General Cardiology
Cardiology 1992:81:213-220
Munich-Schwabing Hospital, Academic Teaching Hospital, Ludwig Maximilians University, Munich. FRG; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Mechanisms Involved in Cardiac Enlargement and Congestive Heart Failure Development after Acute Myocardial Infarction
KeyWords
Abstract
Myocardial infarction Left ventricular enlargement Renin Angiotensin Norepinephrine Atrial natriuretic peptide Ncurohormones ACE inhibition
For 3 months, we followed up 40 patients with acute myocar dial infarction. 20 were randomly assigned to treatment with captopril and 20 to placebo, to elucidate mechanisms inducing left ventricular volume enlargement and development of con gestive heart failure. Echocardiographic follow-up could be obtained in 28 patients, 11 of whom showed more than a 10% increase in left ventricular systolic and/or diastolic volumes (captopril n = 3/15, placebo n = 8/13, p = 0.05). Volume increase was significantly associated with an impairment in exercise capacity (VCUmax in patients with vs. without vol ume enlargement 24.7 ± 1.7 vs. 29.5 ± 1.9 ml CU/kg/min; p < 0.05). Plasma renin activity, angiotensin II and catechol amines were normal in the acute and chronic postinfarction phase in patients on placebo as well as in patients 12-24 h after captopril intake. Plasma atrial natriuretic peptide con centration (ANP) was increased immediately after myocardial infarction, but ANP levels almost normalized in patients with captopril treatment, while they continued to be elevated in patients on placebo. The only technical parameter able to pre dict left ventricular volume increases was the sphericity index (28.7 vs. 35.7; p = 0.07). We concluded that morphologic deformation and filling pressures as estimated from elevated ANP levels arc major factors promoting remodelling following myocardial infarction. ACE inhibitors might exert their favor able effect predominantly by reducing filling pressure.
Received: July 17.1992 Accepted after revision: August 24. 1992
Dr. Franz X. Kleber 1. Med. Klinik. Kardiologie Med. Fakultät / Charité Humboldt-Universität Schumanns.r. 20/21. D-O-1040 Berlin (FRG)
© 1992 S. Karger AG, Basel 0008-6312/92/ 0815-0213S2.75/0
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Franz X. Klebera Jiirg Nussbergerb Lisa Niemôllera Wittich Doeringa
Coronary artery disease with prior myo cardial infarction is the most important cause of chronic congestive heart failure [13]. Increases in left ventricular enddiastolic and endsystolic volumes after myocardial in farction are major determinants of survival after recovery from myocardial infarction [4, 5]. The renin-angiotensin system has been shown to be activated in patients with acute myocardial infarction [6] as well as conges tive heart failure [7]. A left ventricular vol ume increase after myocardial infarction in volves volume hypertrophy [8], and angio tensin II (Ang II) has been shown to be a growth hormone promoting left ventricular hypertrophy [9]. Accordingly, ACE inhibitors have been shown to be effective in preventing left ventricular volume increases after acute myocardial infarction [10, 11], Thus, this study was undertaken to evaluate the patho physiologic role of the renin-angiotensin sys tem in left ventricular volume increases and heart failure development after myocardial infarction.
Patients and Methods This prospective study evaluated clinical, échocar diographie. angiocardiographic and hormonal param eters as well as oxygen uptake on exercise in order to investigate mechanisms promoting left ventricular di latation and congestive heart failure development. In addition, the impact of ACE inhibition on some of these mechanisms was studied by assigning patients in a randomized double-blind manner to captopril or pla cebo treatment for 3 months. The study was approved by the institutional and governmental ethical commit tees. Patients 40 consecutive patients with clinical and electro cardiographic evidence of acute myocardial infarction, irrespective of infarct location, and creatine kinase ele
214
vation of at least 250 U/l were studied. Exclusion crite ria were contraindications to ACE inhibitor therapy, severe pulmonary disease, peripheral vascular disease, systolic blood pressure < 9 5 mm Hg, cardiogenic shock and creatinine > 158 mmol/1. Baseline examination including past history and physical examination, routine laboratory tests and blood sampling for hormone measurements were fol lowed by réévaluation after 1.4 and 12 weeks. Patients with clinical, electrocardiographic or échocardiographie evidence of rcinfarction within the first 3 months were excluded from the follow-up exam inations, as were patients who had bypass surgery within this time interval. Written informed consent was obtained from all patients after detailed explana tion of the study protocol. Echocardiography Echocardiographie evaluations on day 1 and week 1,4 and 12 included the determination of systolic/diastolic volumes and ejection fraction. Volume increases in enddiastolic and/or endsystolic volumes >10% were judged as significant in accordance with Gordon ctal. [12]. Chest X -R ay
Chest X-ray examinations were done at 1,4 and 12 weeks in the upright position to determine the cardiothoracic ratio and signs of pulmonary congestion. Cardiopulmonary Exercise Testing After 4 and 12 weeks, a maximal treadmill exercise test was performed using a modified Naughton proto col. Gas exchange was measured using a Medical Graphics breath-by-breath system. The anaerobic threshold was defined according to Wassermann [13] as a sudden slope increase in CO? delivery or ventila tion in the face of a steady increase in O; uptake. Maxi mal O; uptake was defined as the maximal oxygen uptake reached, usually in the plateau phase of oxygen uptake [14, 15]. Cardiac Catheterization Right and left heart catheterization was performed approximately 2 weeks after myocardial infarction. Left ventricular volumes were determined using the biplane area length method [16], The sphericity index was defined as the percentage of the measured left ven tricular volume compared to the volume of a sphere with a diameter equal to the long axis of the ventricle in the 30° right anterior oblique projection (corrected for the magnification factor). Endsystolic and enddias-
Klebcr/Nussbergcr/Niemdller/Dacring
Mechanisms of Cardiac Enlargement
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Introduction
/ /ormone Measurements Plasma renin activity (PRA), Ang II. norepineph rine. epinephrine and atrial natriuretic peptide (ANP) were measured on day 2 (baseline before captopril/placebo treatment), day 5 and day 90 after myocardial infarction. Blood was collected at 7 a.m. before getting up from supine patients after an overnight fast. On day 90. specimens on exercise were sampled from upright patients in the second stage of the Naughton protocol, i.e. at an oxygen uptake of around two metabolic equivalents (=7 ml OVkg/min) above the resting oxy gen uptake. Velocity was 2.4 km/h. and the slope was 0° at the determination of exercise hormones [ 18. 19]. PRA was measured by antibody trapping and dilution of generated angiotensin I prior to radioimmunoassay [18] as previously described in a modification for our laboratory [19], Ang II [20. 21] and ANP [22] were measured using a radioimmunoassay after solid-phase extraction on phenylsilvlsilica. the catecholamines with a radioenzymatic assay [22]. All blood samples were rapidly drawn into iced syringes mixed with the appropriate anticoagulant and enzyme inhibitors, and centrifuged at 2 °C. For Ang II measurements, phenanthroline and the renin inhibitor CGP 29287 were added in concentrations sufficient to prevent metabolization or generation of Ang II in vitro [21], Plasma aliquots were shockfrozen in dry ice/ethanol and stored at -80 °C until analyzed. Medication and Test Medication Medication other than ACE inhibitors was free to the discretion of the physicians taking care of the patients. Test medication consisted of randomly as signed placebo or captopril (starting dose: 6.25 mg within 72 h after onset of chest pain and with rapid titration to a target dose of 50 mg b.i.d). Statistics Statistical analysis was performed to search for dif ferences between the treatment groups (placebo- vs. captopril-treated patients) and between patients with versus those without left ventricular volume increases by x2 or Fisher’s exact test or the two-sided t test. Only patients being on randomized therapy at the scheduled follow-up examination were investigated and entered into the analysis. Results are means ± SEM.
Results
Demographic Data 40 patients (33 males, 7 females: median age 57 years) were included. Treatment groups were similar with respect to age. height and weight. All but 3 patients had first myo cardial infarctions. Mean and median values of maximal creatine kinase were similar in the two treatment groups (captopril 1,021 and 895: placebo 1,073 and 937 U/l). as were me dian areas under the creatine kinase concen tration-time curve over 72 h (captopril 30.488; placebo 31.107 U/l X hour). There were 21 anterior and 19 inferior myocardial infarctions. Mean ejection fraction at pre treatment baseline (day 2 after myocardial infarction) in 28 patients with technically suf ficient echocardiograms was 45% (captopril 46 ± 2.5; placebo 43 ± 3.9). Test Drug Mean administered captopril doses were 39 and 37 mg b.i.d at 4 and 12 weeks, respec tively. Left Ventricular Volume Changes and Signs o f Congestive Heart Failure In 28 patients, technically adequate echo cardiograms could be obtained to investigate left ventricular volume changes over 3 months. Of these 28 patients. 11 (39%) had left ventricular systolic and/or diastolic vol ume increases of at least 10%. The majority of these patients had systolic and diastolic vol ume increases (n = 8), 1 patient had only dia stolic and 2 patients had only systolic volume increases. 17 patients had no left ventricular volume increase. Patients with left ventricular volume in crease had lower maximal oxygen consump tion at 3 months than patients without left ventricular volume increase (24.7 ± 1.7: n = 10 vs. 29.5 ± 1.9 ml Oy/kg/min: n = 14: p
5-130) Captopril Placebo
36 ±8 31 ±6
32 ±6 30 ±5
37 ±8 36 ± 8
57± 17 66 ± 13
66 ± 14 64 ±8
36 ±5 50± 10
32 ±5** 53 ± 6
ANP. fmol/ml (2-34) Captopril 65 ±26 Placebo 65 ±9
on captopril than on placebo (table 3). Clini cal signs of congestive heart failure, the need for diuretics and X-ray signs of pulmonary congestion were found less often in patients treated with captopril (table 2). The heart size on X-rays was significantly smaller in patients treated with captopril (table 3). Renin-Angiotensin System, Catecholamines and Atrial Natriuretic Peptide On day 2. before treatment was started. PRA, plasma Ang II and catecholamines were well within normal limits, while plasma ANP was twofold above mormal range (table 4). There were no significant differences between the two treatment groups. On days 5 and 90,
hormone concentrations of the placebo group were basically unchanged as compared to baseline on day 2. Treatment with captropril did not induce significant changes in plasma hormone concentrations at rest. In contrast, significant hormonal differ ences were found between captopril and pla cebo groups on exercise, i.e. NE (510 ± 85 vs. 682 ± 61 pg/ml. p < 0.07) ANP levels (32 ± 5 vs. 53 ± 6 fmol/ml, p < 0.01) were lower with captopril. Exercise induced changes in PRA and in plasma Ang II went in opposite directions with captopril and placebo treat ment, respectively. Exercise tended to stimulate both PRA (0.69 ± 0.20 vs. 0.98 ± 0.22 ng/ml/h) and Ang II (2.0 ± 0.28 vs. 4.8 ± 0.97 fmol/ml)
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** p < 0.01; *** p < 0.07. in comparison to placebo. NE = Norepinephrine; E - epinephrine. 1 Before captopril/placebo treatment.
Discussion
Myocardial infarction is by far the most common cause of congestive heart failure in the industrialized world [ 1,2], A considerable proportion of patients develops left ventricu lar endsystolic and enddiastolic volume in creases after myocardial infarction [11, 23. 24], which has been correlated with a poor long-term prognosis in animals [25] and hu mans [4. 5]. Left ventricular remodelling after myocardial infarction comprises early infarct expansion [26] and early and later hypertro phy of the remaining viable myocardium, which is a mixed form of concentric and excentric hypertrophy [8], Left ventricular hy pertrophy has been shown to be an indepen dent prognostic risk factor [27], Left ventricular remodelling after myocar dial infarction can be both adversely in fluenced, e.g. by nonsteroidal anti-inflamma tory agents [28] or by corticosteroids [29], or favorably influenced, e.g. by ACE inhibitors [10, 11] or by nitroglycerin [30]. The aim of this study was to elucidate some of the mecha nisms inducing left ventricular volume in creases after myocardial infarction, which have been incompletely understood so far. We tested particularly the hypothesis that a stimulation of the renin-angiotensin system has a pathophysiologic role in the develop ment of both left ventricular volume increase and congestive heart failure after myocardial infarction.
218
This hypothesis was based on the findings of a stimulated renin-angiotensin system after myocardial infarction [6] and of the sympa thetic nervous system [31], and the known interaction between Ang II and the sympa thetic nervous system. The activation of growth hormone systems in severe congestive heart failure [7. 32] might, however, be a con sequence rather than a cause of congestive heart failure development. Our results show that the renin-angiotensin system and the sympathetic nervous system are not stimu lated in the acute phase of myocardial infarc tion. Earlier studies which showed these sys tems to be stimulated have determined these plasma hormones usually within the first 24 h of myocardial infarction or in the acute phase of hospital admission. Our samples, however, were drawn under well-standardized and ex tremely quiet conditions on the 2nd day after hospital admission, in the early morning hours, before daily activity had begun. Care was taken to get optimal sample handling even under difficult clinical conditions in or der to avoid sampling or in vitro artifacts. Under these conditions, even in the very early phase of myocardial infarction on days 2 and 5, the sympathetic nervous system and the renin-angiotensin system appeared not stimu lated and thus could not be the main stimulus responsible for left ventricular volume in creases. Since blood samples were drawn 1224 h after the last captopril intake, it is un likely that the entire difference can only be accounted to ACE inhibition. The failure of the renin-angiotensin system on day 90 to be stimulated by upright posture and by exercise might either be caused by increased ANP lev els, which have been shown to suppress reninangiotensin activity [33], or directly by an increase in sodium and water retention, sup pressing renin [34], which can be an early sign of ventricular dysfunction. Both hypotheses are underscored by the known effects of ACE
Kleber/Nussbcrger/Niemoller/Doering
Mechanisms of Cardiac Enlargement
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during captopril treatment, but mean PRA fell in the placebo group with exercise from 0.52 ± 0.25 to 0.33 ± 0 .14ng/ml/h and so did mean Ang II (4.5 ± 1.9 to 3.5 ± 1.4 fmol/ ml). Exercise stimulated both epinephrine and norepinephrine secretion as expected (ta ble 4).
inhibitors on filling pressures and by the close correlation between the concentration of ANP and filling pressures [35], This leads us to the hypothesis that the effects of ACE inhibitors on left ventricular remodelling are mainly caused by its effect on filling pressures and not predominantly by its effects on plasma Ang 11 concentrations. The finding that nitroglycerin is also able to hold progres sive volume increase [30] underscores the im portance of preload as a stimulus for further volume increases. Very low concentrations of Ang II, however, may be sufficient as promo tors of left ventricular hypertrophy by stimu lating cell growth. We concluded that left ventricular remod elling with endsystolic and enddiastolic vol ume increase is a frequent complication of acute myocardial infarction and can be favor
ably influenced by ACE inhibition. The sys temic renin-angiotensin system, however, is not necessarily stimulated in this clinical set ting. An increase in filling pressures leads to the stimulation of ANP. which can cause sup pression of the renin-angiotensin system. We postulate that ACE inhibition exerts its posi tive effects mainly by a decrease in filling pressures, which probably are the most im portant promotors of left ventricular remod elling besides infarct artery perfusion and spherical deformation of the left ventricle by the infarction. Acknowledgements The authors thank Catherine Amstutz and Yolande Parisod as well as Evelyn Hitzke for excellent technical assistance.
References 4 Hammermcistcr KE. DeRouen TA. Dodge HT: Variables predictive of survival in patients with coronary disease: Selection univariate and multivariate analyses from the clini cal electrocardiographic, artério graphie, and quantitative angio graphic evaluations. Circulation 1979;59:421-430. 5 White HD. Norris RM, Brown MA, Brandt PWT. Whitlock RML. Wild CJ: Left ventricular end-systolic vol ume as the major determinant of survival after recovery from myo cardial infarction. Circulation 1987: 76:44-51. 6 Vaney C, Waeber B, Turini G, Martgalith D. Brunner HR. Perret C: Renin and the complications of acute myocardial infarction. Chest 1984:86:40-43. 7 Dzau VJ. Colucci WS. Hollenbcrg NK. Williams GH: Relation of the renin-angiotensin-aldosterone sys tem to clinical state in congestive heart failure. Circulation 1981:63: 645-651.
8 Anversa P. Ricci R. Olivetti G: Quantitative structural analysis of the myocardium during physiologic growth and induced cardiac hyper trophy: A review. J Am Coll Cardiol 1986:7:1140-1149. 9 Kromer HP. RieggerGAl: Influence of the renin-angiotensin system on maintenance of left ventricular hy pertrophy in experimental aortic stenosis in the rat. Circulation 1988: 78(suppl II):603. 10 Sharpe N, Smith H, Murphy J. Han nan S: Treatment of patients with symptomless left ventricular dys function after myocardial infarc tion. Lancet !988;i:255-259. 11 Pfeffer MA. Lamas GA. Vaughan DE. Parisi AF. Braunwald E: Effect of captopril on progressive ventricu lar dilatation after anterior myocar dial infarction. N Engl J Med 1988; 319:80-86.
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1 The Captopril-Digoxin Multicenter Research Group; Comparative ef fects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988; 259:539-544. 2 Cohn JN. Archibald DG. Ziesche S. Franciosa JA. Harston WE. Tristani FE. Dunkman WB. Jacobs W. Fran cis GS. Flohr KH, Goldman S. Cobb FR. Shah PM. Saunders R. Fletcher RD. Locb HS. Hughes VC. Baker B: Effects of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration cooperative study. N Engl J Med 1986:314:15471552. 3 Kleber F'X. Niemöller L. Doering W: Impact of converting enzyme in hibition on progression of chronic heart failure. Results of the Munich Mild Heart Failure Trial. Br Heart J 1992:67:289-296.
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28 Hammerman H, Schoen FJ, Braun20 Nussberger J. Brunner DB. Waeber wald E. Kloncr RA: Drug-induced B, Brunner HR: True versus immuexpansion of infarct: Morphologic noreactive angiotensin II in human and functional correlations. Circula plasma. Hypertension 1985;7(suppl tion 1984:69:611-617. I): 1-7. 29 Mannisi JA, Weisman HF. Bush 21 Nussberger J. Brunner DB. Waeber DE. et al: Steroid administration af R. Brunner HR: In vitro renin inhi ter myocardial infarction promotes bition to prevent generation of an early infarct expansion. J Clin In giotensins during determination of vest 1987:79:1431. angiotensin I and II. Life Sei 1988; 30 Jugdutt B. Tymchak W. Humen D, 42:1683-1688. Gulamhusein S, Hales M: Pro 22 Nussberger J. Mooser V, Maridor longed nitroglycerin versus capto G. Juillerat L, Waeber B. Brunner pril therapy on remodeling after HR: Caffeine-induced diuresis and transmural myocardial infarction. atrial natriuretic peptides. J Car Circulation I990:82(suppl lll):442. diovasc Pharmacol 1990:15:68531 Levine TB: Neuroendocrine activa 691. tion in acute myocardial infarction. 23 Jeremy RW. Allman KC. Bautowich Am J Cardiol 1990:65:321-341. G, Harris PJ: Patterns of left ven 32 Cohn JN. Levine B. Olivari MT, tricular dilatation during the six Garberg V. Lura D. Francis GS. Si months after myocardial infarction. mon AB, Rector T: Plasma norepi J Am Coll Cardiol 1989:13:304nephrine as a guide to prognosis in 310. patients with chronic congestive 24 Kleber FX. Einwang HP. Kronski heart failure. N Engl J Med 1984: D. Ohly A, Osterkom K, Doering 311:891-923. W: Progrediente linksventrikuläre 33 Hirsch A, Creager MA. Dzau VJ: Dilatation nach Vorderwancinfarkt Relation of atrial natriuretic factor als Determinante für die Entwick to vasoconstrictor hormones and re lung einer Herzinsuffizienz. Z Kargional blood flow in congestive diol 1990:79:1-7. heart failure. Am J Cardiol 1989:63: 25 Pfeffer MA. Pfeffer JM. Steinberg C, 211-216. Finn P: Survival after an experimen 34 Hostetter TH. Pfeifer JM. Pfeffer tal myocardial infarction: Beneficial MA, Dworkin LD. Braunwald E, effects of long-term therapy with Brenner BM: Cardiorenal hemody captopril. Circulation 1985:72:406— namics and sodium excretion in rats 412. with myocardial infarction. Am J 26 Eaton LW. Weiss JL, Bulkley BH. Physiol 1983:245: H98-H103. Garrison JB, Weisfeldt ML: Re 35 Tsumato T. Bito K. Kinoshita M: gional cardiac dilatation after acute Plasma atrial natriuretic polypep myocardial infarction. N Engl J tide as an index of left ventricular Med 1979;300:57-62. enddiastolic pressure in patients 27 The Coronary Drug Project Re with chronic left-sided heart failure. search Group: Left ventricular hy Am Heart J 1989:117:599-606. pertrophy and prognosis. Experi ence postinfarction in the Coronary Drug Project. Circulation 1974:49: 862-869.
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12 Gordon EP. Schnittger J, Fitzgerald PJ. Williams P. Popp RL: Repro ducibility of left ventricular vol umes by two-dimensional echocar diography. J Am Coll Cardiol 1983: 2:506-513. 13 Wassermann K: New concepts in as sessing cardiovascular function. Cir culation 1988:78:1060-1070. 14 Kleber FX. Niembllcr L, Weissthanncr F, Doering W: Spirocrgometry in post myocardial infarction pa tients with compromised left ven tricular function: in Winter UJ, Wasserman K, Treesc N. Hopp HW (eds): Computerized Cardiopulmo nary Exercise Testing. Darmstadt, Steinkopff, 1991, pp 119-127. 15 Weber KT, Janicki JS: Cardiopul monary Exercise Testing. Physio logic Principles and Clinical Appli cations. Philadelphia, Saunders, 1986. 16 Dodge HT. Sandler H. Ballew DW. Lord JD: The use of biplane angio cardiography for the measurement of left ventricular volume in man. Am Heart J 1960;60:762-776. 17 Mirskv I. Krayenbuehl HP: The role of wall stress in the assessment of ventricular function. Herz 1981:6: 288-299. 18 Poutscn K, Jorgensen J: An easy radioimmunological microassav of re nin activity, concentration and sub strate in human and animal plasma and tissues based on angiotensin 1 trapping by antibody. J Clin Endo crinol Metab 1974:39:816-825. 19 Nussberger J. d’Amore F, Porchet M. Waeber B. Brunner DB. Brunner HR. Kler L, Brown AN. Francis RJ: Repeated administration of the con verting enzyme inhibitor cilazapril to normal volunteers. J Cardiovasc Pharmacol 1987;9:39-44.
Cardiology 1992:81:213-220
Munich-Schwabing Hospital, Academic Teaching Hospital, Ludwig Maximilians University, Munich. FRG; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Mechanisms Involved in Cardiac Enlargement and Congestive Heart Failure Development after Acute Myocardial Infarction
KeyWords
Abstract
Myocardial infarction Left ventricular enlargement Renin Angiotensin Norepinephrine Atrial natriuretic peptide Ncurohormones ACE inhibition
For 3 months, we followed up 40 patients with acute myocar dial infarction. 20 were randomly assigned to treatment with captopril and 20 to placebo, to elucidate mechanisms inducing left ventricular volume enlargement and development of con gestive heart failure. Echocardiographic follow-up could be obtained in 28 patients, 11 of whom showed more than a 10% increase in left ventricular systolic and/or diastolic volumes (captopril n = 3/15, placebo n = 8/13, p = 0.05). Volume increase was significantly associated with an impairment in exercise capacity (VCUmax in patients with vs. without vol ume enlargement 24.7 ± 1.7 vs. 29.5 ± 1.9 ml CU/kg/min; p < 0.05). Plasma renin activity, angiotensin II and catechol amines were normal in the acute and chronic postinfarction phase in patients on placebo as well as in patients 12-24 h after captopril intake. Plasma atrial natriuretic peptide con centration (ANP) was increased immediately after myocardial infarction, but ANP levels almost normalized in patients with captopril treatment, while they continued to be elevated in patients on placebo. The only technical parameter able to pre dict left ventricular volume increases was the sphericity index (28.7 vs. 35.7; p = 0.07). We concluded that morphologic deformation and filling pressures as estimated from elevated ANP levels arc major factors promoting remodelling following myocardial infarction. ACE inhibitors might exert their favor able effect predominantly by reducing filling pressure.
Received: July 17.1992 Accepted after revision: August 24. 1992
Dr. Franz X. Kleber 1. Med. Klinik. Kardiologie Med. Fakultät / Charité Humboldt-Universität Schumanns.r. 20/21. D-O-1040 Berlin (FRG)
© 1992 S. Karger AG, Basel 0008-6312/92/ 0815-0213S2.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/26/2018 2:44:52 PM
Franz X. Klebera Jiirg Nussbergerb Lisa Niemôllera Wittich Doeringa
Coronary artery disease with prior myo cardial infarction is the most important cause of chronic congestive heart failure [13]. Increases in left ventricular enddiastolic and endsystolic volumes after myocardial in farction are major determinants of survival after recovery from myocardial infarction [4, 5]. The renin-angiotensin system has been shown to be activated in patients with acute myocardial infarction [6] as well as conges tive heart failure [7]. A left ventricular vol ume increase after myocardial infarction in volves volume hypertrophy [8], and angio tensin II (Ang II) has been shown to be a growth hormone promoting left ventricular hypertrophy [9]. Accordingly, ACE inhibitors have been shown to be effective in preventing left ventricular volume increases after acute myocardial infarction [10, 11], Thus, this study was undertaken to evaluate the patho physiologic role of the renin-angiotensin sys tem in left ventricular volume increases and heart failure development after myocardial infarction.
Patients and Methods This prospective study evaluated clinical, échocar diographie. angiocardiographic and hormonal param eters as well as oxygen uptake on exercise in order to investigate mechanisms promoting left ventricular di latation and congestive heart failure development. In addition, the impact of ACE inhibition on some of these mechanisms was studied by assigning patients in a randomized double-blind manner to captopril or pla cebo treatment for 3 months. The study was approved by the institutional and governmental ethical commit tees. Patients 40 consecutive patients with clinical and electro cardiographic evidence of acute myocardial infarction, irrespective of infarct location, and creatine kinase ele
214
vation of at least 250 U/l were studied. Exclusion crite ria were contraindications to ACE inhibitor therapy, severe pulmonary disease, peripheral vascular disease, systolic blood pressure < 9 5 mm Hg, cardiogenic shock and creatinine > 158 mmol/1. Baseline examination including past history and physical examination, routine laboratory tests and blood sampling for hormone measurements were fol lowed by réévaluation after 1.4 and 12 weeks. Patients with clinical, electrocardiographic or échocardiographie evidence of rcinfarction within the first 3 months were excluded from the follow-up exam inations, as were patients who had bypass surgery within this time interval. Written informed consent was obtained from all patients after detailed explana tion of the study protocol. Echocardiography Echocardiographie evaluations on day 1 and week 1,4 and 12 included the determination of systolic/diastolic volumes and ejection fraction. Volume increases in enddiastolic and/or endsystolic volumes >10% were judged as significant in accordance with Gordon ctal. [12]. Chest X -R ay
Chest X-ray examinations were done at 1,4 and 12 weeks in the upright position to determine the cardiothoracic ratio and signs of pulmonary congestion. Cardiopulmonary Exercise Testing After 4 and 12 weeks, a maximal treadmill exercise test was performed using a modified Naughton proto col. Gas exchange was measured using a Medical Graphics breath-by-breath system. The anaerobic threshold was defined according to Wassermann [13] as a sudden slope increase in CO? delivery or ventila tion in the face of a steady increase in O; uptake. Maxi mal O; uptake was defined as the maximal oxygen uptake reached, usually in the plateau phase of oxygen uptake [14, 15]. Cardiac Catheterization Right and left heart catheterization was performed approximately 2 weeks after myocardial infarction. Left ventricular volumes were determined using the biplane area length method [16], The sphericity index was defined as the percentage of the measured left ven tricular volume compared to the volume of a sphere with a diameter equal to the long axis of the ventricle in the 30° right anterior oblique projection (corrected for the magnification factor). Endsystolic and enddias-
Klebcr/Nussbergcr/Niemdller/Dacring
Mechanisms of Cardiac Enlargement
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/26/2018 2:44:52 PM
Introduction
/ /ormone Measurements Plasma renin activity (PRA), Ang II. norepineph rine. epinephrine and atrial natriuretic peptide (ANP) were measured on day 2 (baseline before captopril/placebo treatment), day 5 and day 90 after myocardial infarction. Blood was collected at 7 a.m. before getting up from supine patients after an overnight fast. On day 90. specimens on exercise were sampled from upright patients in the second stage of the Naughton protocol, i.e. at an oxygen uptake of around two metabolic equivalents (=7 ml OVkg/min) above the resting oxy gen uptake. Velocity was 2.4 km/h. and the slope was 0° at the determination of exercise hormones [ 18. 19]. PRA was measured by antibody trapping and dilution of generated angiotensin I prior to radioimmunoassay [18] as previously described in a modification for our laboratory [19], Ang II [20. 21] and ANP [22] were measured using a radioimmunoassay after solid-phase extraction on phenylsilvlsilica. the catecholamines with a radioenzymatic assay [22]. All blood samples were rapidly drawn into iced syringes mixed with the appropriate anticoagulant and enzyme inhibitors, and centrifuged at 2 °C. For Ang II measurements, phenanthroline and the renin inhibitor CGP 29287 were added in concentrations sufficient to prevent metabolization or generation of Ang II in vitro [21], Plasma aliquots were shockfrozen in dry ice/ethanol and stored at -80 °C until analyzed. Medication and Test Medication Medication other than ACE inhibitors was free to the discretion of the physicians taking care of the patients. Test medication consisted of randomly as signed placebo or captopril (starting dose: 6.25 mg within 72 h after onset of chest pain and with rapid titration to a target dose of 50 mg b.i.d). Statistics Statistical analysis was performed to search for dif ferences between the treatment groups (placebo- vs. captopril-treated patients) and between patients with versus those without left ventricular volume increases by x2 or Fisher’s exact test or the two-sided t test. Only patients being on randomized therapy at the scheduled follow-up examination were investigated and entered into the analysis. Results are means ± SEM.
Results
Demographic Data 40 patients (33 males, 7 females: median age 57 years) were included. Treatment groups were similar with respect to age. height and weight. All but 3 patients had first myo cardial infarctions. Mean and median values of maximal creatine kinase were similar in the two treatment groups (captopril 1,021 and 895: placebo 1,073 and 937 U/l). as were me dian areas under the creatine kinase concen tration-time curve over 72 h (captopril 30.488; placebo 31.107 U/l X hour). There were 21 anterior and 19 inferior myocardial infarctions. Mean ejection fraction at pre treatment baseline (day 2 after myocardial infarction) in 28 patients with technically suf ficient echocardiograms was 45% (captopril 46 ± 2.5; placebo 43 ± 3.9). Test Drug Mean administered captopril doses were 39 and 37 mg b.i.d at 4 and 12 weeks, respec tively. Left Ventricular Volume Changes and Signs o f Congestive Heart Failure In 28 patients, technically adequate echo cardiograms could be obtained to investigate left ventricular volume changes over 3 months. Of these 28 patients. 11 (39%) had left ventricular systolic and/or diastolic vol ume increases of at least 10%. The majority of these patients had systolic and diastolic vol ume increases (n = 8), 1 patient had only dia stolic and 2 patients had only systolic volume increases. 17 patients had no left ventricular volume increase. Patients with left ventricular volume in crease had lower maximal oxygen consump tion at 3 months than patients without left ventricular volume increase (24.7 ± 1.7: n = 10 vs. 29.5 ± 1.9 ml Oy/kg/min: n = 14: p
5-130) Captopril Placebo
36 ±8 31 ±6
32 ±6 30 ±5
37 ±8 36 ± 8
57± 17 66 ± 13
66 ± 14 64 ±8
36 ±5 50± 10
32 ±5** 53 ± 6
ANP. fmol/ml (2-34) Captopril 65 ±26 Placebo 65 ±9
on captopril than on placebo (table 3). Clini cal signs of congestive heart failure, the need for diuretics and X-ray signs of pulmonary congestion were found less often in patients treated with captopril (table 2). The heart size on X-rays was significantly smaller in patients treated with captopril (table 3). Renin-Angiotensin System, Catecholamines and Atrial Natriuretic Peptide On day 2. before treatment was started. PRA, plasma Ang II and catecholamines were well within normal limits, while plasma ANP was twofold above mormal range (table 4). There were no significant differences between the two treatment groups. On days 5 and 90,
hormone concentrations of the placebo group were basically unchanged as compared to baseline on day 2. Treatment with captropril did not induce significant changes in plasma hormone concentrations at rest. In contrast, significant hormonal differ ences were found between captopril and pla cebo groups on exercise, i.e. NE (510 ± 85 vs. 682 ± 61 pg/ml. p < 0.07) ANP levels (32 ± 5 vs. 53 ± 6 fmol/ml, p < 0.01) were lower with captopril. Exercise induced changes in PRA and in plasma Ang II went in opposite directions with captopril and placebo treat ment, respectively. Exercise tended to stimulate both PRA (0.69 ± 0.20 vs. 0.98 ± 0.22 ng/ml/h) and Ang II (2.0 ± 0.28 vs. 4.8 ± 0.97 fmol/ml)
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** p < 0.01; *** p < 0.07. in comparison to placebo. NE = Norepinephrine; E - epinephrine. 1 Before captopril/placebo treatment.
Discussion
Myocardial infarction is by far the most common cause of congestive heart failure in the industrialized world [ 1,2], A considerable proportion of patients develops left ventricu lar endsystolic and enddiastolic volume in creases after myocardial infarction [11, 23. 24], which has been correlated with a poor long-term prognosis in animals [25] and hu mans [4. 5]. Left ventricular remodelling after myocardial infarction comprises early infarct expansion [26] and early and later hypertro phy of the remaining viable myocardium, which is a mixed form of concentric and excentric hypertrophy [8], Left ventricular hy pertrophy has been shown to be an indepen dent prognostic risk factor [27], Left ventricular remodelling after myocar dial infarction can be both adversely in fluenced, e.g. by nonsteroidal anti-inflamma tory agents [28] or by corticosteroids [29], or favorably influenced, e.g. by ACE inhibitors [10, 11] or by nitroglycerin [30]. The aim of this study was to elucidate some of the mecha nisms inducing left ventricular volume in creases after myocardial infarction, which have been incompletely understood so far. We tested particularly the hypothesis that a stimulation of the renin-angiotensin system has a pathophysiologic role in the develop ment of both left ventricular volume increase and congestive heart failure after myocardial infarction.
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This hypothesis was based on the findings of a stimulated renin-angiotensin system after myocardial infarction [6] and of the sympa thetic nervous system [31], and the known interaction between Ang II and the sympa thetic nervous system. The activation of growth hormone systems in severe congestive heart failure [7. 32] might, however, be a con sequence rather than a cause of congestive heart failure development. Our results show that the renin-angiotensin system and the sympathetic nervous system are not stimu lated in the acute phase of myocardial infarc tion. Earlier studies which showed these sys tems to be stimulated have determined these plasma hormones usually within the first 24 h of myocardial infarction or in the acute phase of hospital admission. Our samples, however, were drawn under well-standardized and ex tremely quiet conditions on the 2nd day after hospital admission, in the early morning hours, before daily activity had begun. Care was taken to get optimal sample handling even under difficult clinical conditions in or der to avoid sampling or in vitro artifacts. Under these conditions, even in the very early phase of myocardial infarction on days 2 and 5, the sympathetic nervous system and the renin-angiotensin system appeared not stimu lated and thus could not be the main stimulus responsible for left ventricular volume in creases. Since blood samples were drawn 1224 h after the last captopril intake, it is un likely that the entire difference can only be accounted to ACE inhibition. The failure of the renin-angiotensin system on day 90 to be stimulated by upright posture and by exercise might either be caused by increased ANP lev els, which have been shown to suppress reninangiotensin activity [33], or directly by an increase in sodium and water retention, sup pressing renin [34], which can be an early sign of ventricular dysfunction. Both hypotheses are underscored by the known effects of ACE
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during captopril treatment, but mean PRA fell in the placebo group with exercise from 0.52 ± 0.25 to 0.33 ± 0 .14ng/ml/h and so did mean Ang II (4.5 ± 1.9 to 3.5 ± 1.4 fmol/ ml). Exercise stimulated both epinephrine and norepinephrine secretion as expected (ta ble 4).
inhibitors on filling pressures and by the close correlation between the concentration of ANP and filling pressures [35], This leads us to the hypothesis that the effects of ACE inhibitors on left ventricular remodelling are mainly caused by its effect on filling pressures and not predominantly by its effects on plasma Ang 11 concentrations. The finding that nitroglycerin is also able to hold progres sive volume increase [30] underscores the im portance of preload as a stimulus for further volume increases. Very low concentrations of Ang II, however, may be sufficient as promo tors of left ventricular hypertrophy by stimu lating cell growth. We concluded that left ventricular remod elling with endsystolic and enddiastolic vol ume increase is a frequent complication of acute myocardial infarction and can be favor
ably influenced by ACE inhibition. The sys temic renin-angiotensin system, however, is not necessarily stimulated in this clinical set ting. An increase in filling pressures leads to the stimulation of ANP. which can cause sup pression of the renin-angiotensin system. We postulate that ACE inhibition exerts its posi tive effects mainly by a decrease in filling pressures, which probably are the most im portant promotors of left ventricular remod elling besides infarct artery perfusion and spherical deformation of the left ventricle by the infarction. Acknowledgements The authors thank Catherine Amstutz and Yolande Parisod as well as Evelyn Hitzke for excellent technical assistance.
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