Annals of Medicine
ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20
Effect of Enalapril on Plasma Atrial Natriuretic Peptide in Late Recovery Phase of Acute Myocardial Infarction Timo Hirvonen, Jouko Remes, Juha Mustonen, Ilkka Tikkanen, Mirja Tenhunen & Kalevi Pyörälä To cite this article: Timo Hirvonen, Jouko Remes, Juha Mustonen, Ilkka Tikkanen, Mirja Tenhunen & Kalevi Pyörälä (1991) Effect of Enalapril on Plasma Atrial Natriuretic Peptide in Late Recovery Phase of Acute Myocardial Infarction, Annals of Medicine, 23:3, 271-275, DOI: 10.3109/07853899109148059 To link to this article: http://dx.doi.org/10.3109/07853899109148059
Published online: 08 Jul 2009.
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Date: 21 March 2016, At: 21:06
Oriainal Article
Effect of Enalapril on Plasma Atrial Natriuretic Peptide in Late Recovery Phase of Acute Myocardial Infarction
Downloaded by [ECU Libraries] at 21:06 21 March 2016
Tim0 Hirvonen’, Jouko Remes’, Juha Mustonen’, llkka Tikkanen3, Mirja Tenhunen2 and Kalevi Pyorala‘
A 12 week randomised, double blind, placebo controlled study on the effect of enalapril (5-20 mg daily) on the concentrationof plasma atrial natriuretic peptide level and activity of the sympathetic nervous system and renin angiotensin system was done on 27 patients who had suffered an uncomplicated acute myocardial infarction two to six months earlier. None of our patients needed drug treatment for heart failure, but their exercise capacity was markedly limited. Plasma neurohormone concentrations at baseline and after 12 weeks of treatment were also compared with those of healthy controls. Concentrations of plasma atrial natriuretic peptide concentrations remained high throughout the study in those patients on beta-blockers. Enalapril treatment had no definite effect on the concentrations of plasma atrial natriuretic peptide or other neurohormone. Key words: ACE-inhibitors; acute myocardial infarction; beta-blockers; drug treatment; heart failure; plasma atrial natriuretic peptide. (Annals of Medicine 23: 271-275,1991)
Methods
Introduction The plasma concentration of atrial natriuretic peptide (ANP) is raised in several conditions associated with increased atrial wall stretch, such as congestive heart failure (1-2) or atrial tachycardia (3). Even asymptomatic left ventricular dysfunction may result in rise in plasma ANP concentration (4), and it has recently been shown that the concentration of plasma ANP is also raised in uncomplicated acute myocardial infarction (AMI) (5-6). On the other hand, no data are available on plasma ANP concentration in the late convalescence period after AMI. We did a randomised, double blind, placebo controlled study on the effect of treatment with enalapril on plasma ANP concentration and the activity of the sympathetic nervous system and renin angiotensin system in patients who had suffered an uncomplicated AM1 on few months earlier.
From the Departments of Medicine’ and Clinical Physiology2of Kuopio University Hospital, Kuopio, and Minerva Foundation Institute for Clinical Research3, Helsinki, Finland. Thisstudywasfinanciallysupportedby agrantfrom Merck Sharp and Dohrne, Helsinki, Finland. Address reprint requests: Tim0 Hirvonen, M.D., Department of Medicine, Kuopio University Hospital, 70210 Kuopio, Finland. Received: January 15, 1991; revision accepted May 6, 1991.
Patients The series comprised 27 patients (14 men and 13 women) who had been treated for AM1 two to six months earlier at Kuopio University Central Hospital. All patients were enrolled in a multicentre study examining the efficacy of enalapril alone as initial treatment in patients with left ventricular dysfunction with minor or no symptoms of heart failure. Inclusion criteria for the study were an impaired exercise capacity (peak oxygen consumption (VO,) of 525 rnliminlkg) documented within the previous two weeks, and all patients had to belong to New York Heart Association (NYHA) functional classes I or II. Patients on digitalis, diuretics or systemic vasodilators (except nitrates) were excluded, as were those whose exercise capacity was limited by chest pain or (3) who had congenital, valvular, pericardial, hypertropic or restrictive hear! disease or sjgnificant pulmonary, renal, hepatic or hematological disease.
Study Protocol Baseline evaluation of patients was carried out during a two week, single blind, placebo period. This included 1) determination of peak VO, by cardiopulmonary exercise testing ( 7 ) ; 2 ) measurement of left ventricular ejection fraction (LVEF) by radionuclide angiocardiography (8); 3)
272
Hirvonen Remes Mustonen Tikkanen Tenhunen
Downloaded by [ECU Libraries] at 21:06 21 March 2016
evaluation of myocardial ischaemia during exercise by thallium scintigraphy (8); 4) assessment of plasma concentration of ANP, epinephrine, norepinephrine, and aldosterone, and plasma renin activity. These baseline studies were undertaken between two and six months (mean 2.4 months) after the onset of AMI. Patients were then randomised to receive either enalapril(l4 patients) or placebo (13 patients) during the double blind active treatment period of 12 weeks. The initial dose of the study drug was 5 mg b i d . and it was increased weekly to a maximum of 20 mg b i d . (mean 18 mg). Additional medication for the cardiac condition was kept constant during the study: 20 patients were on beta-blockers and 10 on long acting nitrates. The control group for plasma hormone measurements comprised 78 randomly selected healthy subjects (33 men and 45 women), initially recruited in another continuing study (9).
Plasma Hormone Measurements Blood samples were taken in the early morning after at least 30 minutes of supine rest. Blood was drawn from a large antebrachial vein through a prepositioned cannula: it was centrifuged immediately at 2°C and the plasma frozen and stored at -70°C until assay. Radioimmunoassay techniques were used to measure plasma ANP concentration (10) and renin activity (11). Plasma aldosterone level was assessed by a commercial radioimmunoassay kit (Abbott Laboratories, Chicago, Illinois), and plasma epinephrine and norepinephrine concentrations were assessed by high performance liquid chromatography with electrochemical detection (12).
Statistics The non-parametric Mann-Whitney U-test was used in comparisons of the control and patients groups, and Student's t-test for paired observations was used in comparisons of neurohormone values at baseline and at 12 weeks in placebo and enalapril groups. Correlations between continuous variables were determined using standard linear regression analyses. P-values of c0.05 were considered significant. All continuous data are expressed as a mean (standard deviation (SO)).
Approval The protocol had been approved by the Ethics Committee
Pyorala
of the University of Kuopio and all patients gave informed consent.
Results Clinical Characteristics at Baseline Initially LVEF and peak VO, were lower in patients than in controls (Table 1). The variables (Table 1) did not differ between the enalapril and placebo groups (data not shown). Seven patients (four in enalapril group and three in placebo group) were asymptomatic, whereas 20 patients (10 in each group) had experienced mild symptoms of breathlessness or leg fatique during exercise. As judged by ST segment depression during an exercise electrocardiogram or by thallium scintigraphy, eight patients (five in enalapril group and three in placebo group) had evidence of myocardial ischaemia, but none exprienced chest pain. Nine patients (69 %) in the placebo group and 11 (79 "/.) in the enalapril group were receiving beta-blockers, and five (39 "/.) in the placebo group and five (36 "/.) in enalapril group were taking long acting nitrates. The size of index infarct on the basis of peak creatine kinase concentration and left ventricular ejection fraction did not differ between those patients taking beta-blockers and those not taking them, nor between those patients taking or not taking nitrates. All study subjects had sinus rhythm.
Neurohormone Measurements at Baseline At start plasma ANP concentration was significantly higher in the total patient series than among the controls, but no differences were observed in other neurohormone measurements between the controls and patients (Table 2). Comparison of enalapril and placebo groups showed no significant differences in any of the neurohormone measurements among the groups (Table 3). Patients taking beta-blockers had a higher plasma ANP level than those not receiving beta-blockers, but the difference was not statistically significant (97, (69) and 64 (21) pg/I, respectively, P=0.07). Plasma ANP concentration was significantly higher in patients treated with beta-blockers than in controls (P=0.008),whereas in patients not receiving betablockers plasma ANP concentration did not differ from that observed in controls. No difference was found in plasma ANP concentration between patients receiving long acting nitrates and those not receiving these drugs (80 (44) and
Table 1. Clinical characteristics in controls and patients at baseline. Control (n=78)
Age (years) Sex (ma1e:female) Heart rate (beatshin) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Body mass index (kg/m2) Peak CK-MB activity (IU/I) Heart volume in chest x-ray (ml/m2) Left ventricular ejection fraction (%) Peak oxygen consumption (ml/min/kg)
61 (8) 33:45 65 (7) 150 (22) 88 (9) 27.2 (2.4)
-
438 (65) 68 (10)' 25.7 (6.3)"'
All (n=27)
Patients Placebo (n=13)
Enalapril
61 (6) 14:13 64 (6) 145 (29) 83 (10) 28.0 (4.2) 111 (49) 462 (68) 47 (1 1)' 18.5 (4.7)
63 (7) 6:7 64 (12) 142 (23) 82 (12) 27.4 (7.8) 98 (97) 465 (63) 46 (12) 17.8 (5.8)
60 (7) 8:6 66 (15) 145 (33) 84 (12) 28.5 (8.1) 124 (78) 459 (76) 49 (10) 19.1 (3.2)
CK-MB=creatine kinase MG-isoenzyme; Determined by echocardiography; 'determined by radionuclide angiography. *** Mann-Whitney U-test: PcO.001 (controls vs patients)
(n=14)
Plasma AN? after Acute Myocardial Infarction
273
Downloaded by [ECU Libraries] at 21:06 21 March 2016
P O !
Baseline 12 weeks Baseline 12 weeks
O !
Baseline 12 weeks Baseline 12 week8
Enal apri I
Placebo
Figure 1. Plasma atrial natriuretic peptide (ANP) concentration in placebo and enalapril groups at baseline and after 12 weeks of treatment. Closed symbols=patients receiving beta-blockers: open syrnbols=patients not receiving them.
78 (32) pg/I, respectively). In the whole patient series no correlation was observed between the concentration of plasma ANP and LVEF or peak VO,.
Changes in Measurements of Neurohormones During 12 Week Treatment All patients completed the 12 week treatment and during Table 2. Plasma neurohormone concentrations in controls and patients at baseline. ~~~~
~
~
Controls (n=78) Atrial natriuretic peptide (pg/rnl) Epinephrine (nrnol/l) Norepinephrine (nrnolil) Aldosterone (pmolil) Renin activitv (nqlmlfhi
Patients (n=27)
88 (62)"' 50 (29) 0.27 (0.17) 0 30 (0 23) 2.36 (1.13) 2 00 (0.79) 135 (75) 140 (79) 2.36 (1.13) 2 63 (1 66)
Mann-Whitney U-test: *"P
ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20
Effect of Enalapril on Plasma Atrial Natriuretic Peptide in Late Recovery Phase of Acute Myocardial Infarction Timo Hirvonen, Jouko Remes, Juha Mustonen, Ilkka Tikkanen, Mirja Tenhunen & Kalevi Pyörälä To cite this article: Timo Hirvonen, Jouko Remes, Juha Mustonen, Ilkka Tikkanen, Mirja Tenhunen & Kalevi Pyörälä (1991) Effect of Enalapril on Plasma Atrial Natriuretic Peptide in Late Recovery Phase of Acute Myocardial Infarction, Annals of Medicine, 23:3, 271-275, DOI: 10.3109/07853899109148059 To link to this article: http://dx.doi.org/10.3109/07853899109148059
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 4
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iann20 Download by: [ECU Libraries]
Date: 21 March 2016, At: 21:06
Oriainal Article
Effect of Enalapril on Plasma Atrial Natriuretic Peptide in Late Recovery Phase of Acute Myocardial Infarction
Downloaded by [ECU Libraries] at 21:06 21 March 2016
Tim0 Hirvonen’, Jouko Remes’, Juha Mustonen’, llkka Tikkanen3, Mirja Tenhunen2 and Kalevi Pyorala‘
A 12 week randomised, double blind, placebo controlled study on the effect of enalapril (5-20 mg daily) on the concentrationof plasma atrial natriuretic peptide level and activity of the sympathetic nervous system and renin angiotensin system was done on 27 patients who had suffered an uncomplicated acute myocardial infarction two to six months earlier. None of our patients needed drug treatment for heart failure, but their exercise capacity was markedly limited. Plasma neurohormone concentrations at baseline and after 12 weeks of treatment were also compared with those of healthy controls. Concentrations of plasma atrial natriuretic peptide concentrations remained high throughout the study in those patients on beta-blockers. Enalapril treatment had no definite effect on the concentrations of plasma atrial natriuretic peptide or other neurohormone. Key words: ACE-inhibitors; acute myocardial infarction; beta-blockers; drug treatment; heart failure; plasma atrial natriuretic peptide. (Annals of Medicine 23: 271-275,1991)
Methods
Introduction The plasma concentration of atrial natriuretic peptide (ANP) is raised in several conditions associated with increased atrial wall stretch, such as congestive heart failure (1-2) or atrial tachycardia (3). Even asymptomatic left ventricular dysfunction may result in rise in plasma ANP concentration (4), and it has recently been shown that the concentration of plasma ANP is also raised in uncomplicated acute myocardial infarction (AMI) (5-6). On the other hand, no data are available on plasma ANP concentration in the late convalescence period after AMI. We did a randomised, double blind, placebo controlled study on the effect of treatment with enalapril on plasma ANP concentration and the activity of the sympathetic nervous system and renin angiotensin system in patients who had suffered an uncomplicated AM1 on few months earlier.
From the Departments of Medicine’ and Clinical Physiology2of Kuopio University Hospital, Kuopio, and Minerva Foundation Institute for Clinical Research3, Helsinki, Finland. Thisstudywasfinanciallysupportedby agrantfrom Merck Sharp and Dohrne, Helsinki, Finland. Address reprint requests: Tim0 Hirvonen, M.D., Department of Medicine, Kuopio University Hospital, 70210 Kuopio, Finland. Received: January 15, 1991; revision accepted May 6, 1991.
Patients The series comprised 27 patients (14 men and 13 women) who had been treated for AM1 two to six months earlier at Kuopio University Central Hospital. All patients were enrolled in a multicentre study examining the efficacy of enalapril alone as initial treatment in patients with left ventricular dysfunction with minor or no symptoms of heart failure. Inclusion criteria for the study were an impaired exercise capacity (peak oxygen consumption (VO,) of 525 rnliminlkg) documented within the previous two weeks, and all patients had to belong to New York Heart Association (NYHA) functional classes I or II. Patients on digitalis, diuretics or systemic vasodilators (except nitrates) were excluded, as were those whose exercise capacity was limited by chest pain or (3) who had congenital, valvular, pericardial, hypertropic or restrictive hear! disease or sjgnificant pulmonary, renal, hepatic or hematological disease.
Study Protocol Baseline evaluation of patients was carried out during a two week, single blind, placebo period. This included 1) determination of peak VO, by cardiopulmonary exercise testing ( 7 ) ; 2 ) measurement of left ventricular ejection fraction (LVEF) by radionuclide angiocardiography (8); 3)
272
Hirvonen Remes Mustonen Tikkanen Tenhunen
Downloaded by [ECU Libraries] at 21:06 21 March 2016
evaluation of myocardial ischaemia during exercise by thallium scintigraphy (8); 4) assessment of plasma concentration of ANP, epinephrine, norepinephrine, and aldosterone, and plasma renin activity. These baseline studies were undertaken between two and six months (mean 2.4 months) after the onset of AMI. Patients were then randomised to receive either enalapril(l4 patients) or placebo (13 patients) during the double blind active treatment period of 12 weeks. The initial dose of the study drug was 5 mg b i d . and it was increased weekly to a maximum of 20 mg b i d . (mean 18 mg). Additional medication for the cardiac condition was kept constant during the study: 20 patients were on beta-blockers and 10 on long acting nitrates. The control group for plasma hormone measurements comprised 78 randomly selected healthy subjects (33 men and 45 women), initially recruited in another continuing study (9).
Plasma Hormone Measurements Blood samples were taken in the early morning after at least 30 minutes of supine rest. Blood was drawn from a large antebrachial vein through a prepositioned cannula: it was centrifuged immediately at 2°C and the plasma frozen and stored at -70°C until assay. Radioimmunoassay techniques were used to measure plasma ANP concentration (10) and renin activity (11). Plasma aldosterone level was assessed by a commercial radioimmunoassay kit (Abbott Laboratories, Chicago, Illinois), and plasma epinephrine and norepinephrine concentrations were assessed by high performance liquid chromatography with electrochemical detection (12).
Statistics The non-parametric Mann-Whitney U-test was used in comparisons of the control and patients groups, and Student's t-test for paired observations was used in comparisons of neurohormone values at baseline and at 12 weeks in placebo and enalapril groups. Correlations between continuous variables were determined using standard linear regression analyses. P-values of c0.05 were considered significant. All continuous data are expressed as a mean (standard deviation (SO)).
Approval The protocol had been approved by the Ethics Committee
Pyorala
of the University of Kuopio and all patients gave informed consent.
Results Clinical Characteristics at Baseline Initially LVEF and peak VO, were lower in patients than in controls (Table 1). The variables (Table 1) did not differ between the enalapril and placebo groups (data not shown). Seven patients (four in enalapril group and three in placebo group) were asymptomatic, whereas 20 patients (10 in each group) had experienced mild symptoms of breathlessness or leg fatique during exercise. As judged by ST segment depression during an exercise electrocardiogram or by thallium scintigraphy, eight patients (five in enalapril group and three in placebo group) had evidence of myocardial ischaemia, but none exprienced chest pain. Nine patients (69 %) in the placebo group and 11 (79 "/.) in the enalapril group were receiving beta-blockers, and five (39 "/.) in the placebo group and five (36 "/.) in enalapril group were taking long acting nitrates. The size of index infarct on the basis of peak creatine kinase concentration and left ventricular ejection fraction did not differ between those patients taking beta-blockers and those not taking them, nor between those patients taking or not taking nitrates. All study subjects had sinus rhythm.
Neurohormone Measurements at Baseline At start plasma ANP concentration was significantly higher in the total patient series than among the controls, but no differences were observed in other neurohormone measurements between the controls and patients (Table 2). Comparison of enalapril and placebo groups showed no significant differences in any of the neurohormone measurements among the groups (Table 3). Patients taking beta-blockers had a higher plasma ANP level than those not receiving beta-blockers, but the difference was not statistically significant (97, (69) and 64 (21) pg/I, respectively, P=0.07). Plasma ANP concentration was significantly higher in patients treated with beta-blockers than in controls (P=0.008),whereas in patients not receiving betablockers plasma ANP concentration did not differ from that observed in controls. No difference was found in plasma ANP concentration between patients receiving long acting nitrates and those not receiving these drugs (80 (44) and
Table 1. Clinical characteristics in controls and patients at baseline. Control (n=78)
Age (years) Sex (ma1e:female) Heart rate (beatshin) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Body mass index (kg/m2) Peak CK-MB activity (IU/I) Heart volume in chest x-ray (ml/m2) Left ventricular ejection fraction (%) Peak oxygen consumption (ml/min/kg)
61 (8) 33:45 65 (7) 150 (22) 88 (9) 27.2 (2.4)
-
438 (65) 68 (10)' 25.7 (6.3)"'
All (n=27)
Patients Placebo (n=13)
Enalapril
61 (6) 14:13 64 (6) 145 (29) 83 (10) 28.0 (4.2) 111 (49) 462 (68) 47 (1 1)' 18.5 (4.7)
63 (7) 6:7 64 (12) 142 (23) 82 (12) 27.4 (7.8) 98 (97) 465 (63) 46 (12) 17.8 (5.8)
60 (7) 8:6 66 (15) 145 (33) 84 (12) 28.5 (8.1) 124 (78) 459 (76) 49 (10) 19.1 (3.2)
CK-MB=creatine kinase MG-isoenzyme; Determined by echocardiography; 'determined by radionuclide angiography. *** Mann-Whitney U-test: PcO.001 (controls vs patients)
(n=14)
Plasma AN? after Acute Myocardial Infarction
273
Downloaded by [ECU Libraries] at 21:06 21 March 2016
P O !
Baseline 12 weeks Baseline 12 weeks
O !
Baseline 12 weeks Baseline 12 week8
Enal apri I
Placebo
Figure 1. Plasma atrial natriuretic peptide (ANP) concentration in placebo and enalapril groups at baseline and after 12 weeks of treatment. Closed symbols=patients receiving beta-blockers: open syrnbols=patients not receiving them.
78 (32) pg/I, respectively). In the whole patient series no correlation was observed between the concentration of plasma ANP and LVEF or peak VO,.
Changes in Measurements of Neurohormones During 12 Week Treatment All patients completed the 12 week treatment and during Table 2. Plasma neurohormone concentrations in controls and patients at baseline. ~~~~
~
~
Controls (n=78) Atrial natriuretic peptide (pg/rnl) Epinephrine (nrnol/l) Norepinephrine (nrnolil) Aldosterone (pmolil) Renin activitv (nqlmlfhi
Patients (n=27)
88 (62)"' 50 (29) 0.27 (0.17) 0 30 (0 23) 2.36 (1.13) 2 00 (0.79) 135 (75) 140 (79) 2.36 (1.13) 2 63 (1 66)
Mann-Whitney U-test: *"P
