- Email: [email protected]
β-blockers, angiotensin II, and ACE inhibitors in patients with heart failure
RESEARCH LETTERS
Research letters
-blockers, angiotensin II, and ACE inhibitors in patients with heart failure Duncan J Campbell, Anuradha Aggarwal, Murray Esler, David Kaye Blood concentrations of angiotensin II are often raised in patients with heart failure, despite treatment with angiotensinconverting-enzyme (ACE) inhibitors. We compared concentrations of angiotensin II in two groups of matched patients, receiving ACE inhibitor therapy with or without concomitant administration of -blockers. Concentrations of angiotensin II were lower in individuals taking -blockers than in those who were not (geometric mean 1·1 [95% CI 0·4–2·7] vs 15·5 [4·6–52·6] fmol/mL, 95% CI for difference 3–59). Our findings indicate that a reduction in angiotensin II concentrations might contribute to the therapeutic benefits of -blockade in heart failure, especially in patients who simultaneously receive ACE inhibitor treatment.
Lancet 2001; 358: 1609–10
Angiotensin II stimulates vasoconstriction, aldosterone release, and cardiovascular growth. Drugs that inhibit angiotensin-converting enzyme (ACE) reduce the amount of angiotensin II in the blood, providing haemodynamic benefit and reducing mortality in patients with heart failure. However, in a proportion of individuals, ACE inhibitor therapy does not suppress the production of angiotensin II, resulting in death or decompensated heart failure.1 Treatment with -blockers, as well as with ACE inhibitors, produces further therapeutic benefit in heart failure. These drugs inhibit the activation of the sympathetic nervous system during heart failure and reduce renin secretion,2 either of which could result in improved outcome.3 Our aim was to ascertain whether or not treatment with -blockers can reduce angiotensin II concentrations in patients with heart failure receiving ACE inhibitors. We compared the concentration of angiotensin peptide in patients with heart failure before and after treatment with -blockers became standard practice at the Heart Centre, Alfred Hospital. All individuals with heart failure (New York Heart Association functional class II–III) received maximum tolerated doses of ACE inhibitor; 11 did not receive -blockers (group A) and 11 received maximum tolerated doses of -blocker (group B). We took blood samples from
Characteristic Age (mean [SD]) (years) Sex (women/men) Cause of heart failure (ischaemic/non-ischaemic) Ejection fraction (mean [SD]) (%) Cardiac output (mean [SD]) (L/min) Right atrial pressure (mean [SD]) (mm Hg) Mean pulmonary artery pressure (mean [SD]) (mm Hg) Pulmonary capillary wedge pressure (mean [SD]) (mm Hg) Plasma norepinephrine (mean [95% CI]) (nmol/L) Blood angiotensin II (geometric mean [95% CI]) (fmol/mL) Blood angiotensin I (geometric mean [95% CI]) (fmol/mL) Blood angiotensin II/angiotensin I ratio (geometric mean [95% CI]) (mol/mol)
these individuals at the time of right-heart catheter assessment of suitability for cardiac transplantation. Ten patients in group A and nine in group B received a loop diuretic, and three individuals in each group were treated with spironolactone. Seven patients in group A received captopril 25–100 mg and four received either enalapril 15 mg, ramipril 5 mg, lisinopril 5 mg, or perindopril 8 mg daily. Five individuals in group B received perindopril 4–6 mg, one received quinapril 2·5 and one 40 mg, and four received either lisinopril 10 mg, ramipril 5 mg, captopril 50 mg, or enalapril 30 mg daily. Ten patients in group B received carvedilol 9–100 mg and one received sotalol 160 mg per day. We began treatment with -blockers after heart failure had been stabilised with diuretics and ACE inhibition. We measured blood concentrations of angiotensin I and angiotensin II by high-performance liquid chromatography-based radioimmunoassay, and concentrations of norepinephrine in the plasma by high-performance liquid chromatography with electrochemical detection. As controls, we also measured concentrations of angiotensin peptide in 28 patients with coronary artery disease, but without heart failure, who were not being treated with ACE inhibitors; 11 did not receive -blocker therapy (group C) and 17 did, either atenolol or metoprolol (group D). The local ethics committees approved the study, and all participants gave written informed consent. We did statistical analyses by ANOVA, and used Fisher’s protected least-significantdifference test for multiple comparisons. We did normal distribution tests with SAS (version 8.1). The two groups of patients with heart failure were well matched for age, sex, haemodynamics, and plasma norepinephrine concentrations. Control patients were older than heart failure patients (p<0·05). The ratio of angiotensin II/angiotensin I was lower in patients with heart failure than in controls (p<0·01), but did not differ between groups A and B, and C and D, indicating a similar degree of ACE inhibition in heart-failure patients, by comparison with controls (table). Concentrations of angiotensin II and angiotensin I for group A were higher than for the other
Group A, heart failure (ACE inhibitor, no -blocker) (n=11)
Group B, heart failure (ACE inhibitor, -blocker) (n=11)
Group C, control Group D, control (no ACE inhibitor, no (no ACE inhibitor, -blocker) (n=11) -blocker) (n=17)
52 (10) 2/9 5/6 17 (5) 3·9 (1·1) 6·8 (3·1) 31 (13) 19 (7) 2·7 (1·2) 15·5 (4·6–52·6) 101 (41–249) 0·15 (0·06–0·38)
56 (9) 1/10 3/8 22 (10) 4·8 (1·2) 6·9 (4·1) 23 (11) 15 (8) 3·5 (1·5) 1·1 (0·4–2·7) 7·2 (2·5–20·8) 0·15 (0·07–0·32)
61 (12) 1/10 ·· ·· ·· ·· ·· ·· ·· 2·3 (1·3–3·8) 1·8 (1·0–3·3) 1·2 (0·6–2·4)
63 (8) 3/14 ·· ·· ·· ·· ·· ·· ·· 1·0 (0·5–1·9) 1·7 (0·9–3·0) 0·6 (0·4–0·9)
Characteristics of patients
THE LANCET • Vol 358 • November 10, 2001
1609
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
Angiotensin I
100
fmol/mL
1000
100
fmol/mL
1000
10 1 0·1
10
10
1
0·01 A B C D
A B C D
Group Blood concentrations of angiotensin II and angiotensin I, and angiotensin II/angiotensin I ratio Group A=patients with heart failure, receiving ACE inhibitors; group B=patients with heart failure, receiving ACE inhibitors and -blockers; group C=controls; group D=controls, receiving -blockers.
groups (p<0·01). Furthermore, individuals in group B had higher concentrations of angiotensin I than those in groups C and D (p<0·02). Only six patients in group A had angiotensin II concentrations in the normal range (<10 fmol/mL) and none had angiotensin II concentrations less than the mean for controls (figure). However, all patients in group B had angiotensin II concentrations less than 10 fmol/mL, and six had angiotensin II concentrations of less than 2 fmol/mL. The raised concentrations of angiotensin II in individuals in group A were caused by increased concentrations of angiotensin I in these patients (figure), indicating increased renin secretion. Conversely, the reduced concentrations of angiotensin I in patients in group B indicate that suppression of angiotensin II concentrations by -blockade was due to suppression of plasma renin activity. ACE inhibition does not suppress concentrations of angiotensin II in many patients with heart failure. The reason for this treatment failure is unclear, but results of studies suggest that more effective blockade of the renin-angiotensin system might be achieved with larger than standard doses of ACE inhibitor,4 or by combination therapy with drugs that induce ACE inhibition and angiotensin II receptor blockade.5 Our results indicate that -blockade results in effective suppression of angiotensin II concentrations in patients with heart failure. Reduction of angiotensin II concentrations might contribute to the therapeutic benefits of -blockade in heart failure, particularly in patients receiving concomitant ACE inhibitor therapy. Our findings provide support for the combination of ACE inhibition and -blockade in treatment of heart failure. Moreover, they indicate that patients treated with ACE inhibitors and -blockers might receive little additional benefit from either higher than standard doses of ACE inhibitor or the addition of an angiotensin II receptor blocker. This work was supported by grants from the National Health and Medical Research Council and the National Heart Foundation of Australia. 1
2 3
4
5
Roig E, Perez-Villa F, Morales M, et al. Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure. Eur Heart J 2000; 21: 53–57. Sharpe N. Benefit of beta-blockers for heart failure: proven in 1999. Lancet 1999; 353: 1988–89. Buhler FR, Laragh JH, Baer L, Vaughan ED, Brunner HR. Propranolol inhibition of renin secretion: a specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. N Engl J Med 1972; 287: 1209–14. Delahaye F, de Gevigney G. Is the optimal dose of angiotensinconverting enzyme inhibitors in patients with congestive heart failure definitely established? J Am Coll Cardiol 2000; 36: 2096–97. McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 1999; 100: 1056–64.
1610
St Vincent’s Institute of Medical Research and University of Melbourne, Department of Medicine, Fitzroy, Victoria 3065, Australia (D J Campbell MD); and Alfred-Baker Medical Unit, Alfred Hospital, Prahran 3081, Australia (A Aggarwal MD, Prof M Esler MD, D Kaye MD) Correspondence to: Dr Duncan J Campbell (e-mail: [email protected])
0·1
1 0·1
A B C D
Angiotensin II/ angiotensin I mol/mol
Angiotensin II
Magnetic resonance: magic angle imaging of the Achilles tendon Angela Oatridge, Amy H Herlihy, Rhidian W Thomas, Andrew L Wallace, Walter L Curati, Joseph V Hajnal, Graeme M Bydder Tendons do not normally produce detectable signals with conventional magnetic-resonance techniques and are recognised as dark signal voids. However, if tendons are examined at 55º to the static magnetic field (the “magic angle”), signals become detectable and the tendons can become the brightest structure on the image. We have used this approach to establish tendon relaxation times and magnetisation transfer ratios and to show contrast enhancement. We have also shown more detail of acute and chronic tendon rupture by this method compared with images made with the tendon parallel to the static magnetic field.
Lancet 2001; 358: 1610–11
When examined with conventional magnetic-resonance imaging (MRI) techniques, tendons and ligaments appear black. This signal void is mainly due to strong magnetic dipolar interactions between protons in semisolid structures that lead to rapid decay of the MR signal, which is then undetectable on the timescales available with clinical MRI systems. Abnormal tissue within tendons can produce a signal (appearing grey or white) and can therefore be recognised against the dark background of the normal tendon.1 However, a major disadvantage of the signal void is that it has not been possible to study tendons with most of the MR techniques used for other organs. An exception to the signal void is an artefact which may be seen with some pulse sequences in tendons when they are obliquely orientated to the static magnetic field.2 This effect, termed the “magic angle artefact” has been recognised as a diagnostic pitfall since these signals may simulate focal disease. The term is derived from magic angle spinning which is a technique used in in-vitro MR spectroscopy.3 If samples are rotated very rapidly (eg, 2–20 kHz) in a spectrometer at an angle relative to the static magnetic field given by the formula (3 cos2ⳮ1)=0, ie, =55˚, transverse relaxation time (T2) is extended due to decoupling of dipolar interactions
Figure 1: Sagittal MRI of acute Achilles tendon rupture using a three-dimensional-gradient recalled echo sequence Relaxation time=21 ms, echo time=7 ms, flip angle=35º at 0·5T with the tendon parallel to the static field (A) and at 55º (B). The distal segment of the tendon is poorly defined in (A) but is clearly shown in (B) by arrows.
THE LANCET • Vol 358 • November 10, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Research letters
-blockers, angiotensin II, and ACE inhibitors in patients with heart failure Duncan J Campbell, Anuradha Aggarwal, Murray Esler, David Kaye Blood concentrations of angiotensin II are often raised in patients with heart failure, despite treatment with angiotensinconverting-enzyme (ACE) inhibitors. We compared concentrations of angiotensin II in two groups of matched patients, receiving ACE inhibitor therapy with or without concomitant administration of -blockers. Concentrations of angiotensin II were lower in individuals taking -blockers than in those who were not (geometric mean 1·1 [95% CI 0·4–2·7] vs 15·5 [4·6–52·6] fmol/mL, 95% CI for difference 3–59). Our findings indicate that a reduction in angiotensin II concentrations might contribute to the therapeutic benefits of -blockade in heart failure, especially in patients who simultaneously receive ACE inhibitor treatment.
Lancet 2001; 358: 1609–10
Angiotensin II stimulates vasoconstriction, aldosterone release, and cardiovascular growth. Drugs that inhibit angiotensin-converting enzyme (ACE) reduce the amount of angiotensin II in the blood, providing haemodynamic benefit and reducing mortality in patients with heart failure. However, in a proportion of individuals, ACE inhibitor therapy does not suppress the production of angiotensin II, resulting in death or decompensated heart failure.1 Treatment with -blockers, as well as with ACE inhibitors, produces further therapeutic benefit in heart failure. These drugs inhibit the activation of the sympathetic nervous system during heart failure and reduce renin secretion,2 either of which could result in improved outcome.3 Our aim was to ascertain whether or not treatment with -blockers can reduce angiotensin II concentrations in patients with heart failure receiving ACE inhibitors. We compared the concentration of angiotensin peptide in patients with heart failure before and after treatment with -blockers became standard practice at the Heart Centre, Alfred Hospital. All individuals with heart failure (New York Heart Association functional class II–III) received maximum tolerated doses of ACE inhibitor; 11 did not receive -blockers (group A) and 11 received maximum tolerated doses of -blocker (group B). We took blood samples from
Characteristic Age (mean [SD]) (years) Sex (women/men) Cause of heart failure (ischaemic/non-ischaemic) Ejection fraction (mean [SD]) (%) Cardiac output (mean [SD]) (L/min) Right atrial pressure (mean [SD]) (mm Hg) Mean pulmonary artery pressure (mean [SD]) (mm Hg) Pulmonary capillary wedge pressure (mean [SD]) (mm Hg) Plasma norepinephrine (mean [95% CI]) (nmol/L) Blood angiotensin II (geometric mean [95% CI]) (fmol/mL) Blood angiotensin I (geometric mean [95% CI]) (fmol/mL) Blood angiotensin II/angiotensin I ratio (geometric mean [95% CI]) (mol/mol)
these individuals at the time of right-heart catheter assessment of suitability for cardiac transplantation. Ten patients in group A and nine in group B received a loop diuretic, and three individuals in each group were treated with spironolactone. Seven patients in group A received captopril 25–100 mg and four received either enalapril 15 mg, ramipril 5 mg, lisinopril 5 mg, or perindopril 8 mg daily. Five individuals in group B received perindopril 4–6 mg, one received quinapril 2·5 and one 40 mg, and four received either lisinopril 10 mg, ramipril 5 mg, captopril 50 mg, or enalapril 30 mg daily. Ten patients in group B received carvedilol 9–100 mg and one received sotalol 160 mg per day. We began treatment with -blockers after heart failure had been stabilised with diuretics and ACE inhibition. We measured blood concentrations of angiotensin I and angiotensin II by high-performance liquid chromatography-based radioimmunoassay, and concentrations of norepinephrine in the plasma by high-performance liquid chromatography with electrochemical detection. As controls, we also measured concentrations of angiotensin peptide in 28 patients with coronary artery disease, but without heart failure, who were not being treated with ACE inhibitors; 11 did not receive -blocker therapy (group C) and 17 did, either atenolol or metoprolol (group D). The local ethics committees approved the study, and all participants gave written informed consent. We did statistical analyses by ANOVA, and used Fisher’s protected least-significantdifference test for multiple comparisons. We did normal distribution tests with SAS (version 8.1). The two groups of patients with heart failure were well matched for age, sex, haemodynamics, and plasma norepinephrine concentrations. Control patients were older than heart failure patients (p<0·05). The ratio of angiotensin II/angiotensin I was lower in patients with heart failure than in controls (p<0·01), but did not differ between groups A and B, and C and D, indicating a similar degree of ACE inhibition in heart-failure patients, by comparison with controls (table). Concentrations of angiotensin II and angiotensin I for group A were higher than for the other
Group A, heart failure (ACE inhibitor, no -blocker) (n=11)
Group B, heart failure (ACE inhibitor, -blocker) (n=11)
Group C, control Group D, control (no ACE inhibitor, no (no ACE inhibitor, -blocker) (n=11) -blocker) (n=17)
52 (10) 2/9 5/6 17 (5) 3·9 (1·1) 6·8 (3·1) 31 (13) 19 (7) 2·7 (1·2) 15·5 (4·6–52·6) 101 (41–249) 0·15 (0·06–0·38)
56 (9) 1/10 3/8 22 (10) 4·8 (1·2) 6·9 (4·1) 23 (11) 15 (8) 3·5 (1·5) 1·1 (0·4–2·7) 7·2 (2·5–20·8) 0·15 (0·07–0·32)
61 (12) 1/10 ·· ·· ·· ·· ·· ·· ·· 2·3 (1·3–3·8) 1·8 (1·0–3·3) 1·2 (0·6–2·4)
63 (8) 3/14 ·· ·· ·· ·· ·· ·· ·· 1·0 (0·5–1·9) 1·7 (0·9–3·0) 0·6 (0·4–0·9)
Characteristics of patients
THE LANCET • Vol 358 • November 10, 2001
1609
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
Angiotensin I
100
fmol/mL
1000
100
fmol/mL
1000
10 1 0·1
10
10
1
0·01 A B C D
A B C D
Group Blood concentrations of angiotensin II and angiotensin I, and angiotensin II/angiotensin I ratio Group A=patients with heart failure, receiving ACE inhibitors; group B=patients with heart failure, receiving ACE inhibitors and -blockers; group C=controls; group D=controls, receiving -blockers.
groups (p<0·01). Furthermore, individuals in group B had higher concentrations of angiotensin I than those in groups C and D (p<0·02). Only six patients in group A had angiotensin II concentrations in the normal range (<10 fmol/mL) and none had angiotensin II concentrations less than the mean for controls (figure). However, all patients in group B had angiotensin II concentrations less than 10 fmol/mL, and six had angiotensin II concentrations of less than 2 fmol/mL. The raised concentrations of angiotensin II in individuals in group A were caused by increased concentrations of angiotensin I in these patients (figure), indicating increased renin secretion. Conversely, the reduced concentrations of angiotensin I in patients in group B indicate that suppression of angiotensin II concentrations by -blockade was due to suppression of plasma renin activity. ACE inhibition does not suppress concentrations of angiotensin II in many patients with heart failure. The reason for this treatment failure is unclear, but results of studies suggest that more effective blockade of the renin-angiotensin system might be achieved with larger than standard doses of ACE inhibitor,4 or by combination therapy with drugs that induce ACE inhibition and angiotensin II receptor blockade.5 Our results indicate that -blockade results in effective suppression of angiotensin II concentrations in patients with heart failure. Reduction of angiotensin II concentrations might contribute to the therapeutic benefits of -blockade in heart failure, particularly in patients receiving concomitant ACE inhibitor therapy. Our findings provide support for the combination of ACE inhibition and -blockade in treatment of heart failure. Moreover, they indicate that patients treated with ACE inhibitors and -blockers might receive little additional benefit from either higher than standard doses of ACE inhibitor or the addition of an angiotensin II receptor blocker. This work was supported by grants from the National Health and Medical Research Council and the National Heart Foundation of Australia. 1
2 3
4
5
Roig E, Perez-Villa F, Morales M, et al. Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure. Eur Heart J 2000; 21: 53–57. Sharpe N. Benefit of beta-blockers for heart failure: proven in 1999. Lancet 1999; 353: 1988–89. Buhler FR, Laragh JH, Baer L, Vaughan ED, Brunner HR. Propranolol inhibition of renin secretion: a specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. N Engl J Med 1972; 287: 1209–14. Delahaye F, de Gevigney G. Is the optimal dose of angiotensinconverting enzyme inhibitors in patients with congestive heart failure definitely established? J Am Coll Cardiol 2000; 36: 2096–97. McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 1999; 100: 1056–64.
1610
St Vincent’s Institute of Medical Research and University of Melbourne, Department of Medicine, Fitzroy, Victoria 3065, Australia (D J Campbell MD); and Alfred-Baker Medical Unit, Alfred Hospital, Prahran 3081, Australia (A Aggarwal MD, Prof M Esler MD, D Kaye MD) Correspondence to: Dr Duncan J Campbell (e-mail: [email protected])
0·1
1 0·1
A B C D
Angiotensin II/ angiotensin I mol/mol
Angiotensin II
Magnetic resonance: magic angle imaging of the Achilles tendon Angela Oatridge, Amy H Herlihy, Rhidian W Thomas, Andrew L Wallace, Walter L Curati, Joseph V Hajnal, Graeme M Bydder Tendons do not normally produce detectable signals with conventional magnetic-resonance techniques and are recognised as dark signal voids. However, if tendons are examined at 55º to the static magnetic field (the “magic angle”), signals become detectable and the tendons can become the brightest structure on the image. We have used this approach to establish tendon relaxation times and magnetisation transfer ratios and to show contrast enhancement. We have also shown more detail of acute and chronic tendon rupture by this method compared with images made with the tendon parallel to the static magnetic field.
Lancet 2001; 358: 1610–11
When examined with conventional magnetic-resonance imaging (MRI) techniques, tendons and ligaments appear black. This signal void is mainly due to strong magnetic dipolar interactions between protons in semisolid structures that lead to rapid decay of the MR signal, which is then undetectable on the timescales available with clinical MRI systems. Abnormal tissue within tendons can produce a signal (appearing grey or white) and can therefore be recognised against the dark background of the normal tendon.1 However, a major disadvantage of the signal void is that it has not been possible to study tendons with most of the MR techniques used for other organs. An exception to the signal void is an artefact which may be seen with some pulse sequences in tendons when they are obliquely orientated to the static magnetic field.2 This effect, termed the “magic angle artefact” has been recognised as a diagnostic pitfall since these signals may simulate focal disease. The term is derived from magic angle spinning which is a technique used in in-vitro MR spectroscopy.3 If samples are rotated very rapidly (eg, 2–20 kHz) in a spectrometer at an angle relative to the static magnetic field given by the formula (3 cos2ⳮ1)=0, ie, =55˚, transverse relaxation time (T2) is extended due to decoupling of dipolar interactions
Figure 1: Sagittal MRI of acute Achilles tendon rupture using a three-dimensional-gradient recalled echo sequence Relaxation time=21 ms, echo time=7 ms, flip angle=35º at 0·5T with the tendon parallel to the static field (A) and at 55º (B). The distal segment of the tendon is poorly defined in (A) but is clearly shown in (B) by arrows.
THE LANCET • Vol 358 • November 10, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.