;57:8495. 23. Pfeffer MA, Pfeffer JM, Steinbert C, Finn P. Survival after an experimental infarction: beneficial effects of long-term therapy with captopril. Circulation 1985;72:406-12. 24. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captoprfl on progressive ventricular dilatation after anterior myocardial infarction. N Engi J Med 1988;319.80-6. 25. Bonaduce D, Petretta M, Arrichiello P, Conforti G, Montemurro MV, Attisano T, Bianchi V, Morgano G. Effects of captopril treatment on left ventricular remodeling and function after anterior myocardial mfarctlon: comparison with digitahs. J Am Coll Cardiol 1992;19:858-63. 26. Unverferth DV. Majorien RD, Lewis RP, Leier CV. The role of suben-

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diac interstitium in systemic hypertension. J Cardiovasc Pharmacol 1991;17(suppl 2):$14-9. Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986; 73:913-9. Ferguson DW, Berg WJ, Sanders JS. Clinical and hemodynamic correlates of sympathetic neural activity in normal humans and patients with heart failure-evidence from direct microneurographic recordings. J Am Coll Cardiol 1990;16:1125-34. Ferguson DW, Berg WJ, Roach PJ, Oren RM, Mark AL. Effects of heart failure on baroreflex control of sympathetic neural activity. Am J Cardiol 1992;69:523-31. Mann DL, Kent TL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992;85:790-804. Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991;69:1185-95. Links JM, Becker LC, Shindledecker JG, Guzman P, Burow RD, Nickoloff EF, Alderson PO, Wagner HN. Measurement of absolute ventricular volume from gated blood pool studies. Circulation 1982;65:82-91.

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